Anomalous Diffusion Reports on the Interaction of Misfolded Proteins with the Quality Control Machinery in the Endoplasmic Reticulum

PubMed Central

Malchus, Nina; Weiss, Matthias

2010-01-01

A multitude of transmembrane proteins enters the endoplasmic reticulum (ER) as unfolded polypeptide chains. During their folding process, they interact repetitively with the ER's quality control machinery. Here, we have used fluorescence correlation spectroscopy to probe these interactions for a prototypical transmembrane protein, VSVG ts045, in vivo. While both folded and unfolded VSVG ts045 showed anomalous diffusion, the unfolded protein had a significantly stronger anomaly. This difference subsided when unfolded VSVG ts045 was in a complex with its chaperone calnexin, or when a mutant form of VSVG ts045 with only one glycan was used. Our experimental data and accompanying simulations suggest that the folding sensor of the quality control (UGT1) oligomerizes unfolded VSVG ts045, leading to a more anomalous/obstructed diffusion. In contrast, calnexin dissolves the oligomers, rendering unfolded VSVG ts045 more mobile, and hence prevents poisoning of the ER. PMID:20713018

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

PubMed Central

Yoo, Yoon Seon; Han, Hye Gyeong

2017-01-01

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

Evaluation of different types of enamel conditioning before application of a fissure sealant.

PubMed

Ciucchi, Philip; Neuhaus, Klaus W; Emerich, Marta; Peutzfeldt, Anne; Lussi, Adrian

2015-01-01

The aim of the study was to compare fissure sealant quality after mechanical conditioning of erbium-doped yttrium aluminium garnet (Er:YAG) laser or air abrasion prior to chemical conditioning of phosphoric acid etching or of a self-etch adhesive. Twenty-five permanent molars were initially divided into three groups: control group (n = 5), phosphoric acid etching; test group 1 (n = 10), air abrasion; and test group 2, (n = 10) Er:YAG laser. After mechanical conditioning, the test group teeth were sectioned buccolingually and the occlusal surface of one half tooth (equal to one sample) was acid etched, while a self-etch adhesive was applied on the other half. The fissure system of each sample was sealed, thermo-cycled and immersed in 5% methylene dye for 24 h. Each sample was sectioned buccolingually, and one slice was analysed microscopically. Using specialized software microleakage, unfilled margin, sealant failure and unfilled area proportions were calculated. A nonparametric ANOVA model was applied to compare the Er:YAG treatment with that of air abrasion and the self-etch adhesive with phosphoric acid (α = 0.05). Test groups were compared to the control group using Wilcoxon rank sum tests (α = 0.05). The control group displayed significantly lower microleakage but higher unfilled area proportions than the Er:YAG laser + self-etch adhesive group and displayed significantly higher unfilled margin and unfilled area proportions than the air-abrasion + self-etch adhesive group. There was no statistically significant difference in the quality of sealants applied in fissures treated with either Er:YAG laser or air abrasion prior to phosphoric acid etching, nor in the quality of sealants applied in fissures treated with either self-etch adhesive or phosphoric acid following Er:YAG or air-abrasion treatment.

Role of N-linked oligosaccharides in the biosynthetic processing of the cystic fibrosis membrane conductance regulator

PubMed Central

Chang, Xiu-bao; Mengos, April; Hou, Yue-xian; Cui, Liying; Jensen, Timothy J.; Aleksandrov, Andrei; Riordan, John R.; Gentzsch, Martina

2009-01-01

Summary The epithelial chloride channel CFTR is a glycoprotein that is modified by two N-linked oligosaccharides. The most common mutant CFTR protein in patients with cystic fibrosis, ΔF508, is misfolded and retained by ER quality control. As oligosaccharide moieties of glycoproteins are known to mediate interactions with ER lectin chaperones, we investigated the role of N-linked glycosylation in the processing of wild-type and ΔF508 CFTR. We found that N-glycosylation and ER lectin interactions are not major determinants of trafficking of wild-type and ΔF508 from the ER to the plasma membrane. Unglycosylated CFTR, generated by removal of glycosylation sites or treatment of cells with the N-glycosylation inhibitor tunicamycin, did not bind calnexin, but did traffic to the cell surface and exhibited chloride channel activity. Most importantly, unglycosylated Δ F508 CFTR still could not escape quality control in the early secretory pathway and remained associated with the ER. However, the absence of N-linked oligosaccharides did reduce the stability of wild-type CFTR, causing significantly more-rapid turnover in post-ER compartments. Surprisingly, the individual N-linked carbohydrates do not play equivalent roles and modulate the fate of the wild-type protein in different ways in its early biosynthetic pathway. PMID:18682497

Role of N-linked oligosaccharides in the biosynthetic processing of the cystic fibrosis membrane conductance regulator.

PubMed

Chang, Xiu-Bao; Mengos, April; Hou, Yue-Xian; Cui, Liying; Jensen, Timothy J; Aleksandrov, Andrei; Riordan, John R; Gentzsch, Martina

2008-09-01

The epithelial chloride channel CFTR is a glycoprotein that is modified by two N-linked oligosaccharides. The most common mutant CFTR protein in patients with cystic fibrosis, DeltaF508, is misfolded and retained by ER quality control. As oligosaccharide moieties of glycoproteins are known to mediate interactions with ER lectin chaperones, we investigated the role of N-linked glycosylation in the processing of wild-type and DeltaF508 CFTR. We found that N-glycosylation and ER lectin interactions are not major determinants of trafficking of wild-type and DeltaF508 from the ER to the plasma membrane. Unglycosylated CFTR, generated by removal of glycosylation sites or treatment of cells with the N-glycosylation inhibitor tunicamycin, did not bind calnexin, but did traffic to the cell surface and exhibited chloride channel activity. Most importantly, unglycosylated DeltaF508 CFTR still could not escape quality control in the early secretory pathway and remained associated with the ER. However, the absence of N-linked oligosaccharides did reduce the stability of wild-type CFTR, causing significantly more-rapid turnover in post-ER compartments. Surprisingly, the individual N-linked carbohydrates do not play equivalent roles and modulate the fate of the wild-type protein in different ways in its early biosynthetic pathway.

The Endoplasmic Reticulum-Associated Degradation Pathways of Budding Yeast

PubMed Central

Thibault, Guillaume; Ng, Davis T.W.

2012-01-01

Protein misfolding is a common cellular event that can produce intrinsically harmful products. To reduce the risk, quality control mechanisms are deployed to detect and eliminate misfolded, aggregated, and unassembled proteins. In the secretory pathway, it is mainly the endoplasmic reticulum-associated degradation (ERAD) pathways that perform this role. Here, specialized factors are organized to monitor and process the folded states of nascent polypeptides. Despite the complex structures, topologies, and posttranslational modifications of client molecules, the ER mechanisms are the best understood among all protein quality-control systems. This is the result of convergent and sometimes serendipitous discoveries by researchers from diverse fields. Although major advances in ER quality control and ERAD came from all model organisms, this review will focus on the discoveries culminating from the simple budding yeast. PMID:23209158

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

PubMed

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

2014-01-01

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

ER stress response mechanisms in the pathogenic yeast Candida glabrata and their roles in virulence

PubMed Central

Miyazaki, Taiga; Kohno, Shigeru

2014-01-01

The maintenance of endoplasmic reticulum (ER) homeostasis is critical for numerous aspects of cell physiology. Eukaryotic cells respond to the accumulation of misfolded proteins in the ER (ER stress) by activating the unfolded protein response (UPR), an intracellular signaling pathway that adjusts the folding capacity of the ER. Recent studies of several pathogenic fungi have revealed that the UPR is important for antifungal resistance and virulence; therefore, the pathway has attracted much attention as a potential therapeutic target. While the UPR is highly conserved among eukaryotes, our group recently discovered that the pathogenic yeast Candida glabrata lacks the typical fungal UPR, but possesses alternative mechanisms to cope with ER stress. This review summarizes how C. glabrata responds to ER stress and discusses the impacts of ER quality control systems on antifungal resistance and virulence. PMID:24335436

Emerging themes of ER organization in the development and maintenance of axons

PubMed Central

Renvoisé, Benoît; Blackstone, Craig

2010-01-01

The endoplasmic reticulum (ER) is a continuous membrane system comprising the nuclear envelope, polyribosome-studded peripheral sheets, and a polygonal network of smooth tubules extending throughout the cell. Though protein biosynthesis, transport, and quality control in the ER have been extensively studied, mechanisms underlying the heterogeneous architecture of the ER have been clarified more recently. These insights have increased interest in ER morphology changes associated with the development of neuronal axons and dendrites as well as their integration with pre- and postsynaptic signaling pathways. A number of proteins involved in shaping and distributing the ER network are mutated in neurological disorders, particularly the hereditary spastic paraplegias, emphasizing the importance of proper ER morphology for the establishment and maintenance of highly-polarized neurons. PMID:20678923

Cholesterol regulates the endoplasmic reticulum exit of the major membrane protein P0 required for peripheral myelin compaction.

PubMed

Saher, Gesine; Quintes, Susanne; Möbius, Wiebke; Wehr, Michael C; Krämer-Albers, Eva-Maria; Brügger, Britta; Nave, Klaus-Armin

2009-05-13

Rapid impulse conduction requires electrical insulation of axons by myelin, a cholesterol-rich extension of the glial cell membrane with a characteristic composition of proteins and lipids. Mutations in several myelin protein genes cause endoplasmic reticulum (ER) retention and disease, presumably attributable to failure of misfolded proteins to pass the ER quality control. Because many myelin proteins partition into cholesterol-rich membrane rafts, their interaction with cholesterol could potentially be part of the ER quality control system. Here, we provide in vitro and in vivo evidence that the major peripheral myelin protein P0 requires cholesterol for exiting the ER and reaching the myelin compartment. Cholesterol dependency of P0 trafficking in heterologous cells is mediated by a cholesterol recognition/interaction amino acid consensus (CRAC) motif. Mutant mice lacking cholesterol biosynthesis in Schwann cells suffer from severe hypomyelination with numerous uncompacted myelin stretches. This demonstrates that high-level cholesterol coordinates P0 export with myelin membrane synthesis, which is required for the correct stoichiometry of myelin components and for myelin compaction.

Comparison of Er:YAG and Er:YSGG laser ablation of dental hard tissues

NASA Astrophysics Data System (ADS)

Stock, Karl; Hibst, Raimund; Keller, Ulrich

1997-12-01

To compare ablation quality of Er:YAG and Er:YSGG laser the surface quality, crater shape, mass loss, and temperature development were determined using the same fiber transmission system and handpiece. Similar crater depths for both lasers but greater diameters for the Er:YAG laser were measured. Also mass loss per pulse of the Er:YAG laser exceeds that of the Er:YSGG laser. Temperature development while ablation of dentin is more pronounced for the Er:YSGG laser. The observed minor ablation quality of the Er:YSGG laser can be explained by the lower absorption coefficient of dental hard substances compared to the Er:YAG laser.

Why might poor sleep quality lead to depression? A role for emotion regulation.

PubMed

O'Leary, Kimberly; Bylsma, Lauren M; Rottenberg, Jonathan

2017-12-01

Disordered sleep is strongly linked to future depression, but the reasons for this link are not well understood. This study tested one possibility - that poorer sleep impairs emotion regulation (ER), which over time leads to increased depressive symptoms. Our sample contained individuals with a wide range of depression symptoms (current depression, N = 54, remitted depression, N = 36, and healthy control, N = 53), who were followed clinically over six months and reassessed for changes in depressive symptom levels. As predicted, maladaptive ER mediated both cross-sectional and prospective relationships between poor sleep quality and depression symptoms. In contrast, an alternative mediator, physical activity levels, did not mediate the link between sleep quality and depression symptoms. Maladaptive ER may help explain why sleep difficulties contribute to depression symptoms; implications for interventions are discussed.

Cyclosporine A suppresses immunoglobulin G biosynthesis via inhibition of cyclophilin B in murine hybridomas and B cells.

PubMed

Lee, Jisun; Choi, Tae Gyu; Ha, Joohun; Kim, Sung Soo

2012-01-01

Immunoglubulin G (IgG) is a major isotype of antibody, which is predominantly involved in immune response. The complete tetramer is needed to fold and assemble in endoplasmic reticulum (ER) prior to secretion from cells. Protein quality control guided by ER chaperons is most essential for full biological activity. Cyclophilin B (CypB) was initially identified as a high-affinity binding protein for the immunosuppressive drug Cyclosporine A (CsA). CsA suppresses organ rejection by halting productions of pro-inflammatory molecules in T cell and abolishes the enzymatic property of CypB that accelerates the folding of proteins by catalysing the isomerization of peptidyl-proline bonds in ER. Here, we reported that CsA significantly inhibited IgG biosynthesis at posttranslational level in antibody secreting cells. Moreover, CsA stimulated the extracellular secretion of CypB and induced ROS generation, leading to expressions of ER stress markers. In addition, the absence of intracellular CypB impaired the formation of ER multiprotein complex, which is most important for resisting ER stress. Interestingly, CsA interrupted IgG folding via occupying the PPIase domain of CypB in ER. Eventually, unfolded IgG is degraded via Herp-dependent ERAD pathway. Furthermore, IgG biosynthesis was really abrogated by inhibition of CypB in primary B cells. We established for the first time the immunosuppressive effect of CsA on B cells. Conclusively, the combined results of the current study suggest that CypB is a pivotal molecule for IgG biosynthesis in ER quality control. Copyright © 2011 Elsevier B.V. All rights reserved.

Protein disulfide isomerases in the endoplasmic reticulum promote anchorage-independent growth of breast cancer cells.

PubMed

Wise, Randi; Duhachek-Muggy, Sara; Qi, Yue; Zolkiewski, Michal; Zolkiewska, Anna

2016-06-01

Metastatic breast cancer cells are exposed to stress of detachment from the extracellular matrix (ECM). Cultured breast cancer cells that survive this stress and are capable of anchorage-independent proliferation form mammospheres. The purpose of this study was to explore a link between mammosphere growth, ECM gene expression, and the protein quality control system in the endoplasmic reticulum (ER). We compared the mRNA and protein levels of ER folding factors in SUM159PT and MCF10DCIS.com breast cancer cells grown as mammospheres versus adherent conditions. Publicly available gene expression data for mammospheres formed by primary breast cancer cells and for circulating tumor cells (CTCs) were analyzed to assess the status of ECM/ER folding factor genes in clinically relevant samples. Knock-down of selected protein disulfide isomerase (PDI) family members was performed to examine their roles in SUM159PT mammosphere growth. We found that cells grown as mammospheres had elevated expression of ECM genes and ER folding quality control genes. CTC gene expression data for an index patient indicated that upregulation of ECM and ER folding factor genes occurred at the time of acquired therapy resistance and disease progression. Knock-down of PDI, ERp44, or ERp57, three members of the PDI family with elevated protein levels in mammospheres, in SUM159PT cells partially inhibited the mammosphere growth. Thus, breast cancer cell survival and growth under detachment conditions require enhanced assistance of the ER protein folding machinery. Targeting ER folding factors, in particular members of the PDI family, may improve the therapeutic outcomes in metastatic breast cancer.

Membrane glycerolipid equilibrium under endoplasmic reticulum stress in Arabidopsis thaliana.

PubMed

Yu, Chao-Yuan; Nguyen, Van Cam; Chuang, Ling; Kanehara, Kazue

2018-06-02

Endoplasmic reticulum (ER) is an indispensable organelle for secretory protein synthesis as well as metabolism of phospholipids and their derivatives in eukaryotic cells. Various external and internal factors may cause an accumulation of aberrant proteins in the ER, which causes ER stress and activates cellular ER stress responses to cope with the stress. In animal research, molecular mechanisms for protein quality control upon ER stress are well documented; however, how cells maintain lipid homeostasis under ER stress is an emerging issue. The ratio of phosphatidylcholine (PC) to phosphatidylethanolamine (PE), two major phospholipid classes, is important under ER stress in animal cells. However, in seed plants, no study has reported on the changes in membrane lipid content under ER stress, although a number of physiologically important environmental stresses, such as heat and salinity, induce ER stress. Here, we investigated membrane glycerolipid metabolism under ER stress in Arabidopsis. ER stress transcriptionally affected PC and PE biosynthesis pathways differentially, with no significant changes in membrane glycerolipid content. Our results suggest that higher plants maintain membrane lipid equilibrium during active transcription of phospholipid biosynthetic genes under ER stress. Copyright © 2018 Elsevier Inc. All rights reserved.

Tributyltin-induced endoplasmic reticulum stress and its Ca(2+)-mediated mechanism.

PubMed

Isomura, Midori; Kotake, Yaichiro; Masuda, Kyoichi; Miyara, Masatsugu; Okuda, Katsuhiro; Samizo, Shigeyoshi; Sanoh, Seigo; Hosoi, Toru; Ozawa, Koichiro; Ohta, Shigeru

2013-10-01

Organotin compounds, especially tributyltin chloride (TBT), have been widely used in antifouling paints for marine vessels, but exhibit various toxicities in mammals. The endoplasmic reticulum (ER) is a multifunctional organelle that controls post-translational modification and intracellular Ca(2+) signaling. When the capacity of the quality control system of ER is exceeded under stress including ER Ca(2+) homeostasis disruption, ER functions are impaired and unfolded proteins are accumulated in ER lumen, which is called ER stress. Here, we examined whether TBT causes ER stress in human neuroblastoma SH-SY5Y cells. We found that 700nM TBT induced ER stress markers such as CHOP, GRP78, spliced XBP1 mRNA and phosphorylated eIF2α. TBT also decreased the cell viability both concentration- and time-dependently. Dibutyltin and monobutyltin did not induce ER stress markers. We hypothesized that TBT induces ER stress via Ca(2+) depletion, and to test this idea, we examined the effect of TBT on intracellular Ca(2+) concentration using fura-2 AM, a Ca(2+) fluorescent probe. TBT increased intracellular Ca(2+) concentration in a TBT-concentration-dependent manner, and Ca(2+) increase in 700nM TBT was mainly blocked by 50μM dantrolene, a ryanodine receptor antagonist (about 70% inhibition). Dantrolene also partially but significantly inhibited TBT-induced GRP78 expression and cell death. These results suggest that TBT increases intracellular Ca(2+) concentration by releasing Ca(2+) from ER, thereby causing ER stress. Copyright © 2013 Elsevier Inc. All rights reserved.

The endoplasmic reticulum in plant immunity and cell death

PubMed Central

Eichmann, Ruth; Schäfer, Patrick

2012-01-01

The endoplasmic reticulum (ER) is a highly dynamic organelle in eukaryotic cells and a major production site of proteins destined for vacuoles, the plasma membrane, or apoplast in plants. At the ER, these secreted proteins undergo multiple processing steps, which are supervised and conducted by the ER quality control system. Notably, processing of secreted proteins can considerably elevate under stress conditions and exceed ER folding capacities. The resulting accumulation of unfolded proteins is defined as ER stress. The efficiency of cells to re-establish proper ER function is crucial for stress adaptation. Besides delivering proteins directly antagonizing and resolving stress conditions, the ER monitors synthesis of immune receptors. This indicates the significance of the ER for the establishment and function of the plant immune system. Recent studies point out the fragility of the entire system and highlight the ER as initiator of programed cell death (PCD) in plants as was reported for vertebrates. This review summarizes current knowledge on the impact of the ER on immune and PCD signaling. Understanding the integration of stress signals by the ER bears a considerable potential to optimize development and to enhance stress resistance of plants. PMID:22936941

The endoplasmic reticulum in plant immunity and cell death.

PubMed

Eichmann, Ruth; Schäfer, Patrick

2012-01-01

The endoplasmic reticulum (ER) is a highly dynamic organelle in eukaryotic cells and a major production site of proteins destined for vacuoles, the plasma membrane, or apoplast in plants. At the ER, these secreted proteins undergo multiple processing steps, which are supervised and conducted by the ER quality control system. Notably, processing of secreted proteins can considerably elevate under stress conditions and exceed ER folding capacities. The resulting accumulation of unfolded proteins is defined as ER stress. The efficiency of cells to re-establish proper ER function is crucial for stress adaptation. Besides delivering proteins directly antagonizing and resolving stress conditions, the ER monitors synthesis of immune receptors. This indicates the significance of the ER for the establishment and function of the plant immune system. Recent studies point out the fragility of the entire system and highlight the ER as initiator of programed cell death (PCD) in plants as was reported for vertebrates. This review summarizes current knowledge on the impact of the ER on immune and PCD signaling. Understanding the integration of stress signals by the ER bears a considerable potential to optimize development and to enhance stress resistance of plants.

Eat it right: ER-phagy and recovER-phagy.

PubMed

Loi, Marisa; Fregno, Ilaria; Guerra, Concetta; Molinari, Maurizio

2018-05-25

The endoplasmic reticulum (ER) is the site of protein, lipid, phospholipid, steroid and oligosaccharide synthesis and modification, calcium ion storage, and detoxification of endogenous and exogenous products. Its volume (and activity) must be maintained under normal growth conditions, must be expanded in a controlled manner on activation of ER stress programs and must be reduced to pre-stress size during the recovery phase that follows ER stress termination. ER-phagy is the constitutive or regulated fragmentation and delivery of ER fragments to lysosomal compartments for clearance. It gives essential contribution to the maintenance of cellular homeostasis, proteostasis, lipidostasis and oligosaccharidostasis (i.e. the capacity to produce the proteome, lipidome and oligosaccharidome in appropriate quality and quantity). ER turnover is activated on ER stress, nutrient deprivation, accumulation of misfolded polypeptides, pathogen attack and by activators of macroautophagy. The selectivity of these poorly characterized catabolic pathways is ensured by proteins displayed at the limiting membrane of the ER subdomain to be removed from cells. These proteins are defined as ER-phagy receptors and engage the cytosolic macroautophagy machinery via specific modules that associate with ubiquitin-like, cytosolic proteins of the Atg8/LC3/GABARAP family. In this review, we give an overview on selective ER turnover and on the yeast and mammalian ER-phagy receptors identified so far. © 2018 The Author(s).

Endoplasmic reticulum-dependent redox reactions control endoplasmic reticulum-associated degradation and pathogen entry.

PubMed

Walczak, Christopher P; Bernardi, Kaleena M; Tsai, Billy

2012-04-15

Protein misfolding within the endoplasmic reticulum (ER) is managed by an ER quality control system that retro-translocates aberrant proteins into the cytosol for proteasomal destruction. This process, known as ER-associated degradation, utilizes the action of ER redox enzymes to accommodate the disulfide-bonded nature of misfolded proteins. Strikingly, various pathogenic viruses and toxins co-opt these redox components to reach the cytosol during entry. These redox factors thus regulate critical cellular homeostasis and host-pathogen interactions. Recent studies identify specific members of the protein disulfide isomerase (PDI) family, which use their chaperone and catalytic activities, in engaging both misfolded ER proteins and pathogens. The precise molecular mechanism by which a dedicated PDI family member disrupts the disulfide bonds in the misfolded ER proteins and pathogens, as well as how they act to unfold these substrates to promote their ER-to-cytosol membrane transport, remain poorly characterized. How PDI family members distinguish folded versus misfolded ER substrates remains enigmatic. What physical characteristics surrounding a substrate's disulfide bond instruct PDI that it is mispaired or native? For the pathogens, as their disulfide bonds normally serve a critical role in providing physical support, what conformational changes experienced in the host enable their disulfide bonds to be disrupted? A combination of more rigorous biochemical and high-resolution structural studies should begin to address these questions.

Children with social anxiety and other anxiety disorders show similar deficits in habitual emotional regulation: evidence for a transdiagnostic phenomenon.

PubMed

Keil, Verena; Asbrand, Julia; Tuschen-Caffier, Brunna; Schmitz, Julian

2017-07-01

Deficits in emotion regulation (ER) are an important factor in maintaining social anxiety disorder (SAD) in adults. As SAD and ER problems typically develop during childhood and adolescence, and are maintained dynamically within the parent-child dyad, research on families can help to reveal the role ER plays in the early development of SAD. The current study assessed self-reported habitual ER in dyads of children with SAD (n = 31), children with mixed anxiety disorders (MAD; n = 41) and healthy control children (HC; n = 36), and their parents. Results indicate a transdiagnostic quality of ER in that, children with SAD and children with MAD similarly reported less adaptive and more maladaptive ER strategies than HC children, whereas no group differences in parental ER strategies emerged. Furthermore, children's ER strategies aggressive action, withdrawal and self-devaluation and the parental ER strategy reappraisal were associated with social anxiety symptoms. These results suggest that there may be deficits in ER which generalize across childhood anxiety disorders. Our results are discussed in relation to current theories and their implications for treatment of childhood SAD.

Tributyltin-induced endoplasmic reticulum stress and its Ca{sup 2+}-mediated mechanism

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

Isomura, Midori; Kotake, Yaichiro, E-mail: yaichiro@hiroshima-u.ac.jp; Masuda, Kyoichi

2013-10-01

Organotin compounds, especially tributyltin chloride (TBT), have been widely used in antifouling paints for marine vessels, but exhibit various toxicities in mammals. The endoplasmic reticulum (ER) is a multifunctional organelle that controls post-translational modification and intracellular Ca{sup 2+} signaling. When the capacity of the quality control system of ER is exceeded under stress including ER Ca{sup 2+} homeostasis disruption, ER functions are impaired and unfolded proteins are accumulated in ER lumen, which is called ER stress. Here, we examined whether TBT causes ER stress in human neuroblastoma SH-SY5Y cells. We found that 700 nM TBT induced ER stress markers suchmore » as CHOP, GRP78, spliced XBP1 mRNA and phosphorylated eIF2α. TBT also decreased the cell viability both concentration- and time-dependently. Dibutyltin and monobutyltin did not induce ER stress markers. We hypothesized that TBT induces ER stress via Ca{sup 2+} depletion, and to test this idea, we examined the effect of TBT on intracellular Ca{sup 2+} concentration using fura-2 AM, a Ca{sup 2+} fluorescent probe. TBT increased intracellular Ca{sup 2+} concentration in a TBT-concentration-dependent manner, and Ca{sup 2+} increase in 700 nM TBT was mainly blocked by 50 μM dantrolene, a ryanodine receptor antagonist (about 70% inhibition). Dantrolene also partially but significantly inhibited TBT-induced GRP78 expression and cell death. These results suggest that TBT increases intracellular Ca{sup 2+} concentration by releasing Ca{sup 2+} from ER, thereby causing ER stress. - Highlights: • We established that tributyltin induces endoplasmic reticulum (ER) stress. • Tributyltin induces ER stress markers in a concentration-dependent manner. • Tributyltin increases Ca{sup 2+} release from ER, thereby causing ER stress. • Dibutyltin and monobutyltin did not increase GRP78 or intracellular Ca{sup 2+}.« less

Quality of Child Care Using the Environment Rating Scales: A Meta-Analysis of International Studies

ERIC Educational Resources Information Center

Vermeer, Harriet J.; van IJzendoorn, Marinus H.; Cárcamo, Rodrigo A.; Harrison, Linda J.

2016-01-01

The current study provides a systematic examination of child care quality around the globe, using the Environment Rating Scales (ERS). Additional goals of this study are to examine associations between ERS process quality and structural features (group size, caregiver-child ratio) that underpin quality and between ERS and more proximal aspects of…

Mfn2 ubiquitination by PINK1/parkin gates the p97-dependent release of ER from mitochondria to drive mitophagy

PubMed Central

McLelland, Gian-Luca; Goiran, Thomas; Yi, Wei; Dorval, Geneviève; Chen, Carol X; Lauinger, Nadine D; Krahn, Andrea I; Valimehr, Sepideh; Rakovic, Aleksandar; Rouiller, Isabelle; Durcan, Thomas M; Trempe, Jean-François

2018-01-01

Despite their importance as signaling hubs, the function of mitochondria-ER contact sites in mitochondrial quality control pathways remains unexplored. Here we describe a mechanism by which Mfn2, a mitochondria-ER tether, gates the autophagic turnover of mitochondria by PINK1 and parkin. Mitochondria-ER appositions are destroyed during mitophagy, and reducing mitochondria-ER contacts increases the rate of mitochondrial degradation. Mechanistically, parkin/PINK1 catalyze a rapid burst of Mfn2 phosphoubiquitination to trigger p97-dependent disassembly of Mfn2 complexes from the outer mitochondrial membrane, dissociating mitochondria from the ER. We additionally demonstrate that a major portion of the facilitatory effect of p97 on mitophagy is epistatic to Mfn2 and promotes the availability of other parkin substrates such as VDAC1. Finally, we reconstitute the action of these factors on Mfn2 and VDAC1 ubiquitination in a cell-free assay. We show that mitochondria-ER tethering suppresses mitophagy and describe a parkin-/PINK1-dependent mechanism that regulates the destruction of mitochondria-ER contact sites. PMID:29676259

Role of N-linked polymannose oligosaccharides in targeting glycoproteins for endoplasmic reticulum-associated degradation.

PubMed

Spiro, R G

2004-05-01

Misfolded or incompletely assembled multisubunit glycoproteins undergo endoplasmic reticulum-associated degradation (ERAD) regulated in large measure by their N-linked polymannose oligosaccharides. In this quality control system lectin interaction with Glc(3)Man(9)GlcNAc(2) glycans after trimming with endoplasmic reticulum (ER) alpha-glucosidases and alpha-mannosidases sorts out persistently unfolded glycoproteins for N-deglycosylation and proteolytic degradation. Monoglucosylated (Glc(1)Man(9)GlcNAc(2)) glycoproteins take part in the calnexin/calreticulin glucosylation-deglucosylation cycle, while the Man(8)GlcNAc(2) isomer B product of ER mannosidase I interacts with EDEM. Proteasomal degradation requires retrotranslocation into the cytosol through a Sec61 channel and deglycosylation by peptide: N-glycosidase (PNGase); in alternate models both PNGase and proteasomes may be either free in the cytosol or ER membrane-imbedded/attached. Numerous proteins appear to undergo nonproteasomal degradation in which deglycosylation and proteolysis take place in the ER lumen. The released free oligosaccharides (OS) are transported to the cytosol as OS-GlcNAc(2) along with similar components produced by the hydrolytic action of the oligosaccharyltransferase, where they together with OS from the proteasomal pathway are trimmed to Man(5)GlcNAc(1) by the action of cytosolic endo-beta- N-acetylglucosaminidase and alpha-mannosidase before entering the lysosomes. Some misfolded glycoproteins can recycle between the ER, intermediate and Golgi compartments, where they are further processed before ERAD. Moreover, properly folded glycoproteins with mannose-trimmed glycans can be deglucosylated in the Golgi by endomannosidase, thereby releasing calreticulin and permitting formation of complex OS. A number of regulatory controls have been described, including the glucosidase-glucosyltransferase shuttle, which controls the level of Glc(3)Man(9)GlcNAc(2)-P-P-Dol, and the unfolded protein response, which enhances synthesis of components of the quality control system.

Endoplasmic Reticulum Stress Response and Mutant Protein Degradation in CHO Cells Accumulating Antithrombin (C95R) in Russell Bodies.

PubMed

Kimura, Koji; Inoue, Kengo; Okubo, Jun; Ueda, Yumiko; Kawaguchi, Kosuke; Sakurai, Hiroaki; Wada, Ikuo; Morita, Masashi; Imanaka, Tsuneo

2015-01-01

Newly synthesized secretory proteins are folded and assembled in the endoplasmic reticulum (ER), where an efficient protein quality control system performs a critically important function. When unfolded or aggregated proteins accumulate in the ER, certain signaling pathways such as the unfolded protein response (UPR) and ER-overload response (EOR) are functionally active in maintaining cell homeostasis. Recently we prepared Chinese hamster ovary (CHO) cells expressing mutant antithrombin (AT)(C95R) under control of the Tet-On system and showed that AT(C95R) accumulated in Russell bodies (RB), large distinctive structures derived from the ER. To characterize whether ER stress takes place in CHO cells, we examined characteristic UPR and EOR in ER stress responses. We found that the induction of ER chaperones such as Grp97, Grp78 and protein disulfide isomerase (PDI) was limited to a maximum of approximately two-fold. The processing of X-box-binding protein-1 (XBP1) mRNA and the phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) subunit were not induced. Furthermore, the activation of nuclear factor-kappa B (NF-κB) was not observed. In contrast, CHO cells displayed UPR and EOR when the cells were treated with thapsigargin and tumor necrosis factor (TNF)-α, respectively. In addition, a portion of the mutant AT(C95R) was degraded through proteasomes and autophagy. CHO cells do respond to ER stress but the folding state of mutant AT(C95R) does not appear to activate the ER stress signal pathway.

Interaction mode between catalytic and regulatory subunits in glucosidase II involved in ER glycoprotein quality control.

PubMed

Satoh, Tadashi; Toshimori, Takayasu; Noda, Masanori; Uchiyama, Susumu; Kato, Koichi

2016-11-01

The glycoside hydrolase family 31 (GH31) α-glucosidases play vital roles in catabolic and regulated degradation, including the α-subunit of glucosidase II (GIIα), which catalyzes trimming of the terminal glucose residues of N-glycan in glycoprotein processing coupled with quality control in the endoplasmic reticulum (ER). Among the known GH31 enzymes, only GIIα functions with its binding partner, regulatory β-subunit (GIIβ), which harbors a lectin domain for substrate recognition. Although the structural data have been reported for GIIα and the GIIβ lectin domain, the interaction mode between GIIα and GIIβ remains unknown. Here, we determined the structure of a complex formed between GIIα and the GIIα-binding domain of GIIβ, thereby providing a structural basis underlying the functional extension of this unique GH31 enzyme. © 2016 The Protein Society.

A randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy and safety of the extended-release tramadol hydrochloride/acetaminophen fixed-dose combination tablet for the treatment of chronic low back pain.

PubMed

Lee, Jae Hyup; Lee, Chong-Suh

2013-11-01

Chronic low back pain is a common condition that is often difficult to treat. The combination of tramadol hydrochloride and acetaminophen in an extended-release formulation has been shown to provide rapid and long-lasting analgesic effects resulting from the synergistic activity of these 2 active ingredients. The goal of this study was to evaluate the efficacy and safety of extended-release tramadol hydrochloride 75-mg/acetaminophen 650-mg fixed-dose combination tablets (TA-ER) for the treatment of chronic low back pain. This Phase III, double-blind, placebo-controlled, parallel-group study enrolled 245 patients with moderate to severe (≥4 cm on a 10-cm visual analog scale) chronic (≥3 months') low back pain insufficiently controlled by previous NSAIDs or cyclooxygenase-2-selective inhibitors and randomly assigned them to receive 4 weeks of either TA-ER or placebo. The primary efficacy end point was the percentage of patients with a pain intensity change rate ≥30% from baseline to final evaluation. Secondary end points included quality of life (Korean Short Form-36), functionality (Korean Oswestry Disability Index), and adverse events. The percentage of patients with a pain intensity change rate ≥30% was significantly higher (P < 0.05) in the TA-ER group than in the placebo group for both the full analysis set and the per-protocol population. Pain relief success rate from baseline was significantly higher with TA-ER versus placebo at days 8 and 15 but not at the final visit. Patients in the TA-ER group had significant improvements versus placebo in role-physical, general health, and reported health transition domains of the Korean Short Form-36 and significantly higher functional improvements in the personal care section of the Korean Oswestry Disability Index. Patient assessment of overall pain control as "very good" was also significantly higher with TA-ER than with placebo. Adverse events were reported more frequently with TA-ER than with placebo; the most common adverse events reported were nausea, dizziness, constipation, and vomiting. TA-ER was significantly more effective than placebo in providing pain relief, functional improvements, and improved quality of life. It exhibited a predictable safety profile in patients with chronic low back pain. ClinicalTrials.gov identifier: NCT01112267. © 2013 The Authors. Published by Elsevier HS Journals, Inc. All rights reserved.

Unfolded protein response activation compensates endoplasmic reticulum-associated degradation deficiency in Arabidopsis.

PubMed

Li, Qingliang; Wei, Hai; Liu, Lijing; Yang, Xiaoyuan; Zhang, Xiansheng; Xie, Qi

2017-07-01

Abiotic stresses often disrupt protein folding and induce endoplasmic reticulum (ER) stress. There is a sophisticated ER quality control (ERQC) system to mitigate the effects of malfunctioning proteins and maintain ER homeostasis. The accumulation of misfolded proteins in the ER activates the unfolded protein response (UPR) to enhance ER protein folding and the degradation of misfolded proteins mediate by ER-associated degradation (ERAD). That ERQC reduces abiotic stress damage has been well studied in mammals and yeast. However, in plants, both ERAD and UPR have been studied separately and found to be critical for plant abiotic stress tolerance. In this study, we discovered that UPR-associated transcription factors AtbZIP17, AtbZIP28 and AtbZIP60 responded to tunicamycin (TM) and NaCl induced ER stress and subsequently enhanced Arabidopsis thaliana abiotic stress tolerance. They regulated the expression level of ER chaperones and the HRD1-complex components. Moreover, overexpression of AtbZIP17, AtbZIP28 and AtbZIP60 could restore stress tolerance via ERAD in the HRD1-complex mutant hrd3a-2, which suggested that UPR and ERAD have an interactive mechanism in Arabidopsis. © 2017 Institute of Botany, Chinese Academy of Sciences.

Interpersonal emotion regulation in Asperger's syndrome and borderline personality disorder.

PubMed

López-Pérez, Belén; Ambrona, Tamara; Gummerum, Michaela

2017-03-01

Interpersonal emotion regulation (ER) plays a significant role in how individuals meet others' emotional needs and shape social interactions, as it is key to initiating and maintaining high-quality social relationships. Given that individuals with borderline personality disorder (BPD) or Asperger's syndrome (AS) exhibit problems in social interactions, the aim of this study was to examine their use of different interpersonal ER strategies compared to normative control participants. Thirty individuals with AS, 30 with BPD, and 60 age-, gender-, and education-matched control participants completed a battery of measures to assess interpersonal ER, which assessed to what extent participants tended to engage in interpersonal affect improvement and worsening and to what extent they used different strategies. Before completing those measures, all groups were screened for disorders of Axis I and Axis II with the Structured Clinical Interview for DSM-IV Axis I and Axis II Disorders. Compared to controls, individuals with AS and with BPD engaged less in affect improvement. No differences were found for affect worsening. Individuals with AS reported to use less adaptive (attention deployment, cognitive change) and more maladaptive (expressive suppression) interpersonal ER strategies, compared to individuals with BPD and control participants who did not differ from each other. The obtained results suggest the need to develop tailored ER interventions for each of the clinical groups studied. Furthermore, they highlight the need to study further potential differences in intrapersonal and interpersonal ER in clinical populations. Individuals with Asperger's syndrome (AS) and borderline personality disorder (BPD) engaged significantly less than healthy controls in interpersonal affect improvement. Individuals with BPD did not differ from healthy controls in the use of interpersonal strategies. Individuals with AS reported to use more maladaptive and less adaptive strategies than BPD individuals and healthy controls. Understanding differences in interpersonal emotion regulation in individuals with AS and with BPD and normative controls might help practitioners develop better interventions. © 2016 The British Psychological Society.

Refractive index of erbium doped GaN thin films

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

Alajlouni, S.; Sun, Z. Y.; Li, J.

2014-08-25

GaN is an excellent host for erbium (Er) to provide optical emission in the technologically important as well as eye-safe 1540 nm wavelength window. Er doped GaN (GaN:Er) epilayers were synthesized on c-plane sapphire substrates using metal organic chemical vapor deposition. By employing a pulsed growth scheme, the crystalline quality of GaN:Er epilayers was significantly improved over those obtained by conventional growth method of continuous flow of reaction precursors. X-ray diffraction rocking curve linewidths of less than 300 arc sec were achieved for the GaN (0002) diffraction peak, which is comparable to the typical results of undoped high quality GaN epilayers andmore » represents a major improvement over previously reported results for GaN:Er. Spectroscopic ellipsometry was used to determine the refractive index of the GaN:Er epilayers in the 1540 nm wavelength window and a linear dependence on Er concentration was found. The observed refractive index increase with Er incorporation and the improved crystalline quality of the GaN:Er epilayers indicate that low loss GaN:Er optical waveguiding structures are feasible.« less

Long-term Safety and Efficacy of Tapentadol Extended Release Following up to 2 Years of Treatment in Patients With Moderate to Severe, Chronic Pain: Results of an Open-label Extension Trial.

PubMed

Buynak, Robert; Rappaport, Stephen A; Rod, Kevin; Arsenault, Pierre; Heisig, Fabian; Rauschkolb, Christine; Etropolski, Mila

2015-11-01

Tapentadol extended release (ER) has demonstrated efficacy and safety for the management of moderate to severe, chronic pain in adults. This study evaluated the long-term safety and tolerability of tapentadol ER in patients with chronic osteoarthritis or low back pain. Patients were enrolled in this 1-year, open-label extension study after completing one of two 15-week, placebo-controlled studies of tapentadol ER and oxycodone controlled release (CR) for osteoarthritis knee pain (NCT00421928) or low back pain (NCT00449176), a 7-week crossover study between tapentadol immediate release and tapentadol ER for low back pain (NCT00594516), or a 1-year safety study of tapentadol ER and oxycodone CR for osteoarthritis or low back pain (NCT00361504). After titrating the drug to an optimal dose, patients received tapentadol ER (100-250 mg BID) for up to 1 year (after finishing treatment in the preceding studies); patients who were previously treated with tapentadol ER in the 1-year safety study received tapentadol ER continuously for up to 2 years in total. Of the 1,154 patients in the safety population, 82.7% were aged >65 years and 57.9% were female; 50.1% had mild baseline pain intensity. Mean (SD) pain intensity scores (11-point numerical rating scale) were 3.9 (2.38) at baseline (end of preceding study) and 3.7 (2.42) at end point, indicating that pain relief was maintained during the extension study. Improvements in measures of quality of life (eg, EuroQol-5 Dimension and the 36-item Short Form Health Survey [SF-36]) health status questionnaires) achieved during the preceding studies were maintained during the open-label extension study. Tapentadol ER was associated with a safety and tolerability profile comparable to that observed in the preceding studies. The most common treatment-emergent adverse events (incidence ≥10%; n = 1154) were headache (13.1%), nausea (11.8%), and constipation (11.1%). Similar efficacy and tolerability results were shown for patients who received up to 2 years of tapentadol ER treatment. Pain relief and improvements in quality of life achieved during the preceding studies were maintained throughout this extension study, during which tapentadol ER was well tolerated for the long-term treatment of chronic osteoarthritis or low back pain over up to 2 years of treatment. (ClinicalTrials.gov identifier: NCT00487435.). Copyright © 2015. Published by Elsevier Inc.

ER stress-induced protein, VIGG, disturbs plant cation homeostasis, which is correlated with growth retardation and robustness to ER stress

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

Katoh, Hironori; Fujita, Keiko; Takuhara, Yuki

2011-02-18

Highlights: {yields} VIGG is an ER stress-induced protein in plant. {yields} We examine the characteristics of VIGG-overexpressing Arabidopsis plants. {yields} VIGG-overexpressing plants reveal growth retardation and robustness to ER stress. {yields} VIGG disturbs cation homeostasis in plant. -- Abstract: VIGG is a putative endoplasmic reticulum (ER) resident protein induced by virus infection and ER stress, and is correlated with fruit quality in grapevine. The present study was undertaken to determine the biological function of VIGG in grapevine. Experiments using fluorescent protein-VIGG fusion protein demonstrated that VIGG is localized in ER and the ER targeting sequence is in the N-terminus. Themore » overexpression of VIGG in Arabidopsis plant led to growth retardation. The rosette leaves of VIGG-overexpressing plants were smaller than those of the control plants and rolled at 42 days after seeding. VIGG-overexpressing plants revealed robustness to ER stress as well as the low expression of ER stress marker proteins, such as the luminal binding proteins. These characteristics of VIGG-overexpressing plants were supported by a microarray experiment that demonstrated the disruption of genes related to ER stress response and flowering, as well as cation mobility, in the plants. Finally, cation homeostasis in the plants was disturbed by the overexpression of VIGG. Taken together, these results suggest that VIGG may disturb cation homeostasis in plant, which is correlated with the robustness to ER stress and growth retardation.« less

Untangling the web: Mechanisms underlying ER network formation

PubMed Central

Goyal, Uma; Blackstone, Craig

2013-01-01

The ER is a continuous membrane system consisting of the nuclear envelope, flat sheets often studded with ribosomes, and a polygonal network of highly-curved tubules extending throughout the cell. Although protein and lipid biosynthesis, protein modification, vesicular transport, Ca2+dynamics, and protein quality control have been investigated in great detail, mechanisms that generate the distinctive architecture of the ER have been uncovered only recently. Several protein families including the reticulons and REEPs/DP1/Yop1p harbor hydrophobic hairpin domains that shape high-curvature ER tubules and mediate intramembrane protein interactions. Members of the atlastin/RHD3/Sey1p family of dynamin-related GTPases interact with the ER-shaping proteins and mediate the formation of three-way junctions responsible for the polygonal structure of the tubular ER network, with Lunapark proteins acting antagonistically. Additional classes of tubular ER proteins including some REEPs and the M1 spastin ATPase interact with the microtubule cytoskeleton. Flat ER sheets possess a different complement of proteins such as p180, CLIMP-63 and kinectin implicated in shaping, cisternal stacking and cytoskeletal interactions. The ER is also in constant motion, and numerous signaling pathways as well as interactions among cytoskeletal elements, the plasma membrane, and organelles cooperate to position and shape the ER dynamically. Finally, many proteins involved in shaping the ER network are mutated in the most common forms of hereditary spastic paraplegia, indicating a particular importance for proper ER morphology and distribution in large, highly-polarized cells such as neurons. PMID:23602970

Development of a stable ERroGFP variant suitable for monitoring redox dynamics in the ER.

PubMed

Hoseki, Jun; Oishi, Asami; Fujimura, Takaaki; Sakai, Yasuyoshi

2016-01-01

The endoplasmic reticulum (ER) is an essential organelle for cellular metabolic homeostasis including folding and maturation of secretory and membrane proteins. Disruption of ER proteostasis has been implicated in the pathogenesis of various diseases such as diabetes and neurodegenerative diseases. The ER redox state, which is an oxidative environment suitable for disulfide-bond formation, is essential for ER protein quality control. Hence, detection of the ER redox state, especially in living cells, is essential to understand the mechanism by which the redox state of the ER is maintained. However, methods to detect the redox state of the ER have not been well-established because of inefficient folding and stability of roGFP variants with oxidative redox potential like roGFP-iL. Here we have improved the folding efficiency of ER-targeted roGFP-iL (ERroGFP-iL) in cells by introducing superfolder GFP (sfGFP) mutations. Four specific amino acid substitutions (S30R, Y39N, T105N and I171V) greatly improved folding efficiency in Escherichia coli and in the ER of HeLa cells, as well as the thermostability of the purified proteins. Introduction of these mutations also enhanced the dynamic range for redox change both in vitro and in the ER of living cells. ER-targeted roGFP-S4 (ERroGFP-S4) possessing these four mutations could detect physiological redox changes within the ER. ERroGFP-S4 is therefore a novel probe suitable for monitoring redox change in the ER. ERroGFP-S4 can be applied to detect aberrant ER redox states associated with various pathological conditions and to identify the mechanisms used to maintain the redox state of the ER. © 2016 The Author(s).

The Role of p58IPK in Protecting the Stressed Endoplasmic Reticulum

PubMed Central

Rutkowski, D. Thomas; Kang, Sang-Wook; Goodman, Alan G.; Garrison, Jennifer L.; Taunton, Jack; Katze, Michael G.

2007-01-01

The preemptive quality control (pQC) pathway protects cells from acute endoplasmic reticulum (ER) stress by attenuating translocation of nascent proteins despite their targeting to translocons at the ER membrane. Here, we investigate the hypothesis that the DnaJ protein p58IPK plays an essential role in this process via HSP70 recruitment to the cytosolic face of translocons for extraction of translocationally attenuated nascent chains. Our analyses revealed that the heightened stress sensitivity of p58−/− cells was not due to an impairment of the pQC pathway or elevated ER substrate burden during acute stress. Instead, the lesion was in the protein processing capacity of the ER lumen, where p58IPK was found to normally reside in association with BiP. ER lumenal p58IPK could be coimmunoprecipitated with a newly synthesized secretory protein in vitro and stimulated protein maturation upon overexpression in cells. These results identify a previously unanticipated location for p58IPK in the ER lumen where its putative function as a cochaperone explains the stress-sensitivity phenotype of knockout cells and mice. PMID:17567950

Late-onset of spinal neurodegeneration in knock-in mice expressing a mutant BiP.

PubMed

Jin, Hisayo; Mimura, Naoya; Kashio, Makiko; Koseki, Haruhiko; Aoe, Tomohiko

2014-01-01

Most human neurodegenerative diseases are sporadic, and appear later in life. While the underlying mechanisms of the progression of those diseases are still unclear, investigations into the familial forms of comparable diseases suggest that endoplasmic reticulum (ER) stress is involved in the pathogenesis. Binding immunoglobulin protein (BiP) is an ER chaperone that is central to ER function. We produced knock-in mice expressing a mutant BiP that lacked the retrieval sequence in order to evaluate the effect of a functional defect in an ER chaperone in multi-cellular organisms. Here we report that heterozygous mutant BiP mice revealed motor disabilities in aging. We found a degeneration of some motoneurons in the spinal cord accompanied by accumulations of ubiquitinated proteins. The defect in retrieval of BiP by the KDEL receptor leads to impaired activities in quality control and autophagy, suggesting that functional defects in the ER chaperones may contribute to the late onset of neurodegenerative diseases.

The Thiazide-sensitive NaCl Cotransporter Is Targeted for Chaperone-dependent Endoplasmic Reticulum-associated Degradation*

PubMed Central

Needham, Patrick G.; Mikoluk, Kasia; Dhakarwal, Pradeep; Khadem, Shaheen; Snyder, Avin C.; Subramanya, Arohan R.; Brodsky, Jeffrey L.

2011-01-01

The thiazide-sensitive NaCl cotransporter (NCC, SLC12A3) mediates salt reabsorption in the distal nephron of the kidney and is the target of thiazide diuretics, which are commonly prescribed to treat hypertension. Mutations in NCC also give rise to Gitelman syndrome, a hereditary salt-wasting disorder thought in most cases to arise from impaired NCC biogenesis through enhanced endoplasmic reticulum-associated degradation (ERAD). Because the machinery that mediates NCC quality control is completely undefined, we employed yeast as a model heterologous expression system to identify factors involved in NCC degradation. We confirmed that NCC was a bona fide ERAD substrate in yeast, as the majority of NCC polypeptide was integrated into ER membranes, and its turnover rate was sensitive to proteasome inhibition. NCC degradation was primarily dependent on the ER membrane-associated E3 ubiquitin ligase Hrd1. Whereas several ER luminal chaperones were dispensable for NCC ERAD, NCC ubiquitination and degradation required the activity of Ssa1, a cytoplasmic Hsp70 chaperone. Compatible findings were observed when NCC was expressed in mammalian kidney cells, as the cotransporter was polyubiquitinated and degraded by the proteasome, and mammalian cytoplasmic Hsp70 (Hsp72) coexpression stimulated the degradation of newly synthesized NCC. Hsp70 also preferentially associated with the ER-localized NCC glycosylated species, indicating that cytoplasmic Hsp70 plays a critical role in selecting immature forms of NCC for ERAD. Together, these results provide the first survey of components involved in the ERAD of a mammalian SLC12 cation chloride cotransporter and provide a framework for future studies on NCC ER quality control. PMID:22027832

Preliminary remediation goals for use at the US Department of Energy Oak Ridge Operations Office. Revision 1

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

NONE

1996-05-01

This technical memorandum presents Preliminary Remediation Goals (PRGs) for use in human health risk assessment efforts under the United States Department of Energy, Oak Ridge Operations Office Environmental Restoration (ER) Division. This document provides the ER Division with standardized PRGs which are integral to the Remedial Investigation/Feasibility Study process. They are used during project scooping (Data Quality Objectives development), in screening level risk assessments to support early action or No Further Investigation decisions, and in the baselines risk assessment where they are employed in the selection of chemicals of potential concern. The primary objective of this document is to standardizemore » these values and eliminate any duplication of effort by providing PRGs to all contractors involved in risk activities. In addition, by managing the assumptions and systems used in PRG derivation, the ER Risk Assessment Program will be able to control the level of quality assurance associated with these risk-based guideline values.« less

The clinical effectiveness and cost-effectiveness of exercise referral schemes: a systematic review and economic evaluation.

PubMed

Pavey, T G; Anokye, N; Taylor, A H; Trueman, P; Moxham, T; Fox, K R; Hillsdon, M; Green, C; Campbell, J L; Foster, C; Mutrie, N; Searle, J; Taylor, R S

2011-12-01

Exercise referral schemes (ERS) aim to identify inactive adults in the primary-care setting. The GP or health-care professional then refers the patient to a third-party service, with this service taking responsibility for prescribing and monitoring an exercise programme tailored to the needs of the individual. To assess the clinical effectiveness and cost-effectiveness of ERS for people with a diagnosed medical condition known to benefit from physical activity (PA). The scope of this report was broadened to consider individuals without a diagnosed condition who are sedentary. MEDLINE; EMBASE; PsycINFO; The Cochrane Library, ISI Web of Science; SPORTDiscus and ongoing trial registries were searched (from 1990 to October 2009) and included study references were checked. Systematic reviews: the effectiveness of ERS, predictors of ERS uptake and adherence, and the cost-effectiveness of ERS; and the development of a decision-analytic economic model to assess cost-effectiveness of ERS. Seven randomised controlled trials (UK, n = 5; non-UK, n = 2) met the effectiveness inclusion criteria, five comparing ERS with usual care, two compared ERS with an alternative PA intervention, and one to an ERS plus a self-determination theory (SDT) intervention. In intention-to-treat analysis, compared with usual care, there was weak evidence of an increase in the number of ERS participants who achieved a self-reported 90-150 minutes of at least moderate-intensity PA per week at 6-12 months' follow-up [pooled relative risk (RR) 1.11, 95% confidence interval 0.99 to 1.25]. There was no consistent evidence of a difference between ERS and usual care in the duration of moderate/vigorous intensity and total PA or other outcomes, for example physical fitness, serum lipids, health-related quality of life (HRQoL). There was no between-group difference in outcomes between ERS and alternative PA interventions or ERS plus a SDT intervention. None of the included trials separately reported outcomes in individuals with medical diagnoses. Fourteen observational studies and five randomised controlled trials provided a numerical assessment of ERS uptake and adherence (UK, n = 16; non-UK, n = 3). Women and older people were more likely to take up ERS but women, when compared with men, were less likely to adhere. The four previous economic evaluations identified suggest ERS to be a cost-effective intervention. Indicative incremental cost per quality-adjusted life-year (QALY) estimates for ERS for various scenarios were based on a de novo model-based economic evaluation. Compared with usual care, the mean incremental cost for ERS was £169 and the mean incremental QALY was 0.008, with the base-case incremental cost-effectiveness ratio at £20,876 per QALY in sedentary people without a medical condition and a cost per QALY of £14,618 in sedentary obese individuals, £12,834 in sedentary hypertensive patients, and £8414 for sedentary individuals with depression. Estimates of cost-effectiveness were highly sensitive to plausible variations in the RR for change in PA and cost of ERS. We found very limited evidence of the effectiveness of ERS. The estimates of the cost-effectiveness of ERS are based on a simple analytical framework. The economic evaluation reports small differences in costs and effects, and findings highlight the wide range of uncertainty associated with the estimates of effectiveness and the impact of effectiveness on HRQoL. No data were identified as part of the effectiveness review to allow for adjustment of the effect of ERS in different populations. There remains considerable uncertainty as to the effectiveness of ERS for increasing activity, fitness or health indicators or whether they are an efficient use of resources in sedentary people without a medical diagnosis. We failed to identify any trial-based evidence of the effectiveness of ERS in those with a medical diagnosis. Future work should include randomised controlled trials assessing the cinical effectiveness and cost-effectivenesss of ERS in disease groups that may benefit from PA. The National Institute for Health Research Health Technology Assessment programme.

Emerging structural insights into glycoprotein quality control coupled with N-glycan processing in the endoplasmic reticulum.

PubMed

Satoh, Tadashi; Yamaguchi, Takumi; Kato, Koichi

2015-01-30

In the endoplasmic reticulum (ER), the sugar chain is initially introduced onto newly synthesized proteins as a triantennary tetradecasaccharide (Glc3Man9GlcNAc2). The attached oligosaccharide chain is subjected to stepwise trimming by the actions of specific glucosidases and mannosidases. In these processes, the transiently expressed N-glycans, as processing intermediates, function as signals for the determination of glycoprotein fates, i.e., folding, transport, or degradation through interactions of a series of intracellular lectins. The monoglucosylated glycoforms are hallmarks of incompletely folded states of glycoproteins in this system, whereas the outer mannose trimming leads to ER-associated glycoprotein degradation. This review outlines the recently emerging evidence regarding the molecular and structural basis of this glycoprotein quality control system, which is regulated through dynamic interplay among intracellular lectins, glycosidases, and glycosyltransferase. Structural snapshots of carbohydrate-lectin interactions have been provided at the atomic level using X-ray crystallographic analyses. Conformational ensembles of uncomplexed triantennary high-mannose-type oligosaccharides have been characterized in a quantitative manner using molecular dynamics simulation in conjunction with nuclear magnetic resonance spectroscopy. These complementary views provide new insights into glycoprotein recognition in quality control coupled with N-glycan processing.

Secreted Proteins Defy the Expression Level-Evolutionary Rate Anticorrelation.

PubMed

Feyertag, Felix; Berninsone, Patricia M; Alvarez-Ponce, David

2017-03-01

The rates of evolution of the proteins of any organism vary across orders of magnitude. A primary factor influencing rates of protein evolution is expression. A strong negative correlation between expression levels and evolutionary rates (the so-called E-R anticorrelation) has been observed in virtually all studied organisms. This effect is currently attributed to the abundance-dependent fitness costs of misfolding and unspecific protein-protein interactions, among other factors. Secreted proteins are folded in the endoplasmic reticulum, a compartment where chaperones, folding catalysts, and stringent quality control mechanisms promote their correct folding and may reduce the fitness costs of misfolding. In addition, confinement of secreted proteins to the extracellular space may reduce misinteractions and their deleterious effects. We hypothesize that each of these factors (the secretory pathway quality control and extracellular location) may reduce the strength of the E-R anticorrelation. Indeed, here we show that among human proteins that are secreted to the extracellular space, rates of evolution do not correlate with protein abundances. This trend is robust to controlling for several potentially confounding factors and is also observed when analyzing protein abundance data for 6 human tissues. In addition, analysis of mRNA abundance data for 32 human tissues shows that the E-R correlation is always less negative, and sometimes nonsignificant, in secreted proteins. Similar observations were made in Caenorhabditis elegans and in Escherichia coli, and to a lesser extent in Drosophila melanogaster, Saccharomyces cerevisiae and Arabidopsis thaliana. Our observations contribute to understand the causes of the E-R anticorrelation. © The Author 2016. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

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

PubMed Central

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

2017-01-01

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

ATF6α/β-mediated adjustment of ER chaperone levels is essential for development of the notochord in medaka fish

PubMed Central

Ishikawa, Tokiro; Okada, Tetsuya; Ishikawa-Fujiwara, Tomoko; Todo, Takeshi; Kamei, Yasuhiro; Shigenobu, Shuji; Tanaka, Minoru; Saito, Taro L.; Yoshimura, Jun; Morishita, Shinichi; Toyoda, Atsushi; Sakaki, Yoshiyuki; Taniguchi, Yoshihito; Takeda, Shunichi; Mori, Kazutoshi

2013-01-01

ATF6α and ATF6β are membrane-bound transcription factors activated by regulated intramembrane proteolysis in response to endoplasmic reticulum (ER) stress to induce various ER quality control proteins. ATF6α- and ATF6β single-knockout mice develop normally, but ATF6α/β double knockout causes embryonic lethality, the reason for which is unknown. Here we show in medaka fish that ATF6α is primarily responsible for transcriptional induction of the major ER chaperone BiP and that ATF6α/β double knockout, but not ATF6α- or ATF6β single knockout, causes embryonic lethality, as in mice. Analyses of ER stress reporters reveal that ER stress occurs physiologically during medaka early embryonic development, particularly in the brain, otic vesicle, and notochord, resulting in ATF6α- and ATF6β-mediated induction of BiP, and that knockdown of the α1 chain of type VIII collagen reduces such ER stress. The absence of transcriptional induction of several ER chaperones in ATF6α/β double knockout causes more profound ER stress and impaired notochord development, which is partially rescued by overexpression of BiP. Thus ATF6α/β-mediated adjustment of chaperone levels to increased demands in the ER is essential for development of the notochord, which synthesizes and secretes large amounts of extracellular matrix proteins to serve as the body axis before formation of the vertebra. PMID:23447699

ATF6α/β-mediated adjustment of ER chaperone levels is essential for development of the notochord in medaka fish.

PubMed

Ishikawa, Tokiro; Okada, Tetsuya; Ishikawa-Fujiwara, Tomoko; Todo, Takeshi; Kamei, Yasuhiro; Shigenobu, Shuji; Tanaka, Minoru; Saito, Taro L; Yoshimura, Jun; Morishita, Shinichi; Toyoda, Atsushi; Sakaki, Yoshiyuki; Taniguchi, Yoshihito; Takeda, Shunichi; Mori, Kazutoshi

2013-05-01

ATF6α and ATF6β are membrane-bound transcription factors activated by regulated intramembrane proteolysis in response to endoplasmic reticulum (ER) stress to induce various ER quality control proteins. ATF6α- and ATF6β single-knockout mice develop normally, but ATF6α/β double knockout causes embryonic lethality, the reason for which is unknown. Here we show in medaka fish that ATF6α is primarily responsible for transcriptional induction of the major ER chaperone BiP and that ATF6α/β double knockout, but not ATF6α- or ATF6β single knockout, causes embryonic lethality, as in mice. Analyses of ER stress reporters reveal that ER stress occurs physiologically during medaka early embryonic development, particularly in the brain, otic vesicle, and notochord, resulting in ATF6α- and ATF6β-mediated induction of BiP, and that knockdown of the α1 chain of type VIII collagen reduces such ER stress. The absence of transcriptional induction of several ER chaperones in ATF6α/β double knockout causes more profound ER stress and impaired notochord development, which is partially rescued by overexpression of BiP. Thus ATF6α/β-mediated adjustment of chaperone levels to increased demands in the ER is essential for development of the notochord, which synthesizes and secretes large amounts of extracellular matrix proteins to serve as the body axis before formation of the vertebra.

Rescue of sarcoglycan mutations by inhibition of endoplasmic reticulum quality control is associated with minimal structural modifications.

PubMed

Soheili, Tayebeh; Gicquel, Evelyne; Poupiot, Jérôme; N'Guyen, Luu; Le Roy, Florence; Bartoli, Marc; Richard, Isabelle

2012-02-01

Sarcoglycanopathies (SGP) are a group of autosomal recessive muscle disorders caused by primary mutations in one of the four sarcoglycan genes. The sarcoglycans (α-, β-, γ-, and δ-sarcoglycan) form a tetrameric complex at the muscle membrane that is part of the dystrophin-glycoprotein complex and plays an essential role for membrane integrity during muscle contractions. We previously showed that the most frequent missense mutation in α-sarcoglycan (p.R77C) leads to the absence of the protein at the cell membrane due to its blockade by the endoplasmic reticulum (ER) quality control. Moreover, we demonstrated that inhibition of the ER α-mannosidase I activity using kifunensine could rescue the mutant protein localization at the cell membrane. Here, we investigate 25 additional disease-causing missense mutations in the sarcoglycan genes with respect to intracellular fate and localization rescue of the mutated proteins by kifunensine. Our studies demonstrate that, similarly to p.R77C, 22 of 25 of the selected mutations lead to defective intracellular trafficking of the SGs proteins. Six of these were saved from ER retention upon kifunensine treatment. The trafficking of SGs mutants rescued by kifunensine was associated with mutations that have moderate structural impact on the protein. © 2011 Wiley Periodicals, Inc.

Supplemental Nutrition Assistance Progam benefits and emergency room visits for hypoglycaemia.

PubMed

Heflin, Colleen; Hodges, Leslie; Mueser, Peter

2017-05-01

The present study examines the connection between the timing and size of Supplemental Nutrition Assistance Program (SNAP) benefits and the occurrence of emergency room (ER) visits for hypoglycaemia, a condition that is highly sensitive to short-term changes in nutritional intake. We used administrative data from Missouri SNAP and Medicaid to identify the timing of issuance and the benefit size of SNAP and the timing of ER claims for hypoglycaemia. We estimated the probability of submitting an ER claim for hypoglycaemia as a function of the calendar week, SNAP benefit week and the size of the SNAP benefit in models that controlled for individual demographic characteristics. Missouri SNAP caseload from January 2010 to December 2013 linked to adult Medicaid claims data for the same time period. ER claims submitted to Medicaid (n 6 508 061). The results indicated no evidence of a SNAP benefit cycle or monthly cycle to ER claims for hypoglycaemia. However, the analysis did find that ER claims for hypoglycaemia are related to the size of the SNAP benefit. These results suggest that more generous SNAP benefits help households avoid nutritional fluctuations in the quality and quantity of food that might result in low blood sugar, thus necessitating fewer ER visits for hypoglycaemia.

[Impact of Emotion Regulation and Emotional Arousal on Quality of Life and Adherence of Couples after Kidney Transplantation].

PubMed

Peters, Luisa; Franke, Laura; Tkachenko, Daria; Schiffer, Mario; Zimmermann, Tanja

2018-05-01

Nonadherence to immunosuppressive medication increases the risk of graft failure. Maladaptive emotion regulation strategies (ERS) seem to be a risk factor for nonadherence, whereas for patients in relationships spousal support appears as a protective resource. Emotional arousal, objectively measured by the fundamental frequency (f 0 ) during spousal supportive communication is associated with supportive behavior. This study examined the relationship between beliefs about immunosuppressive medication, quality of life, ERS, emotions and emotional arousal, assessed during social support interactions of both spouses of N=50 couples after kidney transplantation. Maladaptive ERS of the transplant recipient were associated with lower mental quality of life of the partner, marginally higher own negative affect and lower beliefs about medication. Maladaptive ERS of the partner showed negative correlations with own mental quality of life. Regarding f 0 , gender differences were found. Higher f 0 of the male transplant recipient were associated with more maladaptive ERS of the female partner. Marginally significate correlations were found with lower own beliefs about medication. Higher f 0 of the wife of the male transplant recipient showed correlations with lower own positive affect, more negative affect of the male patient and lower beliefs about medication. Higher f 0 of female transplant recipients were associated with lower own maladaptive ERS and lower maladaptive ERS of the husband. The findings support the relevance of early interventions focusing on identifying and modifying maladaptive ERS for both the patient and partner. © Georg Thieme Verlag KG Stuttgart · New York.

Sorting receptor Rer1 controls surface expression of muscle acetylcholine receptors by ER retention of unassembled alpha-subunits.

PubMed

Valkova, Christina; Albrizio, Marina; Röder, Ira V; Schwake, Michael; Betto, Romeo; Rudolf, Rüdiger; Kaether, Christoph

2011-01-11

The nicotinic acetylcholine receptor of skeletal muscle is composed of five subunits that are assembled in a stepwise manner. Quality control mechanisms ensure that only fully assembled receptors reach the cell surface. Here, we show that Rer1, a putative Golgi-ER retrieval receptor, is involved in the biogenesis of acetylcholine receptors. Rer1 is expressed in the early secretory pathway in the myoblast line C2C12 and in mouse skeletal muscle, and up-regulated during myogenesis. Upon down-regulation of Rer1 in C2C12 cells, unassembled acetylcholine receptor α-subunits escape from the ER and are transported to the plasma membrane and lysosomes, where they are degraded. As a result, the amount of fully assembled receptor at the cell surface is reduced. In vivo Rer1 knockdown and genetic inactivation of one Rer1 allele lead to significantly smaller neuromuscular junctions in mice. Our data show that Rer1 is a functionally important unique factor that controls surface expression of muscle acetylcholine receptors by localizing unassembled α-subunits to the early secretory pathway.

ER stress in Alzheimer's disease: a novel neuronal trigger for inflammation and Alzheimer's pathology

PubMed Central

2009-01-01

The endoplasmic reticulum (ER) is involved in several crucial cellular functions, e.g. protein folding and quality control, maintenance of Ca2+ balance, and cholesterol synthesis. Many genetic and environmental insults can disturb the function of ER and induce ER stress. ER contains three branches of stress sensors, i.e. IRE1, PERK and ATF6 transducers, which recognize the misfolding of proteins in ER and activate a complex signaling network to generate the unfolded protein response (UPR). Alzheimer's disease (AD) is a progressive neurodegenerative disorder involving misfolding and aggregation of proteins in conjunction with prolonged cellular stress, e.g. in redox regulation and Ca2+ homeostasis. Emerging evidence indicates that the UPR is activated in neurons but not in glial cells in AD brains. Neurons display pPERK, peIF2α and pIRE1α immunostaining along with abundant diffuse staining of phosphorylated tau protein. Recent studies have demonstrated that ER stress can also induce an inflammatory response via different UPR transducers. The most potent pathways are IRE1-TRAF2, PERK-eIF2α, PERK-GSK-3, ATF6-CREBH, as well as inflammatory caspase-induced signaling pathways. We will describe the mechanisms which could link the ER stress of neurons to the activation of the inflammatory response and the evolution of pathological changes in AD. PMID:20035627

TMEM258 Is a Component of the Oligosaccharyltransferase Complex Controlling ER Stress and Intestinal Inflammation.

PubMed

Graham, Daniel B; Lefkovith, Ariel; Deelen, Patrick; de Klein, Niek; Varma, Mukund; Boroughs, Angela; Desch, A Nicole; Ng, Aylwin C Y; Guzman, Gaelen; Schenone, Monica; Petersen, Christine P; Bhan, Atul K; Rivas, Manuel A; Daly, Mark J; Carr, Steven A; Wijmenga, Cisca; Xavier, Ramnik J

2016-12-13

Significant insights into disease pathogenesis have been gleaned from population-level genetic studies; however, many loci associated with complex genetic disease contain numerous genes, and phenotypic associations cannot be assigned unequivocally. In particular, a gene-dense locus on chromosome 11 (61.5-61.65 Mb) has been associated with inflammatory bowel disease, rheumatoid arthritis, and coronary artery disease. Here, we identify TMEM258 within this locus as a central regulator of intestinal inflammation. Strikingly, Tmem258 haploinsufficient mice exhibit severe intestinal inflammation in a model of colitis. At the mechanistic level, we demonstrate that TMEM258 is a required component of the oligosaccharyltransferase complex and is essential for N-linked protein glycosylation. Consequently, homozygous deficiency of Tmem258 in colonic organoids results in unresolved endoplasmic reticulum (ER) stress culminating in apoptosis. Collectively, our results demonstrate that TMEM258 is a central mediator of ER quality control and intestinal homeostasis. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

Bap31 enhances the ER export and quality control of human class I MHC molecules

PubMed Central

Ladasky, John J.; Boyle, Sarah; Seth, Malini; Li, Hewang; Pentcheva, Tsvetelina; Abe, Fumiyoshi; Steinberg, Steven J.; Edidin, Michael

2006-01-01

The assembly of class I MHC molecules and their export from the endoplasmic reticulum is governed by chaperones and accessory proteins. We present evidence that the putative cargo receptor protein Bap31 participates in the transport and the quality control of human class I molecules. Transfection of the human adenocarcinoma cell line HeLa with YFP-Bap31 chimeras increased surface levels of class I in a dose-dependent manner, by as much as 3.7-fold. The increase in surface class I resulted from an increase in the rate of export of newly-synthesized class I molecules to the cell surface and from an increase in the stability of the exported molecules. We propose that Bap31 performs quality control on class I molecules in two distinct phases: first, by exporting peptide-loaded class I molecules to the ERGIC and second, by retrieving class I molecules which have lost peptides in the acidic post-ER environment. This function of Bap31 is conditional or redundant, since we find that Bap31 deficiency does not reduce surface class I levels. Overexpression of the Bap31 homolog, Bap29, decreases surface class levels in HeLa, indicating that it does not substitute for Bap31. PMID:17056546

The SITLESS project: exercise referral schemes enhanced by self-management strategies to battle sedentary behaviour in older adults: study protocol for a randomised controlled trial.

PubMed

Giné-Garriga, Maria; Coll-Planas, Laura; Guerra, Míriam; Domingo, Àlex; Roqué, Marta; Caserotti, Paolo; Denkinger, Michael; Rothenbacher, Dietrich; Tully, Mark A; Kee, Frank; McIntosh, Emma; Martín-Borràs, Carme; Oviedo, Guillermo R; Jerez-Roig, Javier; Santiago, Marta; Sansano, Oriol; Varela, Guillermo; Skjødt, Mathias; Wirth, Katharina; Dallmeier, Dhayana; Klenk, Jochen; Wilson, Jason J; Blackburn, Nicole E; Deidda, Manuela; Lefebvre, Guillaume; González, Denise; Salvà, Antoni

2017-05-18

Older adults are the fastest growing segment of the world's population. Recent evidence indicates that excessive sitting time is harmful to health, independent of meeting the recommended moderate to vigorous physical activity (PA) guidelines. The SITLESS project aims to determine whether exercise referral schemes (ERS) can be enhanced by self-management strategies (SMSs) to reduce sedentary behaviour (SB), increase PA and improve health, quality of life and function in the long term, as well as psychosocial outcomes in community-dwelling older European citizens from four countries, within a three-armed pragmatic randomised controlled trial, compared with ERS alone and also with general recommendations about PA. A total of 1338 older adults will be included in this study, recruited from four European countries through different existing primary prevention pathways. Participants will be randomly allocated into an ERS of 16 weeks (32 sessions, 45-60 min per session), ERS enhanced by seven sessions of SMSs and four telephone prompts, or a control group. Outcomes will be assessed at baseline, month 4 (end of ERS intervention), month 16 (12 months post intervention) and month 22 (18 months post intervention). Primary outcomes will include measures of SB (time spent sedentary) and PA (counts per minute). Secondary outcomes will include muscle and physical function, health economics' related outcomes, anthropometry, quality of life, social networks, anxiety and depressive symptoms, disability, fear of falling, executive function and fatigue. A process evaluation will be conducted throughout the trial. The full analysis set will follow an intention-to-treat principle and will include all randomised participants for whom a baseline assessment is conducted. The study hypothesis will be tested with mixed linear models with repeated measures, to assess changes in the main outcomes (SB and PA) over time (baseline to month 22) and between study arms. The findings of this study may help inform the design and implementation of more effective interventions to reduce SB and increase PA levels, and hence improve long-term health outcomes in the older adult population. SITLESS aims to support policy-makers in deciding how or whether ERS should be further implemented or restructured in order to increase its adherence, impact and cost-effectiveness. ClinicalTrials.gov, NCT02629666 . Registered 19 November 2015.

Controlled synthesis and luminescence properties of β-NaGdF4: Yb3+, Er3+ upconversion nanoparticles

NASA Astrophysics Data System (ADS)

Zhang, Yueli; Yao, Lu; Xu, Dekang; Lin, Hao; Yang, Shenghong

2018-06-01

β-NaGdF4:Yb3+,Er3+ upconversion (UC) nanoparticles (UCNPs) were prepared by a facile hydrothermal process with the assistance of sodium ethylene diaminetetraacetate salt (EDTA-2Na). The morphologies of the β-NaGdF4 UCNPs were controlled by changing the doses of EDTA-2Na and NaOH in precursor. With increasing concentration of EDTA-2Na in precursor, the size of crystals decreased, resulting in the decreasing of luminescence intensity. With increasing concentration of NaOH in precursor, the morphology became more homogeneous. However, due to the reduction of grain size and crystal quality, the luminescence intensity decreased. Nevertheless, the above results demonstrated a simple route to fabricate homogeneous UCNPs.

Continuous manufacturing of extended release tablets via powder mixing and direct compression.

PubMed

Ervasti, Tuomas; Simonaho, Simo-Pekka; Ketolainen, Jarkko; Forsberg, Peter; Fransson, Magnus; Wikström, Håkan; Folestad, Staffan; Lakio, Satu; Tajarobi, Pirjo; Abrahmsén-Alami, Susanna

2015-11-10

The aim of the current work was to explore continuous dry powder mixing and direct compression for manufacturing of extended release (ER) matrix tablets. The study was span out with a challenging formulation design comprising ibuprofen compositions with varying particle size and a relatively low amount of the matrix former hydroxypropyl methylcellulose (HPMC). Standard grade HPMC (CR) was compared to a recently developed direct compressible grade (DC2). The work demonstrate that ER tablets with desired quality attributes could be manufactured via integrated continuous mixing and direct compression. The most robust tablet quality (weight, assay, tensile strength) was obtained using high mixer speed and large particle size ibuprofen and HPMC DC2 due to good powder flow. At low mixer speed it was more difficult to achieve high quality low dose tablets. Notably, with HPMC DC2 the processing conditions had a significant effect on drug release. Longer processing time and/or faster mixer speed was needed to achieve robust release with compositions containing DC2 compared with those containing CR. This work confirms the importance of balancing process parameters and material properties to find consistent product quality. Also, adaptive control is proven a pivotal means for control of continuous manufacturing systems. Copyright © 2015 Elsevier B.V. All rights reserved.

Selective Targeting of Proteins within Secretory Pathway for Endoplasmic Reticulum-associated Degradation

PubMed Central

Vecchi, Lara; Petris, Gianluca; Bestagno, Marco; Burrone, Oscar R.

2012-01-01

The endoplasmic reticulum-associated degradation (ERAD) is a cellular quality control mechanism to dispose of misfolded proteins of the secretory pathway via proteasomal degradation. SEL1L is an ER-resident protein that participates in identification of misfolded molecules as ERAD substrates, therefore inducing their ER-to-cytosol retrotranslocation and degradation. We have developed a novel class of fusion proteins, termed degradins, composed of a fragment of SEL1L fused to a target-specific binding moiety located on the luminal side of the ER. The target-binding moiety can be a ligand of the target or derived from specific mAbs. Here, we describe the ability of degradins with two different recognition moieties to promote degradation of a model target. Degradins recognize the target protein within the ER both in secretory and membrane-bound forms, inducing their degradation following retrotranslocation to the cytosol. Thus, degradins represent an effective technique to knock-out proteins within the secretory pathway with high specificity. PMID:22523070

Measurement and control of bias in patient reported outcomes using multidimensional item response theory.

PubMed

Dowling, N Maritza; Bolt, Daniel M; Deng, Sien; Li, Chenxi

2016-05-26

Patient-reported outcome (PRO) measures play a key role in the advancement of patient-centered care research. The accuracy of inferences, relevance of predictions, and the true nature of the associations made with PRO data depend on the validity of these measures. Errors inherent to self-report measures can seriously bias the estimation of constructs assessed by the scale. A well-documented disadvantage of self-report measures is their sensitivity to response style (RS) effects such as the respondent's tendency to select the extremes of a rating scale. Although the biasing effect of extreme responding on constructs measured by self-reported tools has been widely acknowledged and studied across disciplines, little attention has been given to the development and systematic application of methodologies to assess and control for this effect in PRO measures. We review the methodological approaches that have been proposed to study extreme RS effects (ERS). We applied a multidimensional item response theory model to simultaneously estimate and correct for the impact of ERS on trait estimation in a PRO instrument. Model estimates were used to study the biasing effects of ERS on sum scores for individuals with the same amount of the targeted trait but different levels of ERS. We evaluated the effect of joint estimation of multiple scales and ERS on trait estimates and demonstrated the biasing effects of ERS on these trait estimates when used as explanatory variables. A four-dimensional model accounting for ERS bias provided a better fit to the response data. Increasing levels of ERS showed bias in total scores as a function of trait estimates. The effect of ERS was greater when the pattern of extreme responding was the same across multiple scales modeled jointly. The estimated item category intercepts provided evidence of content independent category selection. Uncorrected trait estimates used as explanatory variables in prediction models showed downward bias. A comprehensive evaluation of the psychometric quality and soundness of PRO assessment measures should incorporate the study of ERS as a potential nuisance dimension affecting the accuracy and validity of scores and the impact of PRO data in clinical research and decision making.

Reticulomics: Protein-Protein Interaction Studies with Two Plasmodesmata-Localized Reticulon Family Proteins Identify Binding Partners Enriched at Plasmodesmata, Endoplasmic Reticulum, and the Plasma Membrane.

PubMed

Kriechbaumer, Verena; Botchway, Stanley W; Slade, Susan E; Knox, Kirsten; Frigerio, Lorenzo; Oparka, Karl; Hawes, Chris

2015-11-01

The endoplasmic reticulum (ER) is a ubiquitous organelle that plays roles in secretory protein production, folding, quality control, and lipid biosynthesis. The cortical ER in plants is pleomorphic and structured as a tubular network capable of morphing into flat cisternae, mainly at three-way junctions, and back to tubules. Plant reticulon family proteins (RTNLB) tubulate the ER by dimerization and oligomerization, creating localized ER membrane tensions that result in membrane curvature. Some RTNLB ER-shaping proteins are present in the plasmodesmata (PD) proteome and may contribute to the formation of the desmotubule, the axial ER-derived structure that traverses primary PD. Here, we investigate the binding partners of two PD-resident reticulon proteins, RTNLB3 and RTNLB6, that are located in primary PD at cytokinesis in tobacco (Nicotiana tabacum). Coimmunoprecipitation of green fluorescent protein-tagged RTNLB3 and RTNLB6 followed by mass spectrometry detected a high percentage of known PD-localized proteins as well as plasma membrane proteins with putative membrane-anchoring roles. Förster resonance energy transfer by fluorescence lifetime imaging microscopy assays revealed a highly significant interaction of the detected PD proteins with the bait RTNLB proteins. Our data suggest that RTNLB proteins, in addition to a role in ER modeling, may play important roles in linking the cortical ER to the plasma membrane. © 2015 American Society of Plant Biologists. All Rights Reserved.

EBS7 is a plant-specific component of a highly conserved endoplasmic reticulum-associated degradation system in Arabidopsis

PubMed Central

Liu, Yidan; Zhang, Congcong; Wang, Dinghe; Su, Wei; Liu, Linchuan; Wang, Muyang; Li, Jianming

2015-01-01

Endoplasmic reticulum (ER)-associated degradation (ERAD) is an essential part of an ER-localized protein quality-control system for eliminating terminally misfolded proteins. Recent studies have demonstrated that the ERAD machinery is conserved among yeast, animals, and plants; however, it remains unknown if the plant ERAD system involves plant-specific components. Here we report that the Arabidopsis ethyl methanesulfonate-mutagenized brassinosteroid-insensitive 1 suppressor 7 (EBS7) gene encodes an ER membrane-localized ERAD component that is highly conserved in land plants. Loss-of-function ebs7 mutations prevent ERAD of brassinosteroid insensitive 1-9 (bri1-9) and bri1-5, two ER-retained mutant variants of the cell-surface receptor for brassinosteroids (BRs). As a result, the two mutant receptors accumulate in the ER and consequently leak to the plasma membrane, resulting in the restoration of BR sensitivity and phenotypic suppression of the bri1-9 and bri1-5 mutants. EBS7 accumulates under ER stress, and its mutations lead to hypersensitivity to ER and salt stresses. EBS7 interacts with the ER membrane-anchored ubiquitin ligase Arabidopsis thaliana HMG-CoA reductase degradation 1a (AtHrd1a), one of the central components of the Arabidopsis ERAD machinery, and an ebs7 mutation destabilizes AtHrd1a to reduce polyubiquitination of bri1-9. Taken together, our results uncover a plant-specific component of a plant ERAD pathway and also suggest its likely biochemical function. PMID:26371323

Endoplasmic Reticulum Stress and Homeostasis in Reproductive Physiology and Pathology.

PubMed

Guzel, Elif; Arlier, Sefa; Guzeloglu-Kayisli, Ozlem; Tabak, Mehmet Selcuk; Ekiz, Tugba; Semerci, Nihan; Larsen, Kellie; Schatz, Frederick; Lockwood, Charles Joseph; Kayisli, Umit Ali

2017-04-08

The endoplasmic reticulum (ER), comprises 60% of the total cell membrane and interacts directly or indirectly with several cell organelles i.e., Golgi bodies, mitochondria and proteasomes. The ER is usually associated with large numbers of attached ribosomes. During evolution, ER developed as the specific cellular site of synthesis, folding, modification and trafficking of secretory and cell-surface proteins. The ER is also the major intracellular calcium storage compartment that maintains cellular calcium homeostasis. During the production of functionally effective proteins, several ER-specific molecular steps sense quantity and quality of synthesized proteins as well as proper folding into their native structures. During this process, excess accumulation of unfolded/misfolded proteins in the ER lumen results in ER stress, the homeostatic coping mechanism that activates an ER-specific adaptation program, (the unfolded protein response; UPR) to increase ER-associated degradation of structurally and/or functionally defective proteins, thus sustaining ER homeostasis. Impaired ER homeostasis results in aberrant cellular responses, contributing to the pathogenesis of various diseases. Both female and male reproductive tissues undergo highly dynamic cellular, molecular and genetic changes such as oogenesis and spermatogenesis starting in prenatal life, mainly controlled by sex-steroids but also cytokines and growth factors throughout reproductive life. These reproductive changes require ER to provide extensive protein synthesis, folding, maturation and then their trafficking to appropriate cellular location as well as destroying unfolded/misfolded proteins via activating ER-associated degradation mediated proteasomes. Many studies have now shown roles for ER stress/UPR signaling cascades in the endometrial menstrual cycle, ovarian folliculogenesis and oocyte maturation, spermatogenesis, fertilization, pre-implantation embryo development and pregnancy and parturition. Conversely, the contribution of impaired ER homeostasis by severe/prolong ER stress-mediated UPR signaling pathways to several reproductive tissue pathologies including endometriosis, cancers, recurrent pregnancy loss and pregnancy complications associated with pre-term birth have been reported. This review focuses on ER stress and UPR signaling mechanisms, and their potential roles in female and male reproductive physiopathology involving in menstrual cycle changes, gametogenesis, preimplantation embryo development, implantation and placentation, labor, endometriosis, pregnancy complications and preterm birth as well as reproductive system tumorigenesis.

Endoplasmic Reticulum Stress and Homeostasis in Reproductive Physiology and Pathology

PubMed Central

Guzel, Elif; Arlier, Sefa; Guzeloglu-Kayisli, Ozlem; Tabak, Mehmet Selcuk; Ekiz, Tugba; Semerci, Nihan; Larsen, Kellie; Schatz, Frederick; Lockwood, Charles Joseph; Kayisli, Umit Ali

2017-01-01

The endoplasmic reticulum (ER), comprises 60% of the total cell membrane and interacts directly or indirectly with several cell organelles i.e., Golgi bodies, mitochondria and proteasomes. The ER is usually associated with large numbers of attached ribosomes. During evolution, ER developed as the specific cellular site of synthesis, folding, modification and trafficking of secretory and cell-surface proteins. The ER is also the major intracellular calcium storage compartment that maintains cellular calcium homeostasis. During the production of functionally effective proteins, several ER-specific molecular steps sense quantity and quality of synthesized proteins as well as proper folding into their native structures. During this process, excess accumulation of unfolded/misfolded proteins in the ER lumen results in ER stress, the homeostatic coping mechanism that activates an ER-specific adaptation program, (the unfolded protein response; UPR) to increase ER-associated degradation of structurally and/or functionally defective proteins, thus sustaining ER homeostasis. Impaired ER homeostasis results in aberrant cellular responses, contributing to the pathogenesis of various diseases. Both female and male reproductive tissues undergo highly dynamic cellular, molecular and genetic changes such as oogenesis and spermatogenesis starting in prenatal life, mainly controlled by sex-steroids but also cytokines and growth factors throughout reproductive life. These reproductive changes require ER to provide extensive protein synthesis, folding, maturation and then their trafficking to appropriate cellular location as well as destroying unfolded/misfolded proteins via activating ER-associated degradation mediated proteasomes. Many studies have now shown roles for ER stress/UPR signaling cascades in the endometrial menstrual cycle, ovarian folliculogenesis and oocyte maturation, spermatogenesis, fertilization, pre-implantation embryo development and pregnancy and parturition. Conversely, the contribution of impaired ER homeostasis by severe/prolong ER stress-mediated UPR signaling pathways to several reproductive tissue pathologies including endometriosis, cancers, recurrent pregnancy loss and pregnancy complications associated with pre-term birth have been reported. This review focuses on ER stress and UPR signaling mechanisms, and their potential roles in female and male reproductive physiopathology involving in menstrual cycle changes, gametogenesis, preimplantation embryo development, implantation and placentation, labor, endometriosis, pregnancy complications and preterm birth as well as reproductive system tumorigenesis. PMID:28397763

Emotion regulation and mental well-being before and six months after bariatric surgery.

PubMed

Efferdinger, Christiane; König, Dorothea; Klaus, Alexander; Jagsch, Reinhold

2017-06-01

According to the current state of research, mental health improves due to bariatric surgery. However, improvements in weight and psychosocial aspects often show a gradual decline with time. As emotion regulation (ER) appears to be a key variable in the successful outcome of weight loss treatments, the present study aimed at investigating ER-strategies applied by bariatric surgery candidates pre- and post-surgery and examining interactions between ER, depressive symptoms, health-related quality of life (HrQoL), and post-surgical weight loss. Prior to and 6 months after bariatric surgery, 45 patients (76% women) completed self-report questionnaires assessing depressive symptoms (Beck Depression Inventory-II), HrQoL (Short Form-36 Health Survey), and ER-strategies (Emotion Regulation Inventory for Negative Emotions). Six months post-surgery, the patients reported significant improvements in depressive symptomatology, HrQoL, and satisfaction with ER compared to pre-surgery. Groups differing in their course of ER-satisfaction also differed in psychosocial dimensions pre- to post-surgery, increased satisfaction being related to less impairment and enhanced communication of negative emotions as a form of an adaptive regulation. Patients with higher weight loss applied the strategy of controlled expression more frequently post-surgery than pre-surgery and compared to patients with lower weight loss. Postoperative weight loss leads to improvements in ER-satisfaction and mental well-being. As satisfaction with ER seems to be associated with less impaired mental well-being among bariatric surgery candidates, presumably even more positive psychosocial outcomes could be obtained post-surgery by implementing trainings explicitly encouraging the use of adaptive ER-strategies.

UDP-glucose:glycoprotein glucosyltransferase (UGGT1) promotes substrate solubility in the endoplasmic reticulum

PubMed Central

Ferris, Sean P.; Jaber, Nikita S.; Molinari, Maurizio; Arvan, Peter; Kaufman, Randal J.

2013-01-01

Protein folding in the endoplasmic reticulum (ER) is error prone, and ER quality control (ERQC) processes ensure that only correctly folded proteins are exported from the ER. Glycoproteins can be retained in the ER by ERQC, and this retention contributes to multiple human diseases, termed ER storage diseases. UDP-glucose:glycoprotein glucosyltransferase (UGGT1) acts as a central component of glycoprotein ERQC, monoglucosylating deglucosylated N-glycans of incompletely folded glycoproteins and promoting subsequent reassociation with the lectin-like chaperones calreticulin and calnexin. The extent to which UGGT1 influences glycoprotein folding, however, has only been investigated for a few selected substrates. Using mouse embryonic fibroblasts lacking UGGT1 or those with UGGT1 complementation, we investigated the effect of monoglucosylation on the soluble/insoluble distribution of two misfolded α1-antitrypsin (AAT) variants responsible for AAT deficiency disease: null Hong Kong (NHK) and Z allele. Whereas substrate solubility increases directly with the number of N-linked glycosylation sites, our results indicate that additional solubility is conferred by UGGT1 enzymatic activity. Monoglucosylation-dependent solubility decreases both BiP association with NHK and unfolded protein response activation, and the solubility increase is blocked in cells deficient for calreticulin. These results suggest that UGGT1-dependent monoglucosylation of N-linked glycoproteins promotes substrate solubility in the ER. PMID:23864712

Composite synchronization of three eccentric rotors driven by induction motors in a vibrating system

NASA Astrophysics Data System (ADS)

Kong, Xiangxi; Chen, Changzheng; Wen, Bangchun

2018-03-01

This paper addresses the problem of composite synchronization of three eccentric rotors (ERs) driven by induction motors in a vibrating system. The composite synchronous motion of three ERs is composed of the controlled synchronous motion of two ERs and the self-synchronous motion of the third ER. Combining an adaptive sliding mode control (ASMC) algorithm with a modified master-slave control structure, the controllers are designed to implement controlled synchronous motion of two ERs with zero phase difference. Based on Lyapunov stability theorem and Barbalat's lemma, the stability of the designed controllers is verified. On basis of controlled synchronization of two ERs, self-synchronization of the third ER is introduced to implement composite synchronous motion of three ERs. The feasibility of the proposed composite synchronization method is analyzed by numerical method. The effects of motor and structure parameters on composite synchronous motion are discussed. Experiments on a vibrating test bench driven by three ERs are operated to validate the effectiveness of the proposed composite synchronization method, including a comparison with self-synchronization method.

Enhancement of endoplasmic reticulum (ER) degradation of misfolded Null Hong Kong alpha1-antitrypsin by human ER mannosidase I.

PubMed

Hosokawa, Nobuko; Tremblay, Linda O; You, Zhipeng; Herscovics, Annette; Wada, Ikuo; Nagata, Kazuhiro

2003-07-11

Misfolded glycoproteins synthesized in the endoplasmic reticulum (ER) are degraded by cytoplasmic proteasomes, a mechanism known as ERAD (ER-associated degradation). In the present study, we demonstrate that ERAD of the misfolded genetic variant-null Hong Kong alpha1-antitrypsin is enhanced by overexpression of the ER processing alpha1,2-mannosidase (ER ManI) in HEK 293 cells, indicating the importance of ER ManI in glycoprotein quality control. We showed previously that EDEM, an enzymatically inactive mannosidase homolog, interacts with misfolded alpha1-antitrypsin and accelerates its degradation (Hosokawa, N., Wada, I., Hasegawa, K., Yorihuzi, T., Tremblay, L. O., Herscovics, A., and Nagata, K. (2001) EMBO Rep. 2, 415-422). Herein we demonstrate a combined effect of ER ManI and EDEM on ERAD of misfolded alpha1-antitrypsin. We also show that misfolded alpha1-antitrypsin NHK contains labeled Glc1Man9GlcNAc and Man5-9GlcNAc released by endo-beta-N-acetylglucosaminidase H in pulse-chase experiments with [2-3H]mannose. Overexpression of ER ManI greatly increases the formation of Man8GlcNAc, induces the formation of Glc1Man8GlcNAc and increases trimming to Man5-7GlcNAc. We propose a model whereby the misfolded glycoprotein interacts with ER ManI and with EDEM, before being recognized by downstream ERAD components. This detailed characterization of oligosaccharides associated with a misfolded glycoprotein raises the possibility that the carbohydrate recognition determinant triggering ERAD may not be restricted to Man8GlcNAc2 isomer B as previous studies have suggested.

Investigations on the potential of a low power diode pumped Er:YAG laser system for oral surgery

NASA Astrophysics Data System (ADS)

Stock, Karl; Wurm, Holger; Hausladen, Florian; Wagner, Sophia; Hibst, Raimund

2015-02-01

Flash lamp pumped Er:YAG-lasers are used in clinical practice for dental applications successfully. As an alternative, several diode pumped Er:YAG laser systems (Pantec Engineering AG) become available, with mean laser power of 2W, 15W, and 30W. The aim of the presented study is to investigate the potential of the 2W Er:YAG laser system for oral surgery. At first an appropriate experimental set-up was realized with a beam delivery and both, a focusing unit for non-contact tissue cutting and a fiber tip for tissue cutting in contact mode. In order to produce reproducible cuts, the samples (porcine gingiva) were moved by a computer controlled translation stage. On the fresh samples cutting depth and quality were determined by light microscopy. Afterwards histological sections were prepared and microscopically analyzed regarding cutting depth and thermal damage zone. The experiments show that low laser power ≤ 2W is sufficient to perform efficient oral soft tissue cutting with cut depth up to 2mm (sample movement 2mm/s). The width of the thermal damage zone can be controlled by the irradiation parameters within a range of about 50μm to 110μm. In general, thermal injury is more pronounced using fiber tips in contact mode compared to the focused laser beam. In conclusion the results reveal that even the low power diode pumped Er:YAG laser is an appropriate tool for oral surgery.

Standard Review Plan for Environmental Restoration Program Quality Management Plans. Revision 2

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

Not Available

1993-12-01

The Department of Energy, Richland Operations Office (RL) Manual Environmental Restoration Program Quality System Requirements (QSR) for the Hanford Site, defines all quality requirements governing Hanford Environmental Restoration (ER) Program activities. The QSR requires that ER Program participants develop Quality Management Plans (QMPs) that describe how the QSR requirements will be implemented for their assigned scopes of work. This standard review plan (SRP) describes the ER program participant responsibilities for submittal of QMPs to the RL Environmental Restoration Division for review and the RL methodology for performing the reviews of participant QMPS. The SRP serves the following functions: acts asmore » a guide in the development or revision of QMPs to assure that the content is complete and adequate; acts as a checklist to be used by the RL staff in their review of participant QMPs; acts as an index or matrix between the requirements of the QSR and implementing methodologies described in the QMPs; decreases the time and subjectivity of document reviews; and provides a formal, documented method for describing exceptions, modifications, or waivers to established ER Program quality requirements.« less

High pressure applied to frozen ham at different process stages. 2. Effect on the sensory attributes and on the colour characteristics of dry-cured ham.

PubMed

Serra, X; Grèbol, N; Guàrdia, M D; Guerrero, L; Gou, P; Masoliver, P; Gassiot, M; Sárraga, C; Monfort, J M; Arnau, J

2007-01-01

This paper describes the effect of high pressure (400MPa and 600MPa) applied to frozen hams at early stages of the dry-cured ham process: green hams (GH) and hams at the end of the resting stage (ERS), on the appearance, some texture and flavour parameters and on the instrumental colour characteristics of dry-cured hams. Pressurized hams showed slightly lower visual colour intensity than the control ones. In general, pressurization did not have a significant effect on the flavour characteristics of the final product. The 600-MPa hams from the ERS process showed significantly lower crumbliness and higher fibrousness scores than the control and the 400-MPa hams. However, none of these differences were enough to affect the overall sensory quality of the hams negatively. Regarding instrumental colour characteristics (L(∗)a(∗)b(∗)), an increase in lightness was observed in the biceps femoris muscle from GH hams pressurized at 400MPa and 600MPa but not in the ERS hams.

Involvement of the Nrf2-proteasome pathway in the endoplasmic reticulum stress response in pancreatic β-cells

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

Lee, Sanghwan; Hur, Eu-gene; Ryoo, In-geun

2012-11-01

The ubiquitin-proteasome system plays a central role in protein quality control through endoplasmic reticulum (ER)-associated degradation (ERAD) of unfolded and misfolded proteins. NF-E2‐related factor 2 (Nrf2) is a transcription factor that controls the expression of an array of phase II detoxification and antioxidant genes. Nrf2 signaling has additionally been shown to upregulate the expression of the proteasome catalytic subunits in several cell types. Here, we investigated the role of Nrf2 in tunicamycin-induced ER stress using a murine insulinoma β-cell line, βTC-6. shRNA-mediated silencing of Nrf2 expression in βTC-6 cells significantly increased tunicamycin-induced cytotoxicity, elevated the expression of the pro-apoptotic ERmore » stress marker Chop10, and inhibited tunicamycin-inducible expression of the proteasomal catalytic subunits Psmb5 and Psmb6. The effects of 3H-1,2-dithiole-3-thione (D3T), a small molecule Nrf2 activator, on ER stress were also examined in βTC-6 cells. D3T pretreatment reduced tunicamycin cytotoxicity and attenuated the tunicamycin-inducible Chop10 and protein kinase RNA-activated‐like ER kinase (Perk). The protective effect of D3T was shown to be associated with increased ERAD. D3T increased the expression of Psmb5 and Psmb6 and elevated chymotrypsin-like peptidase activity; proteasome inhibitor treatment blocked D3T effects on tunicamycin cytotoxicity and ER stress marker changes. Similarly, silencing of Nrf2 abolished the protective effect of D3T against ER stress. These results indicate that the Nrf2 pathway contributes to the ER stress response in pancreatic β-cells by enhancing proteasome-mediated ERAD. -- Highlights: ► Nrf2 silencing in pancreatic β-cells enhanced tunicamycin-mediated ER stress. ► Expression of the proteasome was inducible by Nrf2 signaling. ► Nrf2 activator D3T protected β-cells from tunicamycin-mediated ER stress. ► Protective effect of D3T was associated with Nrf2-dependent proteasome induction.« less

Building a Quality Controlled Database of Meteorological Data from NASA Kennedy Space Center and the United States Air Force's Eastern Range

NASA Technical Reports Server (NTRS)

Brenton, James C.; Barbre. Robert E., Jr.; Decker, Ryan K.; Orcutt, John M.

2018-01-01

The National Aeronautics and Space Administration's (NASA) Marshall Space Flight Center (MSFC) Natural Environments Branch (EV44) has provided atmospheric databases and analysis in support of space vehicle design and day-of-launch operations for NASA and commercial launch vehicle programs launching from the NASA Kennedy Space Center (KSC), co-located on the United States Air Force's Eastern Range (ER) at the Cape Canaveral Air Force Station. The ER complex is one of the most heavily instrumented sites in the United States with over 31 towers measuring various atmospheric parameters on a continuous basis. An inherent challenge with large sets of data consists of ensuring erroneous data is removed from databases, and thus excluded from launch vehicle design analyses. EV44 has put forth great effort in developing quality control (QC) procedures for individual meteorological instruments, however no standard QC procedures for all databases currently exists resulting in QC databases that have inconsistencies in variables, methodologies, and periods of record. The goal of this activity is to use the previous efforts by EV44 to develop a standardized set of QC procedures from which to build meteorological databases from KSC and the ER, while maintaining open communication with end users from the launch community to develop ways to improve, adapt and grow the QC database. Details of the QC procedures will be described. As the rate of launches increases with additional launch vehicle programs, it is becoming more important that weather databases are continually updated and checked for data quality before use in launch vehicle design and certification analyses.

Ubiquitin-dependent Protein Degradation at the Yeast Endoplasmic Reticulum and Nuclear Envelope

PubMed Central

Zattas, Dimitrios; Hochstrasser, Mark

2014-01-01

The endoplasmic reticulum (ER) is the primary organelle in eukaryotic cells where membrane and secreted proteins are inserted into or across cell membranes. Its membrane bilayer and luminal compartments provide a favorable environment for the folding and assembly of thousands of newly synthesized proteins. However, protein folding is intrinsically error-prone, and various stress conditions can further increase levels of protein misfolding and damage, particularly in the ER, which can lead to cellular dysfunction and disease. The ubiquitin-proteasome system (UPS) is responsible for the selective destruction of a vast array of protein substrates, either for protein quality control or to allow rapid changes in the levels of specific regulatory proteins. In this review, we will focus on the components and mechanisms of ER-associated protein degradation (ERAD), an important branch of the UPS. ER membranes extend from subcortical regions of the cell to the nuclear envelope, with its continuous outer and inner membranes; the nuclear envelope is a specialized subdomain of the ER. ERAD presents additional challenges to the UPS beyond those faced with soluble substrates of the cytoplasm and nucleus. These include recognition of sugar modifications that occur in the ER, retrotranslocation of proteins across the membrane bilayer, and transfer of substrates from the ER extraction machinery to the proteasome. Here we review characteristics of ERAD substrate degradation signals (degrons), mechanisms underlying substrate recognition and processing by the ERAD machinery, and ideas on the still unresolved problem of how substrate proteins are moved across and extracted from the ER membrane. PMID:25231236

Endoplasmic reticulum proteins SDF2 and SDF2L1 act as components of the BiP chaperone cycle to prevent protein aggregation.

PubMed

Fujimori, Tsutomu; Suno, Ryoji; Iemura, Shun-Ichiro; Natsume, Tohru; Wada, Ikuo; Hosokawa, Nobuko

2017-08-01

The folding of newly synthesized proteins in the endoplasmic reticulum (ER) is assisted by ER-resident chaperone proteins. BiP (immunoglobulin heavy-chain-binding protein), a member of the HSP70 family, plays a central role in protein quality control. The chaperone function of BiP is regulated by its intrinsic ATPase activity, which is stimulated by ER-resident proteins of the HSP40/DnaJ family, including ERdj3. Here, we report that two closely related proteins, SDF2 and SDF2L1, regulate the BiP chaperone cycle. Both are ER-resident, but SDF2 is constitutively expressed, whereas SDF2L1 expression is induced by ER stress. Both luminal proteins formed a stable complex with ERdj3 and potently inhibited the aggregation of different types of misfolded ER cargo. These proteins associated with non-native proteins, thus promoting the BiP-substrate interaction cycle. A dominant-negative ERdj3 mutant that inhibits the interaction between ERdj3 and BiP prevented the dissociation of misfolded cargo from the ERdj3-SDF2L1 complex. Our findings indicate that SDF2 and SDF2L1 associate with ERdj3 and act as components in the BiP chaperone cycle to prevent the aggregation of misfolded proteins, partly explaining the broad folding capabilities of the ER under various physiological conditions. © 2017 Molecular Biology Society of Japan and John Wiley & Sons Australia, Ltd.

Surface segregation effects of erbium in GaAs growth and their implications for optical devices containing ErAs nanostructures

NASA Astrophysics Data System (ADS)

Crook, Adam M.; Nair, Hari P.; Bank, Seth R.

2011-03-01

We report on the integration of semimetallic ErAs nanoparticles with high optical quality GaAs-based semiconductors, grown by molecular beam epitaxy. Secondary ion mass spectrometry and photoluminescence measurements provide evidence of surface segregation and incorporation of erbium into layers grown with the erbium cell hot, despite the closed erbium source shutter. We establish the existence of a critical areal density of the surface erbium layer, below which the formation of ErAs precipitates is suppressed. Based upon these findings, we demonstrate a method for overgrowing ErAs nanoparticles with III-V layers of high optical quality, using subsurface ErAs nanoparticles as a sink to deplete the surface erbium concentration. This approach provides a path toward realizing optical devices based on plasmonic effects in an epitaxially-compatible semimetal/semiconductor system.

Disulfide bonds in ER protein folding and homeostasis

PubMed Central

Feige, Matthias J.; Hendershot, Linda M.

2010-01-01

Proteins that are expressed outside the cell must be synthesized, folded and assembled in a way that ensures they can function in their designate location. Accordingly these proteins are primarily synthesized in the endoplasmic reticulum (ER), which has developed a chemical environment more similar to that outside the cell. This organelle is equipped with a variety of molecular chaperones and folding enzymes that both assist the folding process, while at the same time exerting tight quality control measures that are largely absent outside the cell. A major post-translational modification of ER-synthesized proteins is disulfide bridge formation, which is catalyzed by the family of protein disulfide isomerases. As this covalent modification provides unique structural advantages to extracellular proteins, multiple pathways to their formation have evolved. However, the advantages that disulfide bonds impart to these proteins come at a high cost to the cell. Very recent reports have shed light on how the cell can deal with or even exploit the side reactions of disulfide bond formation to maintain homeostasis of the ER and its folding machinery. PMID:21144725

Secretion of protein disulphide isomerase AGR2 confers tumorigenic properties

PubMed Central

Fessart, Delphine; Domblides, Charlotte; Avril, Tony; Eriksson, Leif A; Begueret, Hugues; Pineau, Raphael; Malrieux, Camille; Dugot-Senant, Nathalie; Lucchesi, Carlo; Chevet, Eric; Delom, Frederic

2016-01-01

The extracellular matrix (ECM) plays an instrumental role in determining the spatial orientation of epithelial polarity and the formation of lumens in glandular tissues during morphogenesis. Here, we show that the Endoplasmic Reticulum (ER)-resident protein anterior gradient-2 (AGR2), a soluble protein-disulfide isomerase involved in ER protein folding and quality control, is secreted and interacts with the ECM. Extracellular AGR2 (eAGR2) is a microenvironmental regulator of epithelial tissue architecture, which plays a role in the preneoplastic phenotype and contributes to epithelial tumorigenicity. Indeed, eAGR2, is secreted as a functionally active protein independently of its thioredoxin-like domain (CXXS) and of its ER-retention domain (KTEL), and is sufficient, by itself, to promote the acquisition of invasive and metastatic features. Therefore, we conclude that eAGR2 plays an extracellular role independent of its ER function and we elucidate this gain-of-function as a novel and unexpected critical ECM microenvironmental pro-oncogenic regulator of epithelial morphogenesis and tumorigenesis. DOI: http://dx.doi.org/10.7554/eLife.13887.001 PMID:27240165

Nonesterified Fatty Acid-Induced Endoplasmic Reticulum Stress in Cattle Cumulus Oocyte Complexes Alters Cell Metabolism and Developmental Competence.

PubMed

Sutton-McDowall, Melanie L; Wu, Linda L Y; Purdey, Malcolm; Abell, Andrew D; Goldys, Ewa M; MacMillan, Keith L; Thompson, Jeremy G; Robker, Rebecca L

2016-01-01

Reduced oocyte quality has been associated with poor fertility of high-performance dairy cows during peak lactation, due to negative energy balance. We examined the role of nonesterified fatty acids (NEFAs), known to accumulate within follicular fluid during under- and overnutrition scenarios, in causing endoplasmic reticulum (ER) stress of in vitro maturated cattle cumulus-oocyte complexes (COCs). NEFA concentrations were: palmitic acid (150 μM), oleic acid (200 μM), and steric acid (75 μM). Abattoir-derived COCs were randomly matured for 24 h in the presence of NEFAs and/or an ER stress inhibitor, salubrinal. Total and hatched blastocyst yields were negatively impacted by NEFA treatment compared with controls, but this was reversed by salubrinal. ER stress markers, activating transcription factor 4 (Atf4) and heat shock protein 5 (Hspa5), but not Atf6, were significantly up-regulated by NEFA treatment within whole COCs but reversed by coincubation with salubrinal. Likewise, glucose uptake and lactate production, measured in spent medium samples, showed a similar pattern, suggesting that cumulus cell metabolism is sensitive to NEFAs via an ER stress-mediated process. In contrast, while mitochondrial DNA copy number was recovered in NEFA-treated oocytes, oocyte autofluorescence of the respiratory chain cofactor, FAD, was lower following NEFA treatment of COCs, and this was not reversed by salubrinal, suggesting the negative impact was via reduced mitochondrial function. These results reveal the significance of NEFA-induced ER stress on bovine COC developmental competence, revealing a potential therapeutic target for improving oocyte quality during peak lactation. © 2016 by the Society for the Study of Reproduction, Inc.

Efficacy of Er,Cr:YSGG Laser in Removing Smear Layer and Debris with Two Different Output Powers

PubMed Central

Bolhari, Behnam; Ehsani, Sara; Etemadi, Ardavan; Shafaq, Mohammad

2014-01-01

Abstract Objective: The purpose of this study was to evaluate the effectiveness of the erbium, chromium: yttrium-scandium-gallium-garnet (Er,Cr:YSGG) laser in removing debris and the smear layer using two different output powers on the apical, middle, and coronal segments of root canal walls. Background data: Previous literature has failed to evaluate the exclusive effect of Er,Cr:YSGG laser on the quality of smear layer and debris removal in all three segments of the root canal space. Methods: Sixty extracted teeth were included in the study. After instrumentation, samples were divided into three experimental groups and one positive control group with no further treatment. In group 1, a final irrigation was performed using ethylenediaminetetraacetic acid (EDTA) and sodium hypochlorite (NaOCl), sequentially. In group 2, the samples were treated with a 2.78 μm Er,Cr:YSGG laser with an output power of 1.5 W. The same laser was used in group 3, but with an output power of 2.5 W. Scanning electron microscope (SEM) images from the coronal, middle, and apical thirds of the roots were prepared and evaluated for both smear layer and debris removal by three blinded observers. Results: The results showed no differences between groups 1 and 2 regarding the quality of smear layer removal in all areas. However, the 2.5 W laser failed to remove the smear layer effectively. Regarding debris removal, the EDTA and NaOCl irrigation showed significantly better outcomes (adjusted p<0.05) in all areas. Conclusions: This study raises questions about the overall cleaning abilities of Er,Cr:YSGG lasers. PMID:25198390

Efficacy of Er,Cr:YSGG laser in removing smear layer and debris with two different output powers.

PubMed

Bolhari, Behnam; Ehsani, Sara; Etemadi, Ardavan; Shafaq, Mohammad; Nosrat, Ali

2014-10-01

The purpose of this study was to evaluate the effectiveness of the erbium, chromium: yttrium-scandium-gallium-garnet (Er,Cr:YSGG) laser in removing debris and the smear layer using two different output powers on the apical, middle, and coronal segments of root canal walls. Previous literature has failed to evaluate the exclusive effect of Er,Cr:YSGG laser on the quality of smear layer and debris removal in all three segments of the root canal space. Sixty extracted teeth were included in the study. After instrumentation, samples were divided into three experimental groups and one positive control group with no further treatment. In group 1, a final irrigation was performed using ethylenediaminetetraacetic acid (EDTA) and sodium hypochlorite (NaOCl), sequentially. In group 2, the samples were treated with a 2.78 μm Er,Cr:YSGG laser with an output power of 1.5 W. The same laser was used in group 3, but with an output power of 2.5 W. Scanning electron microscope (SEM) images from the coronal, middle, and apical thirds of the roots were prepared and evaluated for both smear layer and debris removal by three blinded observers. The results showed no differences between groups 1 and 2 regarding the quality of smear layer removal in all areas. However, the 2.5 W laser failed to remove the smear layer effectively. Regarding debris removal, the EDTA and NaOCl irrigation showed significantly better outcomes (adjusted p<0.05) in all areas. This study raises questions about the overall cleaning abilities of Er,Cr:YSGG lasers.

Cost-effectiveness of omalizumab in severe persistent asthma in Spain: a real-life perspective.

PubMed

Levy, Alberto Nahon; García A Ruiz, Antonio J; García-Agua Soler, Nuria; Sanjuan, María Victoria Hidalgo

2015-03-01

To determine the cost-effectiveness of omalizumab compared with routine clinical practice in the treatment and control of severe persistent asthma. Cost-effectiveness analysis using pre- and post-treatment with omalizumab after 10 months of 47 patients diagnosed with uncontrolled severe persistent asthma attended by the Pneumology Service, Hospital Universitario Virgen de la Victoria, Malaga. Effectiveness was assessed by the number of emergency room (ER) visits for exacerbations and quality-adjusted life years (QALY) gained. The costs of treatment with omalizumab and ER visits were analyzed using the National Health System perspective. Results are expressed in cost per QALY gained and cost per ER visit avoided (costs €2012). Exacerbations with ER visits decreased significantly (p < 0.001) after 10 months of omalizumab treatment compared with the previous 10 months [7.94 (6.52-9.37) vs 0.19 (0.03-0.35)]. Health utilities increased significantly (p < 0.001) during the same period [0.5967 (0.5722-0.6212) vs 0.7566 (0.7232-0.7900)], representing 0.1333 (0.1053-0.1612) QALYs gained (p < 0.001).The mean cost per patient was €1850.78 (1519.46-2182.10) in the 10 months before treatment and €5431.87 (4930.72-5933.02) after 10 months of omalizumab treatment. The incremental cost-effectiveness ratios (ICERs) were €462.08/exacerbation avoided (347.65-606.22) and €26 864.89/QALY gained (21 632.07-33 859.49). Our results confirm that adding omalizumab to the treatment of patients with uncontrolled severe persistent asthma reduces the number of exacerbations with ER visits and increases health-related quality of life after 10 months of treatment and produces ICERs favorable to omalizumab and acceptable from the health system perspective.

Non-ablative Er:YAG laser therapy effect on stress urinary incontinence related to quality of life and sexual function: A randomized controlled trial.

PubMed

Blaganje, Mija; Šćepanović, Darija; Žgur, Lidija; Verdenik, Ivan; Pajk, Franja; Lukanović, Adolf

2018-05-01

Stress urinary incontinence (SUI) is a common complaint in women after childbirth. It affects their quality of life and sexual satisfaction and is one of the major reasons for gynaecological surgery. There is a need for effective non-invasive treatment alternatives. The aim of this study was to evaluate the efficacy and safety of non-ablative Er:YAG laser therapy in the treatment of SUI and improvement of sexual gratification in parous women. 114 premenopausal parous women with SUI were randomized in two groups of 57 women; a laser intervention group and sham group. Both groups were treated according to the IncontiLase ® clinical treatment protocol for SUI with non-ablative thermal-only Er:YAG laser, except that there was no energy output when treating the sham group. Patients were blinded to the allocation. At baseline and 3 months after treatment patients were clinically examined, answered questionnaires for SUI severity and sexual function assessment and their pelvic floor muscle (PFM) function was assessed with perineometry. Validated International Consultation on Incontinence Questionnaire - Urinary Incontinence Short Form (ICIQ-UI SF) was used as the primary outcome measure. The Pelvic Organ Prolapse Urinary Incontinence Sexual Questionnaire short form (PISQ-12) and The Female Sexual Function Index (FSFI) were used to assess the sexual function. Patients were monitored for discomfort and side-effects during treatment and follow-up period. 3 months after treatment the ICIQ-UI SF (p < 0.001), PISQ-12 (p = 0.014) and FSFI (p = 0.025) scores were significantly more improved in the laser group than in the sham control group. All perineometry variables improved in the laser group after treatment; duration and maximum pressure had statistically significantly better improvement than the sham group, whereas average pressure did not. 21% of laser treated patients were dry (ICIQ-UI SF = 0) at follow up compared to only 4% of the sham control patients. No serious adverse effects were observed or reported. The treatment was well tolerated by patients. The non-ablative Er:YAG laser therapy improves the impact of SUI symptoms on quality of life and sexual function in premenopausal parous women significantly better than placebo. It provides a promising minimally-invasive safe treatment alternative for SUI. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Effect of Er,Cr:YSGG laser, air abrasion, and silane application on repaired shear bond strength of composites.

PubMed

Cho, S D; Rajitrangson, P; Matis, B A; Platt, J A

2013-01-01

Aged resin composites have a limited number of carbon-carbon double bonds to adhere to a new layer of resin. Study objectives were to 1) evaluate various surface treatments on repaired shear bond strength between aged and new resin composites and 2) to assess the influence of a silane coupling agent after surface treatments. Eighty disk-shape resin composite specimens were fabricated and thermocycled 5000 times prior to surface treatment. Specimens were randomly assigned to one of the three surface treatment groups (n=20): 1) air abrasion with 50-μm aluminum oxide, 2) tribochemical silica coating (CoJet), or 3) Er,Cr:YSGG (erbium, chromium: yttrium-scandium-gallium-garnet) laser or to a no-treatment control group (n=20). Specimens were etched with 35% phosphoric acid, rinsed, and dried. Each group was divided into two subgroups (n=10): A) no silanization and B) with silanization. The adhesive agent was applied and new resin composite was bonded to each conditioned surface. Shear bond strength was evaluated and data analyzed using two-way analysis of variance (ANOVA). Air abrasion with 50-μm aluminum oxide showed significantly higher repair bond strength than the Er,Cr:YSGG laser and control groups. Air abrasion with 50-μm aluminum oxide was not significantly different from tribochemical silica coating. Tribochemical silica coating had significantly higher repair bond strength than Er,Cr:YSGG laser and the control. Er,Cr:YSGG laser and the control did not have significantly different repair bond strengths. Silanization had no influence on repair bond strength for any of the surface treatment methods. Air abrasion with 50-μm aluminum oxide and tribochemical silica followed by the application of bonding agent provided the highest repair shear bond strength values, suggesting that they might be adequate methods to improve the quality of repairs of resin composites.

Shear mode ER transfer function for robotic applications

NASA Astrophysics Data System (ADS)

Tan, K. P.; Stanway, R.; Bullough, W. A.

2005-06-01

Electro-rheological (ER) fluids are becoming popular in modern industrial applications. The advantage of employing ER devices is due to the ease of energizing the ER fluids at fast speeds of response. One innovation in ER applications could be in the positioning control of the robotic arm using an ER clutch. In order to actuate the manipulator, the ER output torque response is required. However, the behaviour of this ER torque response at different input conditions is not clearly understood. Therefore, in this paper, a sample study of the ER output torque is conducted. The ER output torque responses at different input parameters are studied carefully for the establishment of an appropriate ER transfer function in shear mode. This transfer function will serve as an important feature in future ER-actuated robot arm's control process.

ER fluid applications to vibration control devices and an adaptive neural-net controller

NASA Astrophysics Data System (ADS)

Morishita, Shin; Ura, Tamaki

1993-07-01

Four applications of electrorheological (ER) fluid to vibration control actuators and an adaptive neural-net control system suitable for the controller of ER actuators are described: a shock absorber system for automobiles, a squeeze film damper bearing for rotational machines, a dynamic damper for multidegree-of-freedom structures, and a vibration isolator. An adaptive neural-net control system composed of a forward model network for structural identification and a controller network is introduced for the control system of these ER actuators. As an example study of intelligent vibration control systems, an experiment was performed in which the ER dynamic damper was attached to a beam structure and controlled by the present neural-net controller so that the vibration in several modes of the beam was reduced with a single dynamic damper.

Analysis of ER Resident Proteins in S. cerevisiae: Implementation of H/KDEL Retrieval Sequences

PubMed Central

Young, Carissa L.; Raden, David L.; Robinson, Anne S.

2013-01-01

An elaborate quality control system regulates ER homeostasis by ensuring the fidelity of protein synthesis and maturation. In budding yeast, genomic analyses and high-throughput proteomic studies have identified ER resident proteins that restore homeostasis following local perturbations. Yet, how these folding factors modulate stress has been largely unexplored. In this study, we designed a series of PCR-based modules including codon-optimized epitopes and FP variants complete with C-terminal H/KDEL retrieval motifs. These conserved sequences are inherent to most soluble ER resident proteins. To monitor multiple proteins simultaneously, H/KDEL cassettes are available with six different selection markers, providing optimal flexibility for live-cell imaging and multicolor labeling in vivo. A single pair of PCR primers can be used for the amplification of these 26 modules, enabling numerous combinations of tags and selection markers. The versatility of pCY H/KDEL cassettes was demonstrated by labeling BiP/Kar2p, Pdi1p, and Scj1p with all novel tags, thus providing a direct comparison among FP variants. Furthermore, to advance in vitro studies of yeast ER proteins, Strep-tag II was engineered with a C-terminal retrieval sequence. Here, an efficient purification strategy was established for BiP under physiological conditions. PMID:23324027

Growth, spectroscopic properties and laser output of Er : Ca 4YO(BO 3) 3 and Er : Yb : Ca 4YO(BO 3) 3 crystals

NASA Astrophysics Data System (ADS)

Zhang, Huaijin; Meng, Xianlin; Wang, Changqing; Wang, Pu; Zhu, Li; Liu, Xuesong; Dong, Chunming; Yang, Yuyong; Cheng, Ruiping; Dawes, Judith; Piper, Jim; Zhang, Shaojun; Sun, Lianke

2000-09-01

In this paper, Er : Ca 4YO(BO 3) 3 (Er : YCOB) and Er : Yb : Ca 4YO(BO 3) 3 (Er : Yb : YCOB) crystals with large size and excellent quality have been grown by the Czochralski method. The absorption and emission spectra of Er : YCOB and Er : Yb : YCOB crystals have been measured; the emission spectrum of Er : Yb : YCOB crystal shows that the strongest emission peak is located at 1537 nm. An output power of about 2 mW at the wavelength of 1553 nm has been obtained under the pumping power of a fiber-coupled laser diode (LD) of 1600 mW at 976 nm, using a Y direction cut 2.5 mm thick Er : Yb : YCOB crystal sample.

A meta-analysis of genome-wide association studies of breast cancer identifies two novel susceptibility loci at 6q14 and 20q11.

PubMed

Siddiq, Afshan; Couch, Fergus J; Chen, Gary K; Lindström, Sara; Eccles, Diana; Millikan, Robert C; Michailidou, Kyriaki; Stram, Daniel O; Beckmann, Lars; Rhie, Suhn Kyong; Ambrosone, Christine B; Aittomäki, Kristiina; Amiano, Pilar; Apicella, Carmel; Baglietto, Laura; Bandera, Elisa V; Beckmann, Matthias W; Berg, Christine D; Bernstein, Leslie; Blomqvist, Carl; Brauch, Hiltrud; Brinton, Louise; Bui, Quang M; Buring, Julie E; Buys, Saundra S; Campa, Daniele; Carpenter, Jane E; Chasman, Daniel I; Chang-Claude, Jenny; Chen, Constance; Clavel-Chapelon, Françoise; Cox, Angela; Cross, Simon S; Czene, Kamila; Deming, Sandra L; Diasio, Robert B; Diver, W Ryan; Dunning, Alison M; Durcan, Lorraine; Ekici, Arif B; Fasching, Peter A; Feigelson, Heather Spencer; Fejerman, Laura; Figueroa, Jonine D; Fletcher, Olivia; Flesch-Janys, Dieter; Gaudet, Mia M; Gerty, Susan M; Rodriguez-Gil, Jorge L; Giles, Graham G; van Gils, Carla H; Godwin, Andrew K; Graham, Nikki; Greco, Dario; Hall, Per; Hankinson, Susan E; Hartmann, Arndt; Hein, Rebecca; Heinz, Judith; Hoover, Robert N; Hopper, John L; Hu, Jennifer J; Huntsman, Scott; Ingles, Sue A; Irwanto, Astrid; Isaacs, Claudine; Jacobs, Kevin B; John, Esther M; Justenhoven, Christina; Kaaks, Rudolf; Kolonel, Laurence N; Coetzee, Gerhard A; Lathrop, Mark; Le Marchand, Loic; Lee, Adam M; Lee, I-Min; Lesnick, Timothy; Lichtner, Peter; Liu, Jianjun; Lund, Eiliv; Makalic, Enes; Martin, Nicholas G; McLean, Catriona A; Meijers-Heijboer, Hanne; Meindl, Alfons; Miron, Penelope; Monroe, Kristine R; Montgomery, Grant W; Müller-Myhsok, Bertram; Nickels, Stefan; Nyante, Sarah J; Olswold, Curtis; Overvad, Kim; Palli, Domenico; Park, Daniel J; Palmer, Julie R; Pathak, Harsh; Peto, Julian; Pharoah, Paul; Rahman, Nazneen; Rivadeneira, Fernando; Schmidt, Daniel F; Schmutzler, Rita K; Slager, Susan; Southey, Melissa C; Stevens, Kristen N; Sinn, Hans-Peter; Press, Michael F; Ross, Eric; Riboli, Elio; Ridker, Paul M; Schumacher, Fredrick R; Severi, Gianluca; Dos Santos Silva, Isabel; Stone, Jennifer; Sund, Malin; Tapper, William J; Thun, Michael J; Travis, Ruth C; Turnbull, Clare; Uitterlinden, Andre G; Waisfisz, Quinten; Wang, Xianshu; Wang, Zhaoming; Weaver, Joellen; Schulz-Wendtland, Rüdiger; Wilkens, Lynne R; Van Den Berg, David; Zheng, Wei; Ziegler, Regina G; Ziv, Elad; Nevanlinna, Heli; Easton, Douglas F; Hunter, David J; Henderson, Brian E; Chanock, Stephen J; Garcia-Closas, Montserrat; Kraft, Peter; Haiman, Christopher A; Vachon, Celine M

2012-12-15

Genome-wide association studies (GWAS) of breast cancer defined by hormone receptor status have revealed loci contributing to susceptibility of estrogen receptor (ER)-negative subtypes. To identify additional genetic variants for ER-negative breast cancer, we conducted the largest meta-analysis of ER-negative disease to date, comprising 4754 ER-negative cases and 31 663 controls from three GWAS: NCI Breast and Prostate Cancer Cohort Consortium (BPC3) (2188 ER-negative cases; 25 519 controls of European ancestry), Triple Negative Breast Cancer Consortium (TNBCC) (1562 triple negative cases; 3399 controls of European ancestry) and African American Breast Cancer Consortium (AABC) (1004 ER-negative cases; 2745 controls). We performed in silico replication of 86 SNPs at P ≤ 1 × 10(-5) in an additional 11 209 breast cancer cases (946 with ER-negative disease) and 16 057 controls of Japanese, Latino and European ancestry. We identified two novel loci for breast cancer at 20q11 and 6q14. SNP rs2284378 at 20q11 was associated with ER-negative breast cancer (combined two-stage OR = 1.16; P = 1.1 × 10(-8)) but showed a weaker association with overall breast cancer (OR = 1.08, P = 1.3 × 10(-6)) based on 17 869 cases and 43 745 controls and no association with ER-positive disease (OR = 1.01, P = 0.67) based on 9965 cases and 22 902 controls. Similarly, rs17530068 at 6q14 was associated with breast cancer (OR = 1.12; P = 1.1 × 10(-9)), and with both ER-positive (OR = 1.09; P = 1.5 × 10(-5)) and ER-negative (OR = 1.16, P = 2.5 × 10(-7)) disease. We also confirmed three known loci associated with ER-negative (19p13) and both ER-negative and ER-positive breast cancer (6q25 and 12p11). Our results highlight the value of large-scale collaborative studies to identify novel breast cancer risk loci.

A meta-analysis of genome-wide association studies of breast cancer identifies two novel susceptibility loci at 6q14 and 20q11

PubMed Central

Siddiq, Afshan; Couch, Fergus J.; Chen, Gary K.; Lindström, Sara; Eccles, Diana; Millikan, Robert C.; Michailidou, Kyriaki; Stram, Daniel O.; Beckmann, Lars; Rhie, Suhn Kyong; Ambrosone, Christine B.; Aittomäki, Kristiina; Amiano, Pilar; Apicella, Carmel; Baglietto, Laura; Bandera, Elisa V.; Beckmann, Matthias W.; Berg, Christine D.; Bernstein, Leslie; Blomqvist, Carl; Brauch, Hiltrud; Brinton, Louise; Bui, Quang M.; Buring, Julie E.; Buys, Saundra S.; Campa, Daniele; Carpenter, Jane E.; Chasman, Daniel I.; Chang-Claude, Jenny; Chen, Constance; Clavel-Chapelon, Françoise; Cox, Angela; Cross, Simon S.; Czene, Kamila; Deming, Sandra L.; Diasio, Robert B.; Diver, W. Ryan; Dunning, Alison M.; Durcan, Lorraine; Ekici, Arif B.; Fasching, Peter A.; Feigelson, Heather Spencer; Fejerman, Laura; Figueroa, Jonine D.; Fletcher, Olivia; Flesch-Janys, Dieter; Gaudet, Mia M.; Gerty, Susan M.; Rodriguez-Gil, Jorge L.; Giles, Graham G.; van Gils, Carla H.; Godwin, Andrew K.; Graham, Nikki; Greco, Dario; Hall, Per; Hankinson, Susan E.; Hartmann, Arndt; Hein, Rebecca; Heinz, Judith; Hoover, Robert N.; Hopper, John L.; Hu, Jennifer J.; Huntsman, Scott; Ingles, Sue A.; Irwanto, Astrid; Isaacs, Claudine; Jacobs, Kevin B.; John, Esther M.; Justenhoven, Christina; Kaaks, Rudolf; Kolonel, Laurence N.; Coetzee, Gerhard A.; Lathrop, Mark; Le Marchand, Loic; Lee, Adam M.; Lee, I-Min; Lesnick, Timothy; Lichtner, Peter; Liu, Jianjun; Lund, Eiliv; Makalic, Enes; Martin, Nicholas G.; McLean, Catriona A.; Meijers-Heijboer, Hanne; Meindl, Alfons; Miron, Penelope; Monroe, Kristine R.; Montgomery, Grant W.; Müller-Myhsok, Bertram; Nickels, Stefan; Nyante, Sarah J.; Olswold, Curtis; Overvad, Kim; Palli, Domenico; Park, Daniel J.; Palmer, Julie R.; Pathak, Harsh; Peto, Julian; Pharoah, Paul; Rahman, Nazneen; Rivadeneira, Fernando; Schmidt, Daniel F.; Schmutzler, Rita K.; Slager, Susan; Southey, Melissa C.; Stevens, Kristen N.; Sinn, Hans-Peter; Press, Michael F.; Ross, Eric; Riboli, Elio; Ridker, Paul M.; Schumacher, Fredrick R.; Severi, Gianluca; dos Santos Silva, Isabel; Stone, Jennifer; Sund, Malin; Tapper, William J.; Thun, Michael J.; Travis, Ruth C.; Turnbull, Clare; Uitterlinden, Andre G.; Waisfisz, Quinten; Wang, Xianshu; Wang, Zhaoming; Weaver, JoEllen; Schulz-Wendtland, Rüdiger; Wilkens, Lynne R.; Van Den Berg, David; Zheng, Wei; Ziegler, Regina G.; Ziv, Elad; Nevanlinna, Heli; Easton, Douglas F.; Hunter, David J.; Henderson, Brian E.; Chanock, Stephen J.; Garcia-Closas, Montserrat; Kraft, Peter; Haiman, Christopher A.; Vachon, Celine M.

2012-01-01

Genome-wide association studies (GWAS) of breast cancer defined by hormone receptor status have revealed loci contributing to susceptibility of estrogen receptor (ER)-negative subtypes. To identify additional genetic variants for ER-negative breast cancer, we conducted the largest meta-analysis of ER-negative disease to date, comprising 4754 ER-negative cases and 31 663 controls from three GWAS: NCI Breast and Prostate Cancer Cohort Consortium (BPC3) (2188 ER-negative cases; 25 519 controls of European ancestry), Triple Negative Breast Cancer Consortium (TNBCC) (1562 triple negative cases; 3399 controls of European ancestry) and African American Breast Cancer Consortium (AABC) (1004 ER-negative cases; 2745 controls). We performed in silico replication of 86 SNPs at P ≤ 1 × 10-5 in an additional 11 209 breast cancer cases (946 with ER-negative disease) and 16 057 controls of Japanese, Latino and European ancestry. We identified two novel loci for breast cancer at 20q11 and 6q14. SNP rs2284378 at 20q11 was associated with ER-negative breast cancer (combined two-stage OR = 1.16; P = 1.1 × 10−8) but showed a weaker association with overall breast cancer (OR = 1.08, P = 1.3 × 10–6) based on 17 869 cases and 43 745 controls and no association with ER-positive disease (OR = 1.01, P = 0.67) based on 9965 cases and 22 902 controls. Similarly, rs17530068 at 6q14 was associated with breast cancer (OR = 1.12; P = 1.1 × 10−9), and with both ER-positive (OR = 1.09; P = 1.5 × 10−5) and ER-negative (OR = 1.16, P = 2.5 × 10−7) disease. We also confirmed three known loci associated with ER-negative (19p13) and both ER-negative and ER-positive breast cancer (6q25 and 12p11). Our results highlight the value of large-scale collaborative studies to identify novel breast cancer risk loci. PMID:22976474

33 CFR 222.5 - Water control management (ER 1110-2-240).

Code of Federal Regulations, 2012 CFR

2012-07-01

... 33 Navigation and Navigable Waters 3 2012-07-01 2012-07-01 false Water control management (ER 1110... ARMY, DEPARTMENT OF DEFENSE ENGINEERING AND DESIGN § 222.5 Water control management (ER 1110-2-240). (a... Engineers in carrying out water control management activities, including establishment of water control...

33 CFR 222.5 - Water control management (ER 1110-2-240).

Code of Federal Regulations, 2011 CFR

2011-07-01

... 33 Navigation and Navigable Waters 3 2011-07-01 2011-07-01 false Water control management (ER 1110... ARMY, DEPARTMENT OF DEFENSE ENGINEERING AND DESIGN § 222.5 Water control management (ER 1110-2-240). (a... Engineers in carrying out water control management activities, including establishment of water control...

33 CFR 222.5 - Water control management (ER 1110-2-240).

Code of Federal Regulations, 2010 CFR

2010-07-01

... 33 Navigation and Navigable Waters 3 2010-07-01 2010-07-01 false Water control management (ER 1110... ARMY, DEPARTMENT OF DEFENSE ENGINEERING AND DESIGN § 222.5 Water control management (ER 1110-2-240). (a... Engineers in carrying out water control management activities, including establishment of water control...

33 CFR 222.5 - Water control management (ER 1110-2-240).

Code of Federal Regulations, 2013 CFR

2013-07-01

... 33 Navigation and Navigable Waters 3 2013-07-01 2013-07-01 false Water control management (ER 1110... ARMY, DEPARTMENT OF DEFENSE ENGINEERING AND DESIGN § 222.5 Water control management (ER 1110-2-240). (a... Engineers in carrying out water control management activities, including establishment of water control...

33 CFR 222.5 - Water control management (ER 1110-2-240).

Code of Federal Regulations, 2014 CFR

2014-07-01

... 33 Navigation and Navigable Waters 3 2014-07-01 2014-07-01 false Water control management (ER 1110... ARMY, DEPARTMENT OF DEFENSE ENGINEERING AND DESIGN § 222.5 Water control management (ER 1110-2-240). (a... Engineers in carrying out water control management activities, including establishment of water control...

Efficient 1535 nm light emission from an all-Si-based optical micro-cavity containing Er³⁺ and Yb³⁺ ions.

PubMed

Gallo, I B; Braud, A; Zanatta, A R

2013-11-18

This work reports on the construction and spectroscopic analyses of optical micro-cavities (OMCs) that efficiently emit at ~1535 nm. The emission wavelength matches the third transmission window of commercial optical fibers and the OMCs were entirely based on silicon. The sputtering deposition method was adopted in the preparation of the OMCs, which comprised two Bragg reflectors and one spacer layer made of either Er- or ErYb-doped amorphous silicon nitride. The luminescence signal extracted from the OMCs originated from the 4I(13/2)→<4I(15/2) transition (due to Er3 ions) and its intensity showed to be highly dependent on the presence of Yb3+ ions. According to the results, the Er3+-related light emission was improved by a factor of 48 when combined with Yb3+ ions and inserted in the spacer layer of the OMC. The results also showed the effectiveness of the present experimental approach in producing Si-based light-emitting structures in which the main characteristics are: (a) compatibility with the actual micro-electronics industry, (b) the deposition of optical quality layers with accurate composition control, and (c) no need of uncommon elements-compounds nor extensive thermal treatments. Along with the fundamental characteristics of the OMCs, this work also discusses the impact of the Er3+-Yb3+ ion interaction on the emission intensity as well as the potential of the present findings.

Spirometry in primary care: An analysis of spirometry test quality in a regional primary care asthma program

PubMed Central

Licskai, Christopher J; Sands, Todd W; Paolatto, Lisa; Nicoletti, Ivan; Ferrone, Madonna

2012-01-01

BACKGROUND: Primary care office spirometry can improve access to testing and concordance between clinical practice and asthma guidelines. Compliance with test quality standards is essential to implementation. OBJECTIVE: To evaluate the quality of spirometry performed onsite in a regional primary care asthma program (RAP) by health care professionals with limited training. METHODS: Asthma educators were trained to perform spirometry during two 2 h workshops and supervised during up to six patient encounters. Quality was analyzed using American Thoracic Society (ATS) 1994 and ATS/European Respiratory Society (ERS) 2003 (ATS/ERS) standards. These results were compared with two regional reference sites: a primary care group practice (Family Medical Centre [FMC], Windsor, Ontario) and a teaching hospital pulmonary function laboratory (London Health Sciences Centre [LHSC], London, Ontario). RESULTS: A total of 12,815 flow-volume loops (FVL) were evaluated: RAP – 1606 FVL in 472 patient sessions; reference sites – FMC 4013 FVL in 573 sessions; and LHSC – 7196 in 1151 sessions. RAP: There were three acceptable FVL in 392 of 472 (83%) sessions, two reproducible FVL according to ATS criteria in 428 of 469 (91%) sessions, and 395 of 469 (84%) according to ATS/ERS criteria. All quality criteria – minimum of three acceptable and two reproducible FVL according to ATS criteria in 361 of 472 (77%) sessions and according to ATS/ERS criteria in 337 of 472 (71%) sessions. RAP met ATS criteria more often than the FMC (388 of 573 [68%]); however, less often than LHSC (1050 of 1151 [91%]; P<0.001). CONCLUSIONS: Health care providers with limited training and experience operating within a simple quality program achieved ATS/ERS quality spirometry in the majority of sessions in a primary care setting. The quality performance approached pulmonary function laboratory standards. PMID:22891184

An assessment of resuscitation quality in the television drama Emergency Room: guideline non-compliance and low-quality cardiopulmonary resuscitation lead to a favorable outcome?

PubMed

Hinkelbein, Jochen; Spelten, Oliver; Marks, Jörg; Hellmich, Martin; Böttiger, Bernd W; Wetsch, Wolfgang A

2014-08-01

Two earlier studies found that outcome after cardiopulmonary resuscitation (CPR) in the television medical drama Emergency Room (ER) is not realistic. No study has yet evaluated CPR quality in ER. Retrospective analysis of CPR quality in episodes of ER. Three independent board-certified emergency physicians trained in CPR and the American Heart Association (AHA) guidelines reviewed ER episodes in two 5-year time-frames (2001-2005 and 2005-2009). Congruency with the corresponding 2000 and 2005 AHA guidelines was determined for each CPR scene. None. None. To evaluate whether CPR is in agreement with the specific algorithms of the AHA guidelines. Fisher's exact test and Mann-Whitney-U-test were used to evaluate statistical significance (P<0.05). A total of 136 on-screen cardiac arrests occurred in 174 episodes. Trauma was the leading cause of cardiac arrest (56.6%), which was witnessed in 80.1%. Return of spontaneous circulation occurred in 38.2%. Altogether, 19.1% of patients survived until ICU admission, and 5.1% were discharged alive. Only one CPR scene was in agreement with the published AHA guidelines. However, low-quality CPR and non-compliance with the guidelines resulted in favorable outcomes. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Suspected myofibrillar myopathy in Arabian horses with a history of exertional rhabdomyolysis.

PubMed

Valberg, S J; McKenzie, E C; Eyrich, L V; Shivers, J; Barnes, N E; Finno, C J

2016-09-01

Although exertional rhabdomyolysis (ER) is common in Arabian horses, there are no dedicated studies describing histopathological characteristics of muscle from Arabian horses with ER. To prospectively identify distinctive histopathological features of muscle from Arabian endurance horses with a history of ER (pro-ER) and to retrospectively determine their prevalence in archived samples from Arabian horses with exertional myopathies (retro-ER). Prospective and retrospective histopathological description. Middle gluteal muscle biopsies obtained from Arabian controls (n = 14), pro-ER (n = 13) as well as archived retro-ER (n = 25) muscle samples previously classified with type 2 polysaccharide storage myopathy (15/25), recurrent exertional rhabdomyolysis (7/25) and no pathology (3/25) were scored for histopathology and immunohistochemical staining of cytoskeletal proteins. Glutaraldehyde-fixed samples (2 pro-ER, one control) were processed for electron microscopy. Pro-ER and retro-ER groups were compared with controls using Mann-Whitney U and Fisher's exact tests. Centrally located myonuclei in mature myofibres were found in significantly more (P<0.05) pro-ER (12/13) and retro-ER (21/25) horses than controls (4/14). Degenerating myofibres were not evident in any biopsies. Retro-ER horses had amylase-resistant polysaccharide (6/25, P<0.05) and higher scores for cytoplasmic glycogen, rimmed vacuoles and rod-like bodies. A few control horses (3/14) and significantly (P<0.05) more pro-ER (12/13) and retro-ER (18/25) horses had disrupted myofibrillar alignment and large desmin and αβ-crystallin positive cytoplasmic aggregates. Prominent Z-disc degeneration and focal myofibrillar disruption with regional accumulation of β-glycogen particles were identified on electron microscopy of the 2 pro-ER samples. In a subset of Arabian horses with intermittent episodes of exertional rhabdomyolysis, ectopic accumulation of cytoskeletal proteins and Z-disc degeneration bear a strong resemblance to a myofibrillar myopathy. While many of these horses were previously diagnosed with type 2 polysaccharide storage myopathy, pools of glycogen forming within disrupted myofibrils appeared to give the false appearance of a glycogen storage disorder. © 2015 EVJ Ltd.

Suspected myofibrillar myopathy in Arabian horses with a history of exertional rhabdomyolysis

PubMed Central

VALBERG, S. J.; McKENZIE, E. C.; EYRICH, L. V.; SHIVERS, J.; BARNES, N. E.; FINNO, C. J.

2016-01-01

Summary Reasons for performing study Although exertional rhabdomyolysis (ER) is common in Arabian horses, there are no dedicated studies describing histopathological characteristics of muscle from Arabian horses with ER. Objectives To prospectively identify distinctive histopathological features of muscle from Arabian endurance horses with a history of ER (pro-ER) and to retrospectively determine their prevalence in archived samples from Arabian horses with exertional myopathies (retro-ER). Study design Prospective and retrospective histopathological description. Methods Middle gluteal muscle biopsies obtained from Arabian controls (n = 14), pro-ER (n = 13) as well as archived retro-ER (n = 25) muscle samples previously classified with type 2 polysaccharide storage myopathy (15/25), recurrent exertional rhabdomyolysis (7/25) and no pathology (3/25) were scored for histopathology and immunohistochemical staining of cytoskeletal proteins. Glutaraldehyde-fixed samples (2 pro-ER, one control) were processed for electron microscopy. Pro-ER and retro-ER groups were compared with controls using Mann–Whitney U and Fisher's exact tests. Results Centrally located myonuclei in mature myofibres were found in significantly more (P<0.05) pro-ER (12/13) and retro-ER (21/25) horses than controls (4/14). Degenerating myofibres were not evident in any biopsies. Retro-ER horses had amylase-resistant polysaccharide (6/25, P<0.05) and higher scores for cytoplasmic glycogen, rimmed vacuoles and rod-like bodies. A few control horses (3/14) and significantly (P<0.05) more pro-ER (12/13) and retro-ER (18/25) horses had disrupted myofibrillar alignment and large desmin and αβ-crystallin positive cytoplasmic aggregates. Prominent Z-disc degeneration and focal myofibrillar disruption with regional accumulation of β-glycogen particles were identified on electron microscopy of the 2 pro-ER samples. Conclusions In a subset of Arabian horses with intermittent episodes of exertional rhabdomyolysis, ectopic accumulation of cytoskeletal proteins and Z-disc degeneration bear a strong resemblance to a myofibrillar myopathy. While many of these horses were previously diagnosed with type 2 polysaccharide storage myopathy, pools of glycogen forming within disrupted myofibrils appeared to give the false appearance of a glycogen storage disorder. PMID:26234161

Influence of KDEL on the Fate of Trimeric or Assembly-Defective Phaseolin

PubMed Central

Frigerio, Lorenzo; Pastres, Alessandra; Prada, Alessandra; Vitale, Alessandro

2001-01-01

The tetrapeptide KDEL is commonly found at the C terminus of soluble proteins of the endoplasmic reticulum (ER), and it contributes to their localization by interacting with a receptor that recycles between the Golgi complex and the ER. We investigated the effects of the addition of KDEL to phaseolin, a protein normally delivered from the ER to storage vacuoles via the Golgi complex. We show that KDEL prevents acquisition of trans-Golgi–specific glycan modifications and causes interactions with the chaperone BiP that are distinct from the ones between BiP and defective proteins. KDEL markedly increases the stability of phaseolin, but a small proportion of phaseolin-KDEL slowly reaches the vacuole without undergoing Golgi-mediated glycan modifications, in a process that can be inhibited by brefeldin A but not monensin. Our results indicate that KDEL can operate with high efficiency before proteins can reach the late Golgi cisternae but allows or promotes delivery to vacuoles via an alternative mechanism. However, addition of KDEL does not alter the destiny of an assembly-defective form of phaseolin, suggesting that the plant ER quality control mechanism is dominant over KDEL effects. PMID:11340185

Influence of KDEL on the fate of trimeric or assembly-defective phaseolin: selective use of an alternative route to vacuoles.

PubMed

Frigerio, L; Pastres, A; Prada, A; Vitale, A

2001-05-01

The tetrapeptide KDEL is commonly found at the C terminus of soluble proteins of the endoplasmic reticulum (ER), and it contributes to their localization by interacting with a receptor that recycles between the Golgi complex and the ER. We investigated the effects of the addition of KDEL to phaseolin, a protein normally delivered from the ER to storage vacuoles via the Golgi complex. We show that KDEL prevents acquisition of trans-Golgi-specific glycan modifications and causes interactions with the chaperone BiP that are distinct from the ones between BiP and defective proteins. KDEL markedly increases the stability of phaseolin, but a small proportion of phaseolin-KDEL slowly reaches the vacuole without undergoing Golgi-mediated glycan modifications, in a process that can be inhibited by brefeldin A but not monensin. Our results indicate that KDEL can operate with high efficiency before proteins can reach the late Golgi cisternae but allows or promotes delivery to vacuoles via an alternative mechanism. However, addition of KDEL does not alter the destiny of an assembly-defective form of phaseolin, suggesting that the plant ER quality control mechanism is dominant over KDEL effects.

Combination phentermine and topiramate extended release in the management of obesity.

PubMed

Alfaris, Nasreen; Minnick, Alyssa M; Hopkins, Christina M; Berkowitz, Robert I; Wadden, Thomas A

2015-06-01

Losing ≥ 5% of initial weight improves quality of life and risk factors for cardiovascular disease (CVD) in obese individuals. Lifestyle modification, the cornerstone of weight reduction, may be complemented by pharmacotherapy. In 2012, the FDA approved the combination of phentermine and topiramate extended release (ER) for chronic weight management, as an adjunct to lifestyle modification. This review examines the safety and efficacy of phentermine-topiramate ER, as determined by randomized controlled trials (RCTs). A preliminary study confirmed the benefit of combining the two medications for improving weight loss and reducing adverse effects, as compared to using equivalent-dose monotherapy alone. Across RCTs, groups prescribed phentermine 15 mg/topiramate ER 92 mg lost an average of 10% of initial weight, ∼ 8% more than placebo and 2% more than phentermine 7.5 mg/topiramate 46 mg. Weight loss reduced the risk of developing type 2 diabetes and improved CVD risk factors. Phentermine-topiramate ER, however, was associated with increased heart rate, the clinical significance of which is being investigated in an FDA-required CVD outcomes study. The medication also must be used with caution in women of child-bearing age because of an increased risk to infants of oral cleft.

Efficient bone cutting with the novel diode pumped Er:YAG laser system: in vitro investigation and optimization of the treatment parameters

NASA Astrophysics Data System (ADS)

Stock, Karl; Diebolder, Rolf; Hausladen, Florian; Hibst, Raimund

2014-03-01

It is well known that flashlamp pumped Er:YAG lasers allow efficient bone ablation due to strong absorption at 3μm by water. Preliminary experiments revealed also a newly developed diode pumped Er:YAG laser system (Pantec Engineering AG) to be an efficient tool for use for bone surgery. The aim of the present in vitro study is the investigation of a new power increased version of the laser system with higher pulse energy and optimization of the treatment set-up to get high cutting quality, efficiency, and ablation depth. Optical simulations were performed to achieve various focus diameters and homogeneous beam profile. An appropriate experimental set-up with two different focusing units, a computer controlled linear stage with sample holder, and a shutter unit was realized. By this we are able to move the sample (slices of pig bone) with a defined velocity during the irradiation. Cutting was performed under appropriate water spray by moving the sample back and forth. After each path the ablation depth was measured and the focal plane was tracked to the actual bottom of the groove. Finally, the cuts were analyzed by light microcopy regarding the ablation quality and geometry, and thermal effects. In summary, the results show that with carefully adapted irradiation parameters narrow and deep cuts (ablation depth > 6mm, aspect ratio approx. 20) are possible without carbonization. In conclusion, these in vitro investigations demonstrate that high efficient bone cutting is possible with the diode pumped Er:YAG laser system using appropriate treatment set-up and parameters.

Improving Emotion Regulation and Sibling Relationship Quality: The More Fun with Sisters and Brothers Program

ERIC Educational Resources Information Center

Kennedy, Denise E.; Kramer, Laurie

2008-01-01

We examined the role of emotion regulation (ER) in improving sibling relationship quality (SRQ) by evaluating the More Fun With Sisters and Brothers Program where 4- to 8-year-old siblings from 95 families were taught emotional and social competencies. Parents reported on SRQ and ER, and sibling interactions were observed in homes. SRQ and ER…

Protein quality control: the who’s who, the where’s and therapeutic escapes

PubMed Central

Yam, Gary Hin-Fai; Fan, Jingyu; Hirano, Kiyoko; Gaplovska-Kysela, Katarina; Le Fourn, Valerie; Guhl, Bruno; Santimaria, Roger; Torossi, Tania; Ziak, Martin

2007-01-01

In cells the quality of newly synthesized proteins is monitored in regard to proper folding and correct assembly in the early secretory pathway, the cytosol and the nucleoplasm. Proteins recognized as non-native in the ER will be removed and degraded by a process termed ERAD. ERAD of aberrant proteins is accompanied by various changes of cellular organelles and results in protein folding diseases. This review focuses on how the immunocytochemical labeling and electron microscopic analyses have helped to disclose the in situ subcellular distribution pattern of some of the key machinery proteins of the cellular protein quality control, the organelle changes due to the presence of misfolded proteins, and the efficiency of synthetic chaperones to rescue disease-causing trafficking defects of aberrant proteins. PMID:18075753

Implementation of the Diabetes Practice Guideline in the Army Medical Department: Final Evaluation

DTIC Science & Technology

2005-01-01

Diabetes Quality Improvement Project DRG Diagnosis-Related Group ER Emergency room FMP Family Member Prefix HBA1c Hemoglobin A1c HCSR Health-Care Service...glycemic control by assessing and managing glycosylated hemoglobin, reported as hemoglobin A1c ( HbA1c ) lev- els. Assess HbA1c levels relative to target...frequency involved in adjusting insulin dosages Increase in the percentage of noninsulin patients who fill prescribed medications to control HbA1c

Quality assurance grading guidelines for research and development at DOE facilities

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

Powell, T.B.; Morris, R.N.

1993-01-01

The quality assurance (QA) requirements for the US Department of Energy (DOE) are established in DOE Order 5700.6C. This order is applicable for all DOE departmental elements, management, and maintenance and operating contractors and requires that documented Quality Assurance Programs (QAPs) are prepared at all levels; it has one attachment. The DOE Office of Energy Research (DOE-ER) has issued a standard to ensure implementation of the full intent of this order in the ER community.

Analysis of glycoprotein processing in the endoplasmic reticulum using synthetic oligosaccharides.

PubMed

Ito, Yukishige; Takeda, Yoichi

2012-01-01

Protein quality control (QC) in the endoplasmic reticulum (ER) comprises many steps, including folding and transport of nascent proteins as well as degradation of misfolded proteins. Recent studies have revealed that high-mannose-type glycans play a pivotal role in the QC process. To gain knowledge about the molecular basis of this process with well-defined homogeneous compounds, we achieved a convergent synthesis of high-mannose-type glycans and their functionalized derivatives. We focused on analyses of UDP-Glc: glycoprotein glucosyltransferase (UGGT) and ER Glucosidase II, which play crucial roles in glycoprotein QC; however, their specificities remain unclear. In addition, we established an in vitro assay system mimicking the in vivo condition which is highly crowded because of the presence of various biomacromolecules.

Rkr1/Ltn1 Ubiquitin Ligase-mediated Degradation of Translationally Stalled Endoplasmic Reticulum Proteins*

PubMed Central

Crowder, Justin J.; Geigges, Marco; Gibson, Ryan T.; Fults, Eric S.; Buchanan, Bryce W.; Sachs, Nadine; Schink, Andrea; Kreft, Stefan G.; Rubenstein, Eric M.

2015-01-01

Aberrant nonstop proteins arise from translation of mRNA molecules beyond the coding sequence into the 3′-untranslated region. If a stop codon is not encountered, translation continues into the poly(A) tail, resulting in C-terminal appendage of a polylysine tract and a terminally stalled ribosome. In Saccharomyces cerevisiae, the ubiquitin ligase Rkr1/Ltn1 has been implicated in the proteasomal degradation of soluble cytosolic nonstop and translationally stalled proteins. Rkr1 is essential for cellular fitness under conditions associated with increased prevalence of nonstop proteins. Mutation of the mammalian homolog causes significant neurological pathology, suggesting broad physiological significance of ribosome-associated quality control. It is not known whether and how soluble or transmembrane nonstop and translationally stalled proteins targeted to the endoplasmic reticulum (ER) are detected and degraded. We generated and characterized model soluble and transmembrane ER-targeted nonstop and translationally stalled proteins. We found that these proteins are indeed subject to proteasomal degradation. We tested three candidate ubiquitin ligases (Rkr1 and ER-associated Doa10 and Hrd1) for roles in regulating abundance of these proteins. Our results indicate that Rkr1 plays the primary role in targeting the tested model ER-targeted nonstop and translationally stalled proteins for degradation. These data expand the catalog of Rkr1 substrates and highlight a previously unappreciated role for this ubiquitin ligase at the ER membrane. PMID:26055716

Risk factors for breast cancer by oestrogen receptor status: a population-based case-control study.

PubMed Central

Cooper, J. A.; Rohan, T. E.; Cant, E. L.; Horsfall, D. J.; Tilley, W. D.

1989-01-01

Data from a population-based case-control study conducted in Adelaide, South Australia, and involving 451 case-control pairs, were analysed to determine whether the associations of menstrual, reproductive, dietary and other factors with risk of breast cancer differed by oestrogen receptor (ER) status. Data on ER status were available for 380 cases. The proportion of tumours which were ER+ increased with age, and there was a higher proportion of ER+ tumours in post-menopausal than in premenopausal women. Both oral contraceptive use (P = 0.055) and cigarette smoking (P = 0.047) were associated with increased (unadjusted) risk of ER- cancer, while having little association with risk of ER+ cancer. Most dietary factors had little association with risk of either cancer type, the main exception being the reduction in risk of ER- breast cancer with increasing beta-carotene intake (P for trend = 0.017). In general, however, links with the factors examined were not strong enough to suggest different causal pathways for ER- and ER+ breast cancer. PMID:2757918

Dietary quality changes in response to a sugar-sweetened beverage-reduction intervention: results from the Talking Health randomized controlled clinical trial.

PubMed

Hedrick, Valisa E; Davy, Brenda M; You, Wen; Porter, Kathleen J; Estabrooks, Paul A; Zoellner, Jamie M

2017-04-01

Background: The reduction of sugar-sweetened beverage (SSB) intake may be beneficial for weight management and other related health conditions; however, to our knowledge, no data exist regarding the spontaneous changes in other dietary components or the overall dietary quality after an SSB-reduction intervention. Objectives: We explored longitudinal changes within and between an SSB-reduction intervention (SIPsmartER) and a physical activity intervention (MoveMore) with respect to spontaneous changes in 1 ) energy intake and macronutrients and micronutrients, 2 ) dietary quality [Healthy Eating Index-2010 (HEI)], and 3 ) beverage categories. Design: Participants were enrolled in a 6-mo, community-based behavioral trial and randomly assigned into either the SIPsmartER ( n = 149) intervention group or the MoveMore ( n = 143) matched-contact comparison group. Dietary intake was assessed through a mean of three 24-h dietary recalls at baseline and 6 mo. Dietary recalls were analyzed with the use of nutritional analysis software. A multilevel, mixed-effects linear regression with intention-to-treat analyses is presented. Results: SIPsmartER participants showed a significant reduction in total SSBs (mean decrease: -366 mL; P ≤ 0.001). Several spontaneous changes occurred within the SIPsmartER group and, compared with the MoveMore group, included significant HEI improvements for empty calorie, total vegetable, and total HEI scores (mean increases: 2.6, 0.3, and 2.6, respectively; all P ≤ 0.01). Additional positive changes were shown, including significant decreases in total energy intake, trans fat, added sugars, and total beverage energy (all P ≤ 0.05). Few dietary changes were noted in the MoveMore group over the 6-mo intervention. Conclusions: Intervention of the single dietary component SSB resulted in additional spontaneous and beneficial dietary changes. Interventions that target a single dietary change, such as limiting SSB intake to <240 mL/d (<8 fl oz/d), may improve the overall dietary quality health and provide motivation to make additional dietary changes. This trial was registered at clinicaltrials.gov as NCT02193009. © 2017 American Society for Nutrition.

Automatic control of negative emotions: evidence that structured practice increases the efficiency of emotion regulation.

PubMed

Christou-Champi, Spyros; Farrow, Tom F D; Webb, Thomas L

2015-01-01

Emotion regulation (ER) is vital to everyday functioning. However, the effortful nature of many forms of ER may lead to regulation being inefficient and potentially ineffective. The present research examined whether structured practice could increase the efficiency of ER. During three training sessions, comprising a total of 150 training trials, participants were presented with negatively valenced images and asked either to "attend" (control condition) or "reappraise" (ER condition). A further group of participants did not participate in training but only completed follow-up measures. Practice increased the efficiency of ER as indexed by decreased time required to regulate emotions and increased heart rate variability (HRV). Furthermore, participants in the ER condition spontaneously regulated their negative emotions two weeks later and reported being more habitual in their use of ER. These findings indicate that structured practice can facilitate the automatic control of negative emotions and that these effects persist beyond training.

Rab7a modulates ER stress and ER morphology.

PubMed

Mateus, Duarte; Marini, Elettra Sara; Progida, Cinzia; Bakke, Oddmund

2018-05-01

The Endoplasmic Reticulum (ER) is a membranous organelle with diverse structural and functional domains. Peripheral ER includes interconnected tubules, and dense tubular arrays called "ER matrices" together with bona fide flat cisternae. Transitions between these states are regulated by membrane-associated proteins and cytosolic factors. Recently, the small GTPases Rab10 and Rab18 were reported to control ER shape by regulating ER dynamics and fusion. Here, we present evidence that another Rab protein, Rab7a, modulates the ER morphology by controlling the ER homeostasis and ER stress. Indeed, inhibition of Rab7a expression by siRNA or expression of the dominant negative mutant Rab7aT22 N, leads to enlargement of sheet-like ER structures and spreading towards the cell periphery. Notably, such alterations are ascribable neither to a direct modulation of the ER shaping proteins Reticulon-4b and CLIMP63, nor to interactions with Protrudin, a Rab7a-binding protein known to affect the ER organization. Conversely, depletion of Rab7a leads to basal ER stress, in turn causing ER membrane expansion. Both ER enlargement and basal ER stress are reverted in rescue experiments by Rab7a re-expression, as well as by the ER chemical chaperone tauroursodeoxycholic acid (TUDCA). Collectively, these findings reveal a new role of Rab7a in ER homeostasis, and indicate that genetic and pharmacological ER stress manipulation may restore ER morphology in Rab7a silenced cells. Copyright © 2018 Elsevier B.V. All rights reserved.

Protein Biosynthesis and Maturation in the ER.

PubMed

Pedrazzini, Emanuela; Vitale, Alessandro

2018-01-01

The endoplasmic reticulum takes care of the folding, assembly, and quality control of thousands of proteins destined to the different compartments of the endomembrane system, or to be secreted in the apoplast. Here we describe how these early events in the life of all these proteins can be followed biochemically by using velocity or isopycnic ultracentrifugation, metabolic labeling with radioactive amino acids, and immunoprecipitation in various conditions.

OCT for early quality evaluation of tooth-composite bond in clinical trials.

PubMed

Haak, Rainer; Schmidt, Patrick; Park, Kyung-Jin; Häfer, Matthias; Krause, Felix; Ziebolz, Dirk; Schneider, Hartmut

2018-06-19

To evaluate early quality of composite restorations with a universal adhesive in different application modes clinically and with optical coherence tomography (OCT). 22 patients with four non-carious cervical lesions each received composite restorations (Filtek Supreme TM XTE, 3 M). The universal adhesive Scotchbond Universal TM (SBU, 3 M) was applied with three etching protocols: self-etch (SE), selective-enamel-etch (SEE) and etch-and-rinse (ER). The etch-and-rinse adhesive OptiBond TM FL (OFL, Kerr) served as a control. Restorations were imaged by OCT (Thorlabs) directly after application (t 0 ). After 14 days (t 1 ) and 6 month (t 2 ) OCT imaging (interfacial adhesive defects) was repeated combined with clinical assessment (FDI criteria). Groups were compared by Friedman-/Wilcoxon- and McNemar-Test. No differences were seen clinically between groups (p i ≥ 0.500). OCT assessment revealed more adhesive defects at the enamel interface with SBU/SE at t 0- t 2 compared to all groups (p i ≤ 0.016). OFL showed more defects than SBU/ER (t 1 : p = 0.01; t 2 : p = 0.083). At dentin/cementum interface OFL exhibited more adhesive defects than SBU with all conditioning modes (t 0 , t 1 , p i ≤ 0.003) and at t 2 to SBU/SE and SBU/ER (p < 0.001). Since t 1 defects with SBU were detected more frequently in the SE and SEE modes compared to ER (p i ≤ 0.037). In contrast to SBU defects increased with OFL up to t 2 (p i ≤ 0.007). In contrast to clinical evaluation, OCT revealed subtle adhesive defects directly after application that might interfere with clinical success. It was demonstrated that ER doesn't decrease initial adhesion of SBU to dentin. Copyright © 2018. Published by Elsevier Ltd.

Ubiquitin ligase gp78 increases solubility and facilitates degradation of the Z variant of {alpha}-1-antitrypsin

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

Shen Yuxian; Medical Biotechnology Center, University of Maryland Biotechnology Institute, Baltimore, MD; Ballar, Petek

2006-11-03

Deficiency of circulating {alpha}-1-antitrypsin (AAT) is the most widely recognized abnormality of a proteinase inhibitor that causes lung disease. AAT-deficiency is caused by mutations of the AAT gene that lead to AAT protein retention in the endoplasmic reticulum (ER). Moreover, the mutant AAT accumulated in the ER predisposes the homozygote to severe liver injuries, such as neonatal hepatitis, juvenile cirrhosis, and hepatocellular carcinoma. Despite the fact that mutant AAT protein is subject to ER-associated degradation (ERAD), yeast genetic studies have determined that the ubiquitination machinery, Hrd1/Der3p-cue1p-Ubc7/6p, which plays a prominent role in ERAD, is not involved in degradation of mutantmore » AAT. Here we report that gp78, a ubiquitin ligase (E3) pairing with mammalian Ubc7 for ERAD, ubiquitinates and facilitates degradation of ATZ, the classic deficiency variant of AAT having a Z mutation (Glu 342 Lys). Unexpectedly, gp78 over-expression also significantly increases ATZ solubility. p97/VCP, an AAA ATPase essential for retrotranslocation of misfolded proteins from the ER during ERAD, is involved in gp78-mediated degradation of ATZ. Surprisingly, unlike other ERAD substrates that cause ER stress leading to apoptosis when accumulated in the ER, ATZ, in fact, increases cell proliferation when over-expressed in cells. This effect can be partially inhibited by gp78 over-expression. These data indicate that gp78 assumes multiple unique quality control roles over ATZ, including the facilitation of degradation and inhibition of aggregation of ATZ.« less

Primary investigations on the potential of a novel diode pumped Er:YAG laser system for middle ear surgery

NASA Astrophysics Data System (ADS)

Stock, Karl; Wurm, Holger; Hausladen, Florian

2016-02-01

Flashlamp pumped Er:YAG lasers are successfully used clinically for both precise soft and hard tissue ablation. Since several years a novel diode pumped Er:YAG laser system (Pantec Engineering AG) is available, with mean laser power up to 40 W and pulse repetition rate up to 1 kHz. The aim of the study was to investigate the suitability of the laser system specifically for stapedotomy. Firstly an experimental setup was realized with a beam focusing unit and a computer controlled translation stage to move the samples (slices of porcine bone) with a defined velocity while irradiation with various laser parameters. A microphone was positioned in a defined distance to the ablation point and the resulting acoustic signal of the ablation process was recorded. For comparison, measurements were also performed with a flash lamp pumped Er:YAG laser system. After irradiation the resulting ablation quality and efficacy were determined using light microscopy. Using a high speed camera and "Töpler-Schlierentechnik" the cavitation bubble in water after perforation of a bone slice was investigated. The results show efficient bone ablation using the diode pumped Er:YAG laser system. Also a decrease of the sound level and of the cavitation bubble volume was observed with decreasing pulse duration. Higher repetition rates lead to a slightly increase of thermal side effects but have no influence on the ablation efficiency. In conclusion, these first experiments demonstrate the high potential of the diode pumped Er:YAG laser system for use in middle ear surgery.

Er:YAG Laser Versus Cold Knife Excision in the Treatment of Nondysplastic Oral Lesions: A Randomized Comparative Study for the Postoperative Period.

PubMed

Broccoletti, Roberto; Cafaro, Adriana; Gambino, Alessio; Romagnoli, Ercole; Arduino, Paolo Giacomo

2015-12-01

The aim of this prospective study was to estimate the effects of Erbium substituted: Yttrium Aluminium Garnet (Er:YAG) laser, compared with traditional scalpel, on the early postoperative sequelae of nondysplastic oral lesion removal. There is limited evidence that laser surgery could exhibit advantages over scalpel in oral mucosal surgery. The investigators studied a cohort of 344 patients; 394 lesions were randomized and treated. Outcome statistically evaluated variables were: age, gender, the site and size of investigated lesions, visual analogue score (VAS) of pain, the Oral Health Impact Profile questionnaire (OHIP-14) and the Quality of Life test (QOL), and number of analgesics taken in the 1st week after surgery. Significant differences were found if considering the surgical time, VAS, and QOL and OHIP-14 questionnaires; regarding those data, the Er:YAG laser appeared to be faster and less painful than traditional scalpel (p < 0.05). For bigger lesions, patients statistically took more painkillers if they had undergone traditional surgery. Considering the site of the treated lesions, Er:YAG laser was less painful, especially in the gingiva and palate (p < 0.05). This is the first randomized controlled surgical trial reported for the management of nondysplastic oral lesions with the use of an Er:YAG laser. With many limitations, the present report identifies significant difference in the immediate postoperative surgical period between the two treatments, meaning that the Er:YAG laser seemed to be less painful, and better accepted by patients, than traditional scalpel.

Enhanced recovery clinical education programme improves quality of post-operative care.

PubMed

McDonald, Ruth

2015-01-01

Quality is the driving principle of Enhanced Recovery (ER). It improves the patient experience by getting patients better sooner and changes clinical practice to make care safer and more efficient. As a consequence of ER patients spend less time in hospital. A successful ER programme began to fail after organisational restructuring and staff changes. Patients did not meet their ER goals and length of stay (LOS) increased. An ER nurse was appointed to get the programme back on track. This involved a multidisciplinary approach to an ER clinical education programme. The programme aimed to develop knowledge of the physiology of post-operative recovery and the evidence underpinning the interventions required. This was considered crucial to secure longer term staff engagement while avoiding unthinking protocol driven compliance. Success of the education programme was measured by improved outcomes in patient LOS and readmission statistics. During the four months of the clinical education programme there were no significant changes in monthly LOS. At six months post implementation of the programme there was a reduction in LOS of 0.6 days compared to the previous six months. At 12 months there was a reduction in 1.1 days compared with previous 12 months. There was a mean reduction of 28 day readmissions for all elective gynaecology surgery of 1.1 patients per month in the 12 months post programme implementation compared to the 12 months before. Delivering a multidisciplinary participatory education programme improved overall understanding of ER, and achieved sustained improvement in ER for patient benefit.

Emotion regulation and mania risk: Differential responses to implicit and explicit cues to regulate.

PubMed

Ajaya, Yatrika; Peckham, Andrew D; Johnson, Sheri L

2016-03-01

People prone to mania use emotion regulation (ER) strategies well when explicitly coached to do so in laboratory settings, but they find these strategies ineffective in daily life. We hypothesized that, compared with control participants, mania-prone people would show ER deficits when they received implicit, but not explicit, cues to use ER. Undergraduates (N = 66) completed the Hypomanic Personality Scale (HPS) and were randomly assigned to one of three experimental conditions: automatic ER (scrambled sentence primes), deliberate ER (verbal instructions), or control (no priming or instructions to use ER). Then, participants played a videogame designed to evoke anger. Emotion responses were measured with a multi-modal assessment of self-reported affect, psychophysiology, and facial expressions. Respiratory sinus arrhythmia (RSA) was used to index ER. The videogame effectively elicited subjective anger, angry facial expressions, and heart rate increases when keys malfunctioned. As hypothesized, persons who were more mania prone showed greater RSA increases in the deliberate ER condition than in the automatic or control conditions. One potential limitation is the use of an analog sample. Findings suggest that those at risk for mania require more explicit instruction to engage ER effectively. Copyright © 2015 Elsevier Ltd. All rights reserved.

Effect of the Glucagon-like Peptide-1 Analogue Exenatide Extended Release in Cats with Newly Diagnosed Diabetes Mellitus.

PubMed

Riederer, A; Zini, E; Salesov, E; Fracassi, F; Padrutt, I; Macha, K; Stöckle, T M; Lutz, T A; Reusch, C E

2016-01-01

Exenatide extended release (ER) is a glucagon-like peptide-1 analogue that increases insulin secretion, inhibits glucagon secretion and induces satiation in humans with type 2 diabetes mellitus. The use of exenatide ER is safe and stimulates insulin secretion in healthy cats. The objective of this study is to assess the safety of exenatide ER and its effect on body weight, remission and metabolic control in newly diagnosed diabetic cats receiving insulin and a low-carbohydrate diet. Thirty client-owned cats. Prospective placebo-controlled clinical trial. Cats were treated with exenatide ER or 0.9% saline, administered SC, once weekly. Both groups received insulin glargine and a low-carbohydrate diet. Exenatide ER was administered for 16 weeks, or in cats that achieved remission it was given for 4 weeks after discontinuing insulin treatment. Nonparametric tests were used for statistical analysis. Cats in the exenatide ER and placebo groups had transient adverse signs including decreased appetite (60% vs. 20%, respectively, P = .06) and vomiting (53% vs. 40%, respectively, P = .715). Body weight increased significantly in the placebo group (P = .002), but not in cats receiving exenatide ER. Cats on exenatide ER achieved remission or good metabolic control in 40% or 89%, respectively, whereas in control cats percentages were 20% or 58% (P = .427 and P = .178, respectively). Exenatide ER is safe in diabetic cats and does not result in weight gain. Our pilot study suggests that, should there be an additional clinically relevant beneficial effect of exenatide ER in insulin-treated cats on rate of remission and good metabolic control, it would likely approximate 20% and 30%, respectively. Copyright © 2015 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.

Plant ERD2-like proteins function as endoplasmic reticulum luminal protein receptors and participate in programmed cell death during innate immunity.

PubMed

Xu, Guoyong; Li, Sizhun; Xie, Ke; Zhang, Qiang; Wang, Yan; Tang, Yang; Liu, Dong; Hong, Yiguo; He, Chenyang; Liu, Yule

2012-10-01

The hypersensitive response (HR), a form of programmed cell death (PCD), is a tightly regulated innate immune response in plants that is hypothesized to restrict pathogen growth and disease development. Although considerable efforts have been made to understand HR PCD, it remains unknown whether the retrograde pathway from the Golgi to the endoplasmic reticulum (ER) is involved. Here we provide direct genetic evidence that two Nicotiana benthamiana homologs, ERD2a and ERD2b, function as ER luminal protein receptors and participate in HR PCD. Virus-induced gene silencing (VIGS) of ERD2a and/or ERD2b caused escape of ER-resident proteins from the ER, and resulted in plants that were more sensitive to ER stress. Silencing of ERD2b delayed HR PCD induced by the non-host pathogens Xanthomonas oryzae pv. oryzae and Pseudomonas syringae pv. tomato DC3000. However, both silencing of ERD2a and co-silencing of ERD2a and ERD2b exacerbated HR PCD. Individual and combined suppression of ERD2a and ERD2b exaggerated R gene-mediated cell death. Nevertheless, silencing of ERD2a and/or ERD2b had no detectable effects on bacterial growth. Furthermore, VIGS of several putative ligands of ERD2a/2b, including the ER quality control (ERQC) component genes BiP, CRT3 and UGGT, had different effects on HR PCD induced by different pathogens. This indicates that immunity-related cell death pathways are separate with respect to the genetic requirements for these ERQC components. These results suggest that ERD2a and ERD2b function as ER luminal protein receptors to ensure ERQC and alleviate ER stress, thus affecting HR PCD during the plant innate immune response. © 2012 The Authors. The Plant Journal © 2012 Blackwell Publishing Ltd.

Endoplasmic reticulum stress inhibits expression of genes involved in thyroid hormone synthesis and their key transcriptional regulators in FRTL-5 thyrocytes

PubMed Central

Wen, Gaiping; Eder, Klaus

2017-01-01

Endoplasmic reticulum (ER) stress is characterized by the accumulation of misfolded proteins due to an impairment of ER quality control pathways leading to the activation of a defense system, called unfolded protein response (UPR). While thyrocytes are supposed to be highly susceptible to environmental conditions that cause ER stress due to the synthesis of large amounts of secretory proteins required for thyroid hormone synthesis, systematic investigations on the effect of ER stress on expression of key genes of thyroid hormone synthesis and their transcriptional regulators are lacking. Since the aim of the ER stress-induced UPR is to restore ER homeostasis and to facilitate cell survival through transient shutdown of ribosomal protein translation, we hypothesized that the expression of genes involved in thyroid hormone synthesis and their transcriptional regulators, all of which are not essential for cell survival, are down-regulated in thyrocytes during ER stress, while sterol regulatory element-binding proteins (SREBPs) are activated during ER stress in thyrocytes. Treatment of FRTL-5 thyrocytes with the ER stress inducer tunicamycin (TM) dose-dependently increased the mRNA and/or protein levels of known UPR target genes, stimulated phosphorylation of the ER stress sensor protein kinase RNA-like ER kinase (PERK) and of the PERK target protein eukaryotic initiation factor 2α (eIF2α) and caused splicing of the ER stress-sensitive transcription factor X-box binding protein (XBP-1) (P < 0.05). The mRNA levels and/or protein levels of genes involved in thyroid hormone synthesis, sodium/iodide symporter (NIS), thyroid peroxidase (TPO) and thyroglobulin (TG), their transcriptional regulators and thyrotropin (TSH) receptor and the uptake of Na125I were reduced at the highest concentration of TM tested (0.1 μg/mL; P < 0.05). Proteolytic activation of the SREBP-1c pathway was not observed in FRTL-5 cells treated with TM, whereas TM reduced proteolytic activation of the SREBP-2 pathway at 0.1 μg TM/mL (P < 0.05). In conclusion, the expression of key genes involved in thyroid hormone synthesis and their critical regulators and of the TSH receptor as well as the uptake of iodide is attenuated in thyrocytes during mild ER stress. Down-regulation of NIS, TPO and TG during ER stress is likely the consequence of impaired TSH/TSHR signaling in concert with reduced expression of critical transcriptional regulators of these genes. PMID:29095946

Endoplasmic reticulum stress inhibits expression of genes involved in thyroid hormone synthesis and their key transcriptional regulators in FRTL-5 thyrocytes.

PubMed

Wen, Gaiping; Ringseis, Robert; Eder, Klaus

2017-01-01

Endoplasmic reticulum (ER) stress is characterized by the accumulation of misfolded proteins due to an impairment of ER quality control pathways leading to the activation of a defense system, called unfolded protein response (UPR). While thyrocytes are supposed to be highly susceptible to environmental conditions that cause ER stress due to the synthesis of large amounts of secretory proteins required for thyroid hormone synthesis, systematic investigations on the effect of ER stress on expression of key genes of thyroid hormone synthesis and their transcriptional regulators are lacking. Since the aim of the ER stress-induced UPR is to restore ER homeostasis and to facilitate cell survival through transient shutdown of ribosomal protein translation, we hypothesized that the expression of genes involved in thyroid hormone synthesis and their transcriptional regulators, all of which are not essential for cell survival, are down-regulated in thyrocytes during ER stress, while sterol regulatory element-binding proteins (SREBPs) are activated during ER stress in thyrocytes. Treatment of FRTL-5 thyrocytes with the ER stress inducer tunicamycin (TM) dose-dependently increased the mRNA and/or protein levels of known UPR target genes, stimulated phosphorylation of the ER stress sensor protein kinase RNA-like ER kinase (PERK) and of the PERK target protein eukaryotic initiation factor 2α (eIF2α) and caused splicing of the ER stress-sensitive transcription factor X-box binding protein (XBP-1) (P < 0.05). The mRNA levels and/or protein levels of genes involved in thyroid hormone synthesis, sodium/iodide symporter (NIS), thyroid peroxidase (TPO) and thyroglobulin (TG), their transcriptional regulators and thyrotropin (TSH) receptor and the uptake of Na125I were reduced at the highest concentration of TM tested (0.1 μg/mL; P < 0.05). Proteolytic activation of the SREBP-1c pathway was not observed in FRTL-5 cells treated with TM, whereas TM reduced proteolytic activation of the SREBP-2 pathway at 0.1 μg TM/mL (P < 0.05). In conclusion, the expression of key genes involved in thyroid hormone synthesis and their critical regulators and of the TSH receptor as well as the uptake of iodide is attenuated in thyrocytes during mild ER stress. Down-regulation of NIS, TPO and TG during ER stress is likely the consequence of impaired TSH/TSHR signaling in concert with reduced expression of critical transcriptional regulators of these genes.

Comprehensive proteomic analysis of developing protein bodies in maize (Zea mays) endosperm provides novel insights into its biogenesis.

PubMed

Wang, Guifeng; Wang, Gang; Wang, Jiajia; Du, Yulong; Yao, Dongsheng; Shuai, Bilian; Han, Liang; Tang, Yuanping; Song, Rentao

2016-12-01

Prolamins, the major cereal seed storage proteins, are sequestered and accumulated in the lumen of the endoplasmic reticulum (ER), and are directly assembled into protein bodies (PBs). The content and composition of prolamins are the key determinants for protein quality and texture-related traits of the grain. Concomitantly, the PB-inducing fusion system provides an efficient target to produce therapeutic and industrial products in plants. However, the proteome of the native PB and the detailed mechanisms underlying its formation still need to be determined. We developed a method to isolate highly purified and intact PBs from developing maize endosperm and conducted proteomic analysis of intact PBs of zein, a class of prolamine protein found in maize. We thus identified 1756 proteins, which fall into five major categories: metabolic pathways, response to stimulus, transport, development, and growth, as well as regulation. By comparing the proteomes of crude and enriched extractions of PBs, we found substantial evidence for the following conclusions: (i) ribosomes, ER membranes, and the cytoskeleton are tightly associated with zein PBs, which form the peripheral border; (ii) zein RNAs are probably transported and localized to the PB-ER subdomain; and (iii) ER chaperones are essential for zein folding, quality control, and assembly into PBs. We futher confirmed that OPAQUE1 (O1) cannot directly interact with FLOURY1 (FL1) in yeast, suggesting that the interaction between myosins XI and DUF593-containing proteins is isoform-specific. This study provides a proteomic roadmap for dissecting zein PB biogenesis and reveals an unexpected diversity and complexity of proteins in PBs. © The Author 2016. Published by Oxford University Press on behalf of the Society for Experimental Biology.

Hsp70 and Hsp90 Multichaperone Complexes Sequentially Regulate Thiazide-sensitive Cotransporter Endoplasmic Reticulum-associated Degradation and Biogenesis*

PubMed Central

Donnelly, Bridget F.; Needham, Patrick G.; Snyder, Avin C.; Roy, Ankita; Khadem, Shaheen; Brodsky, Jeffrey L.; Subramanya, Arohan R.

2013-01-01

The thiazide-sensitive NaCl cotransporter (NCC) is the primary mediator of salt reabsorption in the distal convoluted tubule and is a key determinant of the blood pressure set point. Given its complex topology, NCC is inefficiently processed and prone to endoplasmic reticulum (ER)-associated degradation (ERAD), although the mechanisms governing this process remain obscure. Here, we identify factors that impact the ER quality control of NCC. Analyses of NCC immunoprecipitates revealed that the cotransporter formed complexes with the core chaperones Hsp90, Hsp70, and Hsp40. Disruption of Hsp90 function accelerated NCC degradation, suggesting that Hsp90 promotes NCC folding. In addition, two cochaperones, the C terminus of Hsp70-interacting protein (CHIP) and the Hsp70/Hsp90 organizer protein, were associated with NCC. Although CHIP, an E3 ubiquitin ligase, promoted NCC ubiquitination and ERAD, the Hsp70/Hsp90 organizer protein stabilized NCC turnover, indicating that these two proteins differentially remodel the core chaperone systems to favor cotransporter degradation and biogenesis, respectively. Adjusting the folding environment in mammalian cells via reduced temperature enhanced NCC biosynthetic trafficking, increased Hsp90-NCC interaction, and diminished binding to Hsp70. In contrast, cotransporters harboring disease-causing mutations that impair NCC biogenesis failed to escape ERAD as efficiently as the wild type protein when cells were incubated at a lower temperature. Instead, these mutants interacted more strongly with Hsp70, Hsp40, and CHIP, consistent with a role for the Hsp70/Hsp40 system in selecting misfolded NCC for ERAD. Collectively, these observations indicate that Hsp70 and Hsp90 comprise two functionally distinct ER quality control checkpoints that sequentially monitor NCC biogenesis. PMID:23482560

Teacher-implemented joint attention intervention: pilot randomized controlled study for preschoolers with autism.

PubMed

Lawton, Kathy; Kasari, Connie

2012-08-01

The vast majority of children with an autism spectrum disorder (ASD) attend public preschools at some point in their childhood. Community preschool practices often are not evidence based, and almost none target the prelinguistic core deficits of ASD. This study investigated the effectiveness of public preschool teachers implementing a validated intervention (the Joint Attention and Symbolic Play/Engagement and Regulation intervention; JASP/ER) on a core deficit of autism, initiating joint attention. Sixteen dyads (preschoolers with ASD and the public school teachers who worked in the child's classroom) were randomly assigned to the 6-week JASP/ER intervention or a control group. At the end of the intervention, JASP/ER teachers used more JASP/ER strategies than the control teachers, and JASP/ER preschoolers used more joint attention in their classroom than control children. Additionally, JASP/ER children spent more time in supported engagement and less time in object engagement than control preschoolers on a taped play interaction. Findings suggest that teachers were able to improve a core deficit of children with ASD in a public preschool context. © 2012 American Psychological Association

From the endoplasmic reticulum to the plasma membrane: mechanisms of CFTR folding and trafficking.

PubMed

Farinha, Carlos M; Canato, Sara

2017-01-01

CFTR biogenesis starts with its co-translational insertion into the membrane of endoplasmic reticulum and folding of the cytosolic domains, towards the acquisition of a fully folded compact native structure. Efficiency of this process is assessed by the ER quality control system that allows the exit of folded proteins but targets unfolded/misfolded CFTR to degradation. If allowed to leave the ER, CFTR is modified at the Golgi and reaches the post-Golgi compartments to be delivered to the plasma membrane where it functions as a cAMP- and phosphorylation-regulated chloride/bicarbonate channel. CFTR residence at the membrane is a balance of membrane delivery, endocytosis, and recycling. Several adaptors, motor, and scaffold proteins contribute to the regulation of CFTR stability and are involved in continuously assessing its structure through peripheral quality control systems. Regulation of CFTR biogenesis and traffic (and its dysregulation by mutations, such as the most common F508del) determine its overall activity and thus contribute to the fine modulation of chloride secretion and hydration of epithelial surfaces. This review covers old and recent knowledge on CFTR folding and trafficking from its synthesis to the regulation of its stability at the plasma membrane and highlights how several of these steps can be modulated to promote the rescue of mutant CFTR.

Effect of transitioning from extended-release methylphenidate onto osmotic, controlled-release methylphenidate in children/adolescents with ADHD: results of a 3-month non-interventional study.

PubMed

Wolff, Christian; Alfred, Adam; Lindermüller, Anton; Rettig, Klaus; Mattejat, Fritz; Gerwe, Martin; Slawik, Lara; Schäuble, Barbara

2011-01-01

To explore the clinical outcomes of children/adolescents with ADHD who transitioned from extended-release methylphenidate (ER MPH, Medikinet Retard) to osmotic release oral system (OROS) MPH (Concerta). Medikinet Retard is a registered trade name of Medice, Bad Iserlohn, Germany. Concerta is a registered trade name of Janssen-Cilag GmbH, Neuss, Germany. This prospective, non-interventional study included patients aged 6 to 18 years with a confirmed diagnosis of ADHD who experienced insufficient clinical response and/or poor tolerability on ER MPH. Patients transitioned onto OROS MPH and were followed for 12 weeks. Symptoms, functional outcome, health-related quality of life, safety and tolerability were assessed. 180 patients were included in the intention-to-treat analysis. The mean ER MPH dose before switching was 28.2 mg/day; mean OROS MPH starting dose was 38.1 mg/day, increasing to 41.2 mg/day at the final visit. Mean treatment duration was 79.49 ± 24.22 days (median 85; range 7-136). Several symptomatic and functional outcomes under OROS MPH treatment changed from baseline and included the Conners' Parent Rating Scale (CPRS; -11.7 ± 11.3; p < 0.0001), C-GAS (12.3 ± 15.2; p < 0.0001) and ILC-LQ0-28 (parents' rating 2.9 ± 4.3 and patients' rating 2.8 ± 3.8; both p < 0.0001). Improvements in social interactions, playing with other children, doing household chores, or school homework, going to bed, and behavior towards visitors/at visits were noted (p < 0.0001). Approximately 40% of patients reported better sleep quality and appetite (p < 0.0001), and 72.8% expressed satisfaction with OROS MPH therapy compared to previous ER MPH. OROS MPH was well tolerated; the most common AEs after switching, with an incidence >2% and possibly related to therapy, were involuntary muscle contractions (tics; 8.9%), insomnia (7.2%) and anorexia (5.0%). No relevant changes in body weight or vital signs were observed. Three patients reported four serious AEs, but none were considered related to OROS MPH. Limitations included those associated with the uncontrolled, open-label design, possible inclusion bias and non-validation of the CPRS in a German population. Transitioning onto OROS MPH improved functionality, symptom control and decreased burden of disease in patients with ADHD who had insufficient response to, and/or poor tolerability of ER MPH. Similarly, care givers benefited from patients' treatment and reported significant reduction in their burden of disease and improvement of their quality of life upon the child's transition onto OROS MPH.

Mixed methods evaluation of a randomized control pilot trial targeting sugar-sweetened beverage behaviors.

PubMed

Zoellner, Jamie; Cook, Emily; Chen, Yvonnes; You, Wen; Davy, Brenda; Estabrooks, Paul

2013-02-01

This Excessive sugar-sweetened beverage (SSB) consumption and low health literacy skills have emerged as two public health concerns in the United States (US); however, there is limited research on how to effectively address these issues among adults. As guided by health literacy concepts and the Theory of Planned Behavior (TPB), this randomized controlled pilot trial applied the RE-AIM framework and a mixed methods approach to examine a sugar-sweetened beverage (SSB) intervention (SipSmartER), as compared to a matched-contact control intervention targeting physical activity (MoveMore). Both 5-week interventions included two interactive group sessions and three support telephone calls. Executing a patient-centered developmental process, the primary aim of this paper was to evaluate patient feedback on intervention content and structure. The secondary aim was to understand the potential reach (i.e., proportion enrolled, representativeness) and effectiveness (i.e. health behaviors, theorized mediating variables, quality of life) of SipSmartER. Twenty-five participants were randomized to SipSmartER (n=14) or MoveMore (n=11). Participants' intervention feedback was positive, ranging from 4.2-5.0 on a 5-point scale. Qualitative assessments reavealed several opportunties to improve clarity of learning materials, enhance instructions and communication, and refine research protocols. Although SSB consumption decreased more among the SipSmartER participants (-256.9 ± 622.6 kcals), there were no significant group differences when compared to control participants (-199.7 ± 404.6 kcals). Across both groups, there were significant improvements for SSB attitudes, SSB behavioral intentions, and two media literacy constructs. The value of using a patient-centered approach in the developmental phases of this intervention was apparent, and pilot findings suggest decreased SSB may be achieved through targeted health literacy and TPB strategies. Future efforts are needed to examine the potential public health impact of a large-scale trial to address health literacy and reduce SSB.

Ce3+/Yb3+/Er3+ triply doped bismuth borosilicate glass: a potential fiber material for broadband near-infrared fiber amplifiers

PubMed Central

Chu, Yushi; Ren, Jing; Zhang, Jianzhong; Peng, Gangding; Yang, Jun; Wang, Pengfei; Yuan, Libo

2016-01-01

Erbium doped bismuth borosilicate (BBS) glasses, possessing the broadest 1.55 μm near infrared (NIR) emission band among oxide glasses, stand out as excellent fiber material for optical fiber amplifiers. In this work, we demonstrate that both broadened and enhanced NIR emission of Er3+ can be obtained by sensibly combining the effects such as mixed glass former effect, phonon-assisted energy transfer (PAET) and de-excitation effect induced by codopant. Specially, by codoping CeO2 in a controlled manner, it leads to not only much improved optical quality of the glasses, enhanced NIR emission, but also significantly suppressed energy transfer up-conversion (ETU) luminescence which is detrimental to the NIR emission. Cerium incorporated in the glasses exists overwhelmingly as the trivalent oxidation state Ce3+ and its effects on the luminescence properties of Er3+ are discussed. Judd-Ofelt analysis is used to evaluate gain amplification of the glasses. The result indicates that Ce3+/Yb3+/Er3+ triply doped BBS glasses are promising candidate for erbium doped fiber amplifiers. The strategy described here can be readily extended to other rare-earth ions (REs) to improve the performance of REs doped fiber lasers and amplifiers. PMID:27646191

Estrogen receptor positivity in mammary tumors of Wnt-1 transgenic mice is influenced by collaborating oncogenic mutations.

PubMed

Zhang, Xiaomei; Podsypanina, Katrina; Huang, Shixia; Mohsin, Syed K; Chamness, Gary C; Hatsell, Sarah; Cowin, Pam; Schiff, Rachel; Li, Yi

2005-06-16

The majority (75%) of human breast cancers express estrogen receptor (ER). Although ER-positive tumors usually respond to antiestrogen therapies, 30% of them do not. It is not known what controls the ER status of breast cancers or their responsiveness to antihormone interventions. In this report, we document that transgenic (TG) expression of Wnt-1 in mice induces ER-positive tumors. Loss of Pten or gain of Ras mutations during the evolution of tumors in Wnt-1 TG mice has no effect on the expression of ER, but overexpression of Neu or loss of p53 leads to ER-negative tumors. Thus, our results provide compelling evidence that expression of ER in breast cancer may be influenced by specific genetic changes that promote cancer progression. These findings constitute a first step to explore the molecular mechanisms leading to ER-positive or ER-negative mammary tumors. In addition, we find that ER-positive tumors arising in Wnt-1 TG mice are refractory to both ovariectomy and the ER antagonist tamoxifen, but lose ER expression with tamoxifen, suggesting that antiestrogen selects for ER-negative tumor cells and that the ER-positive cell fraction is dispensable for growth of these tumors. This is a first report of a mouse model of antiestrogen-resistant ER-positive breast cancers, and could provide a powerful tool to study the molecular mechanisms that control antiestrogen resistance.

N-glycan based ER molecular chaperone and protein quality control system: the calnexin binding cycle

PubMed Central

Lamriben, Lydia; Graham, Jill B.; Adams, Benjamin M.; Hebert, Daniel N.

2015-01-01

Helenius and colleagues proposed over twenty-years ago a paradigm-shifting model for how chaperone binding in the endoplasmic reticulum was mediated and controlled for a new type of molecular chaperone- the carbohydrate binding chaperones, calnexin and calreticulin. While the originally established basics for this lectin chaperone binding cycle holds true today, there has been a number of important advances that have expanded our understanding of its mechanisms of action, role in protein homeostasis, and its connection to disease states that are highlighted in this review. PMID:26676362

Role of asymmetric cell division in lifespan control in Saccharomyces cerevisiae

PubMed Central

Higuchi-Sanabria, Ryo; Pernice, Wolfgang M A; Vevea, Jason D; Alessi Wolken, Dana M; Boldogh, Istvan R; Pon, Liza A

2014-01-01

Aging determinants are asymmetrically distributed during cell division in S. cerevisiae, which leads to production of an immaculate, age-free daughter cell. During this process, damaged components are sequestered and retained in the mother cell, and higher functioning organelles and rejuvenating factors are transported to and/or enriched in the bud. Here, we will describe the key quality control mechanisms in budding yeast that contribute to asymmetric cell division of aging determinants including mitochondria, endoplasmic reticulum (ER), vacuoles, extrachromosomal rDNA circles (ERCs), and protein aggregates. PMID:25263578

Characteristics of an electro-rheological fluid valve used in an inkjet printhead

NASA Astrophysics Data System (ADS)

Lee, C. Y.; Liao, W. C.

2000-12-01

The demand for non-impact printers has grown considerably with the advent of personal computers. For entry-level mass production, two drop-on-demand techniques have dominated the market - piezoelectric impulse and thermal-bubble types. However, the high cost of the piezoelectric printhead and the thermal problems encountered by the thermal-bubble jet printhead have restrained the use of these techniques in an array-type printhead. In this study, we propose a new design of printhead with an electro-rheological (ER) fluid acting as a control medium. The ER fluid valve controls the ink ejection. As a first step toward developing this new printhead, the characteristics of an ER fluid valve which controls the deflection of the elastic diaphragm are investigated. First, the response of a prototype is tested experimentally to prove the feasibility of using this ER valve for the inkjet printhead. Then, the discretized governing equation of the ER valve is derived. Finally, the prototype of the ER valve is fabricated. The experimental measurement based on the sinusoidal response verifies both the theoretical analysis and the controllability of the response of the ER valve by the applied electric field.

TMBIM3/GRINA is a novel unfolded protein response (UPR) target gene that controls apoptosis through the modulation of ER calcium homeostasis

PubMed Central

Rojas-Rivera, D; Armisén, R; Colombo, A; Martínez, G; Eguiguren, A L; Díaz, A; Kiviluoto, S; Rodríguez, D; Patron, M; Rizzuto, R; Bultynck, G; Concha, M L; Sierralta, J; Stutzin, A; Hetz, C

2012-01-01

Transmembrane BAX inhibitor motif-containing (TMBIM)-6, also known as BAX-inhibitor 1 (BI-1), is an anti-apoptotic protein that belongs to a putative family of highly conserved and poorly characterized genes. Here we report the function of TMBIM3/GRINA in the control of cell death by endoplasmic reticulum (ER) stress. Tmbim3 mRNA levels are strongly upregulated in cellular and animal models of ER stress, controlled by the PERK signaling branch of the unfolded protein response. TMBIM3/GRINA synergies with TMBIM6/BI-1 in the modulation of ER calcium homeostasis and apoptosis, associated with physical interactions with inositol trisphosphate receptors. Loss-of-function studies in D. melanogaster demonstrated that TMBIM3/GRINA and TMBIM6/BI-1 have synergistic activities against ER stress in vivo. Similarly, manipulation of TMBIM3/GRINA levels in zebrafish embryos revealed an essential role in the control of apoptosis during neuronal development and in experimental models of ER stress. These findings suggest the existence of a conserved group of functionally related cell death regulators across species beyond the BCL-2 family of proteins operating at the ER membrane. PMID:22240901

TMBIM3/GRINA is a novel unfolded protein response (UPR) target gene that controls apoptosis through the modulation of ER calcium homeostasis.

PubMed

Rojas-Rivera, D; Armisén, R; Colombo, A; Martínez, G; Eguiguren, A L; Díaz, A; Kiviluoto, S; Rodríguez, D; Patron, M; Rizzuto, R; Bultynck, G; Concha, M L; Sierralta, J; Stutzin, A; Hetz, C

2012-06-01

Transmembrane BAX inhibitor motif-containing (TMBIM)-6, also known as BAX-inhibitor 1 (BI-1), is an anti-apoptotic protein that belongs to a putative family of highly conserved and poorly characterized genes. Here we report the function of TMBIM3/GRINA in the control of cell death by endoplasmic reticulum (ER) stress. Tmbim3 mRNA levels are strongly upregulated in cellular and animal models of ER stress, controlled by the PERK signaling branch of the unfolded protein response. TMBIM3/GRINA synergies with TMBIM6/BI-1 in the modulation of ER calcium homeostasis and apoptosis, associated with physical interactions with inositol trisphosphate receptors. Loss-of-function studies in D. melanogaster demonstrated that TMBIM3/GRINA and TMBIM6/BI-1 have synergistic activities against ER stress in vivo. Similarly, manipulation of TMBIM3/GRINA levels in zebrafish embryos revealed an essential role in the control of apoptosis during neuronal development and in experimental models of ER stress. These findings suggest the existence of a conserved group of functionally related cell death regulators across species beyond the BCL-2 family of proteins operating at the ER membrane.

Enhanced recovery clinical education programme improves quality of post-operative care

PubMed Central

McDonald, Ruth

2015-01-01

Quality is the driving principle of Enhanced Recovery (ER). It improves the patient experience by getting patients better sooner and changes clinical practice to make care safer and more efficient. As a consequence of ER patients spend less time in hospital. A successful ER programme began to fail after organisational restructuring and staff changes. Patients did not meet their ER goals and length of stay (LOS) increased. An ER nurse was appointed to get the programme back on track. This involved a multidisciplinary approach to an ER clinical education programme. The programme aimed to develop knowledge of the physiology of post-operative recovery and the evidence underpinning the interventions required. This was considered crucial to secure longer term staff engagement while avoiding unthinking protocol driven compliance. Success of the education programme was measured by improved outcomes in patient LOS and readmission statistics. During the four months of the clinical education programme there were no significant changes in monthly LOS. At six months post implementation of the programme there was a reduction in LOS of 0.6 days compared to the previous six months. At 12 months there was a reduction in 1.1 days compared with previous 12 months. There was a mean reduction of 28 day readmissions for all elective gynaecology surgery of 1.1 patients per month in the 12 months post programme implementation compared to the 12 months before. Delivering a multidisciplinary participatory education programme improved overall understanding of ER, and achieved sustained improvement in ER for patient benefit. PMID:26734343

Evaluation of the bactericidal effect of Nd:YAG, Er:YAG, Er,Cr:YSGG laser radiation, and antimicrobial photodynamic therapy (aPDT) in experimentally infected root canals.

PubMed

Cheng, Xiaogang; Guan, Sumin; Lu, Hong; Zhao, Chunmiao; Chen, Xingxing; Li, Na; Bai, Qian; Tian, Yu; Yu, Qing

2012-12-01

In recent years, various laser systems have been introduced into the field of laser-assisted endodontic therapy. The aim of this study was to evaluate the bactericidal effect of Nd:YAG, Er:YAG, Er,Cr:YSGG laser radiation, and antimicrobial photodynamic therapy (aPDT) in experimentally infected root canals compared with standard endodontic treatment of 5.25% sodium hypochlorite (NaClO) irrigation. Two hundred and twenty infected root canals from extracted human teeth (contaminated with Enterococcus faecalis ATCC 4083 for 4 weeks) were randomly divided into five experimental groups (Nd:YAG, Er:YAG + 5.25% NaClO + 0.9% normal saline + distilled water (Er:YAG/NaClO/NS/DW), Er:YAG + 0.9% normal saline + distilled water (Er:YAG/NS/DW), Er,Cr:YSGG, and aPDT) and two control groups (5.25% NaClO as positive control and 0.9% normal saline (NS) as negative control). The numbers of bacteria on the surface of root canal walls and at different depths inside dentinal tubules before and after treatment were analyzed by means of one-way analysis of variance (one-way ANOVA). The morphology of bacterial cells before and after treatment was examined by scanning electron microscopy (SEM). After treatment, the bacterial reductions in the experimental groups and the positive control group were significantly greater than that of the negative control group (P < 0.001). However, only Er:YAG/NaClO/NS/DW group showed no bacterial growth (the bacterial reduction reached up to 100%) on the surface of root canal walls or at 100/200 µm inside the dentinal tubules. All the laser radiation protocols tested, especially Er:YAG/NaClO/NS/DW, have effective bactericidal effect in experimentally infected root canals. Er:YAG/NaClO/NS/DW seems to be an ideal protocol for root canal disinfection during endodontic therapy. Copyright © 2012 Wiley Periodicals, Inc.

REFERQUAL: a pilot study of a new service quality assessment instrument in the GP exercise referral scheme setting

PubMed Central

Cock, Don; Adams, Iain C; Ibbetson, Adrian B; Baugh, Phil

2006-01-01

Background The development of an instrument accurately assessing service quality in the GP Exercise Referral Scheme (ERS) industry could potentially inform scheme organisers of the factors that affect adherence rates leading to the implementation of strategic interventions aimed at reducing client drop-out. Methods A modified version of the SERVQUAL instrument was designed for use in the ERS setting and subsequently piloted amongst 27 ERS clients. Results Test re-test correlations were calculated via Pearson's 'r' or Spearman's 'rho', depending on whether the variables were Normally Distributed, to show a significant (mean r = 0.957, SD = 0.02, p < 0.05; mean rho = 0.934, SD = 0.03, p < 0.05) relationship between all items within the questionnaire. In addition, satisfactory internal consistency was demonstrated via Cronbach's 'α'. Furthermore, clients responded favourably towards the usability, wording and applicability of the instrument's items. Conclusion REFERQUAL is considered to represent promise as a suitable tool for future evaluation of service quality within the ERS community. Future research should further assess the validity and reliability of this instrument through the use of a confirmatory factor analysis to scrutinise the proposed dimensional structure. PMID:16725021

Evaluation of sleep profile in schizophrenia patients treated with extended-release paliperidone: an open-label prospective study in Southeast Asia.

PubMed

Kongsakon, Ronnachai; Thavichachart, Nuntika; Chung, Ka Fai; Lim, Leslie; Azucena, Beverly; Rondain, Elizabeth; Go, Benson; Costales, Fe; Nerapusee, Osot

2017-01-01

To evaluate the effect of 6 months of treatment with paliperidone extended-release (ER) tablets on the sleep profile of patients with schizophrenia. A total of 984 patients meeting the The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for schizophrenia who switched their antipsychotic to paliperidone ER were recruited from 61 sites in five countries in Southeast Asia. We recorded patient demographics and assessed sleep quality and daytime drowsiness using visual analog scales. Approximately 70% of patients completed the 6-month study. After the use of paliperidone ER, patients reported significantly better sleep quality (76.44 vs 65.48; p <0.001) and less daytime drowsiness compared with their baseline value (23.18 vs 34.22; p <0.001). Factors predicting sleep profile improvement were completion of the study and higher baseline Positive and Negative Syndrome Scale scores. Paliperidone ER can help schizophrenia patients to improve sleep quality and reduce daytime drowsiness; this was seen especially in the patients who completed the 6-month treatment period and had higher baseline Positive and Negative Syndrome Scale scores.

Evaluation of sleep profile in schizophrenia patients treated with extended-release paliperidone: an open-label prospective study in Southeast Asia

PubMed Central

Kongsakon, Ronnachai; Thavichachart, Nuntika; Chung, Ka Fai; Lim, Leslie; Azucena, Beverly; Rondain, Elizabeth; Go, Benson; Costales, Fe; Nerapusee, Osot

2017-01-01

Objective To evaluate the effect of 6 months of treatment with paliperidone extended-release (ER) tablets on the sleep profile of patients with schizophrenia. Methods A total of 984 patients meeting the The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for schizophrenia who switched their antipsychotic to paliperidone ER were recruited from 61 sites in five countries in Southeast Asia. We recorded patient demographics and assessed sleep quality and daytime drowsiness using visual analog scales. Results Approximately 70% of patients completed the 6-month study. After the use of paliperidone ER, patients reported significantly better sleep quality (76.44 vs 65.48; p<0.001) and less daytime drowsiness compared with their baseline value (23.18 vs 34.22; p<0.001). Factors predicting sleep profile improvement were completion of the study and higher baseline Positive and Negative Syndrome Scale scores. Conclusion Paliperidone ER can help schizophrenia patients to improve sleep quality and reduce daytime drowsiness; this was seen especially in the patients who completed the 6-month treatment period and had higher baseline Positive and Negative Syndrome Scale scores. PMID:29138607

Hip and ankle range of motion and hip muscle strength in young female ballet dancersand controls

PubMed Central

Bennell, K.; Khan, K. M.; Matthews, B.; De Gruyter, M.; Cook, E.; Holzer, K.; Wark, J. D.

1999-01-01

OBJECTIVES: To compare the hip and ankle range of motion and hip muscle strength in 8-11 year old novice female ballet dancers and controls. METHODS: Subjects were 77 dancers and 49 controls (mean (SD) age 9.6 (0.8) and 9.6 (0.7) years respectively). Supine right active hip external rotation (ER) and internal rotation (IR) were measured using an inclinometer. A turnout protractor was used to assess standing active turnout range. The measure of ER achieved from below the hip during turnout (non-hip ER) was calculated by subtracting hip ER range from turnout range, and hip ER:IR was derived by dividing ER range by IR range. Range of right weight bearing ankle dorsiflexion was measured in a standing lunge using two methods: the distance from the foot to the wall (in centimetres) and the angle of the shank to the vertical via an inclinometer (in degrees). Right calf muscle range was measured in weight bearing using an inclinometer. A manual muscle tester was used to assess right isometric hip flexor, internal rotator, external rotator, abductor, and adductor strength. RESULTS: Dancers had less ER (p<0.05) and IR (p<0.01) range than controls but greater ER:IR (p<0.01). Although there was no difference in turnout between groups, the dancers had greater non-hip ER. Dancers had greater range of ankle dorsiflexion than controls, measured in both centimetres (p<0.01) and degrees (p<0.05), but similar calf muscle range. After controlling for body weight, controls had stronger hip muscles than dancers except for hip abductor strength which was similar. Regression analyses disclosed a moderate relation between turnout and hip ER (r = 0.40). There were no significant correlations between range of motion and training years and weekly training hours. CONCLUSIONS: Longitudinal follow up will assist in determining whether or not hip and ankle range in young dancers is genetically fixed and unable to be improved with further balletic training. 


 PMID:10522638

Eukaryotic oligosaccharyltransferase generates free oligosaccharides during N-glycosylation.

PubMed

Harada, Yoichiro; Buser, Reto; Ngwa, Elsy M; Hirayama, Hiroto; Aebi, Markus; Suzuki, Tadashi

2013-11-08

Asparagine (N)-linked glycosylation regulates numerous cellular activities, such as glycoprotein quality control, intracellular trafficking, and cell-cell communications. In eukaryotes, the glycosylation reaction is catalyzed by oligosaccharyltransferase (OST), a multimembrane protein complex that is localized in the endoplasmic reticulum (ER). During N-glycosylation in the ER, the protein-unbound form of oligosaccharides (free oligosaccharides; fOSs), which is structurally related to N-glycan, is released into the ER lumen. However, the enzyme responsible for this process remains unidentified. Here, we demonstrate that eukaryotic OST generates fOSs. Biochemical and genetic analyses using mutant strains of Saccharomyces cerevisiae revealed that the generation of fOSs is tightly correlated with the N-glycosylation activity of OST. Furthermore, we present evidence that the purified OST complex can generate fOSs by hydrolyzing dolichol-linked oligosaccharide, the glycan donor substrate for N-glycosylation. The heterologous expression of a single subunit of OST from the protozoan Leishmania major in S. cerevisiae demonstrated that this enzyme functions both in N-glycosylation and generation of fOSs. This study provides insight into the mechanism of PNGase-independent formation of fOSs.

Lon in maintaining mitochondrial and endoplasmic reticulum homeostasis.

PubMed

Yang, Jieyeqi; Chen, Wenying; Zhang, Boyang; Tian, Fengli; Zhou, Zheng; Liao, Xin; Li, Chen; Zhang, Yi; Han, Yanyan; Wang, Yan; Li, Yuzhe; Wang, Guo-Qing; Shen, Xiao Li

2018-06-01

As a vital member of AAA+ (ATPase associated with diverse cellular activities) protein superfamily, Lon, a homo-hexameric ring-shaped protein complex with a serine-lysine catalytic dyad, is highly conserved throughout almost all prokaryotic and eukaryotic organisms. Lon protease (LONP) plays an important role in maintaining mitoproteostasis through selectively recognizing and degrading oxidatively modified mitoproteins within mitochondrial matrix, such as oxidized aconitase, phosphorylated mitochondrial transcription factor A, etc. Furthermore, the up-regulated LONP increased mitochondrial ROS generation to promote cell survival, cell proliferation, epithelial-mesenchymal transition, and cell migration, which was attributed to the up-regulation of NADH:ubiquinone oxidoreductase core subunit S8 via interaction with chaperone Lon under hypoxic or oxidative stress in tumorigenesis. In addition, Lon also participated in protein kinase RNA (PKR)-like endoplasmic reticulum kinase signaling pathway under endoplasmic reticulum (ER) stress. In short, Lon, as a pivotal stress-responsive protein that involved in the crosstalks among mitochondria, ER and nucleus, participated in multifarious important cellular processes crucial for cell survival, such as the mitochondrial protein quality control system, the mitochondrial unfolded protein response, the mtDNA maintenance, and the ER unfolded protein response.

Genome-wide association studies identify four ER negative-specific breast cancer risk loci.

PubMed

Garcia-Closas, Montserrat; Couch, Fergus J; Lindstrom, Sara; Michailidou, Kyriaki; Schmidt, Marjanka K; Brook, Mark N; Orr, Nick; Rhie, Suhn Kyong; Riboli, Elio; Feigelson, Heather S; Le Marchand, Loic; Buring, Julie E; Eccles, Diana; Miron, Penelope; Fasching, Peter A; Brauch, Hiltrud; Chang-Claude, Jenny; Carpenter, Jane; Godwin, Andrew K; Nevanlinna, Heli; Giles, Graham G; Cox, Angela; Hopper, John L; Bolla, Manjeet K; Wang, Qin; Dennis, Joe; Dicks, Ed; Howat, Will J; Schoof, Nils; Bojesen, Stig E; Lambrechts, Diether; Broeks, Annegien; Andrulis, Irene L; Guénel, Pascal; Burwinkel, Barbara; Sawyer, Elinor J; Hollestelle, Antoinette; Fletcher, Olivia; Winqvist, Robert; Brenner, Hermann; Mannermaa, Arto; Hamann, Ute; Meindl, Alfons; Lindblom, Annika; Zheng, Wei; Devillee, Peter; Goldberg, Mark S; Lubinski, Jan; Kristensen, Vessela; Swerdlow, Anthony; Anton-Culver, Hoda; Dörk, Thilo; Muir, Kenneth; Matsuo, Keitaro; Wu, Anna H; Radice, Paolo; Teo, Soo Hwang; Shu, Xiao-Ou; Blot, William; Kang, Daehee; Hartman, Mikael; Sangrajrang, Suleeporn; Shen, Chen-Yang; Southey, Melissa C; Park, Daniel J; Hammet, Fleur; Stone, Jennifer; Veer, Laura J Van't; Rutgers, Emiel J; Lophatananon, Artitaya; Stewart-Brown, Sarah; Siriwanarangsan, Pornthep; Peto, Julian; Schrauder, Michael G; Ekici, Arif B; Beckmann, Matthias W; Dos Santos Silva, Isabel; Johnson, Nichola; Warren, Helen; Tomlinson, Ian; Kerin, Michael J; Miller, Nicola; Marme, Federick; Schneeweiss, Andreas; Sohn, Christof; Truong, Therese; Laurent-Puig, Pierre; Kerbrat, Pierre; Nordestgaard, Børge G; Nielsen, Sune F; Flyger, Henrik; Milne, Roger L; Perez, Jose Ignacio Arias; Menéndez, Primitiva; Müller, Heiko; Arndt, Volker; Stegmaier, Christa; Lichtner, Peter; Lochmann, Magdalena; Justenhoven, Christina; Ko, Yon-Dschun; Muranen, Taru A; Aittomäki, Kristiina; Blomqvist, Carl; Greco, Dario; Heikkinen, Tuomas; Ito, Hidemi; Iwata, Hiroji; Yatabe, Yasushi; Antonenkova, Natalia N; Margolin, Sara; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M; Balleine, Rosemary; Tseng, Chiu-Chen; Berg, David Van Den; Stram, Daniel O; Neven, Patrick; Dieudonné, Anne-Sophie; Leunen, Karin; Rudolph, Anja; Nickels, Stefan; Flesch-Janys, Dieter; Peterlongo, Paolo; Peissel, Bernard; Bernard, Loris; Olson, Janet E; Wang, Xianshu; Stevens, Kristen; Severi, Gianluca; Baglietto, Laura; McLean, Catriona; Coetzee, Gerhard A; Feng, Ye; Henderson, Brian E; Schumacher, Fredrick; Bogdanova, Natalia V; Labrèche, France; Dumont, Martine; Yip, Cheng Har; Taib, Nur Aishah Mohd; Cheng, Ching-Yu; Shrubsole, Martha; Long, Jirong; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Kauppila, Saila; Knight, Julia A; Glendon, Gord; Mulligan, Anna Marie; Tollenaar, Robertus A E M; Seynaeve, Caroline M; Kriege, Mieke; Hooning, Maartje J; van den Ouweland, Ans M W; van Deurzen, Carolien H M; Lu, Wei; Gao, Yu-Tang; Cai, Hui; Balasubramanian, Sabapathy P; Cross, Simon S; Reed, Malcolm W R; Signorello, Lisa; Cai, Qiuyin; Shah, Mitul; Miao, Hui; Chan, Ching Wan; Chia, Kee Seng; Jakubowska, Anna; Jaworska, Katarzyna; Durda, Katarzyna; Hsiung, Chia-Ni; Wu, Pei-Ei; Yu, Jyh-Cherng; Ashworth, Alan; Jones, Michael; Tessier, Daniel C; González-Neira, Anna; Pita, Guillermo; Alonso, M Rosario; Vincent, Daniel; Bacot, Francois; Ambrosone, Christine B; Bandera, Elisa V; John, Esther M; Chen, Gary K; Hu, Jennifer J; Rodriguez-Gil, Jorge L; Bernstein, Leslie; Press, Michael F; Ziegler, Regina G; Millikan, Robert M; Deming-Halverson, Sandra L; Nyante, Sarah; Ingles, Sue A; Waisfisz, Quinten; Tsimiklis, Helen; Makalic, Enes; Schmidt, Daniel; Bui, Minh; Gibson, Lorna; Müller-Myhsok, Bertram; Schmutzler, Rita K; Hein, Rebecca; Dahmen, Norbert; Beckmann, Lars; Aaltonen, Kirsimari; Czene, Kamila; Irwanto, Astrid; Liu, Jianjun; Turnbull, Clare; Rahman, Nazneen; Meijers-Heijboer, Hanne; Uitterlinden, Andre G; Rivadeneira, Fernando; Olswold, Curtis; Slager, Susan; Pilarski, Robert; Ademuyiwa, Foluso; Konstantopoulou, Irene; Martin, Nicholas G; Montgomery, Grant W; Slamon, Dennis J; Rauh, Claudia; Lux, Michael P; Jud, Sebastian M; Bruning, Thomas; Weaver, Joellen; Sharma, Priyanka; Pathak, Harsh; Tapper, Will; Gerty, Sue; Durcan, Lorraine; Trichopoulos, Dimitrios; Tumino, Rosario; Peeters, Petra H; Kaaks, Rudolf; Campa, Daniele; Canzian, Federico; Weiderpass, Elisabete; Johansson, Mattias; Khaw, Kay-Tee; Travis, Ruth; Clavel-Chapelon, Françoise; Kolonel, Laurence N; Chen, Constance; Beck, Andy; Hankinson, Susan E; Berg, Christine D; Hoover, Robert N; Lissowska, Jolanta; Figueroa, Jonine D; Chasman, Daniel I; Gaudet, Mia M; Diver, W Ryan; Willett, Walter C; Hunter, David J; Simard, Jacques; Benitez, Javier; Dunning, Alison M; Sherman, Mark E; Chenevix-Trench, Georgia; Chanock, Stephen J; Hall, Per; Pharoah, Paul D P; Vachon, Celine; Easton, Douglas F; Haiman, Christopher A; Kraft, Peter

2013-04-01

Estrogen receptor (ER)-negative tumors represent 20-30% of all breast cancers, with a higher proportion occurring in younger women and women of African ancestry. The etiology and clinical behavior of ER-negative tumors are different from those of tumors expressing ER (ER positive), including differences in genetic predisposition. To identify susceptibility loci specific to ER-negative disease, we combined in a meta-analysis 3 genome-wide association studies of 4,193 ER-negative breast cancer cases and 35,194 controls with a series of 40 follow-up studies (6,514 cases and 41,455 controls), genotyped using a custom Illumina array, iCOGS, developed by the Collaborative Oncological Gene-environment Study (COGS). SNPs at four loci, 1q32.1 (MDM4, P = 2.1 × 10(-12) and LGR6, P = 1.4 × 10(-8)), 2p24.1 (P = 4.6 × 10(-8)) and 16q12.2 (FTO, P = 4.0 × 10(-8)), were associated with ER-negative but not ER-positive breast cancer (P > 0.05). These findings provide further evidence for distinct etiological pathways associated with invasive ER-positive and ER-negative breast cancers.

Time-resolved 3D pulmonary perfusion MRI: comparison of different k-space acquisition strategies at 1.5 and 3 T.

PubMed

Attenberger, Ulrike I; Ingrisch, Michael; Dietrich, Olaf; Herrmann, Karin; Nikolaou, Konstantin; Reiser, Maximilian F; Schönberg, Stefan O; Fink, Christian

2009-09-01

Time-resolved pulmonary perfusion MRI requires both high temporal and spatial resolution, which can be achieved by using several nonconventional k-space acquisition techniques. The aim of this study is to compare the image quality of time-resolved 3D pulmonary perfusion MRI with different k-space acquisition techniques in healthy volunteers at 1.5 and 3 T. Ten healthy volunteers underwent contrast-enhanced time-resolved 3D pulmonary MRI on 1.5 and 3 T using the following k-space acquisition techniques: (a) generalized autocalibrating partial parallel acquisition (GRAPPA) with an internal acquisition of reference lines (IRS), (b) GRAPPA with a single "external" acquisition of reference lines (ERS) before the measurement, and (c) a combination of GRAPPA with an internal acquisition of reference lines and view sharing (VS). The spatial resolution was kept constant at both field strengths to exclusively evaluate the influences of the temporal resolution achieved with the different k-space sampling techniques on image quality. The temporal resolutions were 2.11 seconds IRS, 1.31 seconds ERS, and 1.07 VS at 1.5 T and 2.04 seconds IRS, 1.30 seconds ERS, and 1.19 seconds VS at 3 T.Image quality was rated by 2 independent radiologists with regard to signal intensity, perfusion homogeneity, artifacts (eg, wrap around, noise), and visualization of pulmonary vessels using a 3 point scale (1 = nondiagnostic, 2 = moderate, 3 = good). Furthermore, the signal-to-noise ratio in the lungs was assessed. At 1.5 T the lowest image quality (sum score: 154) was observed for the ERS technique and the highest quality for the VS technique (sum score: 201). In contrast, at 3 T images acquired with VS were hampered by strong artifacts and image quality was rated significantly inferior (sum score: 137) compared with IRS (sum score: 180) and ERS (sum score: 174). Comparing 1.5 and 3 T, in particular the overall rating of the IRS technique (sum score: 180) was very similar at both field strengths. At 1.5 T the peak signal-to-noise ratio of the ERS was significantly lower in comparison to the IRS and the VS technique (14.6 vs. 26.7 and 39.6 respectively, P < 0.004). Using the IRS sampling algorithm comparable image quality and SNR can be achieved at 1.5 and 3 T. At 1.5 T VS offers the best possible solution for the conflicting requirements between a further increased temporal resolution and image quality. In consequence the gain of increased scanning efficiency from advanced k[r]-space sampling acquisition techniques can be exploited for a further improvement of image quality of pulmonary perfusion MRI.

Specific emotion regulation impairments in major depression and anorexia nervosa.

PubMed

Brockmeyer, Timo; Bents, Hinrich; Holtforth, Martin Grosse; Pfeiffer, Nils; Herzog, Wolfgang; Friederich, Hans-Christoph

2012-12-30

Emotion regulation (ER) difficulties have been considered to play an important role in the development and maintenance of various mental disorders such as depression and anorexia nervosa. However, previous research has failed to provide detailed insight into the disorder-specificity of ER difficulties. Therefore, the present study investigated specific ER difficulties in female samples of patients with major depression, patients with anorexia nervosa, and healthy controls (total sample: N=140). As compared to healthy controls, both clinical groups reported greater ER difficulties concerning both the experience and the differentiation as well as the attenuation and the modulation of emotions. Patients in both clinical groups reported comparably elevated ER difficulties regarding the experience and differentiation of emotions. However, depressed patients reported stronger ER difficulties regarding the attenuation and modulation of emotions as compared to patients with anorexia nervosa. These findings support the notion of ER difficulties as transdiagnostic phenomena, and suggest that depression may be characterized by broader and greater ER difficulties than anorexia nervosa. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Role of ER Export Signals in Controlling Surface Potassium Channel Numbers

NASA Astrophysics Data System (ADS)

Ma, Dzwokai; Zerangue, Noa; Lin, Yu-Fung; Collins, Anthony; Yu, Mei; Jan, Yuh Nung; Yeh Jan, Lily

2001-01-01

Little is known about the identity of endoplasmic reticulum (ER) export signals and how they are used to regulate the number of proteins on the cell surface. Here, we describe two ER export signals that profoundly altered the steady-state distribution of potassium channels and were required for channel localization to the plasma membrane. When transferred to other potassium channels or a G protein-coupled receptor, these ER export signals increased the number of functional proteins on the cell surface. Thus, ER export of membrane proteins is not necessarily limited by folding or assembly, but may be under the control of specific export signals.

Venlafaxine ER for the Treatment of Pediatric Subjects with Depression: Results of Two Placebo-Controlled Trials

ERIC Educational Resources Information Center

Emslie, Graham J.; Findling, Robert L.; Yeung, Paul P.; Kunz, Nadia R.; Li, Yunfeng

2007-01-01

Objective: The safety, efficacy, and tolerability of venlafaxine extended release (ER) in subjects ages 7 to 17 years with major depressive disorder were evaluated in two multicenter, randomized, double-blind, placebo-controlled trials conducted between October 1997 and August 2001. Method: Participants received venlafaxine ER (flexible dose,…

Genome-wide association studies identify four ER negative–specific breast cancer risk loci

PubMed Central

Garcia-Closas, Montserrat; Couch, Fergus J; Lindstrom, Sara; Michailidou, Kyriaki; Schmidt, Marjanka K; Brook, Mark N; orr, Nick; Rhie, Suhn Kyong; Riboli, Elio; Feigelson, Heather s; Le Marchand, Loic; Buring, Julie E; Eccles, Diana; Miron, Penelope; Fasching, Peter A; Brauch, Hiltrud; Chang-Claude, Jenny; Carpenter, Jane; Godwin, Andrew K; Nevanlinna, Heli; Giles, Graham G; Cox, Angela; Hopper, John L; Bolla, Manjeet K; Wang, Qin; Dennis, Joe; Dicks, Ed; Howat, Will J; Schoof, Nils; Bojesen, Stig E; Lambrechts, Diether; Broeks, Annegien; Andrulis, Irene L; Guénel, Pascal; Burwinkel, Barbara; Sawyer, Elinor J; Hollestelle, Antoinette; Fletcher, Olivia; Winqvist, Robert; Brenner, Hermann; Mannermaa, Arto; Hamann, Ute; Meindl, Alfons; Lindblom, Annika; Zheng, Wei; Devillee, Peter; Goldberg, Mark S; Lubinski, Jan; Kristensen, Vessela; Swerdlow, Anthony; Anton-Culver, Hoda; Dörk, Thilo; Muir, Kenneth; Matsuo, Keitaro; Wu, Anna H; Radice, Paolo; Teo, Soo Hwang; Shu, Xiao-Ou; Blot, William; Kang, Daehee; Hartman, Mikael; Sangrajrang, Suleeporn; Shen, Chen-Yang; Southey, Melissa C; Park, Daniel J; Hammet, Fleur; Stone, Jennifer; Veer, Laura J Van’t; Rutgers, Emiel J; Lophatananon, Artitaya; Stewart-Brown, Sarah; Siriwanarangsan, Pornthep; Peto, Julian; Schrauder, Michael G; Ekici, Arif B; Beckmann, Matthias W; Silva, Isabel dos Santos; Johnson, Nichola; Warren, Helen; Tomlinson, Ian; Kerin, Michael J; Miller, Nicola; Marme, Federick; Schneeweiss, Andreas; Sohn, Christof; Truong, Therese; Laurent-Puig, Pierre; Kerbrat, Pierre; Nordestgaard, Børge G; Nielsen, Sune F; Flyger, Henrik; Milne, Roger L; Perez, Jose Ignacio Arias; Menéndez, Primitiva; Müller, Heiko; Arndt, Volker; Stegmaier, Christa; Lichtner, Peter; Lochmann, Magdalena; Justenhoven, Christina; Ko, Yon-Dschun; Muranen, Taru A; Aittomäki, Kristiina; Blomqvist, Carl; Greco, Dario; Heikkinen, Tuomas; Ito, Hidemi; Iwata, Hiroji; Yatabe, Yasushi; Antonenkova, Natalia N; Margolin, Sara; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M; Balleine, Rosemary; Tseng, Chiu-Chen; Van Den Berg, David; Stram, Daniel O; Neven, Patrick; Dieudonné, Anne-Sophie; Leunen, Karin; Rudolph, Anja; Nickels, Stefan; Flesch-Janys, Dieter; Peterlongo, Paolo; Peissel, Bernard; Bernard, Loris; Olson, Janet E; Wang, Xianshu; Stevens, Kristen; Severi, Gianluca; Baglietto, Laura; Mclean, Catriona; Coetzee, Gerhard A; Feng, Ye; Henderson, Brian E; Schumacher, Fredrick; Bogdanova, Natalia V; Labrèche, France; Dumont, Martine; Yip, Cheng Har; Taib, Nur Aishah Mohd; Cheng, Ching-Yu; Shrubsole, Martha; Long, Jirong; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Kauppila, Saila; knight, Julia A; Glendon, Gord; Mulligan, Anna Marie; Tollenaar, Robertus A E M; Seynaeve, Caroline M; Kriege, Mieke; Hooning, Maartje J; Van den Ouweland, Ans M W; Van Deurzen, Carolien H M; Lu, Wei; Gao, Yu-Tang; Cai, Hui; Balasubramanian, Sabapathy P; Cross, Simon S; Reed, Malcolm W R; Signorello, Lisa; Cai, Qiuyin; Shah, Mitul; Miao, Hui; Chan, Ching Wan; Chia, Kee Seng; Jakubowska, Anna; Jaworska, Katarzyna; Durda, Katarzyna; Hsiung, Chia-Ni; Wu, Pei-Ei; Yu, Jyh-Cherng; Ashworth, Alan; Jones, Michael; Tessier, Daniel C; González-Neira, Anna; Pita, Guillermo; Alonso, M Rosario; Vincent, Daniel; Bacot, Francois; Ambrosone, Christine B; Bandera, Elisa V; John, Esther M; Chen, Gary K; Hu, Jennifer J; Rodriguez-gil, Jorge L; Bernstein, Leslie; Press, Michael F; Ziegler, Regina G; Millikan, Robert M; Deming-Halverson, Sandra L; Nyante, Sarah; Ingles, Sue A; Waisfisz, Quinten; Tsimiklis, Helen; Makalic, Enes; Schmidt, Daniel; Bui, Minh; Gibson, Lorna; Müller-Myhsok, Bertram; Schmutzler, Rita K; Hein, Rebecca; Dahmen, Norbert; Beckmann, Lars; Aaltonen, Kirsimari; Czene, Kamila; Irwanto, Astrid; Liu, Jianjun; Turnbull, Clare; Rahman, Nazneen; Meijers-Heijboer, Hanne; Uitterlinden, Andre G; Rivadeneira, Fernando; Olswold, Curtis; Slager, Susan; Pilarski, Robert; Ademuyiwa, Foluso; Konstantopoulou, Irene; Martin, Nicholas G; Montgomery, Grant W; Slamon, Dennis J; Rauh, Claudia; Lux, Michael P; Jud, Sebastian M; Bruning, Thomas; Weaver, Joellen; Sharma, Priyanka; Pathak, Harsh; Tapper, Will; Gerty, Sue; Durcan, Lorraine; Trichopoulos, Dimitrios; Tumino, Rosario; Peeters, Petra H; Kaaks, Rudolf; Campa, Daniele; Canzian, Federico; Weiderpass, Elisabete; Johansson, Mattias; Khaw, Kay-Tee; Travis, Ruth; Clavel-Chapelon, Françoise; Kolonel, Laurence N; Chen, Constance; Beck, Andy; Hankinson, Susan E; Berg, Christine D; Hoover, Robert N; Lissowska, Jolanta; Figueroa, Jonine D; Chasman, Daniel I; Gaudet, Mia M; Diver, W Ryan; Willett, Walter C; Hunter, David J; Simard, Jacques; Benitez, Javier; Dunning, Alison M; Sherman, Mark E; Chenevix-Trench, Georgia; Chanock, Stephen J; Hall, Per; Pharoah, Paul D P; Vachon, Celine; Easton, Douglas F; Haiman, Christopher A; Kraft, Peter

2013-01-01

Estrogen receptor (ER)-negative tumors represent 20–30% of all breast cancers, with a higher proportion occurring in younger women and women of African ancestry1. The etiology2 and clinical behavior3 of ER-negative tumors are different from those of tumors expressing ER (ER positive), including differences in genetic predisposition4. To identify susceptibility loci specific to ER-negative disease, we combined in a meta-analysis 3 genome-wide association studies of 4,193 ER-negative breast cancer cases and 35,194 controls with a series of 40 follow-up studies (6,514 cases and 41,455 controls), genotyped using a custom Illumina array, iCOGS, developed by the Collaborative Oncological Gene-environment Study (COGS). SNPs at four loci, 1q32.1 (MDM4, P = 2.1 × 10−12 and LGR6, P = 1.4 × 10−8), 2p24.1 (P = 4.6 × 10−8) and 16q12.2 (FTO, P = 4.0 × 10−8), were associated with ER-negative but not ER-positive breast cancer (P > 0.05). These findings provide further evidence for distinct etiological pathways associated with invasive ER-positive and ER-negative breast cancers. PMID:23535733

ER stress and ER stress-induced apoptosis are activated in gastric SMCs in diabetic rats

PubMed Central

Chen, Xia; Fu, Xiang-Sheng; Li, Chang-Ping; Zhao, Hong-Xian

2014-01-01

AIM: To investigate the gastric muscle injury caused by endoplasmic reticulum (ER) stress in rats with diabetic gastroparesis. METHODS: Forty rats were randomly divided into two groups: a control group and a diabetic group. Diabetes was induced by intraperitoneal injection of 60 mg/kg of streptozotocin. Gastric emptying was determined at the 4th and 12th week. The ultrastructural changes in gastric smooth muscle cells (SMCs) were investigated by transmission electron microscopy. TdT-mediated dUTP nick end labeling (TUNEL) assay was performed to assess apoptosis of SMCs. Expression of the ER stress marker, glucose-regulated protein 78 (GRP78), and the ER-specific apoptosis mediator, caspase-12 protein, was determined by immunohistochemistry. RESULTS: Gastric emptying was significantly lower in the diabetic rats than in the control rats at the 12th wk (40.71% ± 2.50%, control rats vs 54.65% ± 5.22%, diabetic rats; P < 0.05). Swollen and distended ER with an irregular shape was observed in gastric SMCs in diabetic rats. Apoptosis of gastric SMCs increased in the diabetic rats in addition to increased expression of GRP78 and caspase-12 proteins. CONCLUSION: ER stress and ER stress-mediated apoptosis are activated in gastric SMCs in diabetic rats with gastroparesis. PMID:25009401

OC30 - Fracture reduction with nitrous oxide at the children's emergency department shortens the length of stay and reduces the use of full anaesthesia in the operating department.

PubMed

Lang, Sigrid; Wentzel, Anna-Pia; Ekstrom, Malin

2016-05-09

Theme: Accreditation and quality improvement. Dislocated fractures are common in the children's emergency department (ER). All forms of fracture reduction are very painful requiring nitrous oxide. The purpose is to shorten the length of stay in the hospital as well as sustain a high quality of care. All nurses received theoretical and practical training in the use of nitrous oxide. Evaluations with the families were made by telephone. A total of 40 enclosed fracture reductions were made at the ER, leading to a reduction of 33 patients in the operating department and the length of stay was shortened - this compared to the same time in 2014. No adverse event was reported and no patient felt any increase in pain during the treatment. All patients would repeat the procedure if necessary. The treatment has reduced the length of stay in the hospital without affecting the other patients in the ER or the quality of care.

N-linked glycosylation at Asn152 on CD147 affects protein folding and stability: promoting tumour metastasis in hepatocellular carcinoma.

PubMed

Li, Jiang-Hua; Huang, Wan; Lin, Peng; Wu, Bo; Fu, Zhi-Guang; Shen, Hao-Miao; Jing, Lin; Liu, Zhen-Yu; Zhou, Yang; Meng, Yao; Xu, Bao-Qing; Chen, Zhi-Nan; Jiang, Jian-Li

2016-11-21

Cluster of differentiation 147 (CD147), also known as extracellular matrix metalloproteinase inducer, is a transmembrane glycoprotein that mediates oncogenic processes partly through N-glycosylation modifications. N-glycosylation has been demonstrated to be instrumental for the regulation of CD147 function during malignant transformation. However, the role that site-specific glycosylation of CD147 plays in its defective function in hepatocellular carcinomacells needs to be determined. Here, we demonstrate that the modification of N-glycosylation at Asn152 on CD147 strongly promotes hepatocellular carcinoma (HCC) invasion and migration. After the removal of N-glycans at Asn152, CD147 was more susceptible to degradation by ER-localized ubiquitin ligase-mediated endoplasmic reticulum-associated degradation (ERAD). Furthermore, N-linked glycans at Asn152 were required for CD147 to acquire and maintain proper folding in the ER. Moreover, N-linked glycans at Asn152 functioned as a recognition motif that was directly mediated by the CNX quality control system. Two phases in the retention-based ER chaperones system drove ER-localized CD147 trafficking to degradation. Deletion of N-linked glycosylation at Asn152 on CD147 significantly suppressed in situ tumour metastasis. These data could potentially shed light on the molecular regulation of CD147 through glycosylation and provide a valuable means of developing drugs that target N-glycans at Asn152 on CD147.

Molecular cloning, cellular expression and characterization of Arabian camel (Camelus dromedarius) endoplasmin.

PubMed

Hoter, Abdullah; Amiri, Mahdi; Warda, Mohamad; Naim, Hassan Y

2018-05-27

Endoplasmin, or GRP94, is an ER-located stress inducible molecular chaperone implicated in the folding and assembly of many proteins. The Arabian one-humped camel lives in an environment of thermal stress, nevertheless is able to encounter the risk of misfolded proteins. Here, the cDNA encoding camel GRP94 was isolated by rapid amplification of cDNA ends. The isolated cDNA contained an open reading frame of 2412 bp encoding a protein of 803 amino acids with predicted molecular mass of 92.5 kDa. Nucleotide and protein BLAST analysis of cGRP94 revealed strong conservation between camel and other domestic mammals. Overexpression of cGRP94 in COS-1 cells revealed multiple isoforms including one N-glycosylated species. Immunofluorescence colocalized cGRP94 with the ER resident protein calnexin. Interestingly, none of the cGRP94 isoforms expressed in CHO cells was N-glycosylated, presumably due to folding determinants that mask the N-glycosylation sites as proposed by in silico modelling. Surprisingly, isoforms of cGRP94 were detected in the culture media of transfected cells indicating that the protein, although an ER resident, also is trafficked and secreted into the exterior milieu. The overall striking structural homologies of GRP94s among mammalian reflects their pivotal role in the ER quality control and protein homeostasis. Copyright © 2017. Published by Elsevier B.V.

ErbB2 Trafficking and Signaling in Human Vestibular Schwannomas

DTIC Science & Technology

2008-10-01

E -Mail...R ho G D I A. B. C. D. E . ER K /R ho G D I ER K /R ho G D I pE R K/ ER K pE R K/ ER K pE R K/ ER K pE R K/ ER K pE R K/ ER K pE R K/ ER K pE R K/ ER...c on tr ol ) 0 20 40 60 80 100 Control I-JIP 30 μM I-JIP 100 μM SP60025 20 μM B rd U- po si tiv e V S ce lls (% c on tr ol ) B rd U- po si tiv e

33 CFR 236.3 - References.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 33 Navigation and Navigable Waters 3 2010-07-01 2010-07-01 false References. 236.3 Section 236.3 Navigation and Navigable Waters CORPS OF ENGINEERS, DEPARTMENT OF THE ARMY, DEPARTMENT OF DEFENSE WATER... QUALITY § 236.3 References. (a) PL 89-72 (b) ER 1105-2-10 (c) ER 1105-2-200 ...

CHARACTERISTICS OF HIGH-QUALITY DATA FOR QSARS: AN ER CASE STUDY

EPA Science Inventory

The USEPA is mandated by Congress to screen industrial chemicals and pesticides for potential endocrine activity. To evaluate this potential in fish, the affinity of chemicals for the rainbow trout estreogen receptor (rtER) is assessed. A subset of chemicals are also tested for t...

A common variant at the TERT-CLPTM1L locus is associated with estrogen receptor-negative breast cancer.

PubMed

Haiman, Christopher A; Chen, Gary K; Vachon, Celine M; Canzian, Federico; Dunning, Alison; Millikan, Robert C; Wang, Xianshu; Ademuyiwa, Foluso; Ahmed, Shahana; Ambrosone, Christine B; Baglietto, Laura; Balleine, Rosemary; Bandera, Elisa V; Beckmann, Matthias W; Berg, Christine D; Bernstein, Leslie; Blomqvist, Carl; Blot, William J; Brauch, Hiltrud; Buring, Julie E; Carey, Lisa A; Carpenter, Jane E; Chang-Claude, Jenny; Chanock, Stephen J; Chasman, Daniel I; Clarke, Christine L; Cox, Angela; Cross, Simon S; Deming, Sandra L; Diasio, Robert B; Dimopoulos, Athanasios M; Driver, W Ryan; Dünnebier, Thomas; Durcan, Lorraine; Eccles, Diana; Edlund, Christopher K; Ekici, Arif B; Fasching, Peter A; Feigelson, Heather S; Flesch-Janys, Dieter; Fostira, Florentia; Försti, Asta; Fountzilas, George; Gerty, Susan M; Giles, Graham G; Godwin, Andrew K; Goodfellow, Paul; Graham, Nikki; Greco, Dario; Hamann, Ute; Hankinson, Susan E; Hartmann, Arndt; Hein, Rebecca; Heinz, Judith; Holbrook, Andrea; Hoover, Robert N; Hu, Jennifer J; Hunter, David J; Ingles, Sue A; Irwanto, Astrid; Ivanovich, Jennifer; John, Esther M; Johnson, Nicola; Jukkola-Vuorinen, Arja; Kaaks, Rudolf; Ko, Yon-Dschun; Kolonel, Laurence N; Konstantopoulou, Irene; Kosma, Veli-Matti; Kulkarni, Swati; Lambrechts, Diether; Lee, Adam M; Marchand, Loïc Le; Lesnick, Timothy; Liu, Jianjun; Lindstrom, Sara; Mannermaa, Arto; Margolin, Sara; Martin, Nicholas G; Miron, Penelope; Montgomery, Grant W; Nevanlinna, Heli; Nickels, Stephan; Nyante, Sarah; Olswold, Curtis; Palmer, Julie; Pathak, Harsh; Pectasides, Dimitrios; Perou, Charles M; Peto, Julian; Pharoah, Paul D P; Pooler, Loreall C; Press, Michael F; Pylkäs, Katri; Rebbeck, Timothy R; Rodriguez-Gil, Jorge L; Rosenberg, Lynn; Ross, Eric; Rüdiger, Thomas; Silva, Isabel dos Santos; Sawyer, Elinor; Schmidt, Marjanka K; Schulz-Wendtland, Rüdiger; Schumacher, Fredrick; Severi, Gianluca; Sheng, Xin; Signorello, Lisa B; Sinn, Hans-Peter; Stevens, Kristen N; Southey, Melissa C; Tapper, William J; Tomlinson, Ian; Hogervorst, Frans B L; Wauters, Els; Weaver, JoEllen; Wildiers, Hans; Winqvist, Robert; Van Den Berg, David; Wan, Peggy; Xia, Lucy Y; Yannoukakos, Drakoulis; Zheng, Wei; Ziegler, Regina G; Siddiq, Afshan; Slager, Susan L; Stram, Daniel O; Easton, Douglas; Kraft, Peter; Henderson, Brian E; Couch, Fergus J

2011-10-30

Estrogen receptor (ER)-negative breast cancer shows a higher incidence in women of African ancestry compared to women of European ancestry. In search of common risk alleles for ER-negative breast cancer, we combined genome-wide association study (GWAS) data from women of African ancestry (1,004 ER-negative cases and 2,745 controls) and European ancestry (1,718 ER-negative cases and 3,670 controls), with replication testing conducted in an additional 2,292 ER-negative cases and 16,901 controls of European ancestry. We identified a common risk variant for ER-negative breast cancer at the TERT-CLPTM1L locus on chromosome 5p15 (rs10069690: per-allele odds ratio (OR) = 1.18 per allele, P = 1.0 × 10(-10)). The variant was also significantly associated with triple-negative (ER-negative, progesterone receptor (PR)-negative and human epidermal growth factor-2 (HER2)-negative) breast cancer (OR = 1.25, P = 1.1 × 10(-9)), particularly in younger women (<50 years of age) (OR = 1.48, P = 1.9 × 10(-9)). Our results identify a genetic locus associated with estrogen receptor negative breast cancer subtypes in multiple populations.

Configuration Analysis of the ERS Points in Large-Volume Metrology System

PubMed Central

Jin, Zhangjun; Yu, Cijun; Li, Jiangxiong; Ke, Yinglin

2015-01-01

In aircraft assembly, multiple laser trackers are used simultaneously to measure large-scale aircraft components. To combine the independent measurements, the transformation matrices between the laser trackers’ coordinate systems and the assembly coordinate system are calculated, by measuring the enhanced referring system (ERS) points. This article aims to understand the influence of the configuration of the ERS points that affect the transformation matrix errors, and then optimize the deployment of the ERS points to reduce the transformation matrix errors. To optimize the deployment of the ERS points, an explicit model is derived to estimate the transformation matrix errors. The estimation model is verified by the experiment implemented in the factory floor. Based on the proposed model, a group of sensitivity coefficients are derived to evaluate the quality of the configuration of the ERS points, and then several typical configurations of the ERS points are analyzed in detail with the sensitivity coefficients. Finally general guidance is established to instruct the deployment of the ERS points in the aspects of the layout, the volume size and the number of the ERS points, as well as the position and orientation of the assembly coordinate system. PMID:26402685

The quality control theory of aging.

PubMed

Ladiges, Warren

2014-01-01

The quality control (QC) theory of aging is based on the concept that aging is the result of a reduction in QC of cellular systems designed to maintain lifelong homeostasis. Four QC systems associated with aging are 1) inadequate protein processing in a distressed endoplasmic reticulum (ER); 2) histone deacetylase (HDAC) processing of genomic histones and gene silencing; 3) suppressed AMPK nutrient sensing with inefficient energy utilization and excessive fat accumulation; and 4) beta-adrenergic receptor (BAR) signaling and environmental and emotional stress. Reprogramming these systems to maintain efficiency and prevent aging would be a rational strategy for increased lifespan and improved health. The QC theory can be tested with a pharmacological approach using three well-known and safe, FDA-approved drugs: 1) phenyl butyric acid, a chemical chaperone that enhances ER function and is also an HDAC inhibitor, 2) metformin, which activates AMPK and is used to treat type 2 diabetes, and 3) propranolol, a beta blocker which inhibits BAR signaling and is used to treat hypertension and anxiety. A critical aspect of the QC theory, then, is that aging is associated with multiple cellular systems that can be targeted with drug combinations more effectively than with single drugs. But more importantly, these drug combinations will effectively prevent, delay, or reverse chronic diseases of aging that impose such a tremendous health burden on our society.

Early Weight Loss with Liraglutide 3.0 mg Predicts 1-Year Weight Loss and is Associated with Improvements in Clinical Markers.

PubMed

Fujioka, Ken; O'Neil, Patrick M; Davies, Melanie; Greenway, Frank; C W Lau, David; Claudius, Birgitte; Skjøth, Trine Vang; Bjørn Jensen, Christine; P H Wilding, John

2016-11-01

To identify an early response criterion for predicting ≥5% weight loss with liraglutide 3.0 mg at week 56 and to compare efficacy outcomes in early responders (ERs) and early nonresponders (ENRs). Using pooled data from the SCALE Obesity and Prediabetes and SCALE Diabetes trials, weight loss of ≥4% at 16 weeks best predicted ≥5% weight loss after 56 weeks. Weight loss and changes in cardiometabolic risk factors and health-related quality of life were evaluated in ERs (≥4% weight loss at week 16) and ENRs (<4% weight loss at week 16) completing 56 weeks' treatment. Proportions of ERs/ENRs to liraglutide 3.0 mg were 77.3%/22.7% (individuals without type 2 diabetes, T2D) and 62.7%/37.3% (those with T2D). Greater mean weight loss was observed in ERs versus ENRs: 10.8% versus 3.0% (without T2D) and 8.5% versus 3.1% (T2D). In both trials, greater proportions of ERs versus ENRs achieved ≥5%, >10%, and >15% weight loss at week 56 with liraglutide 3.0 mg. Greater improvements in cardiometabolic risk factors and health-related quality of life scores were observed in ERs versus ENRs. The early response criterion was clinically useful to identify individuals who would achieve clinically meaningful weight loss at 56 weeks. © 2016 The Authors Obesity published by Wiley Periodicals, Inc. on behalf of The Obesity Society (TOS).

Early Weight Loss with Liraglutide 3.0 mg Predicts 1‐Year Weight Loss and is Associated with Improvements in Clinical Markers

PubMed Central

O'Neil, Patrick M.; Davies, Melanie; Greenway, Frank; C.W. Lau, David; Claudius, Birgitte; Skjøth, Trine Vang; Bjørn Jensen, Christine; P.H. Wilding, John

2016-01-01

Objective To identify an early response criterion for predicting ≥5% weight loss with liraglutide 3.0 mg at week 56 and to compare efficacy outcomes in early responders (ERs) and early nonresponders (ENRs). Methods Using pooled data from the SCALE Obesity and Prediabetes and SCALE Diabetes trials, weight loss of ≥4% at 16 weeks best predicted ≥5% weight loss after 56 weeks. Weight loss and changes in cardiometabolic risk factors and health‐related quality of life were evaluated in ERs (≥4% weight loss at week 16) and ENRs (<4% weight loss at week 16) completing 56 weeks’ treatment. Results Proportions of ERs/ENRs to liraglutide 3.0 mg were 77.3%/22.7% (individuals without type 2 diabetes, T2D) and 62.7%/37.3% (those with T2D). Greater mean weight loss was observed in ERs versus ENRs: 10.8% versus 3.0% (without T2D) and 8.5% versus 3.1% (T2D). In both trials, greater proportions of ERs versus ENRs achieved ≥5%, >10%, and >15% weight loss at week 56 with liraglutide 3.0 mg. Greater improvements in cardiometabolic risk factors and health‐related quality of life scores were observed in ERs versus ENRs. Conclusions The early response criterion was clinically useful to identify individuals who would achieve clinically meaningful weight loss at 56 weeks. PMID:27804269

Different redox sensitivity of endoplasmic reticulum associated degradation clients suggests a novel role for disulphide bonds in secretory proteins.

PubMed

Medraño-Fernandez, Iria; Fagioli, Claudio; Mezghrani, Alexandre; Otsu, Mieko; Sitia, Roberto

2014-04-01

To maintain proteostasis in the endoplasmic reticulum (ER), terminally misfolded secretory proteins must be recognized, partially unfolded, and dislocated to the cytosol for proteasomal destruction, in a complex process called ER-associated degradation (ERAD). Dislocation implies reduction of inter-chain disulphide bonds. When in its reduced form, protein disulphide isomerase (PDI) can act not only as a reductase but also as an unfoldase, preparing substrates for dislocation. PDI oxidation by Ero1 favours substrate release and transport across the ER membrane. Here we addressed the redox dependency of ERAD and found that DTT stimulates the dislocation of proteins with DTT-resistant disulphide bonds (i.e., orphan Ig-μ chains) but stabilizes a ribophorin mutant (Ri332) devoid of them. DTT promotes the association of Ri332, but not of Ig-µ, with PDI. This discrepancy may suggest that disulphide bonds in cargo proteins can be utilized to oxidize PDI, hence facilitating substrate detachment and degradation also in the absence of Ero1. Accordingly, Ero1 silencing retards Ri332 degradation, but has little if any effect on Ig-µ. Thus, some disulphides can increase the stability and simultaneously favour quality control of secretory proteins.

The risk of breast cancer associated with specific patterns of migraine history

PubMed Central

Lowry, Sarah J.; Malone, Kathleen E.; Cushing-Haugen, Kara L.; Li, Christopher I.

2014-01-01

Purpose Studies have suggested that a history of migraines may be associated with a lower risk of some types of breast cancer, though biological mechanisms are unclear. Identifying specific characteristics of migraines which are most strongly associated with breast cancer risk could improve our understanding of this relationship. Methods We ascertained specific characteristics of women's migraine histories (severity, timing features, presence of migraine aura). We used polytomous logistic regression to estimate the risk of ER+ ductal, ER- ductal, ER+ lobular, and ER+ ductal-lobular breast cancer associated with self-reported characteristics of migraine history. 715 breast cancer cases (276 ER+ ductal, 46 ER- ductal, 191 ER+ lobular, 202 ER+ ductal-lobular) and 376 controls ages 55-74 years were included in this population-based case-control study. Results Compared to women without a migraine history, women with a >30-year history of migraines had a 60% (95% CI: 0.2-0.6) lower risk of ER+ ductal breast cancer; those who had their first migraine before age 20 had 50% lower risks of ER+ ductal and ER+ lobular breast cancer (both 95%CIs: 0.3-0.9), and women who experienced migraine with aura had 30% (95%CI 0.5-0.98) and 40% (95%CI: 0.4-0.9) lower risks of ER+ ductal and ER+ lobular breast cancer, respectively. Conclusion The lower risk of ER+ breast cancer associated with migraine appears to be limited to those women with early onset or long duration of migraine history, or those who experienced migraine with aura. This expands our understanding of the relationship between migraine and breast cancer and provides additional insight into potential underlying biological mechanisms. PMID:25359301

Microtensile bond strength analysis of adhesive systems to Er:YAG and Er,Cr:YSGG laser-treated dentin.

PubMed

Ramos, Thaysa Monteiro; Ramos-Oliveira, Thayanne Monteiro; Moretto, Simone Gonçalves; de Freitas, Patricia Moreira; Esteves-Oliveira, Marcella; de Paula Eduardo, Carlos

2014-03-01

The aim of this in vitro study was to evaluate the effect of different surface treatments (control, diamond bur, erbium-doped yttrium aluminum garnet (Er:YAG) laser, and erbium, chromium:yttrium-scandium-gallium-garnet (Er,Cr:YSGG) laser) on sound dentin surface morphology and on microtensile bond strength (μTBS). Sixteen dentin fragments were randomly divided into four groups (n = 4), and different surface treatments were analyzed by scanning electron microscopy. Ninety-six third molars were randomly divided into eight groups (n = 12) according to type of surface treatment and adhesive system: G1 = Control + Clearfil SE Bond (SE); G2 = Control + Single Bond (SB); G3 = diamond bur (DB) + SE; G4 = DB + SB, G5 = Er:YAG laser (2.94 μm, 60 mJ, 2 Hz, 0.12 W, 19.3 J/cm(2)) + SE; G6 = Er:YAG + SB, G7 = Er,Cr:YSGG laser (2.78 μm, 50 mJ, 30 Hz, 1.5 W, 4.5 J/cm(2)) + SE; and G8 = Er,Cr:YSGG + SB. Composite blocks were bonded to the samples, and after 24-h storage in distilled/deionized water (37 °C), stick-shaped samples were obtained and submitted to μTBS test. Bond strength values (in megapascal) were analyzed by two-way ANOVA and Tukey tests (α = 0.05). G1 (54.69 ± 7.8 MPa) showed the highest mean, which was statistically significantly higher than all the other groups (p < 0.05). For all treatments, SE showed higher bond strength than SB, except only for Er,Cr:YSGG treatment, in which the systems did not differ statistically from each other. Based on the irradiation parameters considered in this study, it can be concluded that Er:YAG and Er,Cr:YSGG irradiation presented lower values than the control group; however, their association with self-etching adhesive does not have a significantly negative effect on sound dentin (μTBS values of >20 MPa).

Making Long-Lasting Changes with the Environment Rating Scales

ERIC Educational Resources Information Center

Harms, Thelma

2010-01-01

An assessment with the Environment Rating Scales (ERS) is designed to give early childhood administrators and teaching staff much more than a set of quality scores. Appropriately used, an ERS assessment can provide a blueprint for planning and carrying out both immediate and long-range program improvements. Unfortunately, programs often complete…

A study of the feasibility of using sea and wind information from the ERS-1 satellite. Part 1: Wind scatterometer data

NASA Technical Reports Server (NTRS)

Anderson, D.; Hollingsworth, A.; Uppala, S.; Woiceshyn, P.

1987-01-01

The use of scatterometer and altimeter data in wind and wave assimilation, and the benefits this offers for quality assurance and validation of ERS-1 data were examined. Real time use of ERS-1 data was simulated through assimilation of Seasat scatterometer data. The potential for quality assurance and validation is demonstrated by documenting a series of substantial problems with the scatterometer data, which are known but took years to establish, or are new. A data impact study, and an analysis of the performance of ambiguity removal algorithms on real and simulated data were conducted. The impact of the data on analyses and forecasts is large in the Southern Hemisphere, generally small in the Northern Hemisphere, and occasionally large in the Tropics. Tests with simulated data give more optimistic results than tests with real data. Errors in ambiguity removal results occur in clusters. The probabilities which can be calculated for the ambiguous wind directions on ERS-1 contain more information than is given by a simple ranking of the directions.

Building a QC Database of Meteorological Data From NASA KSC and the United States Air Force's Eastern Range

NASA Technical Reports Server (NTRS)

Brenton, James C.; Barbre, Robert E.; Orcutt, John M.; Decker, Ryan K.

2018-01-01

The National Aeronautics and Space Administration's (NASA) Marshall Space Flight Center (MSFC) Natural Environments Branch (EV44) has provided atmospheric databases and analysis in support of space vehicle design and day-of-launch operations for NASA and commercial launch vehicle programs launching from the NASA Kennedy Space Center (KSC), co-located on the United States Air Force's Eastern Range (ER) at the Cape Canaveral Air Force Station. The ER is one of the most heavily instrumented sites in the United States measuring various atmospheric parameters on a continuous basis. An inherent challenge with the large databases that EV44 receives from the ER consists of ensuring erroneous data are removed from the databases, and thus excluded from launch vehicle design analyses. EV44 has put forth great effort in developing quality control (QC) procedures for individual meteorological instruments; however, no standard QC procedures for all databases currently exist resulting in QC databases that have inconsistencies in variables, methodologies, and periods of record. The goal of this activity is to use the previous efforts by EV44 to develop a standardized set of QC procedures from which to build flags within the meteorological databases from KSC and the ER, while maintaining open communication with end users from the launch community to develop ways to improve, adapt and grow the QC database. Details of the QC checks are described. The flagged data points will be plotted in a graphical user interface (GUI) as part of a manual confirmation that the flagged data do indeed need to be removed from the archive. As the rate of launches increases with additional launch vehicle programs, more emphasis is being placed to continually update and check weather databases for data quality before use in launch vehicle design and certification analyses.

Evaluation of Quality of Life, Functioning, Disability, and Work/School Productivity Following Treatment with an Extended-Release Hydrocodone Tablet Formulated with Abuse-Deterrence Technology: A 12-month Open-label Study in Patients with Chronic Pain.

PubMed

Hale, Martin E; Zimmerman, Thomas R; Ma, Yuju; Malamut, Richard

2017-02-01

This phase 3 study evaluated quality of life, functioning, and productivity after treatment with extended-release (ER) hydrocodone formulated with CIMA ® Abuse-Deterrence Technology platform. Patients with chronic pain were rolled over from a 12-week placebo-controlled hydrocodone ER study or were newly enrolled. Hydrocodone ER doses were titrated (15 to 90 mg every 12 hours) to an analgesic dose, and patients received up to 52 weeks of open-label treatment. Assessments included Clinician Assessment of Patient Function (CAPF), Patient Assessment of Function (PAF), Brief Pain Inventory-Short Form (BPI-SF), 36-item Short-Form Health Survey (SF-36), Sheehan Disability Scale (SDS), and World Health Organization Health and Work Performance Questionnaire-Short Form (HPQ-SF). Of 330 enrolled patients, 291 composed the full analysis population. By week 4, ≥ 50% of patients showed improvement from baseline in all 5 CAPF domains (general activities, walking, work/daily living, relationships, and enjoyment of life) and 6 of 7 PAF domains (work attendance, work performance, walking, exercise, socializing, and enjoying life). Mean decreases from baseline of 2 to 3 points were noted for BPI-SF pain interference questions from week 4 through endpoint. Mean improvements from baseline to endpoint in SF-36 subscales ranged from 3.3 to 22.3, and SDS scores improved from moderate (4.8 to 5.1) to mild (2.5 to 2.8) disruptions in work/school, social life, and family life. At endpoint, mean HPQ-SF absolute absenteeism scores decreased from 13.6 to 10.0 hours lost/month and absolute presenteeism scores improved from 67.0 to 77.1. Patients receiving hydrocodone ER showed early numeric improvements in functioning that continued throughout this 12-month study. © 2016 World Institute of Pain.

Cost-effectiveness of supervised exercise therapy compared with endovascular revascularization for intermittent claudication.

PubMed

van den Houten, M M L; Lauret, G J; Fakhry, F; Fokkenrood, H J P; van Asselt, A D I; Hunink, M G M; Teijink, J A W

2016-11-01

Current guidelines recommend supervised exercise therapy (SET) as the preferred initial treatment for patients with intermittent claudication. The availability of SET programmes is, however, limited and such programmes are often not reimbursed. Evidence for the long-term cost-effectiveness of SET compared with endovascular revascularization (ER) as primary treatment for intermittent claudication might aid widespread adoption in clinical practice. A Markov model was constructed to determine the incremental costs, incremental quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratio of SET versus ER for a hypothetical cohort of patients with newly diagnosed intermittent claudication, from the Dutch healthcare payer's perspective. In the event of primary treatment failure, possible secondary interventions were repeat ER, open revascularization or major amputation. Data sources for model parameters included original data from two RCTs, as well as evidence from the medical literature. The robustness of the results was tested with probabilistic and one-way sensitivity analysis. Considering a 5-year time horizon, probabilistic sensitivity analysis revealed that SET was associated with cost savings compared with ER (-€6412, 95 per cent credibility interval (CrI) -€11 874 to -€1939). The mean difference in effectiveness was -0·07 (95 per cent CrI -0·27 to 0·16) QALYs. ER was associated with an additional €91 600 per QALY gained compared with SET. One-way sensitivity analysis indicated more favourable cost-effectiveness for ER in subsets of patients with low quality-of-life scores at baseline. SET is a more cost-effective primary treatment for intermittent claudication than ER. These results support implementation of supervised exercise programmes in clinical practice. © 2016 BJS Society Ltd Published by John Wiley & Sons Ltd.

The ERS Research Agency: the beginning.

PubMed

Soriano, Joan B; Paton, James; Martin Burrieza, Fernando; Bill, Werner; Pannetier, Carine; Aliberti, Stefano; Adcock, Ian M; Wagers, Scott; Migliori, Giovanni Battista

2016-04-01

There is at the current time a significant opportunity for the ERS to leverage its experience and reputation as an international umbrella organisation to promote high-quality, multinational respiratory research with the goal of improving the health of respiratory patients. This editorial proposes a model for the role and structure of an ERS Research Agency. It is based upon research, implicit knowledge and explicit feedback from ERS members and selected external individuals and organisations.As with any new endeavour there are challenges and threats. Building a Research Agency will be a major undertaking that will require significant organisational planning, resources, effort and commitment.Organisations with multiple stakeholders tend to have a status quo inertia that has to be overcome for any significant new endeavour. The ERS Research Agency could be an investment in the future of respiratory research.

A common variant at the TERT-CLPTM1L locus is associated with estrogen receptor–negative breast cancer

PubMed Central

Haiman, Christopher A; Chen, Gary K; Vachon, Celine M; Canzian, Federico; Dunning, Alison; Millikan, Robert C; Wang, Xianshu; Ademuyiwa, Foluso; Ahmed, Shahana; Ambrosone, Christine B; Baglietto, Laura; Balleine, Rosemary; Bandera, Elisa V; Beckmann, Matthias W; Berg, Christine D; Bernstein, Leslie; Blomqvist, Carl; Blot, William J; Brauch, Hiltrud; Buring, Julie E; Carey, Lisa A; Carpenter, Jane E; Chang-Claude, Jenny; Chanock, Stephen J; Chasman, Daniel I; Clarke, Christine L; Cox, Angela; Cross, Simon S; Deming, Sandra L; Diasio, Robert B; Dimopoulos, Athanasios M; Driver, W Ryan; Dünnebier, Thomas; Durcan, Lorraine; Eccles, Diana; Edlund, Christopher K; Ekici, Arif B; Fasching, Peter A; Feigelson, Heather S; Flesch-Janys, Dieter; Fostira, Florentia; Försti, Asta; Fountzilas, George; Gerty, Susan M; Giles, Graham G; Godwin, Andrew K; Goodfellow, Paul; Graham, Nikki; Greco, Dario; Hamann, Ute; Hankinson, Susan E; Hartmann, Arndt; Hein, Rebecca; Heinz, Judith; Holbrook, Andrea; Hoover, Robert N; Hu, Jennifer J; Hunter, David J; Ingles, Sue A; Irwanto, Astrid; Ivanovich, Jennifer; John, Esther M; Johnson, Nicola; Jukkola-Vuorinen, Arja; Kaaks, Rudolf; Ko, Yon-Dschun; Kolonel, Laurence N; Konstantopoulou, Irene; Kosma, Veli-Matti; Kulkarni, Swati; Lambrechts, Diether; Lee, Adam M; Le Marchand, Loïc; Lesnick, Timothy; Liu, Jianjun; Lindstrom, Sara; Mannermaa, Arto; Margolin, Sara; Martin, Nicholas G; Miron, Penelope; Montgomery, Grant W; Nevanlinna, Heli; Nickels, Stephan; Nyante, Sarah; Olswold, Curtis; Palmer, Julie; Pathak, Harsh; Pectasides, Dimitrios; Perou, Charles M; Peto, Julian; Pharoah, Paul D P; Pooler, Loreall C; Press, Michael F; Pylkäs, Katri; Rebbeck, Timothy R; Rodriguez-Gil, Jorge L; Rosenberg, Lynn; Ross, Eric; Rüdiger, Thomas; Silva, Isabel dos Santos; Sawyer, Elinor; Schmidt, Marjanka K; Schulz-Wendtland, Rüdiger; Schumacher, Fredrick; Severi, Gianluca; Sheng, Xin; Signorello, Lisa B; Sinn, Hans-Peter; Stevens, Kristen N; Southey, Melissa C; Tapper, William J; Tomlinson, Ian; Hogervorst, Frans B L; Wauters, Els; Weaver, JoEllen; Wildiers, Hans; Winqvist, Robert; Van Den Berg, David; Wan, Peggy; Xia, Lucy Y; Yannoukakos, Drakoulis; Zheng, Wei; Ziegler, Regina G; Siddiq, Afshan; Slager, Susan L; Stram, Daniel O; Easton, Douglas; Kraft, Peter; Henderson, Brian E; Couch, Fergus J

2012-01-01

Estrogen receptor (ER)-negative breast cancer shows a higher incidence in women of African ancestry compared to women of European ancestry. In search of common risk alleles for ER-negative breast cancer, we combined genome-wide association study (GWAS) data from women of African ancestry (1,004 ER-negative cases and 2,745 controls) and European ancestry (1,718 ER-negative cases and 3,670 controls), with replication testing conducted in an additional 2,292 ER-negative cases and 16,901 controls of European ancestry. We identified a common risk variant for ER-negative breast cancer at the TERT-CLPTM1L locus on chromosome 5p15 (rs10069690: per-allele odds ratio (OR) = 1.18 per allele, P = 1.0 × 10−10). The variant was also significantly associated with triple-negative (ER-negative, progesterone receptor (PR)-negative and human epidermal growth factor-2 (HER2)-negative) breast cancer (OR = 1.25, P = 1.1 × 10−9), particularly in younger women (<50 years of age) (OR = 1.48, P = 1.9 × 10−9). Our results identify a genetic locus associated with estrogen receptor negative breast cancer subtypes in multiple populations. PMID:22037553

IMG ER: a system for microbial genome annotation expert review and curation.

PubMed

Markowitz, Victor M; Mavromatis, Konstantinos; Ivanova, Natalia N; Chen, I-Min A; Chu, Ken; Kyrpides, Nikos C

2009-09-01

A rapidly increasing number of microbial genomes are sequenced by organizations worldwide and are eventually included into various public genome data resources. The quality of the annotations depends largely on the original dataset providers, with erroneous or incomplete annotations often carried over into the public resources and difficult to correct. We have developed an Expert Review (ER) version of the Integrated Microbial Genomes (IMG) system, with the goal of supporting systematic and efficient revision of microbial genome annotations. IMG ER provides tools for the review and curation of annotations of both new and publicly available microbial genomes within IMG's rich integrated genome framework. New genome datasets are included into IMG ER prior to their public release either with their native annotations or with annotations generated by IMG ER's annotation pipeline. IMG ER tools allow addressing annotation problems detected with IMG's comparative analysis tools, such as genes missed by gene prediction pipelines or genes without an associated function. Over the past year, IMG ER was used for improving the annotations of about 150 microbial genomes.

A repeated short educational intervention improves asthma control and quality of life.

PubMed

Plaza, Vicente; Peiró, Meritxell; Torrejón, Montserrat; Fletcher, Monica; López-Viña, Antolín; Ignacio, José María; Quintano, José Antonio; Bardagí, Santiago; Gich, Ignasi

2015-11-01

We assessed the effectiveness of an asthma educational programme based on a repeated short intervention (AEP-RSI) to improve asthma control (symptom control and future risk) and quality of life. A total of 230 adults with mild-to-moderate persistent uncontrolled asthma participated in a 1-year cluster randomised controlled multicentre study. The AEP-RSI was given in four face-to-face sessions at 3-month intervals, and included administration of a written personalised action plan and training on inhaler technique. Centres were randomised to the AEP-RSI (intervention) group or usual clinical practice group. Specialised centres using a standard educational programme were the gold standard group. A significant improvement in the Asthma Control Test score was observed in all three groups (p<0.001), but improvements were higher in the intervention and gold standard groups than in the usual clinical practice group (p=0.042), which also showed fewer exacerbations (mean±sd; 1.20±2.02 and 0.56±1.5 versus 2.04±2.72, respectively) and greater increases in the Mini Asthma Quality of Life Questionnaire scores (0.95±1.04 and 0.89±0.84 versus 0.52±0.97, respectively). The AEP-RSI was effective in improving asthma symptom control, future risk and quality of life. Copyright ©ERS 2015.

The reliability and utility of spirometry performed on people with asthma in community pharmacies.

PubMed

Lei Burton, Deborah; LeMay, Kate S; Saini, Bandana; Smith, Lorraine; Bosnic-Anticevich, Sinthia; Southwell, Phillipa; Cooke, Julie; Emmerton, Lynne; Stewart, Kay; Krass, Ines; Reddel, Helen; Armour, Carol

2015-01-01

To investigate the reliability and the utility of spirometry generated by community pharmacists participating in two large asthma intervention trials of 892 people. The Pharmacy Asthma Care Program (PACP) and the Pharmacy Asthma Management Service (PAMS) involved up to four visits to the pharmacy over 6 months for counseling and goal setting. Pharmacists performed spirometry according to ATS/ERS guidelines to inform management. The proportion of A-E, F quality tests, as per EasyOne QC grades, were recorded. Lung function results between visits and for participants referred/not referred to their general practitioner on the basis of spirometry were compared. Complete data from 2593 spirometry sessions were recorded, 68.5% of spirometry sessions achieved three acceptable tests with between-test repeatability of 150 ml or less (A or B quality), 96% of spirometry sessions included at least one test that met ATS/ERS acceptability criteria. About 39.1% of participants had FEV1/FVC values below the lower limit of normal (LNN), indicating a respiratory obstruction. As a result of the service, there was a significant increase in FEV1 and FEV1/FVC and asthma control. Lung function values were significantly poorer for participants referred to their general practitioner, compared with those not referred, on the basis of spirometry. Community pharmacists are able to reliably achieve spirometry results meeting ATS/ERS guidelines in people with asthma. Significant improvements in airway obstruction were demonstrated with the pharmacy services. Pharmacists interpreted lung function results to identify airway obstruction for referral, making this a useful technique for review of people with asthma in the community.

Building a QC Database of Meteorological Data from NASA KSC and the United States Air Force's Eastern Range

NASA Technical Reports Server (NTRS)

Brenton, J. C.; Barbre, R. E.; Decker, R. K.; Orcutt, J. M.

2018-01-01

The National Aeronautics and Space Administration's (NASA) Marshall Space Flight Center (MSFC) Natural Environments Branch (EV44) provides atmospheric databases and analysis in support of space vehicle design and day-of-launch operations for NASA and commercial launch vehicle programs launching from the NASA Kennedy Space Center (KSC), co-located on the United States Air Force's Eastern Range (ER) at the Cape Canaveral Air Force Station. The ER complex is one of the most heavily instrumented sites in the United States with over 31 towers measuring various atmospheric parameters on a continuous basis. An inherent challenge with large datasets consists of ensuring erroneous data are removed from databases, and thus excluded from launch vehicle design analyses. EV44 has put forth great effort in developing quality control (QC) procedures for individual meteorological instruments, however no standard QC procedures for all databases currently exists resulting in QC databases that have inconsistencies in variables, development methodologies, and periods of record. The goal of this activity is to use the previous efforts to develop a standardized set of QC procedures from which to build meteorological databases from KSC and the ER, while maintaining open communication with end users from the launch community to develop ways to improve, adapt and grow the QC database. Details of the QC procedures will be described. As the rate of launches increases with additional launch vehicle programs, It is becoming more important that weather databases are continually updated and checked for data quality before use in launch vehicle design and certification analyses.

Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer.

PubMed

Couch, Fergus J; Kuchenbaecker, Karoline B; Michailidou, Kyriaki; Mendoza-Fandino, Gustavo A; Nord, Silje; Lilyquist, Janna; Olswold, Curtis; Hallberg, Emily; Agata, Simona; Ahsan, Habibul; Aittomäki, Kristiina; Ambrosone, Christine; Andrulis, Irene L; Anton-Culver, Hoda; Arndt, Volker; Arun, Banu K; Arver, Brita; Barile, Monica; Barkardottir, Rosa B; Barrowdale, Daniel; Beckmann, Lars; Beckmann, Matthias W; Benitez, Javier; Blank, Stephanie V; Blomqvist, Carl; Bogdanova, Natalia V; Bojesen, Stig E; Bolla, Manjeet K; Bonanni, Bernardo; Brauch, Hiltrud; Brenner, Hermann; Burwinkel, Barbara; Buys, Saundra S; Caldes, Trinidad; Caligo, Maria A; Canzian, Federico; Carpenter, Jane; Chang-Claude, Jenny; Chanock, Stephen J; Chung, Wendy K; Claes, Kathleen B M; Cox, Angela; Cross, Simon S; Cunningham, Julie M; Czene, Kamila; Daly, Mary B; Damiola, Francesca; Darabi, Hatef; de la Hoya, Miguel; Devilee, Peter; Diez, Orland; Ding, Yuan C; Dolcetti, Riccardo; Domchek, Susan M; Dorfling, Cecilia M; Dos-Santos-Silva, Isabel; Dumont, Martine; Dunning, Alison M; Eccles, Diana M; Ehrencrona, Hans; Ekici, Arif B; Eliassen, Heather; Ellis, Steve; Fasching, Peter A; Figueroa, Jonine; Flesch-Janys, Dieter; Försti, Asta; Fostira, Florentia; Foulkes, William D; Friebel, Tara; Friedman, Eitan; Frost, Debra; Gabrielson, Marike; Gammon, Marilie D; Ganz, Patricia A; Gapstur, Susan M; Garber, Judy; Gaudet, Mia M; Gayther, Simon A; Gerdes, Anne-Marie; Ghoussaini, Maya; Giles, Graham G; Glendon, Gord; Godwin, Andrew K; Goldberg, Mark S; Goldgar, David E; González-Neira, Anna; Greene, Mark H; Gronwald, Jacek; Guénel, Pascal; Gunter, Marc; Haeberle, Lothar; Haiman, Christopher A; Hamann, Ute; Hansen, Thomas V O; Hart, Steven; Healey, Sue; Heikkinen, Tuomas; Henderson, Brian E; Herzog, Josef; Hogervorst, Frans B L; Hollestelle, Antoinette; Hooning, Maartje J; Hoover, Robert N; Hopper, John L; Humphreys, Keith; Hunter, David J; Huzarski, Tomasz; Imyanitov, Evgeny N; Isaacs, Claudine; Jakubowska, Anna; James, Paul; Janavicius, Ramunas; Jensen, Uffe Birk; John, Esther M; Jones, Michael; Kabisch, Maria; Kar, Siddhartha; Karlan, Beth Y; Khan, Sofia; Khaw, Kay-Tee; Kibriya, Muhammad G; Knight, Julia A; Ko, Yon-Dschun; Konstantopoulou, Irene; Kosma, Veli-Matti; Kristensen, Vessela; Kwong, Ava; Laitman, Yael; Lambrechts, Diether; Lazaro, Conxi; Lee, Eunjung; Le Marchand, Loic; Lester, Jenny; Lindblom, Annika; Lindor, Noralane; Lindstrom, Sara; Liu, Jianjun; Long, Jirong; Lubinski, Jan; Mai, Phuong L; Makalic, Enes; Malone, Kathleen E; Mannermaa, Arto; Manoukian, Siranoush; Margolin, Sara; Marme, Frederik; Martens, John W M; McGuffog, Lesley; Meindl, Alfons; Miller, Austin; Milne, Roger L; Miron, Penelope; Montagna, Marco; Mazoyer, Sylvie; Mulligan, Anna M; Muranen, Taru A; Nathanson, Katherine L; Neuhausen, Susan L; Nevanlinna, Heli; Nordestgaard, Børge G; Nussbaum, Robert L; Offit, Kenneth; Olah, Edith; Olopade, Olufunmilayo I; Olson, Janet E; Osorio, Ana; Park, Sue K; Peeters, Petra H; Peissel, Bernard; Peterlongo, Paolo; Peto, Julian; Phelan, Catherine M; Pilarski, Robert; Poppe, Bruce; Pylkäs, Katri; Radice, Paolo; Rahman, Nazneen; Rantala, Johanna; Rappaport, Christine; Rennert, Gad; Richardson, Andrea; Robson, Mark; Romieu, Isabelle; Rudolph, Anja; Rutgers, Emiel J; Sanchez, Maria-Jose; Santella, Regina M; Sawyer, Elinor J; Schmidt, Daniel F; Schmidt, Marjanka K; Schmutzler, Rita K; Schumacher, Fredrick; Scott, Rodney; Senter, Leigha; Sharma, Priyanka; Simard, Jacques; Singer, Christian F; Sinilnikova, Olga M; Soucy, Penny; Southey, Melissa; Steinemann, Doris; Stenmark-Askmalm, Marie; Stoppa-Lyonnet, Dominique; Swerdlow, Anthony; Szabo, Csilla I; Tamimi, Rulla; Tapper, William; Teixeira, Manuel R; Teo, Soo-Hwang; Terry, Mary B; Thomassen, Mads; Thompson, Deborah; Tihomirova, Laima; Toland, Amanda E; Tollenaar, Robert A E M; Tomlinson, Ian; Truong, Thérèse; Tsimiklis, Helen; Teulé, Alex; Tumino, Rosario; Tung, Nadine; Turnbull, Clare; Ursin, Giski; van Deurzen, Carolien H M; van Rensburg, Elizabeth J; Varon-Mateeva, Raymonda; Wang, Zhaoming; Wang-Gohrke, Shan; Weiderpass, Elisabete; Weitzel, Jeffrey N; Whittemore, Alice; Wildiers, Hans; Winqvist, Robert; Yang, Xiaohong R; Yannoukakos, Drakoulis; Yao, Song; Zamora, M Pilar; Zheng, Wei; Hall, Per; Kraft, Peter; Vachon, Celine; Slager, Susan; Chenevix-Trench, Georgia; Pharoah, Paul D P; Monteiro, Alvaro A N; García-Closas, Montserrat; Easton, Douglas F; Antoniou, Antonis C

2016-04-27

Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P<5 × 10(-8)) with oestrogen receptor (ER)-negative breast cancer and BRCA1-associated breast cancer risk. In this study, to identify new ER-negative susceptibility loci, we performed a meta-analysis of 11 genome-wide association studies (GWAS) consisting of 4,939 ER-negative cases and 14,352 controls, combined with 7,333 ER-negative cases and 42,468 controls and 15,252 BRCA1 mutation carriers genotyped on the iCOGS array. We identify four previously unidentified loci including two loci at 13q22 near KLF5, a 2p23.2 locus near WDR43 and a 2q33 locus near PPIL3 that display genome-wide significant associations with ER-negative breast cancer. In addition, 19 known breast cancer risk loci have genome-wide significant associations and 40 had moderate associations (P<0.05) with ER-negative disease. Using functional and eQTL studies we implicate TRMT61B and WDR43 at 2p23.2 and PPIL3 at 2q33 in ER-negative breast cancer aetiology. All ER-negative loci combined account for ∼11% of familial relative risk for ER-negative disease and may contribute to improved ER-negative and BRCA1 breast cancer risk prediction.

Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer

PubMed Central

Couch, Fergus J.; Kuchenbaecker, Karoline B.; Michailidou, Kyriaki; Mendoza-Fandino, Gustavo A.; Nord, Silje; Lilyquist, Janna; Olswold, Curtis; Hallberg, Emily; Agata, Simona; Ahsan, Habibul; Aittomäki, Kristiina; Ambrosone, Christine; Andrulis, Irene L.; Anton-Culver, Hoda; Arndt, Volker; Arun, Banu K.; Arver, Brita; Barile, Monica; Barkardottir, Rosa B.; Barrowdale, Daniel; Beckmann, Lars; Beckmann, Matthias W.; Benitez, Javier; Blank, Stephanie V.; Blomqvist, Carl; Bogdanova, Natalia V.; Bojesen, Stig E.; Bolla, Manjeet K.; Bonanni, Bernardo; Brauch, Hiltrud; Brenner, Hermann; Burwinkel, Barbara; Buys, Saundra S.; Caldes, Trinidad; Caligo, Maria A.; Canzian, Federico; Carpenter, Jane; Chang-Claude, Jenny; Chanock, Stephen J.; Chung, Wendy K.; Claes, Kathleen B. M.; Cox, Angela; Cross, Simon S.; Cunningham, Julie M.; Czene, Kamila; Daly, Mary B.; Damiola, Francesca; Darabi, Hatef; de la Hoya, Miguel; Devilee, Peter; Diez, Orland; Ding, Yuan C.; Dolcetti, Riccardo; Domchek, Susan M.; Dorfling, Cecilia M.; dos-Santos-Silva, Isabel; Dumont, Martine; Dunning, Alison M.; Eccles, Diana M.; Ehrencrona, Hans; Ekici, Arif B.; Eliassen, Heather; Ellis, Steve; Fasching, Peter A.; Figueroa, Jonine; Flesch-Janys, Dieter; Försti, Asta; Fostira, Florentia; Foulkes, William D.; Friebel, Tara; Friedman, Eitan; Frost, Debra; Gabrielson, Marike; Gammon, Marilie D.; Ganz, Patricia A.; Gapstur, Susan M.; Garber, Judy; Gaudet, Mia M.; Gayther, Simon A.; Gerdes, Anne-Marie; Ghoussaini, Maya; Giles, Graham G.; Glendon, Gord; Godwin, Andrew K.; Goldberg, Mark S.; Goldgar, David E.; González-Neira, Anna; Greene, Mark H.; Gronwald, Jacek; Guénel, Pascal; Gunter, Marc; Haeberle, Lothar; Haiman, Christopher A.; Hamann, Ute; Hansen, Thomas V. O.; Hart, Steven; Healey, Sue; Heikkinen, Tuomas; Henderson, Brian E.; Herzog, Josef; Hogervorst, Frans B. L.; Hollestelle, Antoinette; Hooning, Maartje J.; Hoover, Robert N.; Hopper, John L.; Humphreys, Keith; Hunter, David J.; Huzarski, Tomasz; Imyanitov, Evgeny N.; Isaacs, Claudine; Jakubowska, Anna; James, Paul; Janavicius, Ramunas; Jensen, Uffe Birk; John, Esther M.; Jones, Michael; Kabisch, Maria; Kar, Siddhartha; Karlan, Beth Y.; Khan, Sofia; Khaw, Kay-Tee; Kibriya, Muhammad G.; Knight, Julia A.; Ko, Yon-Dschun; Konstantopoulou, Irene; Kosma, Veli-Matti; Kristensen, Vessela; Kwong, Ava; Laitman, Yael; Lambrechts, Diether; Lazaro, Conxi; Lee, Eunjung; Le Marchand, Loic; Lester, Jenny; Lindblom, Annika; Lindor, Noralane; Lindstrom, Sara; Liu, Jianjun; Long, Jirong; Lubinski, Jan; Mai, Phuong L.; Makalic, Enes; Malone, Kathleen E.; Mannermaa, Arto; Manoukian, Siranoush; Margolin, Sara; Marme, Frederik; Martens, John W. M.; McGuffog, Lesley; Meindl, Alfons; Miller, Austin; Milne, Roger L.; Miron, Penelope; Montagna, Marco; Mazoyer, Sylvie; Mulligan, Anna M.; Muranen, Taru A.; Nathanson, Katherine L.; Neuhausen, Susan L.; Nevanlinna, Heli; Nordestgaard, Børge G.; Nussbaum, Robert L.; Offit, Kenneth; Olah, Edith; Olopade, Olufunmilayo I.; Olson, Janet E.; Osorio, Ana; Park, Sue K.; Peeters, Petra H.; Peissel, Bernard; Peterlongo, Paolo; Peto, Julian; Phelan, Catherine M.; Pilarski, Robert; Poppe, Bruce; Pylkäs, Katri; Radice, Paolo; Rahman, Nazneen; Rantala, Johanna; Rappaport, Christine; Rennert, Gad; Richardson, Andrea; Robson, Mark; Romieu, Isabelle; Rudolph, Anja; Rutgers, Emiel J.; Sanchez, Maria-Jose; Santella, Regina M.; Sawyer, Elinor J.; Schmidt, Daniel F.; Schmidt, Marjanka K.; Schmutzler, Rita K.; Schumacher, Fredrick; Scott, Rodney; Senter, Leigha; Sharma, Priyanka; Simard, Jacques; Singer, Christian F.; Sinilnikova, Olga M.; Soucy, Penny; Southey, Melissa; Steinemann, Doris; Stenmark-Askmalm, Marie; Stoppa-Lyonnet, Dominique; Swerdlow, Anthony; Szabo, Csilla I.; Tamimi, Rulla; Tapper, William; Teixeira, Manuel R.; Teo, Soo-Hwang; Terry, Mary B.; Thomassen, Mads; Thompson, Deborah; Tihomirova, Laima; Toland, Amanda E.; Tollenaar, Robert A. E. M.; Tomlinson, Ian; Truong, Thérèse; Tsimiklis, Helen; Teulé, Alex; Tumino, Rosario; Tung, Nadine; Turnbull, Clare; Ursin, Giski; van Deurzen, Carolien H. M.; van Rensburg, Elizabeth J.; Varon-Mateeva, Raymonda; Wang, Zhaoming; Wang-Gohrke, Shan; Weiderpass, Elisabete; Weitzel, Jeffrey N.; Whittemore, Alice; Wildiers, Hans; Winqvist, Robert; Yang, Xiaohong R.; Yannoukakos, Drakoulis; Yao, Song; Zamora, M Pilar; Zheng, Wei; Hall, Per; Kraft, Peter; Vachon, Celine; Slager, Susan; Chenevix-Trench, Georgia; Pharoah, Paul D. P.; Monteiro, Alvaro A. N.; García-Closas, Montserrat; Easton, Douglas F.; Antoniou, Antonis C.

2016-01-01

Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P<5 × 10−8) with oestrogen receptor (ER)-negative breast cancer and BRCA1-associated breast cancer risk. In this study, to identify new ER-negative susceptibility loci, we performed a meta-analysis of 11 genome-wide association studies (GWAS) consisting of 4,939 ER-negative cases and 14,352 controls, combined with 7,333 ER-negative cases and 42,468 controls and 15,252 BRCA1 mutation carriers genotyped on the iCOGS array. We identify four previously unidentified loci including two loci at 13q22 near KLF5, a 2p23.2 locus near WDR43 and a 2q33 locus near PPIL3 that display genome-wide significant associations with ER-negative breast cancer. In addition, 19 known breast cancer risk loci have genome-wide significant associations and 40 had moderate associations (P<0.05) with ER-negative disease. Using functional and eQTL studies we implicate TRMT61B and WDR43 at 2p23.2 and PPIL3 at 2q33 in ER-negative breast cancer aetiology. All ER-negative loci combined account for ∼11% of familial relative risk for ER-negative disease and may contribute to improved ER-negative and BRCA1 breast cancer risk prediction. PMID:27117709

Halloysite nanotube incorporation into adhesive systems—effect on bond strength to human dentin.

PubMed

Alkatheeri, Mohammed S; Palasuk, Jadesada; Eckert, George J; Platt, Jeffrey A; Bottino, Marco C

2015-11-01

This study aimed to evaluate the effect of Halloysite® aluminosilicate clay nanotube (HNT) incorporation into a two-step etch-and-rinse (ER) and a one-step self-etch (SE) adhesive on human dentin shear bond strength (SBS). Ten groups (n = 12) were prepared according to the adhesive system (i.e., ER or SE) and amount of HNT incorporated (5-20%, w/v), as follows: commercial control (i.e., the adhesive was used as purchased, 0% HNT); experimental control (i.e., the adhesive was processed through mixing/stirring and sonication similarly to the HNT-incorporated experimental groups, but without HNT); and 5, 10, and 20% HNT. SBS testing was performed after 24 h of storage in deionized water at 37 °C. Failure modes were examined using a stereomicroscope (×40). Scanning electron microscopy (SEM) of the resin-dentin interface of selected specimens was carried out. Two-way ANOVA revealed that incorporation of HNT up to 20% (w/v) in ER and up to 10% (w/v) in SE demonstrated an increased SBS compared to their experimental controls. Compared to the commercial control, SBS of HNT-modified dentin adhesives was not significantly different for ER adhesives (p > 0.05) but was significantly higher with 5% HNT in the SE adhesive (p < 0.05). Failure modes were predominantly adhesive and mixed failures. SEM micrographs of resin-dentin interfaces for ER-commercial control and ER-10% showed a similar morphology. A thicker adhesive layer and the presence of agglomerated HNT on the resin tags were seen in ER-10%. An increased number of short resin tags in SE-5% compared with SE-commercial control were observed. HNT addition up to 20% in ER and up to 10 % in SE showed increased SBS to dentin compared with the experimental control. HNT can be used not only to reinforce adhesive resins but also hold potential for the development of bioactive adhesives by the encapsulation of matrix metalloproteinase (MMP) inhibitors or anticariogenic agents.

Calmodulin Lobes Facilitate Dimerization and Activation of Estrogen Receptor-α*

PubMed Central

Li, Zhigang; Zhang, Yonghong; Hedman, Andrew C.; Ames, James B.

2017-01-01

Estrogen receptor α (ER-α) is a nuclear hormone receptor that controls selected genes, thereby regulating proliferation and differentiation of target tissues, such as breast. Gene expression controlled by ER-α is modulated by Ca2+ via calmodulin (CaM). Here we present the NMR structure of Ca2+-CaM bound to two molecules of ER-α (residues 287–305). The two lobes of CaM bind to the same site on two separate ER-α molecules (residues 292, 296, 299, 302, and 303), which explains why CaM binds two molecules of ER-α in a 1:2 complex and stabilizes ER-α dimerization. Exposed glutamate residues in CaM (Glu-11, Glu-14, Glu-84, and Glu-87) form salt bridges with key lysine residues in ER-α (Lys-299, Lys-302, and Lys-303), which is likely to prevent ubiquitination at these sites and inhibit degradation of ER-α. Transfection of cells with full-length CaM slightly increased the ability of estrogen to enhance transcriptional activation by ER-α of endogenous estrogen-responsive genes. By contrast, expression of either the N- or C-lobe of CaM abrogated estrogen-stimulated transcription of the estrogen responsive genes pS2 and progesterone receptor. These data suggest that CaM-induced dimerization of ER-α is required for estrogen-stimulated transcriptional activation by the receptor. In light of the critical role of ER-α in breast carcinoma, our data suggest that small molecules that selectively disrupt the interaction of ER-α with CaM may be useful in the therapy of breast carcinoma. PMID:28174300

Effort-reward imbalance and quality of life of healthcare workers in military hospitals: a cross-sectional study.

PubMed

Tzeng, Dong-Sheng; Chung, Wei-Ching; Lin, Chi-Hung; Yang, Chun-Yuh

2012-09-08

Taiwan's National Defense Bureau has been merging its hospitals and adjusting hospital accreditation levels since the beginning of 2006. These changes have introduced many stressors to the healthcare workers in these hospitals. This study investigates the association between job stress, psychological morbidity and quality of life in healthcare workers in three military hospitals. We posted surveys to 1269 healthcare workers in three military hospitals located in southern Taiwan. The surveys included the General Health Questionnaire (GHQ), the World Health Organization Quality of Life Questionnaire (WHOQOL-BREF), and the Effort-Reward Imbalance (ERI) Questionnaire. High effort-reward (ER) ratio and overcommitment were defined when scores fell into the upper tertile of the total distribution. The survey was completed by 791 healthcare workers. On average, women reported a higher ERI than men. High ERI was associated with younger age, higher psychological morbidity, and poor physical and psychological QOL domains in this population. High ER ratio and high overcommitment were associated with psychological morbidity and poor QOL in both sexes. However, high ER ratio was not significantly associated with the social QOL domain in either sexes or the physical QOL domain in males. There was a clear association between ERI and QOL in the healthcare workers in the military hospitals under reorganization and accreditation in this study. We found ER ratio and overcommitment to be suitable indicators of job stress.

Fabrication and Sintering Behavior of Er:SrF₂ Transparent Ceramics using Chemically Derived Powder.

PubMed

Liu, Jun; Liu, Peng; Wang, Jun; Xu, Xiaodong; Li, Dongzhen; Zhang, Jian; Nie, Xinming

2018-03-22

In this paper, we report the fabrication of high-quality 5 at. % Er 3+ ions doped SrF₂ transparent ceramics, the potential candidate materials for a mid-infrared laser-gain medium by hot-pressing at 700 °C for 40 h using a chemically-derived powder. The phase structure, densification, and microstructure evolution of the Er:SrF₂ ceramics were systematically investigated. In addition, the grain growth kinetic mechanism of Er:SrF₂ was clarified. The results showed lattice diffusion to be the grain growth mechanism in the Er:SrF₂ transparent ceramic of which highest in-line transmittance reached 92% at 2000 nm, i.e., very close to the theoretical transmittance value of SrF₂ single crystal. Furthermore, the emission spectra showed that the strongest emission band was located at 2735 nm. This means that it is possible to achieve a laser output of approximately 2.7 μm in the 5 at. % Er 3+ ions doped SrF₂ transparent ceramics.

Angiogenin Mediates Cell-Autonomous Translational Control under Endoplasmic Reticulum Stress and Attenuates Kidney Injury

PubMed Central

Mami, Iadh; Bouvier, Nicolas; El Karoui, Khalil; Gallazzini, Morgan; Rabant, Marion; Laurent-Puig, Pierre; Li, Shuping; Tharaux, Pierre-Louis; Beaune, Philippe; Thervet, Eric; Chevet, Eric; Hu, Guo-Fu

2016-01-01

Endoplasmic reticulum (ER) stress is involved in the pathophysiology of kidney disease and aging, but the molecular bases underlying the biologic outcomes on the evolution of renal disease remain mostly unknown. Angiogenin (ANG) is a ribonuclease that promotes cellular adaptation under stress but its contribution to ER stress signaling remains elusive. In this study, we investigated the ANG-mediated contribution to the signaling and biologic outcomes of ER stress in kidney injury. ANG expression was significantly higher in samples from injured human kidneys than in samples from normal human kidneys, and in mouse and rat kidneys, ANG expression was specifically induced under ER stress. In human renal epithelial cells, ER stress induced ANG expression in a manner dependent on the activity of transcription factor XBP1, and ANG promoted cellular adaptation to ER stress through induction of stress granules and inhibition of translation. Moreover, the severity of renal lesions induced by ER stress was dramatically greater in ANG knockout mice (Ang−/−) mice than in wild-type mice. These results indicate that ANG is a critical mediator of tissue adaptation to kidney injury and reveal a physiologically relevant ER stress-mediated adaptive translational control mechanism. PMID:26195817

Localization of androgen receptors and estrogen receptors in the same cells of the songbird brain.

PubMed Central

Gahr, M

1990-01-01

Estrogens and androgens each have unique effects but act together for the neural differentiation and control of sexual behaviors in male vertebrates, such as the canary. The neuronal basis for these synergistic effects is elusive because the spatial relation between estrogen target cells and androgen target cells is unknown. This study localized estrogen receptor (ER)-containing cells by using immunocytochemistry and androgen receptor (AR)-containing cells by using autoradiography in the same sections of the male canary brain. Three cell types, those containing only ER, those containing only AR, and those containing both ER and AR, were found in tissue-specific frequencies. The midbrain nucleus intercollicularis exhibited the highest number of cells expressing both ER and AR, whereas ER and AR are expressed only in disjunctive cell populations in the forebrain nucleus hyperstriatalis ventrale, pars caudale. Synergistic effects of androgens and estrogens for the neural behavorial control could result from cells containing both ER and AR (intracellular) and from neural circuits containing ER and AR in different cells (intercellular). Images PMID:2251286

Live-cell topology assessment of URG7, MRP6{sub 102} and SP-C using glycosylatable green fluorescent protein in mammalian cells

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

Lee, Hunsang; Lara, Patricia; Ostuni, Angela

2014-08-08

Highlights: • Glycosylatable GFP (gGFP) is developed for the use in mammalian cells. • gGFP selectively loses its fluorescence upon N-linked glycosylation in the ER lumen. • Differential fluorescence/glycosylation pattern probes membrane protein topology. • Membrane topology of URG7, MRP6{sub 102}, and SP-C was determined by gGFP tagging in vivo. - Abstract: Experimental tools to determine membrane topology of a protein are rather limited in higher eukaryotic organisms. Here, we report the use of glycosylatable GFP (gGFP) as a sensitive and versatile membrane topology reporter in mammalian cells. gGFP selectively loses its fluorescence upon N-linked glycosylation in the ER lumen.more » Thus, positive fluorescence signal assigns location of gGFP to the cytosol whereas no fluorescence signal and a glycosylated status of gGFP map the location of gGFP to the ER lumen. By using mammalian gGFP, the membrane topology of disease-associated membrane proteins, URG7, MRP6{sub 102}, SP-C(Val) and SP-C(Leu) was confirmed. URG7 is partially targeted to the ER, and inserted in C{sub in} form. MRP6{sub 102} and SP-C(Leu/Val) are inserted into the membrane in C{sub out} form. A minor population of untargeted SP-C is removed by proteasome dependent quality control system.« less

N-linked glycosylation at Asn152 on CD147 affects protein folding and stability: promoting tumour metastasis in hepatocellular carcinoma

PubMed Central

Li, Jiang-Hua; Huang, Wan; Lin, Peng; Wu, Bo; Fu, Zhi-Guang; Shen, Hao-Miao; Jing, Lin; Liu, Zhen-Yu; Zhou, Yang; Meng, Yao; Xu, Bao-Qing; Chen, Zhi-Nan; Jiang, Jian-Li

2016-01-01

Cluster of differentiation 147 (CD147), also known as extracellular matrix metalloproteinase inducer, is a transmembrane glycoprotein that mediates oncogenic processes partly through N-glycosylation modifications. N-glycosylation has been demonstrated to be instrumental for the regulation of CD147 function during malignant transformation. However, the role that site-specific glycosylation of CD147 plays in its defective function in hepatocellular carcinomacells needs to be determined. Here, we demonstrate that the modification of N-glycosylation at Asn152 on CD147 strongly promotes hepatocellular carcinoma (HCC) invasion and migration. After the removal of N-glycans at Asn152, CD147 was more susceptible to degradation by ER-localized ubiquitin ligase-mediated endoplasmic reticulum-associated degradation (ERAD). Furthermore, N-linked glycans at Asn152 were required for CD147 to acquire and maintain proper folding in the ER. Moreover, N-linked glycans at Asn152 functioned as a recognition motif that was directly mediated by the CNX quality control system. Two phases in the retention-based ER chaperones system drove ER-localized CD147 trafficking to degradation. Deletion of N-linked glycosylation at Asn152 on CD147 significantly suppressed in situ tumour metastasis. These data could potentially shed light on the molecular regulation of CD147 through glycosylation and provide a valuable means of developing drugs that target N-glycans at Asn152 on CD147. PMID:27869218

[Central interdisciplinary emergency department. Organization of emergency medicine from the perspective of hospital management].

PubMed

Mayer, U; Debatin, J F

2011-04-01

The treatment of emergencies in a hospital should be organized in a central interdisciplinary emergency department (ER). It is the main entrance for all patients with acute illness or injuries. There are multiple advantages of such a central unit. Quality of treatment and economic efficiency is improved. The interdisciplinary diagnostics and treatment at one place prevents time-consuming and unnecessary transport. The fact that more complex diseases and injuries need specialized doctors in specific disciplines should be considered in personnel planning of the ER. To reinsure that the entire medical staff of the hospital is familiar with the daily routine and clinical pathways of the ER, doctors from other departments of the hospital should always be part of the ER team.

Growth, and magnetic study of Sm0.4Er0.6FeO3 single crystal grown by optical floating zone technique

NASA Astrophysics Data System (ADS)

Wu, Anhua; Zhao, Xiangyang; Man, Peiwen; Su, Liangbi; Kalashnikova, A. M.; Pisarev, R. V.

2018-03-01

Sm0.4Er0.6FeO3 single crystals were successfully grown by optical floating zone method; high quality samples with various orientations were manufactured. Based on these samples, Magnetic property of Sm0.4Er0.6FeO3 single crystals were investigated systemically by means of the temperature dependence of magnetization. It indicated that compositional variations not only alter the spin reorientation temperature, but also the compensation temperature of the orthoferrites. Unlike single rare earth orthoferrites, the reversal transition temperature point of Sm0.4Er0.6FeO3 increases as magnetic field increases, which is positive for designing novel spin switching or magnetic sensor device.

Ins(1,4,5)P{sub 3} facilitates ATP accumulation via phosphocreatine/creatine kinase in the endoplasmic reticulum extracted from MDCK cells

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

Sun, Jing; Department of Dental Implantology, School of Stomatology, Tongji University, Shanghai 200072; Ogata, Shigenori

2010-07-02

So far, the content and accumulation of ATP in isolated endoplasmic reticulum (ER) are little understood. First, we confirmed using electron microscopic and Western blotting techniques that the samples extracted from MDCK cells are endoplasmic reticulum (ER). The amounts of ATP in the extracted ER were measured from the filtrate after a spinning down of ultrafiltration spin column packed with ER. When the ER sample (5 {mu}g) after 3 days freezing was suspended in intracellular medium (ICM), 0.1% Triton X and ultrapure water (UPW), ATP amounts from the ER with UPW were the highest and over 10 times compared withmore » that from the control with ICM, indicating that UPW is the most effective tool in destroying the ER membrane. After a 10-min-incubation with ICM containing phosphocreatine (PCr)/creatine kinase (CK) of the fresh ER. ATP amounts in the filtrate obtained by spinning down were not changed from that in the control (no PCr/CK). However, ATP amounts in the filtrate from the second spinning down of the ER (treated with PCr/CK) suspended in UPW became over 10-fold compared with the control. When 1 {mu}M inositol(1,4,5)trisphosphate (Ins(1,4,5)P{sub 3}) was added in the incubation medium (ICM with PCr/CK), ATP amounts from the filtrate after the second spinning down were further enhanced around three times. This enhancement was almost canceled by Ca{sup 2+}-removal from ICM and by adding thapsigargin, a Ca{sup 2+}-ATPase inhibitor, but not by 2-APB and heparin, Ins(1,4,5)P{sub 3} receptor antagonists. Administration of 500 {mu}M adenosine to the incubation medium (with PCr/CK) failed to enhance the accumulation of ATP in the ER. These findings suggest that the ER originally contains ATP and ATP accumulation in the ER is promoted by PCr/CK and Ins(1,4,5)P{sub 3}.« less

Coffee consumption modifies risk of estrogen-receptor negative breast cancer

PubMed Central

2011-01-01

Introduction Breast cancer is a complex disease and may be sub-divided into hormone-responsive (estrogen receptor (ER) positive) and non-hormone-responsive subtypes (ER-negative). Some evidence suggests that heterogeneity exists in the associations between coffee consumption and breast cancer risk, according to different estrogen receptor subtypes. We assessed the association between coffee consumption and postmenopausal breast cancer risk in a large population-based study (2,818 cases and 3,111 controls), overall, and stratified by ER tumour subtypes. Methods Odds ratios (OR) and corresponding 95% confidence intervals (CI) were estimated using the multivariate logistic regression models fitted to examine breast cancer risk in a stratified case-control analysis. Heterogeneity among ER subtypes was evaluated in a case-only analysis, by fitting binary logistic regression models, treating ER status as a dependent variable, with coffee consumption included as a covariate. Results In the Swedish study, coffee consumption was associated with a modest decrease in overall breast cancer risk in the age-adjusted model (OR> 5 cups/day compared to OR≤ 1 cup/day: 0.80, 95% CI: 0.64, 0.99, P trend = 0.028). In the stratified case-control analyses, a significant reduction in the risk of ER-negative breast cancer was observed in heavy coffee drinkers (OR> 5 cups/day compared to OR≤ 1 cup/day : 0.43, 95% CI: 0.25, 0.72, P trend = 0.0003) in a multivariate-adjusted model. The breast cancer risk reduction associated with higher coffee consumption was significantly higher for ER-negative compared to ER-positive tumours (P heterogeneity (age-adjusted) = 0.004). Conclusions A high daily intake of coffee was found to be associated with a statistically significant decrease in ER-negative breast cancer among postmenopausal women. PMID:21569535

A meta-analytic study of event rate effects on Go/No-Go performance in attention-deficit/hyperactivity disorder.

PubMed

Metin, Baris; Roeyers, Herbert; Wiersema, Jan R; van der Meere, Jaap; Sonuga-Barke, Edmund

2012-12-15

According to the state regulation deficit model, event rate (ER) is an important determinant of performance of children with attention-deficit/hyperactivity disorder (ADHD). Fast ER is predicted to create overactivation and produce errors of commission, whereas slow ER is thought to create underactivation marked by slow and variable reaction times (RT) and errors of omission. To test these predictions, we conducted a systematic search of the literature to identify all reports of comparisons of ADHD and control individuals' performance on Go/No-Go tasks published between 2000 and 2011. In one analysis, we included all trials with at least two event rates and calculated the difference between ER conditions. In a second analysis, we used metaregression to test for the moderating role of ER on ADHD versus control differences seen across Go/No-Go studies. There was a significant and disproportionate slowing of reaction time in ADHD relative to controls on trials with slow event rates in both meta-analyses. For commission errors, the effect sizes were larger on trials with fast event rates. No ER effects were seen for RT variability. There were also general effects of ADHD on performance for all variables that persisted after effects of ER were taken into account. The results provide support for the state regulation deficit model of ADHD by showing the differential effects of fast and slow ER. The lack of an effect of ER on RT variability suggests that this behavioral characteristic may not be a marker of cognitive energetic effects in ADHD. Copyright © 2012 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Modulation of Endoplasmic Reticulum Stress Controls CD4+ T-cell Activation and Antitumor Function.

PubMed

Thaxton, Jessica E; Wallace, Caroline; Riesenberg, Brian; Zhang, Yongliang; Paulos, Chrystal M; Beeson, Craig C; Liu, Bei; Li, Zihai

2017-08-01

The endoplasmic reticulum (ER) is an energy-sensing organelle with intimate ties to programming cell activation and metabolic fate. T-cell receptor (TCR) activation represents a form of acute cell stress and induces mobilization of ER Ca 2+ stores. The role of the ER in programming T-cell activation and metabolic fate remains largely undefined. Gp96 is an ER protein with functions as a molecular chaperone and Ca 2+ buffering protein. We hypothesized that the ER stress response may be important for CD4 + T-cell activation and that gp96 may be integral to this process. To test our hypothesis, we utilized genetic deletion of the gp96 gene Hsp90b1 in a CD4 + T cell-specific manner. We show that gp96-deficient CD4 + T cells cannot undergo activation-induced glycolysis due to defective Ca 2+ mobilization upon TCR engagement. We found that activating naïve CD4 + T cells while inhibiting ER Ca 2+ exchange, through pharmacological blockade of the ER Ca 2+ channel inositol trisphosphate receptor (IP 3 R), led to a reduction in cytosolic Ca 2+ content and generated a pool of CD62L high /CD44 low CD4 + T cells compared with wild-type (WT) matched controls. In vivo IP 3 R-inhibited CD4 + T cells exhibited elevated tumor control above WT T cells. Together, these data show that ER-modulated cytosolic Ca 2+ plays a role in defining CD4 + T-cell phenotype and function. Factors associated with the ER stress response are suitable targets for T cell-based immunotherapies. Cancer Immunol Res; 5(8); 666-75. ©2017 AACR . ©2017 American Association for Cancer Research.

Efficacy and Safety of Paliperidone Extended Release 1.5 mg/day—A Double-blind, Placebo- and Active-Controlled, Study in the Treatment of Patients with Schizophrenia

PubMed Central

Coppola, Danielle; Melkote, Rama; Lannie, Caroline; Singh, Jaskaran; Nuamah, Isaac; Gopal, Srihari; Hough, David; Palumbo, Joseph

2011-01-01

Background Paliperidone extended-release (paliperidone ER) is an approved oral antipsychotic medication (dosing range 3–12 mg/day) for treatment of schizophrenia and schizoaffective disorder in adults. Methods In this 3-arm, double-blind, placebo- and active-controlled, parallel-group study, paliperidone ER 1.5 mg was assessed to determine the lowest efficacious dose in patients (N = 201) with acute schizophrenia. Paliperidone ER 6 mg was included for assay sensitivity. Results Patients (intent-to-treat analysis set) had a mean age of 39.4 years; 74% were men, 43% Asian, and 40% black. The baseline mean (SD) Positive and Negative Syndrome Scale (PANSS) total score was 92.6 (13.02) and the mean (SD) change from baseline to endpoint was: placebo group, –11.4 (20.81); paliperidone ER 1.5 mg group, –8.9 (23.31); and paliperidone ER 6 mg group, –15.7 (26.25). Differences between paliperidone groups versus placebo were not significant (paliperidone ER 1.5 mg [p = 0.582], paliperidone ER 6 mg, [p = 0.308]). Safety results of paliperidone ER 1.5 mg and placebo were comparable. The most frequently reported treatment emergent adverse events (≥10%) were: placebo group—headache (15.6%) and psychotic disorder (14.1%); paliperidone ER 1.5 mg group—insomnia (13.6%); and paliperidone ER 6 mg group—headache (11.4%), insomnia (10%), and tremor (10%). Conclusions In this study, paliperidone ER 1.5 mg did not demonstrate efficacy in patients with acute schizophrenia. A markedly high placebo response was noted. Assay sensitivity with the 6 mg dose was not established. Paliperidone ER 1.5 mg was generally tolerable with a safety profile comparable to placebo. PMID:27738355

Efficacy and Safety of Paliperidone Extended Release 1.5 mg/day-A Double-blind, Placebo- and Active-Controlled, Study in the Treatment of Patients with Schizophrenia.

PubMed

Coppola, Danielle; Melkote, Rama; Lannie, Caroline; Singh, Jaskaran; Nuamah, Isaac; Gopal, Srihari; Hough, David; Palumbo, Joseph

2011-05-15

Paliperidone extended-release (paliperidone ER) is an approved oral antipsychotic medication (dosing range 3-12 mg/day) for treatment of schizophrenia and schizoaffective disorder in adults. In this 3-arm, double-blind, placebo- and active-controlled, parallel-group study, paliperidone ER 1.5 mg was assessed to determine the lowest efficacious dose in patients (N = 201) with acute schizophrenia. Paliperidone ER 6 mg was included for assay sensitivity. Patients (intent-to-treat analysis set) had a mean age of 39.4 years; 74% were men, 43% Asian, and 40% black. The baseline mean (SD) Positive and Negative Syndrome Scale (PANSS) total score was 92.6 (13.02) and the mean (SD) change from baseline to endpoint was: placebo group, -11.4 (20.81); paliperidone ER 1.5 mg group, -8.9 (23.31); and paliperidone ER 6 mg group, -15.7 (26.25). Differences between paliperidone groups versus placebo were not significant (paliperidone ER 1.5 mg [p = 0.582], paliperidone ER 6 mg, [p = 0.308]). Safety results of paliperidone ER 1.5 mg and placebo were comparable. The most frequently reported treatment emergent adverse events (≥10%) were: placebo group-headache (15.6%) and psychotic disorder (14.1%); paliperidone ER 1.5 mg group-insomnia (13.6%); and paliperidone ER 6 mg group-headache (11.4%), insomnia (10%), and tremor (10%). In this study, paliperidone ER 1.5 mg did not demonstrate efficacy in patients with acute schizophrenia. A markedly high placebo response was noted. Assay sensitivity with the 6 mg dose was not established. Paliperidone ER 1.5 mg was generally tolerable with a safety profile comparable to placebo.

Protein quality control at the inner nuclear membrane

PubMed Central

Khmelinskii, Anton; Blaszczak, Ewa; Pantazopoulou, Marina; Fischer, Bernd; Omnus, Deike J.; Le Dez, Gaëlle; Brossard, Audrey; Gunnarsson, Alexander; Barry, Joseph D.; Meurer, Matthias; Kirrmaier, Daniel; Boone, Charles; Huber, Wolfgang; Rabut, Gwenaël; Ljungdahl, Per O.; Knop, Michael

2015-01-01

The nuclear envelope is a double membrane that separates the nucleus from the cytoplasm. The inner nuclear membrane (INM) functions in essential nuclear processes including chromatin organization and regulation of gene expression1. The outer nuclear membrane is continuous with the endoplasmic reticulum (ER) and is the site of membrane protein synthesis. Protein homeostasis in this compartment is ensured by ER-associated protein degradation (ERAD) pathways that in yeast involve the integral membrane E3 ubiquitin ligases Hrd1 and Doa10 operating with the E2 ubiquitin-conjugating enzymes Ubc6 and Ubc72,3. However, little is known regarding protein quality control at the INM. Here we describe a protein degradation pathway at the INM mediated by the Asi complex consisting of the RING domain proteins Asi1 and Asi34. We report that the As complex functions together with the ubiquitin conjugating enzymes Ubc6andUbc7to degrade soluble and integral membrane proteins. Genetic evidence suggest that the Asi ubiquitin ligase defines a pathway distinct from but complementary to ERAD. Using unbiased screening with a novel genome-wide yeast library based on a tandem fluorescent protein timer (tFT)5, we identify more than 50 substrates of the Asi, Hrd1 and Doa10 E3 ubiquity ligases. We show that the Asi ubiquitin ligase is involved in degradation of mislocalised integral membrane proteins, thus acting to maintain and safeguard the identity of the INM. PMID:25519137

Timely event-related synchronization fading and phase de-locking and their defects in migraine.

PubMed

Yum, Myung-Kul; Moon, Jin-Hwa; Kang, Joong Koo; Kwon, Oh-Young; Park, Ki-Jong; Shon, Young-Min; Lee, Il Keun; Jung, Ki-Young

2014-07-01

To investigate the characteristics of event-related synchronization (ERS) fading and phase de-locking of alpha waves during passive auditory stimulation (PAS) in the migraine patients. The subjects were 16 adult women with migraine and 16 normal controls. Electroencephalographic (EEG) data obtained during PAS with standard (SS) and deviant stimuli (DS) were used. Alpha ERS fading, the phase locking index (PLI) and de-locking index (DLI) were evaluated from the 10 Hz complex Morlet wavelet components at 100 ms (t100) and 300 ms (t300) after PAS. At t100, significant ERS was found with SS and DS in the migraineurs and controls (P=0.000). At t300 in the controls, ERS faded to zero for DS while in the migraineurs there was no fading for DS. In both groups the PLI for SS and DS was significantly reduced, i.e. de-locked, at t300 compared to t100 (P=0.000). In the migraineurs, the DLI for DS was significantly lower than in the controls (P=0.003). The alpha ERS fading and phase de-locking are defective in migraineurs during passive auditory cognitive processing. The defects in timely alpha ERS fading and in de-locking may play a role in the different attention processing in migraine patients. Copyright © 2013 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

Creatine phosphate disodium salt protects against Dox-induced cardiotoxicity by increasing calumenin.

PubMed

Wang, Yu; Sun, Ying; Guo, Xin; Fu, Yao; Long, Jie; Wei, Cheng-Xi; Zhao, Ming

2018-06-01

Inhibiting endoplasmic reticulum stress (ERS)-induced apoptosis may be a new therapeutic target in cardiovascular diseases. Creatine phosphate disodium salt (CP) has been reported to have cardiovascular protective effect, but its effects on ERS are unknown. The aim of this study was to identify the mechanism by which CP exerts its cardioprotection in doxorubicin (Dox)-induced cardiomyocytes injury. In our study, neonatal rats cardiomyocytes (NRC) was randomly divided into control group, model group, and treatment group. The cell viability and apoptosis were detected. grp78, grp94, and calumenin of the each group were monitored. To investigate the role of calumenin, Dox-induced ERS was compared in control and down-regulated calumenin cardiomyocytes. Our results showed that CP decreased Dox-induced apoptosis and relieved ERS. We found calumenin increased in Dox-induced apoptosis with CP. ERS effector C/EBP homologous protein was down-regulated by CP and it was influenced by calumenin. CP could protect NRC by inhibiting ERS, this mechanisms may be associated with its increasing of calumenin.

Characterization of aromatic residue-controlled protein retention in the endoplasmic reticulum of Saccharomyces cerevisiae.

PubMed

Mei, Meng; Zhai, Chao; Li, Xinzhi; Zhou, Yu; Peng, Wenfang; Ma, Lixin; Wang, Qinhong; Iverson, Brent L; Zhang, Guimin; Yi, Li

2017-12-15

An endoplasmic reticulum (ER) retention sequence (ERS) is a characteristic short sequence that mediates protein retention in the ER of eukaryotic cells. However, little is known about the detailed molecular mechanism involved in ERS-mediated protein ER retention. Using a new surface display-based fluorescence technique that effectively quantifies ERS-promoted protein ER retention within Saccharomyces cerevisiae cells, we performed comprehensive ERS analyses. We found that the length, type of amino acid residue, and additional residues at positions -5 and -6 of the C-terminal HDEL motif all determined the retention of ERS in the yeast ER. Moreover, the biochemical results guided by structure simulation revealed that aromatic residues (Phe-54, Trp-56, and other aromatic residues facing the ER lumen) in both the ERS (at positions -6 and -4) and its receptor, Erd2, jointly determined their interaction with each other. Our studies also revealed that this aromatic residue interaction might lead to the discriminative recognition of HDEL or KDEL as ERS in yeast or human cells, respectively. Our findings expand the understanding of ERS-mediated residence of proteins in the ER and may guide future research into protein folding, modification, and translocation affected by ER retention. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

The Next Generation of Ground Operations Command and Control; Scripting in C no. and Visual Basic

NASA Technical Reports Server (NTRS)

Ritter, George; Pedoto, Ramon

2010-01-01

Scripting languages have become a common method for implementing command and control solutions in space ground operations. The Systems Test and Operations Language (STOL), the Huntsville Operations Support Center (HOSC) Scripting Language Processor (SLP), and the Spacecraft Control Language (SCL) offer script-commands that wrap tedious operations tasks into single calls. Since script-commands are interpreted, they also offer a certain amount of hands-on control that is highly valued in space ground operations. Although compiled programs seem to be unsuited for interactive user control and are more complex to develop, Marshall Space flight Center (MSFC) has developed a product called the Enhanced and Redesign Scripting (ERS) that makes use of the graphical and logical richness of a programming language while offering the hands-on and ease of control of a scripting language. ERS is currently used by the International Space Station (ISS) Payload Operations Integration Center (POIC) Cadre team members. ERS integrates spacecraft command mnemonics, telemetry measurements, and command and telemetry control procedures into a standard programming language, while making use of Microsoft's Visual Studio for developing Visual Basic (VB) or C# ground operations procedures. ERS also allows for script-style user control during procedure execution using a robust graphical user input and output feature. The availability of VB and C# programmers, and the richness of the languages and their development environment, has allowed ERS to lower our "script" development time and maintenance costs at the Marshall POIC.

Endothelin receptor-specific control of endoplasmic reticulum stress and apoptosis in the kidney

PubMed Central

De Miguel, Carmen; Hamrick, William C.; Hobbs, Janet L.; Pollock, David M.; Carmines, Pamela K.; Pollock, Jennifer S.

2017-01-01

Endothelin-1 (ET-1) promotes renal damage during cardiovascular disease; yet, the molecular mechanisms involved remain unknown. Endoplasmic reticulum (ER) stress, triggered by unfolded protein accumulation in the ER, contributes to apoptosis and organ injury. These studies aimed to determine whether the ET-1 system promotes renal ER stress development in response to tunicamycin. ETB deficient (ETB def) or transgenic control (TG-con) rats were used in the presence or absence of ETA receptor antagonism. Tunicamycin treatment similarly increased cortical ER stress markers in both rat genotypes; however, only ETB def rats showed a 14–24 fold increase from baseline for medullary GRP78, sXBP-1, and CHOP. Pre-treatment of TG-con rats with the ETA blocker ABT-627 for 1 week prior to tunicamycin injection significantly reduced the ER stress response in cortex and medulla, and also inhibited renal apoptosis. Pre-treatment with ABT-627 failed to decrease renal ER stress and apoptosis in ETB def rats. In conclusion, the ET-1 system is important for the development of tunicamycin-induced renal ER stress and apoptosis. ETA receptor activation induces renal ER stress genes and apoptosis, while functional activation of the ETB receptor has protective effects. These results highlight targeting the ETA receptor as a therapeutic approach against ER stress-induced kidney injury. PMID:28230089

Endothelin receptor-specific control of endoplasmic reticulum stress and apoptosis in the kidney.

PubMed

De Miguel, Carmen; Hamrick, William C; Hobbs, Janet L; Pollock, David M; Carmines, Pamela K; Pollock, Jennifer S

2017-02-23

Endothelin-1 (ET-1) promotes renal damage during cardiovascular disease; yet, the molecular mechanisms involved remain unknown. Endoplasmic reticulum (ER) stress, triggered by unfolded protein accumulation in the ER, contributes to apoptosis and organ injury. These studies aimed to determine whether the ET-1 system promotes renal ER stress development in response to tunicamycin. ET B deficient (ET B def) or transgenic control (TG-con) rats were used in the presence or absence of ET A receptor antagonism. Tunicamycin treatment similarly increased cortical ER stress markers in both rat genotypes; however, only ET B def rats showed a 14-24 fold increase from baseline for medullary GRP78, sXBP-1, and CHOP. Pre-treatment of TG-con rats with the ET A blocker ABT-627 for 1 week prior to tunicamycin injection significantly reduced the ER stress response in cortex and medulla, and also inhibited renal apoptosis. Pre-treatment with ABT-627 failed to decrease renal ER stress and apoptosis in ET B def rats. In conclusion, the ET-1 system is important for the development of tunicamycin-induced renal ER stress and apoptosis. ET A receptor activation induces renal ER stress genes and apoptosis, while functional activation of the ET B receptor has protective effects. These results highlight targeting the ET A receptor as a therapeutic approach against ER stress-induced kidney injury.

Endoplasmic reticulum stress in the pathogenesis of hypertension.

PubMed

Young, Colin N

2017-08-01

What is the topic of this review? This review highlights the emerging role of disruptions in endoplasmic reticulum (ER) function, namely ER stress, as a contributor to hypertension. What advances does it highlight? This review presents an integrative view of ER stress in cardiovascular control systems, including systems within the brain, kidney and peripheral vasculature, as related to development of hypertension. The endoplasmic reticulum (ER) is a cellular organelle specialized in the synthesis, folding, assembly and modification of proteins. In situations of increased protein demand, complex signalling pathways, termed the unfolded protein response, influence a series of cellular feedback loops to control ER function strictly. Although this is initially a compensatory attempt to maintain cellular homeostasis, chronic activation of the unfolded protein response, known as ER stress, leads to sustained changes in cellular function. A growing body of literature points to ER stress in diverse cardioregulatory systems, including the brain, kidney and vasculature, as central to the development of hypertension. Here, these recent findings from essential and obesity-related forms of hypertension are highlighted in an integrative manner, with discussion of the potential upstream causes and downstream consequences of ER stress. Given that hypertension is a leading medical and socio-economic global challenge, emerging findings suggest that targeting ER stress might represent a viable strategy for the treatment of hypertensive disease. © 2017 The Authors. Experimental Physiology © 2017 The Physiological Society.

The Error Reporting in the ATLAS TDAQ System

NASA Astrophysics Data System (ADS)

Kolos, Serguei; Kazarov, Andrei; Papaevgeniou, Lykourgos

2015-05-01

The ATLAS Error Reporting provides a service that allows experts and shift crew to track and address errors relating to the data taking components and applications. This service, called the Error Reporting Service (ERS), gives to software applications the opportunity to collect and send comprehensive data about run-time errors, to a place where it can be intercepted in real-time by any other system component. Other ATLAS online control and monitoring tools use the ERS as one of their main inputs to address system problems in a timely manner and to improve the quality of acquired data. The actual destination of the error messages depends solely on the run-time environment, in which the online applications are operating. When an application sends information to ERS, depending on the configuration, it may end up in a local file, a database, distributed middleware which can transport it to an expert system or display it to users. Thanks to the open framework design of ERS, new information destinations can be added at any moment without touching the reporting and receiving applications. The ERS Application Program Interface (API) is provided in three programming languages used in the ATLAS online environment: C++, Java and Python. All APIs use exceptions for error reporting but each of them exploits advanced features of a given language to simplify the end-user program writing. For example, as C++ lacks language support for exceptions, a number of macros have been designed to generate hierarchies of C++ exception classes at compile time. Using this approach a software developer can write a single line of code to generate a boilerplate code for a fully qualified C++ exception class declaration with arbitrary number of parameters and multiple constructors, which encapsulates all relevant static information about the given type of issues. When a corresponding error occurs at run time, the program just need to create an instance of that class passing relevant values to one of the available class constructors and send this instance to ERS. This paper presents the original design solutions exploited for the ERS implementation and describes how it was used during the first ATLAS run period. The cross-system error reporting standardization introduced by ERS was one of the key points for the successful implementation of automated mechanisms for online error recovery.

[Study on the relationship between ER Rsa I gene polymorphism and children's dental fluorosis].

PubMed

Ba, Yue; Li, Hai-Xia; Yin, Gong-Ju; Wu, Wei-Hua; Yu, Bo; Cheng, Xue-Min; Cui, Liu-Xin

2009-09-01

To explore the distribution of ER Rsa I genotype in children who lived in the areas with or without high fluoride, and evaluate the relationship between ER Rsa I gene polymorphism and children's dental fluorosis. Children aged 8 to 12 years, born and raised in high fluoride areas and control areas in two counties of Henan Province were recruited. The Rsa I marker of ER gene was genotyped in 237 children composed of both dental fluorosis cases and controls by PCR-RFLP procedure. Urine fluoride was detected with fluoride ion selective electrode method. The frequency distribution of ER Rsa I genotype was rr 60.81% (45/74), Rr 27.02% (20/74), RR 12.16% (9/74) in children with fluorosis; rr 73.91% (51/69), Rr 20.29% (14/69), RR 5.80% (4/69) in children without fluorosis from high fluoride areas, and rr 63.83% (60/94), Rr 34.04% (32/94), RR 2.13% (2/94) in the children without fluorosis from control areas respectively. There were no significant differences in the three groups (P>0.05), but children carrying allele R of ER Rsa I had a significantly increased risk of dental fluorosis (OR=1.821, 95% CI: 1.013-3.274) compared to children carrying the allele r in endemic fluorosis areas. Although no significant difference was found in ER Rsa I genotype between cases and non-dental fluorosis in endemic fluorosis areas, children carrying R allele of ER Rsa I had a higher risk compared to children carrying r allele, and the further study is needed.

Prx1 and 3.2 kb Col1a1 promoters target distinct bone cell populations in transgenic mice

PubMed Central

Ouyang, Zhufeng; Chen, Zhijun; Ishikawa, Masakazu; Yue, Xiuzhen; Kawanami, Aya; Leahy, Patrick; Greenfield, Edward M.; Murakami, Shunichi

2014-01-01

Bones consist of a number of cell types including osteoblasts and their precursor cells at various stages of differentiation. To analyze cellular organization within the bone, we generated Col1a1CreER-DsRed transgenic mice that express, in osteoblasts, CreER and DsRed under the control of a mouse 3.2 kb Col1a1 promoter. We further crossed Col1a1CreER-DsRed mice with Prx1CreER-GFP mice that express CreER and GFP in osteochondro progenitor cells under the control of a 2.4 kb Prx1 promoter. Since the 3.2 kb Col1a1 promoter becomes active in osteoblasts at early stages of differentiation, and Prx1CreER-GFP-expressing periosteal cells show endogenous Col1a1 expression, we expected to find a cell population in which both the 2.4 kb Prx1 promoter and the 3.2 kb Col1a1 promoter are active. However, our histological and flow cytometric analyses demonstrated that these transgenes are expressed in distinct cell populations. In the periosteum of long bones, Col1a1CreER-DsRed is expressed in the innermost layer directly lining the bone surface, while Prx1CreER-GFP-expressing cells are localized immediately outside of the Col1a1CreER-DsRed-expressing osteoblasts. In the calvaria, Prx1CreER-GFP-expressing cells are also localized in the cranial suture mesenchyme. Our experiments further showed that Col1a1CreER-DsRed-expressing cells lack chondrogenic potential, while the Prx1CreER-GFP-expressing cells show both chondrogenic and osteogenic potential. Our results indicate that Col1a1CreER-DsRed-expressing cells are committed osteoblasts, while Prx1CreER-GFP-expressing cells are osteochondro progenitor cells. The Prx1CreER-GFP and Col1a1CreER-DsRed transgenes will offer novel approaches for analyzing lineage commitment and early stages of osteoblast differentiation under physiologic and pathologic conditions. PMID:24513582

Validation of QuEChERS analytical technique for organochlorines and synthetic pyrethroids in fruits and vegetables using GC-ECD.

PubMed

Dubey, J K; Patyal, S K; Sharma, Ajay

2018-03-19

In the present day scenario of increasing awareness and concern about the pesticides, it is very important to ensure the quality of data being generated in pesticide residue analysis. To impart confidence in the products, terms like quality assurance and quality control are used as an integral part of quality management. In order to ensure better quality of results in pesticide residue analysis, validation of analytical methods to be used is extremely important. Keeping in view the importance of validation of method, the validation of QuEChERS (quick, easy, cheap, effective, rugged, and safe) a multiresidue method for extraction of 13 organochlorines and seven synthetic pyrethroids in fruits and vegetables followed by GC ECD for quantification was done so as to use this method for analysis of samples received in the laboratory. The method has been validated as per the Guidelines issued by SANCO (French words Sante for Health and Consommateurs for Consumers) in accordance with their document SANCO/XXXX/2013. Various parameters analyzed, viz., linearity, specificity, repeatability, reproducibility, and ruggedness were found to have acceptable values with a per cent RSD of less than 10%. Limit of quantification (LOQ) for the organochlorines was established to be 0.01 and 0.05 mg kg -1 for the synthetic pyrethroids. The uncertainty of the measurement (MU) for all these compounds ranged between 1 and 10%. The matrix-match calibration was used to compensate the matrix effect on the quantification of the compounds. The overall recovery of the method ranged between 80 and 120%. These results demonstrate the applicability and acceptability of this method in routine estimation of pesticide residues of these 20 pesticides in the fruits and vegetables by the laboratory.

Effort-reward imbalance at work, over-commitment personality and diet quality in Central and Eastern European populations.

PubMed

Chen, Sung-Wei; Peasey, Anne; Stefler, Denes; Malyutina, Sofia; Pajak, Andrzej; Kubinova, Ruzena; Chan, Jen-Hui; Bobak, Martin; Pikhart, Hynek

2016-04-14

The aims of this study were to investigate the associations between work stress defined by the effort-reward imbalance (ERI) model and diet quality and to examine the potential role of over-commitment (OC) personality in ERI-diet relationships. A cross-sectional study was conducted in random population samples of 6340 men and 5792 women (age 45-69 years) from the Czech Republic, Russia and Poland. Dietary data were collected using FFQ. The healthy diet indicator (HDI) was constructed using eight nutrient/food intakes (HDI components) to reflect the adherence to WHO dietary guideline. The extent of imbalance between effort and reward was measured by the effort:reward (ER) ratio; the effort score was the numerator and the reward score was multiplied by a factor adjusting for unequal number of items in the denominator. Logistic regression and linear regression were used to assess the associations between exposures (ER ratio and OC) and outcomes (HDI components and HDI) after adjustment for confounders and mediators. The results showed that high ER ratio and high OC were significantly associated with unhealthy diet quality. For a 1-SD increase in the ER ratio, HDI was reduced by 0·030 and 0·033 sd in men and women, and for a 1-SD increase in OC, HDI was decreased by 0·036 and 0·032 sd in men and women, respectively. The modifying role of OC in ERI-diet relationships was non-significant. To improve diet quality at workplace, a multiple-level approach combining organisational intervention for work stress and individual intervention for vulnerable personality is recommended.

Endoplasmic reticulum turnover: ER-phagy and other flavors in selective and non-selective ER clearance.

PubMed

Fregno, Ilaria; Molinari, Maurizio

2018-01-01

The endoplasmic reticulum (ER) is a highly dynamic organelle in eukaryotic cells. It is deputed to lipid and protein biosynthesis, calcium storage, and the detoxification of various exogenous and endogenous harmful compounds. ER activity and size must be adapted rapidly to environmental and developmental conditions or biosynthetic demand. This is achieved on induction of thoroughly studied transcriptional/translational programs defined as "unfolded protein responses" that increase the ER volume and the expression of ER-resident proteins regulating the numerous ER functions. Less understood are the lysosomal catabolic processes that maintain ER size at steady state, that prevent excessive ER expansion during ER stresses, or that ensure return to physiologic ER size during recovery from ER stresses. These catabolic processes may also be activated to remove ER subdomains where proteasome-resistant misfolded proteins or damaged lipids have been segregated. Insights into these catabolic mechanisms have only recently emerged with the identification of so-called ER-phagy receptors, which label specific ER subdomains for selective lysosomal delivery for clearance. Here, in eight chapters and one addendum, we comment on recent advances in ER turnover pathways induced by ER stress, nutrient deprivation, misfolded proteins, and live bacteria. We highlight the role of yeast (Atg39 and Atg40) and mammalian (FAM134B, SEC62, RTN3, and CCPG1) ER-phagy receptors and of autophagy genes in selective and non-selective catabolic processes that regulate cellular proteostasis by controlling ER size, turnover, and function.

Effort-reward imbalance and quality of life of healthcare workers in military hospitals: a cross-sectional study

PubMed Central

2012-01-01

Background Taiwan’s National Defense Bureau has been merging its hospitals and adjusting hospital accreditation levels since the beginning of 2006. These changes have introduced many stressors to the healthcare workers in these hospitals. This study investigates the association between job stress, psychological morbidity and quality of life in healthcare workers in three military hospitals. Methods We posted surveys to 1269 healthcare workers in three military hospitals located in southern Taiwan. The surveys included the General Health Questionnaire (GHQ), the World Health Organization Quality of Life Questionnaire (WHOQOL-BREF), and the Effort-Reward Imbalance (ERI) Questionnaire. High effort-reward (ER) ratio and overcommitment were defined when scores fell into the upper tertile of the total distribution. Results The survey was completed by 791 healthcare workers. On average, women reported a higher ERI than men. High ERI was associated with younger age, higher psychological morbidity, and poor physical and psychological QOL domains in this population. High ER ratio and high overcommitment were associated with psychological morbidity and poor QOL in both sexes. However, high ER ratio was not significantly associated with the social QOL domain in either sexes or the physical QOL domain in males. Conclusions There was a clear association between ERI and QOL in the healthcare workers in the military hospitals under reorganization and accreditation in this study. We found ER ratio and overcommitment to be suitable indicators of job stress. PMID:22958365

78 FR 4857 - Agency Information Collection Activities: Petition for Amerasian, Widow(er), or Special Immigrant...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-01-23

... DEPARTMENT OF HOMELAND SECURITY U.S. Citizenship and Immigration Services [OMB Control Number 1615-0020] Agency Information Collection Activities: Petition for Amerasian, Widow(er), or Special Immigrant...(er), or Special Immigrant (3) Agency form number, if any, and the applicable component of the DHS...

77 FR 65704 - Agency Information Collection Activities: Petition for Amerasian, Widow(er), or Special Immigrant...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-10-30

... DEPARTMENT OF HOMELAND SECURITY U.S. Citizenship and Immigration Services [OMB Control Number 1615-0020] Agency Information Collection Activities: Petition for Amerasian, Widow(er), or Special Immigrant.../Collection: Petition for Amerasian, Widow(er), or Special Immigrant. (3) Agency form number, if any, and the...

A role for post-transcriptional control of endoplasmic reticulum dynamics and function in C. elegans germline stem cell maintenance.

PubMed

Maheshwari, Richa; Pushpa, Kumari; Subramaniam, Kuppuswamy

2016-09-01

Membrane-bound receptors, which are crucial for mediating several key developmental signals, are synthesized on endoplasmic reticulum (ER). The functional integrity of ER must therefore be important for the regulation of at least some developmental programs. However, the developmental control of ER function is not well understood. Here, we identify the C. elegans protein FARL-11, an ortholog of the mammalian STRIPAK complex component STRIP1/2 (FAM40A/B), as an ER protein. In the C. elegans embryo, we find that FARL-11 is essential for the cell cycle-dependent morphological changes of ER and for embryonic viability. In the germline, FARL-11 is required for normal ER morphology and for membrane localization of the GLP-1/Notch receptor involved in germline stem cell (GSC) maintenance. Furthermore, we provide evidence that PUF-8, a key translational regulator in the germline, promotes the translation of farl-11 mRNA. These findings reveal that ER form and function in the C. elegans germline are post-transcriptionally regulated and essential for the niche-GSC signaling mediated by GLP-1. © 2016. Published by The Company of Biologists Ltd.

Evaluation of the bond strength of resin cements used to lute ceramics on laser-etched dentin.

PubMed

Giray, Figen Eren; Duzdar, Lale; Oksuz, Mustafa; Tanboga, Ilknur

2014-07-01

The purpose of this study was to investigate the shear bond strength (SBS) of two different adhesive resin cements used to lute ceramics on laser-etched dentin. Erbium, chromium: yttrium, scandium, gallium, garnet (Er,Cr:YSGG) laser irradiation has been claimed to improve the adhesive properties of dentin, but results to date have been controversial, and its compatibility with existing adhesive resin cements has not been conclusively determined. Two adhesive cements, one "etch-and-rinse" [Variolink II (V)] and one "self-etch" [Clearfil Esthetic Cement (C)] luting cement, were used to lute ceramic blocks (Vita Celay Blanks, Vita) onto dentin surfaces. In total, 80 dentin specimens were distributed randomly into eight experimental groups according to the dentin surface-etching technique used Er,Cr:YSGG laser and Er:YAG laser: (1) 37% orthophosphoric acid+V (control group), (2) Er,Cr:YSGG laser+V, (3) Er,Cr:YSGG laser+acid+V, (4) Er:YAG laser+V, (5) Er:YAG laser+acid+V, (6) C, (7) Er,Cr:YSGG laser+C, and (8) Er:YAG laser+C. Following these applications, the ceramic discs were bonded to prepared surfaces and were shear loaded in a universal testing machine until fracture. SBS was recorded for each group in MPa. Shear test values were evaluated statistically using the Mann-Whitney U test. No statistically significant differences were evident between the control group and the other groups (p>0.05). The Er,Cr:YSGG laser+A+V group demonstrated significantly higher SBS than did the Er,Cr:YSGG laser+V group (p=0.034). The Er,Cr:YSGG laser+C and Er:YAG laser+C groups demonstrated significantly lower SBS than did the C group (p<0.05). Dentin surfaces prepared with lasers may provide comparable ceramic bond strengths, depending upon the adhesive cement used.

Ga flux dependence of Er-doped GaN luminescent thin films

NASA Astrophysics Data System (ADS)

Lee, D. S.; Steckl, A. J.

2002-02-01

Er-doped GaN thin films have been grown on (111) Si substrates with various Ga fluxes in a radio frequency plasma molecular beam epitaxy system. Visible photoluminescence (PL) and electroluminescence (EL) emission at 537/558 nm and infrared (IR) PL emission at 1.5 μm from GaN:Er films exhibited strong dependence on the Ga flux. Both visible and IR PL and visible EL increase with the Ga flux up to the stoichiometric growth condition, as determined by growth rate saturation. Beyond this condition, all luminescence levels abruptly dropped to the detection limit with increasing Ga flux. The Er concentration, measured by secondary ion mass spectroscopy and Rutherford backscattering, decreases with increasing Ga flux under N-rich growth conditions and remains constant above the stoichiometric growth condition. X-ray diffraction indicated that the crystalline quality of the GaN:Er film was improved with increasing Ga flux up to stoichiometric growth condition and then saturated. Er ions in the films grown under N-rich conditions appear much more optically active than those in the films grown under Ga-rich conditions.

Fabrication and Sintering Behavior of Er:SrF2 Transparent Ceramics using Chemically Derived Powder

PubMed Central

Liu, Jun; Liu, Peng; Wang, Jun; Xu, Xiaodong; Li, Dongzhen; Zhang, Jian; Nie, Xinming

2018-01-01

In this paper, we report the fabrication of high-quality 5 at. % Er3+ ions doped SrF2 transparent ceramics, the potential candidate materials for a mid-infrared laser-gain medium by hot-pressing at 700 °C for 40 h using a chemically-derived powder. The phase structure, densification, and microstructure evolution of the Er:SrF2 ceramics were systematically investigated. In addition, the grain growth kinetic mechanism of Er:SrF2 was clarified. The results showed lattice diffusion to be the grain growth mechanism in the Er:SrF2 transparent ceramic of which highest in-line transmittance reached 92% at 2000 nm, i.e., very close to the theoretical transmittance value of SrF2 single crystal. Furthermore, the emission spectra showed that the strongest emission band was located at 2735 nm. This means that it is possible to achieve a laser output of approximately 2.7 μm in the 5 at. % Er3+ ions doped SrF2 transparent ceramics. PMID:29565322

Aging induced ER stress alters sleep and sleep homeostasis

PubMed Central

Brown, Marishka K.; Chan, May T.; Zimmerman, John E.; Pack, Allan I.; Jackson, Nicholas E.; Naidoo, Nirinjini

2014-01-01

Alterations in the quality, quantity and architecture of baseline and recovery sleep have been shown to occur during aging. Sleep deprivation induces endoplasmic reticular (ER) stress and upregulates a protective signaling pathway termed the unfolded protein response (UPR). The effectiveness of the adaptive UPR is diminished by age. Previously, we showed that endogenous chaperone levels altered recovery sleep in Drosophila melanogaster. We now report that acute administration of the chemical chaperone sodium 4-phenylbutyrate (PBA) reduces ER stress and ameliorates age-associated sleep changes in Drosophila. PBA consolidates both baseline and recovery sleep in aging flies. The behavioral modifications of PBA are linked to its suppression of ER stress. PBA decreased splicing of x-box binding protein 1 (XBP1) and upregulation of phosphorylated elongation initiation factor 2 α (p-eIF2α), in flies that were subjected to sleep deprivation. We also demonstrate that directly activating ER stress in young flies fragments baseline sleep and alters recovery sleep. Alleviating prolonged/sustained ER stress during aging contributes to sleep consolidation and improves recovery sleep/ sleep debt discharge. PMID:24444805

Characterization of WDR20: A new regulator of the ERAD machinery.

PubMed

Ju, Lin-Gao; Lin, Xiang; Yan, Dong; Li, Qing-Lan; Wu, Min; Li, Lian-Yun

2018-07-01

ERAD is an important process of protein quality control that eliminates misfolded or unassembled proteins from ER. Before undergoing proteasome degradation, the misfolded proteins are dislocated from ER membrane into cytosol, which requires the AAA ATPase p97/VCP and its cofactor, the NPL4-UFD1 dimer. Here, we performed a CRISPR-based screen and identify many candidates for ERAD regulation. We further confirmed four proteins, FBOX2, TRIM6, UFL1 and WDR20, are novel regulators for ERAD. Then the molecular mechanism for WDR20 in ERAD is further characterized. Depletion of WDR20 inhibits the degradation of TCRα, a typical ERAD substrate, while WDR20 overexpression reduces TCRα protein level. WDR20 associates with TCRα and central regulators of the ERAD system, p97, GP78 and HRD1. A portion of WDR20 localizes to the ER-containing microsomal membrane. WDR20 expression increases TCRα ubiquitination, and HRD1 E3 ligase is essential for the process. WDR20 seems to serve as an adaptor protein to mediate the interaction between p97 and TCRα. Our study provides novel candidates and reveals an unexpected role of WDR20 in ERAD regulation. Copyright © 2018 Elsevier B.V. All rights reserved.

Impaired down-regulation of negative emotion in self-referent social situations in bipolar disorder: A pilot study of a novel experimental paradigm.

PubMed

Kjærstad, Hanne L; Vinberg, Maj; Goldin, Philippe R; Køster, Nicolai; Støttrup, Mette Marie D; Knorr, Ulla; Kessing, Lars V; Miskowiak, Kamilla W

2016-04-30

Emotion dysregulation is a core feature of bipolar disorder (BD) that persists into periods of remission. Neuroimaging studies show aberrant neural responses during emotion regulation (ER) in patients with BD relative to healthy controls, but behavioural evidence for ER deficits is sparse and conflicting. This study aimed to explore ER in BD using a novel, personally relevant experimental paradigm. Twenty patients with BD and 20 patients with unipolar disorder (UD), in full or partial remission, and 20 healthy controls were given a novel computerised test. Participants were instructed to react naturally or dampen their emotional response to positive and negative social scenarios and associated self-beliefs. They were also given an established experimental task for comparison, involving reappraisal of negative affective picture stimuli, as well as a questionnaire of habitual ER strategies. BD patients showed reduced ability to down-regulate emotional responses in negative, but not positive, social scenarios relative to healthy controls and UD patients. In contrast, there were no between-group differences in the established ER task or in self-reported habitual reappraisal strategies. Findings highlight the novel social scenario paradigm as a sensitive test for detection of ER difficulties in BD. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

The comER Gene Plays an Important Role in Biofilm Formation and Sporulation in both Bacillus subtilis and Bacillus cereus.

PubMed

Yan, Fang; Yu, Yiyang; Wang, Luyao; Luo, Yuming; Guo, Jian-Hua; Chai, Yunrong

2016-01-01

Bacteria adopt alternative cell fates during development. In Bacillus subtilis, the transition from planktonic growth to biofilm formation and sporulation is controlled by a complex regulatory circuit, in which the most important event is activation of Spo0A, a transcription factor and a master regulator for genes involved in both biofilm formation and sporulation. In B. cereus, the regulatory pathway controlling biofilm formation and cell differentiation is much less clear. In this study, we show that a novel gene, comER, plays a significant role in biofilm formation as well as sporulation in both B. subtilis and B. cereus. Mutations in the comER gene result in defects in biofilm formation and a delay in spore formation in the two Bacillus species. Our evidence supports the idea that comER may be part of the regulatory circuit that controls Spo0A activation. comER likely acts upstream of sda, a gene encoding a small checkpoint protein for both sporulation and biofilm formation, by blocking the phosphor-relay and thereby Spo0A activation. In summary, our studies outlined a conserved, positive role for comER, a gene whose function was previously uncharacterized, in the regulation of biofilm formation and sporulation in the two Bacillus species.

The comER Gene Plays an Important Role in Biofilm Formation and Sporulation in both Bacillus subtilis and Bacillus cereus

PubMed Central

Yan, Fang; Yu, Yiyang; Wang, Luyao; Luo, Yuming; Guo, Jian-hua; Chai, Yunrong

2016-01-01

Bacteria adopt alternative cell fates during development. In Bacillus subtilis, the transition from planktonic growth to biofilm formation and sporulation is controlled by a complex regulatory circuit, in which the most important event is activation of Spo0A, a transcription factor and a master regulator for genes involved in both biofilm formation and sporulation. In B. cereus, the regulatory pathway controlling biofilm formation and cell differentiation is much less clear. In this study, we show that a novel gene, comER, plays a significant role in biofilm formation as well as sporulation in both B. subtilis and B. cereus. Mutations in the comER gene result in defects in biofilm formation and a delay in spore formation in the two Bacillus species. Our evidence supports the idea that comER may be part of the regulatory circuit that controls Spo0A activation. comER likely acts upstream of sda, a gene encoding a small checkpoint protein for both sporulation and biofilm formation, by blocking the phosphor-relay and thereby Spo0A activation. In summary, our studies outlined a conserved, positive role for comER, a gene whose function was previously uncharacterized, in the regulation of biofilm formation and sporulation in the two Bacillus species. PMID:27446060

Torque Measurement of 3-DOF Haptic Master Operated by Controllable Electrorheological Fluid

NASA Astrophysics Data System (ADS)

Oh, Jong-Seok; Choi, Seung-Bok; Lee, Yang-Sub

2015-02-01

This work presents a torque measurement method of 3-degree-of-freedom (3-DOF) haptic master featuring controllable electrorheological (ER) fluid. In order to reflect the sense of an organ for a surgeon, the ER haptic master which can generate the repulsive torque of an organ is utilized as a remote controller for a surgery robot. Since accurate representation of organ feeling is essential for the success of the robot-assisted surgery, it is indispensable to develop a proper torque measurement method of 3-DOF ER haptic master. After describing the structural configuration of the haptic master, the torque models of ER spherical joint are mathematically derived based on the Bingham model of ER fluid. A new type of haptic device which has pitching, rolling, and yawing motions is then designed and manufactured using a spherical joint mechanism. Subsequently, the field-dependent parameters of the Bingham model are identified and generating repulsive torque according to applied electric field is measured. In addition, in order to verify the effectiveness of the proposed torque model, a comparative work between simulated and measured torques is undertaken.

Performance Analysis of AN Engine Mount Featuring ER Fluids and Piezoactuators

NASA Astrophysics Data System (ADS)

Choi, S. H.; Choi, Y. T.; Choi, S. B.; Cheong, C. C.

Conventional rubber mounts and various types of passive or semi-active hydraulic engine mounts for a passenger vehicle have their own functional aims on the limited frequency band in the broad engine operating frequency range. In order to achieve high system performance over all frequency ranges of the engine operation, a new type of engine mount featuring electro-rheological(ER) fluids and piezoactuators is proposed in this study. A mathematical model of the proposed engine mount is derived using the bond graph method which is inherently adequate to model the interconnected hydromechanical system. In the low frequency domain, the ER fluid is activated upon imposing an electric field for vibration isolation while the piezoactuator is activated in the high frequency domain. A neuro-control algorithm is utilized to determine control electric field for the ER fluid, and H∞ control technique is adopted for the piezoactuator Comparative works between the proposed and single-actuating(ER fluid only or piezoactuator only) engine mounts are undertaken by evaluating force transmissibility over a wide operating frequency range.

Influence of estrogen receptor status on dietary risk factors for breast cancer.

PubMed Central

Hislop, T G; Kan, L; Coldman, A J; Band, P R; Brauer, G

1988-01-01

It has been suggested that the relation between diet and breast cancer may depend on estrogen receptor (ER) status. We examined the responses to a self-administered questionnaire on frequency of consumption of various foods by 493 women with breast cancer (160 with ER-negative tumours and 333 with ER-positive tumours) and 527 controls whose menopausal status was known. Analysis of the reported consumption of foods selected for their fat or carotene content showed no clear distinction in dietary factors between the ER-negative and ER-positive groups. Frequent consumption of meat fats generally increased the risk of both ER-negative and ER-positive tumours; there were no clear trends in risk associated with vegetable consumption for either ER group. Fish was the only item affecting the risk for ER-negative and ER-positive tumours differently, frequent consumption reducing the risk for the former (p = 0.02). The results do not support the hypothesis that ER status influences the relation between dietary fat consumption and risk of breast cancer. PMID:3342359

ER trapping reveals Golgi enzymes continually revisit the ER through a recycling pathway that controls Golgi organization

PubMed Central

Sengupta, Prabuddha; Satpute-Krishnan, Prasanna; Seo, Arnold Y.; Burnette, Dylan T.; Patterson, George H.; Lippincott-Schwartz, Jennifer

2015-01-01

Whether Golgi enzymes remain localized within the Golgi or constitutively cycle through the endoplasmic reticulum (ER) is unclear, yet is important for understanding Golgi dependence on the ER. Here, we demonstrate that the previously reported inefficient ER trapping of Golgi enzymes in a rapamycin-based assay results from an artifact involving an endogenous ER-localized 13-kD FK506 binding protein (FKBP13) competing with the FKBP12-tagged Golgi enzyme for binding to an FKBP-rapamycin binding domain (FRB)-tagged ER trap. When we express an FKBP12-tagged ER trap and FRB-tagged Golgi enzymes, conditions precluding such competition, the Golgi enzymes completely redistribute to the ER upon rapamycin treatment. A photoactivatable FRB-Golgi enzyme, highlighted only in the Golgi, likewise redistributes to the ER. These data establish Golgi enzymes constitutively cycle through the ER. Using our trapping scheme, we identify roles of rab6a and calcium-independent phospholipase A2 (iPLA2) in Golgi enzyme recycling, and show that retrograde transport of Golgi membrane underlies Golgi dispersal during microtubule depolymerization and mitosis. PMID:26598700

Functional shoulder ratios with high velocities of shoulder internal rotation are most sensitive to determine shoulder rotation torque imbalance: a cross-sectional study with elite handball players and controls.

PubMed

Castro, Marcelo Peduzzi de; Fonseca, Pedro; Morais, Sara Tribuzi; Borgonovo-Santos, Márcio; Coelho, Eduardo Filipe Cruz; Ribeiro, Daniel Cury; Vilas-Boas, João Paulo

2017-12-04

The aim of the present study was to determine which approach to calculating shoulder ratios is the most sensitive for determining shoulder torque imbalance in handball players. Twenty-six participants (handball athletes, n = 13; healthy controls, n = 13) performed isokinetic concentric and eccentric shoulder internal rotation (IR) and external rotation (ER) assessment at 60, 180 and 300°/s. We used eight approaches to calculating shoulder ratios: four concentric (i.e. concentric ER torque divided by concentric IR torque), and four functional (i.e. eccentric ER torque divided by concentric IR torque) at the velocities of 60, 180 and 300°/s for both IR and ER, and combining 60°/s of ER and 300°/s of IR. A three factorial ANOVA (factors: shoulder ratios, upper limb sides, and groups) along with Tukey's post-hoc analysis, and effect sizes were calculated. The findings suggested the functional shoulder ratio combining 60°/s of ER and 300°/s of IR is the most sensitive to detect differences between upper limbs for handball players, and between players and controls for the dominant side. The functional shoulder ratio combining 60°/s of ER with 300°/s of IR seems to present advantages over the other approaches for identifying upper limb asymmetries and differences in shoulder torque balance related to throwing.

Dynamic survey of mitochondria by ubiquitin

PubMed Central

Escobar-Henriques, Mafalda; Langer, Thomas

2014-01-01

Ubiquitin is a post-translational modifier with proteolytic and non-proteolytic roles in many biological processes. At mitochondria, it performs regulatory homeostatic functions and contributes to mitochondrial quality control. Ubiquitin is essential for mitochondrial fusion, regulates mitochondria-ER contacts, and participates in maternal mtDNA inheritance. Under stress, mitochondrial dysfunction induces ubiquitin-dependent responses that involve mitochondrial proteome remodeling and culminate in organelle removal by mitophagy. In addition, many ubiquitin-dependent mechanisms have been shown to regulate innate immune responses and xenophagy. Here, we review the emerging roles of ubiquitin at mitochondria. PMID:24569520

Mutations in the pancreatic secretory enzymes CPA1 and CPB1 are associated with pancreatic cancer.

PubMed

Tamura, Koji; Yu, Jun; Hata, Tatsuo; Suenaga, Masaya; Shindo, Koji; Abe, Toshiya; MacGregor-Das, Anne; Borges, Michael; Wolfgang, Christopher L; Weiss, Matthew J; He, Jin; Canto, Marcia Irene; Petersen, Gloria M; Gallinger, Steven; Syngal, Sapna; Brand, Randall E; Rustgi, Anil; Olson, Sara H; Stoffel, Elena; Cote, Michele L; Zogopoulos, George; Potash, James B; Goes, Fernando S; McCombie, Richard W; Zandi, Peter P; Pirooznia, Mehdi; Kramer, Melissa; Parla, Jennifer; Eshleman, James R; Roberts, Nicholas J; Hruban, Ralph H; Klein, Alison Patricia; Goggins, Michael

2018-05-01

To evaluate whether germline variants in genes encoding pancreatic secretory enzymes contribute to pancreatic cancer susceptibility, we sequenced the coding regions of CPB1 and other genes encoding pancreatic secretory enzymes and known pancreatitis susceptibility genes ( PRSS1 , CPA1 , CTRC , and SPINK1 ) in a hospital series of pancreatic cancer cases and controls. Variants in CPB1 , CPA1 (encoding carboxypeptidase B1 and A1), and CTRC were evaluated in a second set of cases with familial pancreatic cancer and controls. More deleterious CPB1 variants, defined as having impaired protein secretion and induction of endoplasmic reticulum (ER) stress in transfected HEK 293T cells, were found in the hospital series of pancreatic cancer cases (5/986, 0.5%) than in controls (0/1,045, P = 0.027). Among familial pancreatic cancer cases, ER stress-inducing CPB1 variants were found in 4 of 593 (0.67%) vs. 0 of 967 additional controls ( P = 0.020), with a combined prevalence in pancreatic cancer cases of 9/1,579 vs. 0/2,012 controls ( P < 0.01). More ER stress-inducing CPA1 variants were also found in the combined set of hospital and familial cases with pancreatic cancer than in controls [7/1,546 vs. 1/2,012; P = 0.025; odds ratio, 9.36 (95% CI, 1.15-76.02)]. Overall, 16 (1%) of 1,579 pancreatic cancer cases had an ER stress-inducing CPA1 or CPB1 variant, compared with 1 of 2,068 controls ( P < 0.00001). No other candidate genes had statistically significant differences in variant prevalence between cases and controls. Our study indicates ER stress-inducing variants in CPB1 and CPA1 are associated with pancreatic cancer susceptibility and implicate ER stress in pancreatic acinar cells in pancreatic cancer development.

European union standards for tuberculosis care.

PubMed

Migliori, G B; Zellweger, J P; Abubakar, I; Ibraim, E; Caminero, J A; De Vries, G; D'Ambrosio, L; Centis, R; Sotgiu, G; Menegale, O; Kliiman, K; Aksamit, T; Cirillo, D M; Danilovits, M; Dara, M; Dheda, K; Dinh-Xuan, A T; Kluge, H; Lange, C; Leimane, V; Loddenkemper, R; Nicod, L P; Raviglione, M C; Spanevello, A; Thomsen, V Ø; Villar, M; Wanlin, M; Wedzicha, J A; Zumla, A; Blasi, F; Huitric, E; Sandgren, A; Manissero, D

2012-04-01

The European Centre for Disease Prevention and Control (ECDC) and the European Respiratory Society (ERS) jointly developed European Union Standards for Tuberculosis Care (ESTC) aimed at providing European Union (EU)-tailored standards for the diagnosis, treatment and prevention of tuberculosis (TB). The International Standards for TB Care (ISTC) were developed in the global context and are not always adapted to the EU setting and practices. The majority of EU countries have the resources and capacity to implement higher standards to further secure quality TB diagnosis, treatment and prevention. On this basis, the ESTC were developed as standards specifically tailored to the EU setting. A panel of 30 international experts, led by a writing group and the ERS and ECDC, identified and developed the 21 ESTC in the areas of diagnosis, treatment, HIV and comorbid conditions, and public health and prevention. The ISTCs formed the basis for the 21 standards, upon which additional EU adaptations and supplements were developed. These patient-centred standards are targeted to clinicians and public health workers, providing an easy-to-use resource, guiding through all required activities to ensure optimal diagnosis, treatment and prevention of TB. These will support EU health programmes to identify and develop optimal procedures for TB care, control and elimination.

Dietary protein level and source differentially affect bone metabolism, strength, and intestinal calcium transporter expression during ad libitum and food-restricted conditions in male rats

USDA-ARS?s Scientific Manuscript database

High protein diets may attenuate bone loss during energy restriction (ER). The objective of the current study was to determine whether high protein diets suppress bone turnover and improve bone quality in rats during ER and whether dietary protein source affects this relationship. Eighty 12-week o...

Frequency and reliability of oestrogen receptor, progesterone receptor and HER2 in breast carcinoma determined by immunohistochemistry in Australasia: results of the RCPA Quality Assurance Program.

PubMed

Francis, Glenn D; Dimech, Margaret; Giles, Leanne; Hopkins, Alison

2007-11-01

Immunohistochemistry (IHC) has replaced radioligand binding assay for the determination of oestrogen receptor (ER) status in breast carcinoma. IHC is also used for assessment of progesterone receptor (PR) and HER2. The Royal College of Pathologists of Australasia (RCPA) Quality Assurance Program (QAP) introduced a breast markers module in 2003 to evaluate the performance of laboratories with IHC for ER, PR and HER2. An audit of laboratories reporting breast carcinomas was performed in 2005 and 2006 to evaluate in-house results. Laboratories were asked to submit the hormone receptor and HER2 status on each invasive breast carcinoma for the previous 6 month period up to a maximum of 100 cases. The time periods were 1 July 2004 to 31 December 2004, and 1 July 2005 to 31 December 2005. A total of 55 laboratories returned information for 2004 and 67 for 2005. Complete data on 8128 patients was returned for both surveys, 3353 cases for 2004 and 4775 for 2005. The results were similar for both surveys. Of the 8128 cases, 59.0% were ER+/PR+, 15.9% ER+/PR-, 2.4% ER-/PR+ and 22.7% ER-/PR-. HER2 data were submitted for a total of 6512 patients (excludes 52 patients with incomplete data sets); 17.1% were reported as 3+ positive on IHC, 12.5% as 2+ and 70.4% as negative. A laboratory audit was introduced into the RCPA QAP for breast markers due to concerns raised by participating laboratories about technical differences in supplied tissues for testing. This audit indicates that overall the results for ER, PR and HER2 fall inside established parameters. However, a number of individual laboratories do not meet the target values and variation in results would impact on patient treatment decisions.

Imputing at-work productivity loss using results of a randomized controlled trial comparing tapentadol extended release and oxycodone controlled release for osteoarthritis pain.

PubMed

Lerner, Debra; Chang, Hong; Rogers, William H; Benson, Carmela; Chow, Wing; Kim, Myoung S; Biondi, David

2012-08-01

: To determine the impact of tapentadol extended release (ER) versus placebo or oxycodone controlled release (CR) on the work productivity of adults with chronic moderate to severe knee osteoarthritis pain. : Using clinical trial data on pain outcomes, a validated methodology imputed treatment group differences in at-work productivity and associated differences in productivity costs (assuming a $100,000 annual salary per participant). : Imputed improvements in at-work productivity were significantly greater for tapentadol ER compared with either placebo (mean, 1.96% vs 1.51%; P = 0.001) or oxycodone CR (mean, 1.96% vs 1.40%; P < 0.001). Mean net savings per participant were $450 (P < 0.01) for tapentadol ER versus placebo and $560 (P = 0.001) for tapentadol ER versus oxycodone CR. : Effective osteoarthritis pain treatment also may help employees to function better at work and reduce their employers' productivity costs.

Phytoestrogens/insoluble fibers and colonic estrogen receptor β: Randomized, double-blind, placebo-controlled study

PubMed Central

Principi, Mariabeatrice; Di Leo, Alfredo; Pricci, Maria; Scavo, Maria Principia; Guido, Raffaella; Tanzi, Sabina; Piscitelli, Domenico; Pisani, Antonio; Ierardi, Enzo; Comelli, Maria Cristina; Barone, Michele

2013-01-01

AIM: To assess the safety and effect of the supplementation of a patented blend of dietary phytoestrogens and insoluble fibers on estrogen receptor (ER)-β and biological parameters in sporadic colonic adenomas. METHODS: A randomized, double-blind placebo-controlled trial was performed. Patients scheduled to undergo surveillance colonoscopy for previous sporadic colonic adenomas were identified, and 60 eligible patients were randomized to placebo or active dietary intervention (ADI) twice a day, for 60 d before surveillance colonoscopy. ADI was a mixture of 175 mg milk thistle extract, 20 mg secoisolariciresinol and 750 mg oat fiber extract. ER-β and ER-α expression, apoptosis and proliferation (Ki-67 LI) were assessed in colon samples. RESULTS: No adverse event related to ADI was recorded. ADI administration showed a significant increases in ER-β protein (0.822 ± 0.08 vs 0.768 ± 0.10, P = 0.04) and a general trend to an increase in ER-β LI (39.222 ± 2.69 vs 37.708 ± 5.31, P = 0.06), ER-β/ER-α LI ratio (6.564 ± 10.04 vs 2.437 ± 1.53, P = 0.06), terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (35.592 ± 14.97 vs 31.541 ± 11.54, P = 0.07) and Ki-67 (53.923 ± 20.91 vs 44.833 ± 10.38, P = 0.07) approximating statistical significance. A significant increase of ER-β protein (0.805 ± 0.13 vs 0.773 ± 0.13, P = 0.04), mRNA (2.278 ± 1.19 vs 1.105 ± 1.07, P < 0.02) and LI (47.533 ± 15.47 vs 34.875 ± 16.67, P < 0.05) and a decrease of ER-α protein (0.423 ± 0.06 vs 0.532 ± 0.11, P < 0.02) as well as a trend to increase of ER-β/ER-α protein in ADI vs placebo group were observed in patients without polyps (1.734 ± 0.20 vs 1.571 ± 0.42, P = 0.07). CONCLUSION: The role of ER-β on the control of apoptosis, and its amenability to dietary intervention, are supported in our study. PMID:23885143

An early shoulder repositioning program in birth-related brachial plexus injury: a pilot study of the Sup-ER protocol.

PubMed

Verchere, Cynthia; Durlacher, Kim; Bellows, Doria; Pike, Jeffrey; Bucevska, Marija

2014-06-01

Birth-related brachial plexus injury (BRBPI) occurs in 1.2/1,000 births in British Columbia. Even in children with "good" recovery, external rotation (ER) and supination (Sup) are often weaker, and permanent skeletal imbalance ensues. A preventive early infant shoulder passive repositioning program was created using primarily a novel custom splint holding the affected arm in full ER and Sup: the Sup-ER splint. The details of the splint and the shoulder repositioning program evolved with experience over several years. This study reviews the first 4 years. A retrospective review of BCCH patients managed with the Sup-ER protocol from 2008 to 2011 compared their recovery scores to matched historical controls selected from our database by two independent reviewers. The protocol was initiated in 18 children during the study period. Six were excluded due to the following: insufficient data points, non-compliance, late splint initiation, and loss to follow-up. Of the 12 matches, the Sup-ER group final score at 2 years was better than controls by 1.18 active movement scale (AMS) points (p = 0.036) in Sup and 0.96 AMS points in ER (but not statistically significant (p = 0.13)). Unexpectedly, but importantly, during the study period, zero subjects were assessed to have the active functional criteria to indicate brachial plexus reconstruction, where previously we operated on 13 %. Early application of passive shoulder repositioning into Sup and ER may improve outcomes in function of the arm in infants with BRBPI. A North American multi-site randomized control trial has been approved and has started recruitment.

Final disposition and quality auditing of the rehabilitation process in wild raptors admitted to a Wildlife Rehabilitation Centre in Catalonia, Spain, during a twelve year period (1995-2007).

PubMed

Molina-López, Rafael A; Casal, Jordi; Darwich, Laila

2013-01-01

Variability in reporting and classification methods in previous published data of the final dispositions in the rehabilitation of wild raptors makes use of this data limited in trying to audit the quality of the rehabilitation process. Crude as well as stratified disposition rates are needed if quality auditing of the rehabilitation process is to be adequately performed. Final dispositions of 6221 hospitalized wild raptors admitted at a wildlife rehabilitation centre (WRC) of Catalonia during 1995-2007 were analyzed. These dispositions were calculated as the euthanasia (Er), unassisted mortality (Mr), release (Rr) and captivity rates (Cr)., time to death (Td) for dead and euthanized raptors, and length of stay for released (Tr) raptors was estimated. Stratified analyses by main causes of admission and clinical signs were performed. THE DISPOSITION FOR THE TOTAL POPULATION WERE: Er = 30.6%, Mr = 19.1%, Rr = 47.2%, and Cr = 3%. By main causes of admission, Er was higher in the trauma category (34.2%), whereas Mr was found similar between trauma (37.4%) and non-trauma categories (34.8%). The highest Rr was observed for the orphaned group (77.9%). Furthermore, Cr was low in all the categories (<4%). By clinical signs, the highest Er was found in animals suffering musculoskeletal (37.9%) or skin (32.3%) lesions; Mr was high in infectious/parasitic diseases (66.7%) and in case of neurological symptoms (64.5%). The euthanized birds had a median Td = 1 day (P10 = 0-P90 = 59) for both trauma and non-trauma categories, and Td = 36 days for the orphaned young group (P10 = 0; P90 = 596). The median Td in the unassisted dead birds was 2 days for all the categories (P10 = 0-P90 = 31). Finally, the median Tr in the centre was variable among categories. Reporting of final dispositions in wildlife rehabilitation should include the crude and stratified rates (Er, Mr, Rr, and Cr), by causes and clinical presentation, as well as Td and Tr, to allow meaningful auditing of the rehabilitation process quality.

Proteomic insights into the protective mechanisms of an in vitro oxidative stress model of early stage Parkinson's disease.

PubMed

Bauereis, Brian; Haskins, William E; Lebaron, Richard G; Renthal, Robert

2011-01-13

Previous studies in Parkinson's disease (PD) models suggest that early events along the path to neurodegeneration involve activation of the ubiquitin-proteasome system (UPS), endoplasmic reticulum-associated degradation (ERAD), and the unfolded protein response (UPR) pathways, in both the sporadic and familial forms of the disease, and thus ER stress may be a common feature. Furthermore, impairments in protein degradation have been linked to oxidative stress as well as pathways associated with ER stress. We hypothesize that oxidative stress is a primary initiator in a multi-factorial cascade driving dopaminergic (DA) neurons towards death in the early stages of the disease. We now report results from proteomic analysis of a rotenone-induced oxidative stress model of PD in the human neuroblastoma cell line, SH-SY5Y. Cells were exposed to sub-micromolar concentrations of rotenone for 48h prior to whole cell protein extraction and shotgun proteomic analysis. Evidence for activation of the UPR comes from our observation of up-regulated binding immunoglobulin protein (BiP), heat shock proteins, and foldases. We also observed up-regulation of proteins that contribute to the degradation of misfolded or unfolded proteins controlled by the UPS and ERAD pathways. Activation of the UPR may allow neurons to maintain protein homeostasis in the cytosol and ER despite an increase in reactive oxygen species due to oxidative stress, and activation of the UPS and ERAD may further augment clean-up and quality control in the cell. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Primary investigations on the potential of a novel diode pumped Er:YAG laser system for bone surgery

NASA Astrophysics Data System (ADS)

Stock, Karl; Diebolder, Rolf; Hausladen, Florian; Wurm, Holger; Lorenz, Swetlana; Hibst, Raimund

2013-03-01

Flashlamp pumped Er:YAG-lasers are successfully clinically used for both precise soft and hard tissue ablation. As an alternative, actually a novel diode pumped Er:YAG laser system (Pantec Engineering AG) becomes available, with mean laser power up to 15W and pulse repetition rate up to 1kHz. The aim of the presented study is to investigate the effect of this laser system on bone tissue at various irradiation parameters, particular at repetition rates exceeding 100 Hz. For reproducible experiments, firstly an appropriate experimental set-up was realized with a beam delivery and focusing unit, a computer controlled stepper unit with sample holder, and a shutter unit. It allowed to move the sample (1mm- 3mm sawed slices of pig bone) with a defined velocity while irradiation by various laser parameters. A water spray served to moisten the sample surfaces. After irradiation the grooves were analyzed by light microscopy and laser scanning microscopy regarding to the ablation quality, the groove geometry, the ablation efficacy, and the thermal effects. The resulting grooves are slightly cone shaped (groove depth up to 3mm, width about 200μm) with sharp edges at the surface. At 1W, 200Hz, 5mm/s sample movement and with water irrigation the measured ablation speed Δz/Δt is 10.8 mm/s. The ablation depth per pulse is 54μm. In conclusion, these first experiments demonstrate that the diode pumped Er:YAG laser system is an efficient tool for use in bone surgery.

Efficacy and tolerability of paliperidone ER in patients with unsatisfactorily controlled schizophrenia by other antipsychotics: a flexible-dose approach

PubMed Central

Mauri, Massimo C.; Adami, Marina; Reggiardo, Giorgio; Giulio, Corrivetti

2015-01-01

This study evaluates the effectiveness of paliperidone ER in patients with symptomatic but not highly acute schizophrenia in terms of efficacy, safety, and patients’ perception of their social functioning and well-being. This is a multicenter, open-label prospective study with a flexible-dose approach; 133 patients were enrolled and followed for 13 weeks after switching to paliperidone ER. Outcome efficacy measures were as follows: the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impression-Severity (CGI-S) scale, and the Personal and Social Performance (PSP) scale; in addition, the Subjective Well-being under Neuroleptics (SWN-20) scale, the Drug Attitude Inventory (DAI-30), and the sleep evaluation scale were used. Symptom Rating Scale (ESRS), adverse events, and subjective side effects were recorded. 118/133(88.7%) patients completed the study. The mean PANSS score decreased (88.98±10.09 to 66.52±16.29; P<0.001); 40.5% of the patients achieved improvement of at least 30%. PSP and CGI-S scores as well as DAI-30 and SWN-20 decreased (P<0.001). ESRS (P<0.001) decreased significantly from the baseline. Throughout the trial, no deaths occurred and only one serious adverse event was reported. Paliperidone ER has proved to be efficacious, safe, and well tolerated also with this approach more closely resembling actual clinical practice. Patient-relevant outcome parameters such as social functioning and quality of life improved, which is crucial for treatment adherence in clinical practice. PMID:26230269

Efficacy and tolerability of paliperidone ER in patients with unsatisfactorily controlled schizophrenia by other antipsychotics: a flexible-dose approach.

PubMed

Mauri, Mauro; Mauri, Massimo C; Adami, Marina; Reggiardo, Giorgio; Giulio, Corrivetti

2015-11-01

This study evaluates the effectiveness of paliperidone ER in patients with symptomatic but not highly acute schizophrenia in terms of efficacy, safety, and patients' perception of their social functioning and well-being. This is a multicenter, open-label prospective study with a flexible-dose approach; 133 patients were enrolled and followed for 13 weeks after switching to paliperidone ER. Outcome efficacy measures were as follows: the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impression-Severity (CGI-S) scale, and the Personal and Social Performance (PSP) scale; in addition, the Subjective Well-being under Neuroleptics (SWN-20) scale, the Drug Attitude Inventory (DAI-30), and the sleep evaluation scale were used. Symptom Rating Scale (ESRS), adverse events, and subjective side effects were recorded. 118/133(88.7%) patients completed the study. The mean PANSS score decreased (88.98 ± 10.09 to 66.52 ± 16.29; P < 0.001); 40.5% of the patients achieved improvement of at least 30%. PSP and CGI-S scores as well as DAI-30 and SWN-20 decreased (P < 0.001). ESRS (P < 0.001) decreased significantly from the baseline. Throughout the trial, no deaths occurred and only one serious adverse event was reported. Paliperidone ER has proved to be efficacious, safe, and well tolerated also with this approach more closely resembling actual clinical practice. Patient-relevant outcome parameters such as social functioning and quality of life improved, which is crucial for treatment adherence in clinical practice.

Azaglycomimetics: Natural Occurrence, Biological Activity, and Application

NASA Astrophysics Data System (ADS)

Asano, Naoki

A large number of alkaloids mimicking the structures of monosaccharides or oligosaccharides have been isolated from plants and microorganisms. The sugar mimicking alkaloids with a nitrogen in the ring are called azasugars or iminosugars. Naturally occurring azasugars are classified into five structural classes: polyhydroxylated piperidines, pyrrolidines, indolizidines, pyrrolizidines, and nortropanes. They are easily soluble in water because of their polyhydroxylated structures and inhibit glycosidases because of a structural resemblance to the sugar moiety of the natural substrate. Glycosidases are involved in a wide range of anabolic and catabolic processes, such as digestion, lysosomal catabolism of glycoconjugates, biosynthesis of glycoproteins, and the endoplasmic reticulum (ER) quality control and ER-associated degradation of glycoproteins. Hence, modifying or blocking these processes in vivo by inhibitors is of great interest from a therapeutic point of view. Azasugars are an important class of glycosidase inhibitors and are arousing great interest for instance as antidiabetics, antiobesity drugs, antivirals, and therapeutic agents for some genetic disorders. This review describes the recent studies on isolation, characterization, glycosidase inhibitory activity, and therapeutic application of azaglycomimetics.

Determination of 105 antibiotic, anti-inflammatory, antiparasitic agents and tranquilizers by LC-MS/MS based on an acidic QuEChERS-like extraction.

PubMed

Desmarchelier, Aurélien; Fan, Kaïli; Minh Tien, Mai; Savoy, Marie-Claude; Tarres, Adrienne; Fuger, Denis; Goyon, Alexandre; Bessaire, Thomas; Mottier, Pascal

2018-04-01

A procedure for screening 105 veterinary drugs in foods by liquid chromatography tandem mass-spectrometry (LC-MS/MS) is presented. Its scope encompasses raw materials of animal origin (milk, meat, fish, egg and fat) but also related processed ingredients and finished products commonly used and manufactured by food business operators. Due to the complexity of the matrices considered and to efficiently deal with losses during extraction and matrix effects during MS source ionisation, each sample was analysed twice, that is 'unspiked' and 'spiked at the screening target concentration' using a QuEChERS-like extraction. The entire procedure was validated according to the European Community Reference Laboratories Residues Guidelines. False-negative and false-positive rates were below 5% for all veterinary drugs whatever the food matrix. Effectiveness of the procedure was further demonstrated through participation to five proficiency tests and its ruggedness demonstrated in quality control operations by a second laboratory.

Inhibition of endoplasmic reticulum stress improves coronary artery function in type 2 diabetic mice.

PubMed

Choi, Soo-Kyoung; Lim, Mihwa; Yeon, Soo-In; Lee, Young-Ho

2016-06-01

What is the central question of this study? Endoplasmic reticulum (ER) stress has been reported to be involved in type 2 diabetes; however, the role of exacerbated ER stress in vascular dysfunction in type 2 diabetes remains unknown. What is the main finding and its importance? The main findings of this study are that ER stress is increased in the coronary arteries in type 2 diabetes, and inhibition of ER stress using taurine-conjugated ursodeoxycholic acid improves vascular function, which is associated with normalization of the myogenic response and endothelium-dependent relaxation. Vascular dysfunction is a major complication in type 2 diabetes. Although endoplasmic reticulum (ER) stress has been suggested to be a contributory factor in cardiovascular diseases, the relationship between ER stress and vascular dysfunction in type 2 diabetes remains unclear. Thus, in the present study, we examined whether ER stress contributes to coronary artery dysfunction and whether inhibition of ER stress ameliorates vascular function in type 2 diabetes. Type 2 diabetic mice and their control counterparts were treated with an ER stress inhibitor (taurine-conjugated ursodeoxycholic acid, 150 mg kg(-1)  day(-1) , by i.p. injection) for 2 weeks or not treated. The myogenic response and endothelium-dependent relaxation were measured in pressurized coronary arteries. In type 2 diabetic mice, blood glucose and body weight were elevated compared with control mice. The myogenic response was potentiated and endothelium-dependent relaxation impaired in coronary arteries from the type 2 diabetic mice. Interestingly, treatment with the ER stress inhibitor normalized the myogenic responses and endothelium-dependent relaxation. These data were associated with an increase in ER stress marker expression or phosphorylation (IRE1-XBP-1 and PERK-eIF2α) in type 2 diabetic mice, which were reduced by treatment with the ER stress inhibitor. Inhibition of ER stress normalizes the myogenic response and improves vascular function in type 2 diabetes. Therefore, ER stress could be a potential target for cardiovascular diseases in diabetes mellitus. © 2016 The Authors. Experimental Physiology © 2016 The Physiological Society.

Specific application for Oak Ridge National Laboratory dismantlement of Building 3004. Appendix A -- Quality assurance plan; Appendix B -- Records management plan

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

NONE

This quality assurance (QA) plan defines the QA requirements for the dismantlement and removal of Building 3004 at Oak Ridge National Laboratory (ORNL). The building is a four-story wooden trained structure with wooden siding, which resides approximately 150 ft west of the Bulk Shielding Reactor, and only several feet away from the visitors entrance to the Graphite Reactor museum. Complete descriptions and sketches are in the Performance Specification document for this project. This project is being conducted as a non-CERCLA maintenance action. This plan is an appendix to the QA plan for the ORNL Environmental Restoration (ER) Program. ORNL/ER-225, whichmore » is the source of the project QA requirements, tailors those QA requirements to the specific needs of this project as defined in ORNL/ER-225. Project-specific description and organization are also provided in this plan. Appendix B, Records Management Plan, is included.« less

The Entangled ER-Mitochondrial axis as a potential therapeutic strategy in Neurodegeneration: A Tangled Duo Unchained

PubMed Central

Joshi, Amit U.; Kornfeld, Opher S.; Mochly-Rosen, Daria

2016-01-01

Endoplasmic reticulum (ER) and mitochondrial function have both been shown to be critical events in neurodegenerative diseases. The ER mediates protein folding, maturation, sorting as well acts as calcium storage. The unfolded protein response (UPR) is a stress response of the ER that is activated by the accumulation of misfolded proteins within the ER lumen. Although the molecular mechanisms underlying ER stress-induced apoptosis are not completely understood, increasing evidence suggests that ER and mitochondria cooperate to signal cell death. Similarly, calcium-mediated mitochondrial function and dynamics not only contribute to ATP generation and calcium buffering but are also a linchpin in mediating cell fate. Mitochondria and ER form structural and functional networks (mitochondria-associated ER membranes [MAMs]) essential to maintaining cellular homeostasis and determining cell fate under various pathophysiological conditions. Regulated Ca2+ transfer from the ER to the mitochondria is important in maintaining control of pro-survival/pro-death pathways. In this review, we summarize the latest therapeutic strategies that target these essential organelles in the context of neurodegenerative diseases. PMID:27212603

Pilot randomised trial of a healthy eating behavioural intervention in uncontrolled asthma.

PubMed

Ma, Jun; Strub, Peg; Lv, Nan; Xiao, Lan; Camargo, Carlos A; Buist, A Sonia; Lavori, Philip W; Wilson, Sandra R; Nadeau, Kari C; Rosas, Lisa G

2016-01-01

Rigorous research on the benefit of healthy eating patterns for asthma control is lacking.We randomised 90 adults with objectively confirmed uncontrolled asthma and a low-quality diet (Dietary Approaches to Stop Hypertension (DASH) scores <6 out of 9) to a 6-month DASH behavioural intervention (n=46) or usual-care control (n=44). Intention-to-treat analyses used repeated-measures mixed models.Participants were middle-aged, 67% female and multiethnic. Compared with controls, intervention participants improved on DASH scores (mean change (95% CI) 0.6 (0, 1.1) versus -0.3 (-0.8, 0.2); difference 0.8 (0.2, 1.5)) and the primary outcome, Asthma Control Questionnaire scores (-0.2 (-0.5, 0) versus 0 (-0.3, 0.3); difference -0.2 (-0.5, 0.1)) at 6 months. The mean group differences in changes in Mini Asthma Quality of Life Questionnaire overall and subdomain scores consistently favoured the intervention over the control group: overall 0.4 (95% CI 0, 0.8), symptoms 0.5 (0, 0.9), environment 0.4 (-0.1, 1.0), emotions 0.4 (-0.2, 0.9) and activities 0.3 (0, 0.7). These differences were modest, but potentially clinical significant.The DASH behavioural intervention improved diet quality with promising clinical benefits for better asthma control and functional status among adults with uncontrolled asthma. A full-scale efficacy trial is warranted. Copyright ©ERS 2016.

Characterization Of Ocean Wind Vector Retrievals Using ERS-2 High-Resolution Long-Term Dataset And Buoy Measurements

NASA Astrophysics Data System (ADS)

Polverari, F.; Talone, M.; Crapolicchio, R. Levy, G.; Marzano, F.

2013-12-01

The European Remote-sensing Satellite (ERS)-2 scatterometer provides wind retrievals over Ocean. To satisfy the needs of high quality and homogeneous set of scatterometer measurements, the European Space Agency (ESA) has developed the project Advanced Scatterometer Processing System (ASPS) with which a long-term dataset of new ERS-2 wind products, with an enhanced resolution of 25km square, has been generated by the reprocessing of the entire ERS mission. This paper presents the main results of the validation work of such new dataset using in situ measurements provided by the Prediction and Research Moored Array in the Tropical Atlantic (PIRATA). The comparison indicates that, on average, the scatterometer data agree well with buoys measurements, however the scatterometer tends to overestimates lower winds and underestimates higher winds.

ER Stress Induced by Tunicamycin Triggers α-Synuclein Oligomerization, Dopaminergic Neurons Death and Locomotor Impairment: a New Model of Parkinson's Disease.

PubMed

Cóppola-Segovia, Valentín; Cavarsan, Clarissa; Maia, Flavia G; Ferraz, Anete C; Nakao, Lia S; Lima, Marcelo Ms; Zanata, Silvio M

2017-10-01

Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive death of dopaminergic neurons of the substantia nigra pars compacta (SNpc), leading to the major clinical abnormalities that characterize this disease. Although PD's etiology is unknown, α-synuclein aggregation plays a pivotal role in PD pathogenesis, which could be associated to some pathological processes such as oxidative stress, endoplasmic reticulum (ER) stress, impaired protein degradation, and mitochondrial dysfunction. Increasing experimental evidence indicates that ER stress is involved in PD, however most of the described results employed cultured cell lines and genetically modified animal models. In this study, we developed a new ER stress rat model employing the well-known ER stressor tunicamycin (Tm). To evaluate if ER stress was able to induce PD features, we performed an intranigral injection of Tm (0.1 μg/cerebral hemisphere) and animals (male Wistar rats) were analyzed 7 days post injection. The classical 6-OHDA neurotoxin model (1 μg/cerebral hemisphere) was used as an established positive control for PD. We show that Tm injection induced locomotor impairment, dopaminergic neurons death, and activation of astroglia. In addition, we observed an extensive α-synuclein oligomerization in SNpc of Tm-injected animals when compared with DMSO-injected controls. Finally, both Tm and 6-OHDA treated animals presented increased levels of ER stress markers. Taken together, these findings show for the first time that the ER stressor Tm recapitulates some of the phenotypic characteristics observed in rodent models of PD, reinforcing the concept that ER stress could be an important contributor to the pathophysiology of PD. Therefore, we propose the intranigral Tm injection as a new ER stress-based model for the study of PD in vivo.

Body weight and incidence of breast cancer defined by estrogen and progesterone receptor status--a meta-analysis.

PubMed

Suzuki, Reiko; Orsini, Nicola; Saji, Shigehira; Key, Timothy J; Wolk, Alicja

2009-02-01

Epidemiological evidence indicates that the association between body weight and breast cancer risk may differ across menopausal status as well as the estrogen receptor (ER) and progesterone receptor (PR) tumor status. To date, no meta-analysis has been conducted to assess the association between body weight and ER/PR defined breast cancer risk, taking into account menopausal status and study design. We searched MEDLINE for relevant studies published from January 1, 1970 through December 31, 2007. Summarized risk estimates with 95% confidence intervals (CIs) were calculated using a random-effects model. The summarized results of 9 cohorts and 22 case-control studies comparing the highest versus the reference categories of relative body weight showed that the risk for ER+PR+ tumors was 20% lower (95% CI=-30% to -8%) among premenopausal (2,643 cases) and 82% higher (95% CI=55-114%) among postmenopausal (5,469 cases) women. The dose-response meta-analysis of ER+PR+ tumors showed that each 5-unit increase in body mass index (BMI, kg/m2) was associated with a 33% increased risk among postmenopausal women (95% CI=20-48%) and 10% decreased risk among premenopausal women (95% CI=-18% to -1%). No associations were observed for ER-PR- or ER+PR- tumors. For discordant tumors ER+PR- (pre) and ER-PR+ (pre/post) the number of cases were too small (<200) to interpret results. The relation between body weight and breast cancer risk is critically dependent on the tumor's ER/PR status and the woman's menopausal status. Body weight control is the effective strategy for preventing ER+PR+ tumors after menopause. Copyright (c) 2008 Wiley-Liss, Inc.

Reproductive factors, hormone use, estrogen receptor expression and risk of non small-cell lung cancer in women.

PubMed

Schwartz, Ann G; Wenzlaff, Angela S; Prysak, Geoffrey M; Murphy, Valerie; Cote, Michele L; Brooks, Sam C; Skafar, Debra F; Lonardo, Fulvio

2007-12-20

Estrogen receptor (ER) expression in lung tumors suggests that estrogens may play a role in the development of lung cancer. We evaluated the role of hormone-related factors in determining risk of non-small-cell lung cancer (NSCLC) in women. We also evaluated whether risk factors were differentially associated with cytoplasmic ER-alpha and/or nuclear ER-beta expression-defined NSCLC in postmenopausal women. Population-based participants included women aged 18 to 74 years diagnosed with NSCLC in metropolitan Detroit between November 1, 2001 and October 31, 2005. Population-based controls were identified through random digit dialing, matched to patient cases on race and 5-year age group. Interview data were analyzed for 488 patient cases (241 with tumor ER results) and 498 controls. Increased duration of hormone replacement therapy (HRT) use in quartiles was associated with decreased risk of NSCLC in postmenopausal women (odds ratio = 0.88; 95% CI, 0.78 to 1.00; P = .04), adjusting for age, race, pack-years, education, family history of lung cancer, current body mass index, years exposed to second-hand smoke in the workplace, and obstructive lung disease history. Among postmenopausal women, ever using HRT, increasing HRT duration of use in quartiles, and increasing quartiles of estrogen use were significant predictors of reduced risk of NSCLC characterized as ER-alpha and/or ER-beta positive. None of the hormone-related variables were associated with nuclear ER-alpha- or ER-beta-negative NSCLC. These findings suggest that postmenopausal hormone exposures are associated with reduced risk of ER-alpha- and ER-beta-expressing NSCLC. Understanding tumor characteristics may direct development of targeted treatment for this disease.

Six-Year Outcome of Subjects Without Overt Heart Disease With an Early Repolarization/J Wave Electrocardiographic Pattern.

PubMed

Lanza, Gaetano Antonio; Argirò, Alessia; Mollo, Roberto; De Vita, Antonio; Spera, Francesco; Golino, Michele; Rota, Elisabetta; Filice, Monica; Crea, Filippo

2017-12-01

"Early repolarization" (ER) is a frequent finding at standard electrocardiogram (ECG). In this study we assessed whether ER is associated with an increased risk of events, as recently suggested by some studies. We prospectively enrolled 4,176 consecutive subjects without any heart disease who underwent routine ECG recording. ER was diagnosed in case of typical concave ST-segment elevation ≥0.1 mV; a J wave was diagnosed when the QRS showed a notch or a slur in its terminal part. In this study we compared the 6-year outcome of all 687 subjects with ER/J wave and 687 matched subjects without ER/J wave (controls). Both groups included 335 males and 352 females, and age was 48.8 ± 18 years. Overall, 145 deaths occurred (11%), only 11 of which attributed to cardiac causes. No sudden death was reported. Cardiac deaths occurred in 5 (0.8%) and 6 (0.9%) ER/J wave subjects and controls, respectively (odds ratio [OR] 0.85, 95% confidence interval [CI] 0.26 to 2.80, p = 0.79). Both ER (OR 1.68, 95% CI 0.21 to 13.3, p = 0.62) and J wave (OR 0.91, 95% CI 0.28 to 3.00, p = 0.88) showed no association with cardiac death. Total mortality was 11.5% in the ER/J wave group and 10.6% in the control group (OR 1.10, 95% CI 0.78 to 1.56, p = 0.58). Both ER (OR 0.44, 95% CI 0.16 to 1.24, p = 0.12) and J wave (OR 1.20, 95% CI 0.85 to 1.70, p = 0.30) showed also no association with all-cause death. In subjects without any evidence of heart disease, we found no significant association of ER/J wave with the risk of cardiac, as well as all-cause, death at medium-term follow-up. Copyright © 2017 Elsevier Inc. All rights reserved.

Local Anaesthetic Infiltration and Indwelling Postoperative Wound Catheters for Patients with Hip Fracture Reduce Death Rates and Length of Stay

PubMed Central

Harrison, William D.; Lees, Deborah; A'Court, Jamie; Ankers, Thomas; Harper, Ian; Inman, Dominic; Reed, Mike R.

2015-01-01

Background. An analgesic enhanced recovery (ER) protocol for patients with a hip fracture was introduced. It was hypothesised that the ER would reduce pain, length of stay and improve clinical outcomes. The protocol used intraoperative infiltration of levobupivacaine followed by ongoing wound infusions. Methods. Consecutive patients admitted to two hospitals were eligible for the ER protocol. Numerical Reporting Scale pain scores (0–10) were recorded alongside opiate requirements. 434 patients in the ER group (316 full ER, 90 partial ER, and 28 no ER) were compared to a control group (CG) of 100 consecutive patients managed with traditional opiate analgesia. Results. Mean opiate requirement was 49.2 mg (CG) versus 32.5 mg (ER). Pain scores were significantly reduced in the full ER group, p < 0.0001. Direct discharge home and mean acute inpatient stay were significantly reduced (p = 0.0031 and p < 0.0001, resp.). 30-day mortality was 15% (CG) versus 5.5% (ER), p = 0.0024. Conclusions. This analgesic ER protocol for patients with a hip fracture was safe and effective and was associated with reduced inpatient stay and mortality. PMID:26649330

Genome-wide screen identifies a novel p97/CDC-48-dependent pathway regulating ER-stress-induced gene transcription.

PubMed

Marza, Esther; Taouji, Saïd; Barroso, Kim; Raymond, Anne-Aurélie; Guignard, Léo; Bonneu, Marc; Pallares-Lupon, Néstor; Dupuy, Jean-William; Fernandez-Zapico, Martin E; Rosenbaum, Jean; Palladino, Francesca; Dupuy, Denis; Chevet, Eric

2015-03-01

The accumulation of misfolded proteins in the endoplasmic reticulum (ER) activates the Unfolded Protein Response (UPR(ER)) to restore ER homeostasis. The AAA(+) ATPase p97/CDC-48 plays key roles in ER stress by promoting both ER protein degradation and transcription of UPR(ER) genes. Although the mechanisms associated with protein degradation are now well established, the molecular events involved in the regulation of gene transcription by p97/CDC-48 remain unclear. Using a reporter-based genome-wide RNAi screen in combination with quantitative proteomic analysis in Caenorhabditis elegans, we have identified RUVB-2, a AAA(+) ATPase, as a novel repressor of a subset of UPR(ER) genes. We show that degradation of RUVB-2 by CDC-48 enhances expression of ER stress response genes through an XBP1-dependent mechanism. The functional interplay between CDC-48 and RUVB-2 in controlling transcription of select UPR(ER) genes appears conserved in human cells. Together, these results describe a novel role for p97/CDC-48, whereby its role in protein degradation is integrated with its role in regulating expression of ER stress response genes. © 2015 The Authors.

LOCAL TRANSLATION. Comment on "Principles of ER cotranslational translocation revealed by proximity-specific ribosome profiling".

PubMed

Reid, David W; Nicchitta, Christopher V

2015-06-12

Jan et al. (Research Articles, 7 November 2014, p. 716) propose that ribosomes translating secretome messenger RNAs (mRNAs) traffic from the cytosol to the endoplasmic reticulum (ER) upon emergence of the signal peptide and return to the cytosol after termination. An accounting of controls demonstrates that mRNAs initiate translation on ER-bound ribosomes and that ribosomes are retained on the ER through many cycles of translation. Copyright © 2015, American Association for the Advancement of Science.

A Role for MEK-Interacting Protein 1 in Hormone Responsiveness of ER Positive Breast Cancer Cells

DTIC Science & Technology

2010-07-01

positive, but not ER-negative, breast cancer cell lines. 2) The cell death observed in ER- positiv e cell lin es was associated with an a pproximate...and stained after 24 h, then counted. Top panel: photographs of stained cells. Bottom panel: Quantitation of migrated cells, normalized to control...function and breast cancer biology. W e therefore hypothesized that MP1 m ight play an im portant role in ER positiv e breast cancer cells. To test this

Females and males are highly similar in language performance and cortical activation patterns during verb generation.

PubMed

Allendorfer, Jane B; Lindsell, Christopher J; Siegel, Miriam; Banks, Christi L; Vannest, Jennifer; Holland, Scott K; Szaflarski, Jerzy P

2012-10-01

To test the existence of sex differences in cortical activation during verb generation when performance is controlled for. Twenty male and 20 female healthy adults underwent functional magnetic resonance imaging (fMRI) using a covert block-design verb generation task (BD-VGT) and its event-related version (ER-VGT) that allowed for intra-scanner recordings of overt responses. Task-specific activations were determined using the following contrasts: BD-VGT covert generation>finger-tapping; ER-VGT overt generation>repetition; ER-VGT overt>covert generation. Lateral cortical regions activated during each contrast were used for calculating language lateralization index scores. Voxelwise regressions were used to determine sex differences in activation, with and without controlling for performance. Each brain region showing male/female activation differences for ER-VGT overt generation>repetition (isolating noun-verb association) was defined as a region of interest (ROI). For each subject, the signal change in each ROI was extracted, and the association between ER-VGT activation related to noun-verb association and performance was assessed separately for each sex. Males and females performed similarly on language assessments, had similar patterns of language lateralization, and exhibited similar activation patterns for each fMRI task contrast. Regression analysis controlling for overt intra-scanner performance either abolished (BD-VGT) or reduced (ER-VGT) the observed differences in activation between sexes. The main difference between sexes occurred during ER-VGT processing of noun-verb associations, where males showed greater activation than females in the right middle/superior frontal gyrus (MFG/SFG) and the right caudate/anterior cingulate gyrus (aCG) after controlling for performance. Better verb generation performance was associated with increased right caudate/aCG activation in males and with increased right MFG/SFG activation in females. Males and females exhibit similar activation patterns during verb generation fMRI, and controlling for intra-scanner performance reduces or even abolishes sex differences in language-related activation. These results suggest that previous findings of sex differences in neuroimaging studies that did not control for task performance may reflect false positives. Copyright © 2011 Elsevier Srl. All rights reserved.

Gel-Free/Label-Free Proteomic Analysis of Endoplasmic Reticulum Proteins in Soybean Root Tips under Flooding and Drought Stresses.

PubMed

Wang, Xin; Komatsu, Setsuko

2016-07-01

Soybean is a widely cultivated crop; however, it is sensitive to flooding and drought stresses. The adverse environmental cues cause the endoplasmic reticulum (ER) stress due to accumulation of unfolded or misfolded proteins. To investigate the mechanisms in response to flooding and drought stresses, ER proteomics was performed in soybean root tips. The enzyme activity of NADH cytochrome c reductase was two-fold higher in the ER than other fractions, indicating that the ER was isolated with high purity. Protein abundance of ribosomal proteins was decreased under both stresses compared to control condition; however, the percentage of increased ribosomes was two-fold higher in flooding compared to drought. The ER proteins related to protein glycosylation and signaling were in response to both stresses. Compared to control condition, calnexin was decreased under both stresses; however, protein disulfide isomerase-like proteins and heat shock proteins were markedly decreased under flooding and drought conditions, respectively. Furthermore, fewer glycoproteins and higher levels of cytosolic calcium were identified under both stresses compared to control condition. These results suggest that reduced accumulation of glycoproteins in response to both stresses might be due to dysfunction of protein folding through calnexin/calreticulin cycle. Additionally, the increased cytosolic calcium levels induced by flooding and drought stresses might disturb the ER environment for proper protein folding in soybean root tips.

Endometrial Polyps in Women Affected by Levothyroxine-Treated Hypothyroidism—Histological Features, Immunohistochemical Findings, and Possible Explanation of Etiopathogenic Mechanism: A Pilot Study

PubMed Central

Saccardi, Carlo; Gizzo, Salvatore; Ludwig, Kathrin; Guido, Maria; Scarton, Mara; Gangemi, Michele; Tinelli, Raffaele; Litta, Pietro Salvatore

2013-01-01

The aim of the study was to investigate the possible overexpression of estrogen (ERs) and progesterone (PRs) receptors both in EPs glandular and stromal cells in postmenopausal women with levothyroxine-treated hypothyroidism in comparison to EPs detected in women with physiological thyroid hormone levels. During the study period (January-February 2013) 22 patients were eligible (12 treated, 10 controls). The two groups were homogenous for general, EPs sonographic and hysteroscopic features. None of the cases of atypia was found. Immunohistochemistry showed that the two groups were similar for ERs and PRs intensity rates in EPs glandular cells despite a trend of ERs percentage expression more than 60% in 2/3 of treated patients versus 1/3 of controls. In stromal EPs components, ERs intensity was high positive in 10 (83,3%) treated cases while it was high positive in 1 control (10%). Percentage of ERs stromal expression showed a different trend between the two groups despite a borderline statistical significance. Our hypothesis is based on a possible double action of hypothyroidism and thyroxine intake: the subclinical TSH increased levels and its possible circadian oscillation could stimulate the endometrial TSHRs (increasing type 2 DIO activity); the circulating levels of exogenous thyroxine could be locally metabolized in active form by type 2 DIO stimulating ERs. PMID:24058909

A Systems Biological View of Life-and-Death Decision with Respect to Endoplasmic Reticulum Stress-The Role of PERK Pathway.

PubMed

Márton, Margita; Kurucz, Anita; Lizák, Beáta; Margittai, Éva; Bánhegyi, Gábor; Kapuy, Orsolya

2017-01-05

Accumulation of misfolded/unfolded proteins in the endoplasmic reticulum (ER) leads to the activation of three branches (Protein kinase (RNA)-like endoplasmic reticulum kinase [PERK], Inositol requiring protein 1 [IRE-1] and Activating trascription factor 6 [ATF6], respectively) of unfolded protein response (UPR). The primary role of UPR is to try to drive back the system to the former or a new homeostatic state by self-eating dependent autophagy, while excessive level of ER stress results in apoptotic cell death. Our study focuses on the role of PERK- and IRE-1-induced arms of UPR in life-or-death decision. Here we confirm that silencing of PERK extends autophagy-dependent survival, whereas the IRE-1-controlled apoptosis inducer is downregulated during ER stress. We also claim that the proper order of surviving and self-killing mechanisms is controlled by a positive feedback loop between PERK and IRE-1 branches. This regulatory network makes possible a smooth, continuous activation of autophagy with respect to ER stress, while the induction of apoptosis is irreversible and switch-like. Using our knowledge of molecular biological techniques and systems biological tools we give a qualitative description about the dynamical behavior of PERK- and IRE-1-controlled life-or-death decision. Our model claims that the two arms of UPR accomplish an altered upregulation of autophagy and apoptosis inducers during ER stress. Since ER stress is tightly connected to aging and age-related degenerative disorders, studying the signaling pathways of UPR and their role in maintaining ER proteostasis have medical importance.

Endoplasmatic reticulum shaping by generic mechanisms and protein-induced spontaneous curvature.

PubMed

Sackmann, Erich

2014-06-01

The endoplasmatic reticulum (ER) comprises flattened vesicles (cisternae) with worm holes dubbed with ribosomes coexisting with a network of interconnected tubes which can extend to the cell periphery or even penetrate nerve axons. The coexisting topologies enclose a continuous luminal space. The complex ER topology is specifically controlled by a group of ER-shaping proteins often called reticulons (discovered by the group of Tom Rapoport). They include atlastin, reticulon, REEP and the MT severing protein spastin. A generic ER shape controlling factor is the necessity to maximize the area-to-volume ratio of ER membranes in the highly crowded cytoplasmic space. I present a model of the ER-shaping function of the reticulons based on the Helfrich bending elasticity concept of soft shell shape changes. Common structural motifs of the reticulons are hydrophobic sequences forming wedge shaped hairpins which penetrate the lipid bilayer of the cell membranes. The wedge-like hydrophobic anchors can both induce the high curvature of the tubular ER fraction and ensure the preferred distribution of the reticulons along the tubules. Tubular junctions may be stabilized by the reticulons forming two forceps twisted by 90°. The ER extensions to the cell periphery and the axons are mediated by coupling of the tubes to the microtubules which is mediated by REEP and spastin. At the end I present a model of the tension driven homotype fusion of ER-membranes by atlastin, based on analogies to the SNARE-complexin-SNARE driven heterotype fusion process. Copyright © 2014 Elsevier B.V. All rights reserved.

The Next Generation of Ground Operations Command and Control; Scripting in C Sharp and Visual Basic

NASA Technical Reports Server (NTRS)

Ritter, George; Pedoto, Ramon

2010-01-01

This slide presentation reviews the use of scripting languages in Ground Operations Command and Control. It describes the use of scripting languages in a historical context, the advantages and disadvantages of scripts. It describes the Enhanced and Redesigned Scripting (ERS) language, that was designed to combine the features of a scripting language and the graphical and IDE richness of a programming language with the utility of scripting languages. ERS uses the Microsoft Visual Studio programming environment and offers custom controls that enable an ERS developer to extend the Visual Basic and C sharp language interface with the Payload Operations Integration Center (POIC) telemetry and command system.

All optical mode controllable Er-doped random fiber laser with distributed Bragg gratings.

PubMed

Zhang, W L; Ma, R; Tang, C H; Rao, Y J; Zeng, X P; Yang, Z J; Wang, Z N; Gong, Y; Wang, Y S

2015-07-01

An all-optical method to control the lasing modes of Er-doped random fiber lasers (RFLs) is proposed and demonstrated. In the RFL, an Er-doped fiber (EDF) recoded with randomly separated fiber Bragg gratings (FBG) is used as the gain medium and randomly distributed reflectors, as well as the controllable element. By combining random feedback of the FBG array and Fresnel feedback of a cleaved fiber end, multi-mode coherent random lasing is obtained with a threshold of 14 mW and power efficiency of 14.4%. Moreover, a laterally-injected control light is used to induce local gain perturbation, providing additional gain for certain random resonance modes. As a result, active mode selection of the RFL is realized by changing locations of the laser cavity that is exposed to the control light.

Controlling the 1 μm spontaneous emission in Er/Yb co-doped fiber amplifiers.

PubMed

Sobon, Grzegorz; Kaczmarek, Pawel; Antonczak, Arkadiusz; Sotor, Jaroslaw; Abramski, Krzysztof M

2011-09-26

In this paper we present our experimental studies on controlling the amplified spontaneous emission (ASE) from Yb(3+) ions in Er/Yb co-doped fiber amplifiers. We propose a new method of controlling the Yb-ASE by stimulating a laser emission at 1064 nm in the amplifier, by providing a positive 1 μm signal feedback loop. The results are discussed and compared to a conventional amplifier setup without 1 μm ASE control and to an amplifier with auxiliary 1064 nm seeding. We have shown, that applying a 1064 nm signal loop in an Er/Yb amplifier can increase the output power at 1550 nm and provide stable operation without parasitic lasing at 1 μm. © 2011 Optical Society of America

A Comparison of Wind Speed Data from Mechanical and Ultrasonic Anemometers

NASA Technical Reports Server (NTRS)

Short, D.; Wells, L.; Merceret, F.; Roeder, W. P.

2006-01-01

This study compared the performance of mechanical and ultrasonic anemometers at the Eastern Range (ER; Kennedy Space Center and Cape Canaveral Air Force Station on Florida's Atlantic coast) and the Western Range (WR; Vandenberg Air Force Base on California's Pacific coast). Launch Weather Officers, forecasters, and Range Safety analysts need to understand the performance of wind sensors at the ER and WR for weather warnings, watches, advisories, special ground processing operations, launch pad exposure forecasts, user Launch Commit Criteria (LCC) forecasts and evaluations, and toxic dispersion support. The current ER and WR weather tower wind instruments are being changed from the current propeller-and-vane (ER) and cup-and-vane (WR) sensors to ultrasonic sensors through the Range Standardization and Automation (RSA) program. The differences between mechanical and ultrasonic techniques have been found to cause differences in the statistics of peak wind speed in previous studies. The 45th Weather Squadron (45 WS) and the 30th Weather Squadron (30 WS) requested the Applied Meteorology Unit (AMU) to compare data between RSA and current sensors to determine if there are significant differences. Approximately 3 weeks of Legacy and RSA wind data from each range were used in the study, archived during May and June 2005. The ER data spanned the full diurnal cycle, while the WR data was confined to 1000-1600 local time. The sample of 1-minute data from numerous levels on 5 different towers on each range totaled more than 500,000 minutes of data (482,979 minutes of data after quality control). The 10 towers were instrumented at several levels, ranging from 12 ft to 492 ft above ground level. The RSA sensors were collocated at the same vertical levels as the present sensors and typically within 15 ft horizontally of each another. Data from a total of 53 RSA ultrasonic sensors, collocated with present sensors were compared. The 1-minute average wind speed/direction and the 1-second peak wind speed/direction were compared.

Anthropometric, metabolic, psychosocial and dietary factors associated with dropout in overweight and obese postmenopausal women engaged in a 6-month weight loss programme: a MONET study.

PubMed

Messier, Virginie; Hayek, Jessy; Karelis, Antony D; Messier, Lyne; Doucet, Eric; Prud'homme, Denis; Rabasa-Lhoret, Rémi; Strychar, Irene

2010-04-01

The objective of the present study was to examine anthropometric, metabolic, psychosocial and dietary factors associated with dropout in a 6-month weight loss intervention aimed at reducing body weight by 10 %. The study sample included 137 sedentary, overweight and obese postmenopausal women, participating in a weight loss intervention that consisted of either energy restriction (ER) or ER with resistance training (ER+RT). Anthropometric (BMI, percent lean body mass, percent fat mass, visceral adipose tissue and waist circumference), metabolic (total energy expenditure, RMR, insulin sensitivity and fasting plasma levels of leptin and ghrelin), psychosocial (body esteem, self-esteem, stress, dietary restraint, disinhibition, hunger, quality of life, self-efficacy, perceived benefits for controlling weight and perceived risk) and dietary (3-d food record) variables were measured. Thirty subjects out of 137 dropped out of the weight loss programme (22 %), with no significant differences in dropout rates between those in the ER and the ER+RT groups. Overall, amount of weight loss was significantly lower in dropouts than in completers ( - 1.7 (sd 3.5) v. - 5.6 (sd 4.3) kg, P < 0.05); weekly weight loss during the first 4 weeks was also significantly lower. Dropouts consumed fewer fruit servings than completers (1.7 (sd 1.1) v. 2.7 (sd 1.53), P < 0.05) and had higher insulin sensitivity levels (12.6 (sd 3.8) v. 11.1 (sd 2.8) mg glucose/min per kg fat-free mass, P < 0.05). The present results suggest that the rate of weight loss during the first weeks of an intervention plays an important role in the completion of the programme. Thus, participants with low rates of initial weight loss should be monitored intensely to undertake corrective measures to increase the likelihood of completion.

Trafficking-deficient hERG K+ channels linked to long QT syndrome are regulated by a microtubule-dependent quality control compartment in the ER

PubMed Central

Smith, Jennifer L.; McBride, Christie M.; Nataraj, Parvathi S.; Bartos, Daniel C.; January, Craig T.

2011-01-01

The human ether-a-go-go related gene (hERG) encodes the voltage-gated K+ channel that underlies the rapidly activating delayed-rectifier current in cardiac myocytes. hERG is synthesized in the endoplasmic reticulum (ER) as an “immature” N-linked glycoprotein and is terminally glycosylated in the Golgi apparatus. Most hERG missense mutations linked to long QT syndrome type 2 (LQT2) reduce the terminal glycosylation and functional expression. We tested the hypothesis that a distinct pre-Golgi compartment negatively regulates the trafficking of some LQT2 mutations to the Golgi apparatus. We found that treating cells in nocodazole, a microtubule depolymerizing agent, altered the subcellular localization, functional expression, and glycosylation of the LQT2 mutation G601S-hERG differently from wild-type hERG (WT-hERG). G601S-hERG quickly redistributed to peripheral compartments that partially colocalized with KDEL (Lys-Asp-Glu-Leu) chaperones but not calnexin, Sec31, or the ER golgi intermediate compartment (ERGIC). Treating cells in E-4031, a drug that increases the functional expression of G601S-hERG, prevented the accumulation of G601S-hERG to the peripheral compartments and increased G601S-hERG colocalization with the ERGIC. Coexpressing the temperature-sensitive mutant G protein from vesicular stomatitis virus, a mutant N-linked glycoprotein that is retained in the ER, showed it was not restricted to the same peripheral compartments as G601S-hERG at nonpermissive temperatures. We conclude that the trafficking of G601S-hERG is negatively regulated by a microtubule-dependent compartment within the ER. Identifying mechanisms that prevent the sorting or promote the release of LQT2 channels from this compartment may represent a novel therapeutic strategy for LQT2. PMID:21490315

Homeostatic Regulation of the PI(4,5)P2-Ca2+ Signaling System at ER-PM Junctions

PubMed Central

Chang, Chi-Lun; Liou, Jen

2016-01-01

The phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2)-Ca2+ signaling system is important for cell activation in response to various extracellular stimuli. This signaling system is initiated by receptor-induced hydrolysis of PI(4,5)P2 in the plasma membrane (PM) to generate the soluble second messenger inositol 1,4,5-trisphosphate (IP3). IP3 subsequently triggers the release of Ca2+ from the endoplasmic reticulum (ER) store to the cytosol to activate Ca2+-mediated responses, such as secretion and proliferation. The consumed PM PI(4,5)P2 and ER Ca2+ must be quickly restored to sustain signaling responses, and to maintain the homeostasis of PI(4,5)P2 and Ca2+. Since phosphatidylinositol (PI), the precursor lipid for PM PI(4,5)P2, is synthesized in the ER membrane, and a Ca2+ influx across the PM is required to refill the ER Ca2+ store, efficient communications between the ER and the PM are critical for the homeostatic regulation of the PI(4,5)P2-Ca2+ signaling system. This review describes the major findings that established the framework of the PI(4,5)P2-Ca2+ signaling system, and recent discoveries on feedback control mechanisms at ER-PM junctions that sustain the PI(4,5)P2-Ca2+ signaling system. Particular emphasis is placed on the characterization of ER-PM junctions where efficient communications between the ER and the PM occurs, and the activation mechanisms of proteins that dynamically localize to ER-PM junctions to provide the feedback control during PI(4,5)P2-Ca2+ signaling, including the ER Ca2+ sensor STIM1, the extended synaptotagmin E-Syt1, and the PI transfer protein Nir2. This review is part of a Special Issue entitled The Cellular Lipid Landscape. PMID:26924250

Kinesin-dependent mechanism for controlling triglyceride secretion from the liver.

PubMed

Rai, Priyanka; Kumar, Mukesh; Sharma, Geetika; Barak, Pradeep; Das, Saumitra; Kamat, Siddhesh S; Mallik, Roop

2017-12-05

Despite massive fluctuations in its internal triglyceride content, the liver secretes triglyceride under tight homeostatic control. This buffering function is most visible after fasting, when liver triglyceride increases manyfold but circulating serum triglyceride barely fluctuates. How the liver controls triglyceride secretion is unknown, but is fundamentally important for lipid and energy homeostasis in animals. Here we find an unexpected cellular and molecular mechanism behind such control. We show that kinesin motors are recruited to triglyceride-rich lipid droplets (LDs) in the liver by the GTPase ARF1, which is a key activator of lipolysis. This recruitment is activated by an insulin-dependent pathway and therefore responds to fed/fasted states of the animal. In fed state, ARF1 and kinesin appear on LDs, consequently transporting LDs to the periphery of hepatocytes where the smooth endoplasmic reticulum (sER) is present. Because the lipases that catabolize LDs in hepatocytes reside on the sER, LDs can now be catabolized efficiently to provide triglyceride for lipoprotein assembly and secretion from the sER. Upon fasting, insulin is lowered to remove ARF1 and kinesin from LDs, thus down-regulating LD transport and sER-LD contacts. This tempers triglyceride availabiity for very low density lipoprotein assembly and allows homeostatic control of serum triglyceride in a fasted state. We further show that kinesin knockdown inhibits hepatitis-C virus replication in hepatocytes, likely because translated viral proteins are unable to transfer from the ER to LDs. Copyright © 2017 the Author(s). Published by PNAS.

Survival with breast cancer: the importance of estrogen receptor quantity.

PubMed

Shek, L L; Godolphin, W

1989-02-01

The survival of 1184 British Columbian women whose primary breast cancers were diagnosed and assayed for estrogen receptor (ER) between 1975 and 1981 was studied. Median follow-up was 60 months. ER concentrations yielded greater prognostic information than simple positive and negative categories. When ER data were divided into four strata: less than or equal to 1, 2-9, 10-159 and greater than or equal to 160 fmol/mg cytosol protein, the association of higher ER with prolonged survival was highly significant (P less than 0.0001) and independent of TNM stage, nodal status and menopausal status. ER less than or equal to 1 and ER = 2-9 groups were distinct with respect to overall disease-specific survival. Patient age did not predict survival when controlled for ER. Prolonged recurrence-free survival was associated with higher ER (P = 0.0001) for at least 5 years after diagnosis. This significant trend persisted after adjustments for nodal status, TNM stage, menopausal status and the type of systemic adjuvant therapy.

Phase and speed synchronization control of four eccentric rotors driven by induction motors in a linear vibratory feeder with unknown time-varying load torques using adaptive sliding mode control algorithm

NASA Astrophysics Data System (ADS)

Kong, Xiangxi; Zhang, Xueliang; Chen, Xiaozhe; Wen, Bangchun; Wang, Bo

2016-05-01

In this paper, phase and speed synchronization control of four eccentric rotors (ERs) driven by induction motors in a linear vibratory feeder with unknown time-varying load torques is studied. Firstly, the electromechanical coupling model of the linear vibratory feeder is established by associating induction motor's model with the dynamic model of the system, which is a typical under actuated model. According to the characteristics of the linear vibratory feeder, the complex control problem of the under actuated electromechanical coupling model converts to phase and speed synchronization control of four ERs. In order to keep the four ERs operating synchronously with zero phase differences, phase and speed synchronization controllers are designed by employing adaptive sliding mode control (ASMC) algorithm via a modified master-slave structure. The stability of the controllers is proved by Lyapunov stability theorem. The proposed controllers are verified by simulation via Matlab/Simulink program and compared with the conventional sliding mode control (SMC) algorithm. The results show the proposed controllers can reject the time-varying load torques effectively and four ERs can operate synchronously with zero phase differences. Moreover, the control performance is better than the conventional SMC algorithm and the chattering phenomenon is attenuated. Furthermore, the effects of reference speed and parametric perturbations are discussed to show the strong robustness of the proposed controllers. Finally, experiments on a simple vibratory test bench are operated by using the proposed controllers and without control, respectively, to validate the effectiveness of the proposed controllers further.

Endoplasmic Reticulum Transport of Glutathione by Sec61 Is Regulated by Ero1 and Bip.

PubMed

Ponsero, Alise J; Igbaria, Aeid; Darch, Maxwell A; Miled, Samia; Outten, Caryn E; Winther, Jakob R; Palais, Gael; D'Autréaux, Benoit; Delaunay-Moisan, Agnès; Toledano, Michel B

2017-09-21

In the endoplasmic reticulum (ER), Ero1 catalyzes disulfide bond formation and promotes glutathione (GSH) oxidation to GSSG. Since GSSG cannot be reduced in the ER, maintenance of the ER glutathione redox state and levels likely depends on ER glutathione import and GSSG export. We used quantitative GSH and GSSG biosensors to monitor glutathione import into the ER of yeast cells. We found that glutathione enters the ER by facilitated diffusion through the Sec61 protein-conducting channel, while oxidized Bip (Kar2) inhibits transport. Increased ER glutathione import triggers H 2 O 2 -dependent Bip oxidation through Ero1 reductive activation, which inhibits glutathione import in a negative regulatory loop. During ER stress, transport is activated by UPR-dependent Ero1 induction, and cytosolic glutathione levels increase. Thus, the ER redox poise is tuned by reciprocal control of glutathione import and Ero1 activation. The ER protein-conducting channel is permeable to small molecules, provided the driving force of a concentration gradient. Copyright © 2017 Elsevier Inc. All rights reserved.

Growth studies of erbium-doped GaAs deposited by metalorganic vapor phase epitaxy using noval cyclopentadienyl-based erbium sources

NASA Technical Reports Server (NTRS)

Redwing, J. M.; Kuech, T. F.; Gordon, D. C.; Vaartstra, B. A.; Lau, S. S.

1994-01-01

Erbium-doped GaAS layers were grown by metalorganic vapor phase epitaxy using two new sources, bis(i-propylcyclopentadienyl)cyclopentadienyl erbium and tris(t-butylcyclopentadienyl) erbium. Controlled Er doping in the range of 10(exp 17) - 10(exp 18)/cu cm was achieved using a relatively low source temperature of 90 C. The doping exhibits a second-order dependence on inlet source partial pressure, similar to behavior obtained with cyclopentadienyl Mg dopant sources. Equivalent amounts of oxygen and Er are present in 'as-grown' films indicating that the majority of Er dopants probably exist as Er-O complexes in the material. Er(+3) luminescence at 1.54 micrometers was measured from the as-grown films, but ion implantation of additional oxygen decreases the emission intensity. Electrical compensation of n-type GaAs layers codoped with Er and Si is directly correlated to the Er concentration is proposed to arise from the deep centers associated with Er which are responsible for a broad emission band near 0.90 micrometers present in the photoluminescence spectra of GaAs:Si, Er films.

Regulation of mitochondrial function and endoplasmic reticulum stress by nitric oxide in pluripotent stem cells

PubMed Central

Caballano-Infantes, Estefania; Terron-Bautista, José; Beltrán-Povea, Amparo; Cahuana, Gladys M; Soria, Bernat; Nabil, Hajji; Bedoya, Francisco J; Tejedo, Juan R

2017-01-01

Mitochondrial dysfunction and endoplasmic reticulum stress (ERS) are global processes that are interrelated and regulated by several stress factors. Nitric oxide (NO) is a multifunctional biomolecule with many varieties of physiological and pathological functions, such as the regulation of cytochrome c inhibition and activation of the immune response, ERS and DNA damage; these actions are dose-dependent. It has been reported that in embryonic stem cells, NO has a dual role, controlling differentiation, survival and pluripotency, but the molecular mechanisms by which it modulates these functions are not yet known. Low levels of NO maintain pluripotency and induce mitochondrial biogenesis. It is well established that NO disrupts the mitochondrial respiratory chain and causes changes in mitochondrial Ca2+ flux that induce ERS. Thus, at high concentrations, NO becomes a potential differentiation agent due to the relationship between ERS and the unfolded protein response in many differentiated cell lines. Nevertheless, many studies have demonstrated the need for physiological levels of NO for a proper ERS response. In this review, we stress the importance of the relationships between NO levels, ERS and mitochondrial dysfunction that control stem cell fate as a new approach to possible cell therapy strategies. PMID:28289506

Regulation of mitochondrial function and endoplasmic reticulum stress by nitric oxide in pluripotent stem cells.

PubMed

Caballano-Infantes, Estefania; Terron-Bautista, José; Beltrán-Povea, Amparo; Cahuana, Gladys M; Soria, Bernat; Nabil, Hajji; Bedoya, Francisco J; Tejedo, Juan R

2017-02-26

Mitochondrial dysfunction and endoplasmic reticulum stress (ERS) are global processes that are interrelated and regulated by several stress factors. Nitric oxide (NO) is a multifunctional biomolecule with many varieties of physiological and pathological functions, such as the regulation of cytochrome c inhibition and activation of the immune response, ERS and DNA damage; these actions are dose-dependent. It has been reported that in embryonic stem cells, NO has a dual role, controlling differentiation, survival and pluripotency, but the molecular mechanisms by which it modulates these functions are not yet known. Low levels of NO maintain pluripotency and induce mitochondrial biogenesis. It is well established that NO disrupts the mitochondrial respiratory chain and causes changes in mitochondrial Ca 2+ flux that induce ERS. Thus, at high concentrations, NO becomes a potential differentiation agent due to the relationship between ERS and the unfolded protein response in many differentiated cell lines. Nevertheless, many studies have demonstrated the need for physiological levels of NO for a proper ERS response. In this review, we stress the importance of the relationships between NO levels, ERS and mitochondrial dysfunction that control stem cell fate as a new approach to possible cell therapy strategies.

The impact of luteal phase support on endometrial estrogen and progesterone receptor expression: a randomized control trial

PubMed Central

2012-01-01

Background To assess the impact of luteal phase support on the expression of estrogen receptor (ER) alpha and progesterone receptors B (PR-B) on the endometrium of oocyte donors undergoing controlled ovarian hyperstimulation (COH). Methods A prospective, randomized study was conducted in women undergoing controlled ovarian hyperstimulation for oocyte donation. Participants were randomized to receive no luteal support, vaginal progesterone alone, or vaginal progesterone plus orally administered 17 Beta estradiol. Endometrial biopsies were obtained at 4 time points in the luteal phase and evaluated by tissue microarray for expression of ER alpha and PR-B. Results One-hundred and eight endometrial tissue samples were obtained from 12 patients. No differences were found in expression of ER alpha and PR-B among all the specimens with the exception of one sample value. Conclusions The administration of progesterone during the luteal phase of COH for oocyte donor cycles, either with or without estrogen, does not significantly affect the endometrial expression of ER alpha and PR. PMID:22360924

SR/ER-mitochondrial local communication: Calcium and ROS

PubMed Central

Csordás, György; Hajnóczky, György

2009-01-01

Mitochondria form junctions with the sarco/endoplasmic reticulum (SR/ER), which support signal transduction and biosynthetic pathways and affect organellar distribution. Recently, these junctions have received attention because of their pivotal role in mediating calcium signal propagation to the mitochondria, which is important for both ATP production and mitochondrial cell death. Many of the SR/ER-mitochondrial calcium transporters and signaling proteins are sensitive to redox regulation and are directly exposed to the reactive oxygen species (ROS) produced in the mitochondria and SR/ER. Although ROS has been emerging as a novel signaling entity, the redox signaling of the SR/ER-mitochondrial interface is yet to be elucidated. We describe here possible mechanisms of the mutual interaction between local Ca2+ and ROS signaling in the control of SR/ER-mitochondrial function. PMID:19527680

Endoplasmic reticulum stress is important for the manifestations of α-synucleinopathy in vivo

PubMed Central

Colla, Emanuela; Coune, Philippe; Liu, Ying; Pletnikova, Olga; Troncoso, Juan C; Iwatsubo, Takeshi; Schneider, Bernard L.; Lee, Michael K.

2012-01-01

Accumulation of misfolded α-synuclein (αS) is mechanistically linked to neurodegeneration in Parkinson's disease (PD) and other α-synucleinopathies. However, how αS causes neurodegeneration is unresolved. Because cellular accumulation of misfolded proteins can lead to endoplasmic reticulum stress/unfolded protein response (ERS/UPR), chronic ERS could contribute to neurodegeneration in α-synucleinopathy. Using the A53T mutant human αS transgenic (A53TαS Tg) mouse model of α-synucleinopathy, we show that disease onset in the αS Tg model is coincident with induction of ER chaperone in neurons exhibiting αS pathology. However, the neuronal ER chaperone induction was not accompanied by the activation of phospho-eIF2α, indicating that α-synucleinopathy is associated with abnormal UPR that could promote cell death. Induction of ERS/UPR was associated with increased levels of ER/microsomal (ER/M) associated αS monomers and aggregates. Significantly, human PD cases also exhibit higher relative levels of ER/M αS than the control cases. Moreover, αS interacts with ER chaperones and overexpression of αS sensitizes neuronal cells to ERS-induced toxicity, suggesting that αS may have direct impact on ER function. This view is supported by the presence of ERS-activated caspase-12 and the accumulation of ER-associated polyubiquitin. More important, treatment with Salubrinal, an anti-ERS compound, significantly attenuates disease manifestations in both the A53TαS Tg mouse model and the Adeno-associated Virus-transduced rat model of A53T α S-dependent dopaminergic neurodegeneration. Our data indicate that the accumulation αS within ER leads to chronic ER stress conditions that contribute to neurodegeneration in α-synucleinopathies. Attenuating chronic ERS could be an effective therapy for PD and other α-synucleinopathies. PMID:22399753

Do People With Psychosis Have Specific Difficulties Regulating Emotions?

PubMed

Lincoln, Tania M; Hartmann, Maike; Köther, Ulf; Moritz, Steffen

2015-01-01

Difficulties in emotion regulation (ER) are present in psychotic disorders, but their precise nature is not yet fully understood and it is unclear which difficulties are unique to psychosis compared with other disorders. This study investigated whether ER difficulties in psychosis are more prominent for the ability to modify emotions or for the ability to tolerate and accept them. Furthermore, it investigated whether ER difficulties occur for sadness, anxiety, anger and shame likewise. ER skills were assessed in participants with psychotic disorders (n = 37), participants with depression (n = 30) and healthy controls (n = 28) using the Emotion Regulation Skill Questionnaire that asks participants to rate the intensity of different emotions over the past week and the skills employed to handle each of them. Compared with healthy controls, participants with psychosis showed reduced skills related to awareness, understanding and acceptance of potentially distressing emotions, but not in the ability to modify them. These differences remained significant after controlling for depression. Participants with psychosis showed reduced ER skills in regard to all of the assessed emotions compared with the healthy controls, despite the fact that they only reported sadness as being significantly more intense. The participants with depression showed a similar pattern of ER skills to the psychosis sample, although with a tendency towards even more pronounced difficulties. It is concluded that psychosis is characterized by difficulties in using specific ER skills related to awareness, understanding and acceptance to regulate anger, shame, anxiety and sadness. These difficulties are not unique to psychosis but nevertheless present a promising treatment target. The participants with psychosis found it more difficult to be aware of their emotions, to understand them and to accept them than the healthy control group. However, they reported equal skills when it came to actively modifying emotions. The difficulties in emotion regulation reported by the participants with psychosis were comparable with those reported by the participants with depression, and they occurred for all types of negative emotions likewise. The difficulties in using specific ER skills related to awareness, understanding and acceptance are a promising target for psychological treatment of psychosis. Interventions that are aimed specifically at increasing these skills need to be further developed. Copyright © 2014 John Wiley & Sons, Ltd.

Monitoring Endoplasmic Reticulum Calcium Homeostasis Using a Gaussia Luciferase SERCaMP.

PubMed

Henderson, Mark J; Wires, Emily S; Trychta, Kathleen A; Yan, Xiaokang; Harvey, Brandon K

2015-09-06

The endoplasmic reticulum (ER) contains the highest level of intracellular calcium, with concentrations approximately 5,000-fold greater than cytoplasmic levels. Tight control over ER calcium is imperative for protein folding, modification and trafficking. Perturbations to ER calcium can result in the activation of the unfolded protein response, a three-prong ER stress response mechanism, and contribute to pathogenesis in a variety of diseases. The ability to monitor ER calcium alterations during disease onset and progression is important in principle, yet challenging in practice. Currently available methods for monitoring ER calcium, such as calcium-dependent fluorescent dyes and proteins, have provided insight into ER calcium dynamics in cells, however these tools are not well suited for in vivo studies. Our lab has demonstrated that a modification to the carboxy-terminus of Gaussia luciferase confers secretion of the reporter in response to ER calcium depletion. The methods for using a luciferase based, secreted ER calcium monitoring protein (SERCaMP) for in vitro and in vivo applications are described herein. This video highlights hepatic injections, pharmacological manipulation of GLuc-SERCaMP, blood collection and processing, and assay parameters for longitudinal monitoring of ER calcium.

Rab32 modulates apoptosis onset and mitochondria-associated membrane (MAM) properties.

PubMed

Bui, Michael; Gilady, Susanna Y; Fitzsimmons, Ross E B; Benson, Matthew D; Lynes, Emily M; Gesson, Kevin; Alto, Neal M; Strack, Stefan; Scott, John D; Simmen, Thomas

2010-10-08

The mitochondria-associated membrane (MAM) has emerged as an endoplasmic reticulum (ER) signaling hub that accommodates ER chaperones, including the lectin calnexin. At the MAM, these chaperones control ER homeostasis but also play a role in the onset of ER stress-mediated apoptosis, likely through the modulation of ER calcium signaling. These opposing roles of MAM-localized chaperones suggest the existence of mechanisms that regulate the composition and the properties of ER membrane domains. Our results now show that the GTPase Rab32 localizes to the ER and mitochondria, and we identify this protein as a regulator of MAM properties. Consistent with such a role, Rab32 modulates ER calcium handling and disrupts the specific enrichment of calnexin on the MAM, while not affecting the ER distribution of protein-disulfide isomerase and mitofusin-2. Furthermore, Rab32 determines the targeting of PKA to mitochondrial and ER membranes and through its overexpression or inactivation increases the phosphorylation of Bad and of Drp1. Through a combination of its functions as a PKA-anchoring protein and a regulator of MAM properties, the activity and expression level of Rab32 determine the speed of apoptosis onset.

High power eye-safe Er3+:YVO4 laser diode-pumped at 976 nm and emitting at 1603 nm

NASA Astrophysics Data System (ADS)

Newburgh, G. A.; Dubinskii, M.

2016-02-01

We report on the performance of an eye-safe laser based on a Er:YVO4 single crystal, diode-pumped at 976 nm (4I15/2-->4I11/2 transition) and operating at 1603 nm (4I13/2-->4I15/2 transition) with good beam quality. A 10 mm long Er3+:YVO4 slab, cut with its c-axis perpendicular to the laser cavity axis, was pumped in σ-polarization and lased in π-polarization. The laser operated in a quasi-continuous wave (Q-CW) regime with nearly 9 W output power, and with a slope efficiency of about 39% with respect to absorbed power. This is believed to be the highest efficiency and highest power achieved from an Er3+:YVO4 laser pumped in the 970-980 nm absorption band.

MW peak power Er/Yb-doped fiber femtosecond laser amplifier at 1.5 µm center wavelength

NASA Astrophysics Data System (ADS)

Han, Seongheum; Jang, Heesuk; Kim, Seungman; Kim, Young-Jin; Kim, Seung-Woo

2017-08-01

An erbium (Er)/ytterbium (Yb) co-doped double-clad fiber is configured to amplify single-mode pulses with a high average power of 10 W at a 1.5 µm center wavelength. The pulse duration at the exit of the Er/Yb fiber amplifier is measured to be ~440 fs after grating-based compression. The whole single-mode operation of the amplifier system permits the M 2-value of the output beam quality to be evaluated better than 1.05. By tuning the repetition rate from 100 MHz down to 600 kHz, the pulse peak power is scaled up to 19.1 MW to be the highest ever reported using an Er/Yb single-mode fiber. The proposed amplifier system is well suited for strong-power applications such as free-space LIDAR, non-thermal machining and medical surgery.

On the accuracy of ERS-1 orbit predictions

NASA Technical Reports Server (NTRS)

Koenig, Rolf; Li, H.; Massmann, Franz-Heinrich; Raimondo, J. C.; Rajasenan, C.; Reigber, C.

1993-01-01

Since the launch of ERS-1, the D-PAF (German Processing and Archiving Facility) provides regularly orbit predictions for the worldwide SLR (Satellite Laser Ranging) tracking network. The weekly distributed orbital elements are so called tuned IRV's and tuned SAO-elements. The tuning procedure, designed to improve the accuracy of the recovery of the orbit at the stations, is discussed based on numerical results. This shows that tuning of elements is essential for ERS-1 with the currently applied tracking procedures. The orbital elements are updated by daily distributed time bias functions. The generation of the time bias function is explained. Problems and numerical results are presented. The time bias function increases the prediction accuracy considerably. Finally, the quality assessment of ERS-1 orbit predictions is described. The accuracy is compiled for about 250 days since launch. The average accuracy lies in the range of 50-100 ms and has considerably improved.

30 CFR 285.659 - What requirements must I include in my SAP, COP, or GAP regarding air quality?

Code of Federal Regulations, 2011 CFR

2011-07-01

..., or GAP regarding air quality? 285.659 Section 285.659 Mineral Resources BUREAU OF OCEAN ENERGY... Pipeline Deviations § 285.659 What requirements must I include in my SAP, COP, or GAP regarding air quality..., according to the following table. ER29AP09.130 (b) For air quality modeling that you perform in support of...

Can functional emotion regulation protect children's mental health from war trauma? A Palestinian study.

PubMed

Diab, Marwan; Peltonen, Kirsi; Qouta, Samir R; Palosaari, Esa; Punamäki, Raija-Leena

2017-04-19

Effective emotion regulation (ER) is expected to protect mental health in traumatic stress. We first analysed the protective (moderator) function of different ER strategies and the associations between ER and mental health. Second, we tested gender differences in the protective function of ER and the associations between ER strategies and mental health. Participants were 482 Palestinian children (girls 49.4%; 10-13 years, M = 11.29, SD = .68) whose ER was assessed by the Emotion Regulation Questionnaire and mental health by post-traumatic stress (Children's Impact Event Scale), depressive, and psychological distress (Strengths and Difficulties Questionnaire) symptoms, and by psychosocial well-being (Mental Health Continuum-Short Form). War trauma involved 42 events. Results showed, first, that none of the ER strategies could protect a child's mental health from negative impact of war trauma, but self-focused ER was associated with low depressive symptoms, and other-facilitated ER with high psychological well-being. However, controlling of emotions formed a comprehensive risk for children's mental health. Second, gender differences were found in the protective role of ER, as self-focused and distractive ER formed a vulnerability among boys. The results are discussed in the context of emotional and regulative demands of war and life-threat. © 2017 International Union of Psychological Science.

ERS/ECDC Statement: European Union standards for tuberculosis care, 2017 update.

PubMed

Migliori, Giovanni Battista; Sotgiu, Giovanni; Rosales-Klintz, Senia; Centis, Rosella; D'Ambrosio, Lia; Abubakar, Ibrahim; Bothamley, Graham; Caminero, Jose Antonio; Cirillo, Daniela Maria; Dara, Masoud; de Vries, Gerard; Aliberti, Stefano; Dinh-Xuan, Anh Tuan; Duarte, Raquel; Midulla, Fabio; Solovic, Ivan; Subotic, Dragan R; Amicosante, Massimo; Correia, Ana Maria; Cirule, Andra; Gualano, Gina; Kunst, Heinke; Palmieri, Fabrizio; Riekstina, Vija; Tiberi, Simon; Verduin, Remi; van der Werf, Marieke J

2018-05-01

The International Standards for Tuberculosis Care define the essential level of care for managing patients who have or are presumed to have tuberculosis, or are at increased risk of developing the disease. The resources and capacity in the European Union (EU) and the European Economic Area permit higher standards of care to secure quality and timely TB diagnosis, prevention and treatment. On this basis, the European Union Standards for Tuberculosis Care (ESTC) were published in 2012 as standards specifically tailored to the EU setting. Since the publication of the ESTC, new scientific evidence has become available and, therefore, the standards were reviewed and updated.A panel of international experts, led by a writing group from the European Respiratory Society (ERS) and the European Centre for Disease Prevention and Control (ECDC), updated the ESTC on the basis of new published evidence. The underlying principles of these patient-centred standards remain unchanged. The second edition of the ESTC includes 21 standards in the areas of diagnosis, treatment, HIV and comorbidities, and public health and prevention.The ESTC target clinicians and public health workers, provide an easy-to-use resource and act as a guide through all the required activities to ensure optimal diagnosis, treatment and prevention of TB. The content of this work is copyright of the authors or their employers. Design and branding are copyright ©ERS 2018.

cld and lec23 are disparate mutations that affect maturation of lipoprotein lipase in the endoplasmic reticulum.

PubMed

Briquet-Laugier, V; Ben-Zeev, O; White, A; Doolittle, M H

1999-11-01

The mutations cld (combined lipase deficiency) and lec23 disrupt in a similar manner the expression of lipoprotein lipase (LPL). Whereas cld affects an unknown gene, lec23 abolishes the activity of alpha-glucosidase I, an enzyme essential for proper folding and assembly of nascent glycoproteins. The hypothesis that cld, like lec23, affects the folding/assembly of nascent LPL was confirmed by showing that in cell lines homozygous for these mutations (Cld and Lec23, respectively), the majority of LPL was inactive, displayed heterogeneous aggregation, and had a decreased affinity for heparin. While inactive LPL was retained in the ER, a small amount of LPL that had attained a native conformation was transported through the Golgi and secreted. Thus, Cld and Lec23 cells recognized and retained the majority of LPL as misfolded, maintaining the standard of quality control. Examination of candidate factors affecting protein maturation, such as glucose addition and trimming, proteins involved in lectin chaperone cycling, and other abundant ER chaperones, revealed that calnexin levels were dramatically reduced in livers from cld/cld mice; this finding was also confirmed in Cld cells. We conclude that cld may affect components in the ER, such as calnexin, that play a role in protein maturation. Whether the reduced calnexin levels per se contribute to the LPL deficiency awaits confirmation.

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

PubMed Central

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

2013-01-01

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

Unique effects of The transporters animated series and of parental support on emotion recognition skills of children with ASD: Results of a randomized controlled trial.

PubMed

Gev, Tali; Rosenan, Ruthie; Golan, Ofer

2017-05-01

Emotion recognition (ER) and understanding deficits are characteristic of autism spectrum disorder (ASD). The Transporters (TT) animated series has shown promising results in teaching children with ASD to recognize emotions, with mixed findings about generalization and maintenance of effects. This study aimed to evaluate the unique role of TT and of parental support in the acquisition, generalization, and maintenance of acquired ER skills in children with ASD. 77 Israeli children with high functioning ASD, aged 4-7 were randomly assigned into four groups according to a 2 × 2 design of the factors Series (TT, control series) and Parental Support (with/without). Thirty typically developing children, matched to the ASD groups on mental age, were tested with no intervention. Participants' ER (on three generalization levels) and emotional vocabulary (EV) were tested pre and post 8 weeks of intervention, and at 3 months' follow-up. Compared to the control series, watching TT significantly improved children's ER skills at all generalization levels, with good skill maintenance. All groups improved equally on EV. The amount of parental support given, in the groups that had received it, contributed to the generalization and maintenance of ER skills. Autism severity negatively correlated with ER improvement. The current study provides evidence to the unique role of TT in ER skill acquisition, generalization, and maintenance in children with high functioning ASD. In addition, this study provides evidence for a successful cultural adaptation of TT to a non-English speaking culture. Autism Res 2017, 10: 993-1003. © 2016 International Society for Autism Research, Wiley Periodicals, Inc. © 2016 International Society for Autism Research, Wiley Periodicals, Inc.

Recycling stainless steel orthodontic brackets with Er:YAG laser - An environmental scanning electron microscope and shear bond strength study.

PubMed

Chacko, Prince K; Kodoth, Jithesh; John, Jacob; Kumar, Kishore

2013-07-01

TO DETERMINE THE EFFICIENCY OF ERBIUM: Yttrium aluminum garnet (Er:YAG) laser with Environmental Scanning Electron Microscope (ESEM) and shear bond strength analysis as a method of recycling stainless steel orthodontic brackets and compare with other methods of recycling. Eighty samples of extracted premolar teeth bonded to SS brackets were tested for rebonded shear bond strength after recycling by four methods and compared with a control group of 20 samples. These 80 samples were randomized into four groups which were recycled by four methods, namely, sandblasting, thermal method, adhesive grinding by tungsten carbide bur, and Er: YAG laser method. After recycling, ESEM and shear bond strength analysis were used to analyze the efficiency of the recycling methods. ER: YAG laser group was found to be having the greatest bond strength among the recycled brackets (8.33±2.51 followed by the sandblasting at 6.12±1.12 MPa, thermal and electropolishing at 4.44±0.95 MPa, and lastly the adhesive grinding method at 3.08±1.07 MPa. The shear bond strength of Er: YAG laser group was found to be having no statistically significant difference with that of the control group (P>0.05 and had statistical signifance with sandblasting, thermal and electropolishing and adhesive grinding groups at P>0.001. ESEM analysis showed complete removal of adhesive from the brackets recycled with Er: YAG laser which mimicked that of the control group. ER: YAG laser (2940 nm) was found to be the most efficient method for recycling, followed by the sandblasting, thermal, and the tungsten carbide methods, which had the least shear bond strength value and is not fit for clinical usage.

Influence of ER leak on resting cytoplasmic Ca2+ and receptor-mediated Ca2+ signalling in human macrophage.

PubMed

Layhadi, Janice A; Fountain, Samuel J

2017-06-03

Mechanisms controlling endoplasmic reticulum (ER) Ca 2+ homeostasis are important regulators of resting cytoplasmic Ca 2+ concentration ([Ca 2+ ] cyto ) and receptor-mediated Ca 2+ signalling. Here we investigate channels responsible for ER Ca 2+ leak in THP-1 macrophage and human primary macrophage. In the absence of extracellular Ca 2+ we employ ionomycin action at the plasma membrane to stimulate ER Ca 2+ leak. Under these conditions ionomycin elevates [Ca 2+ ] cyto revealing a Ca 2+ leak response which is abolished by thapsigargin. IP 3 receptors (Xestospongin C, 2-APB), ryanodine receptors (dantrolene), and translocon (anisomycin) inhibition facilitated ER Ca 2+ leak in model macrophage, with translocon inhibition also reducing resting [Ca 2+ ] cyto . In primary macrophage, translocon inhibition blocks Ca 2+ leak but does not influence resting [Ca 2+ ] cyto . We identify a role for translocon-mediated ER Ca 2+ leak in receptor-mediated Ca 2+ signalling in both model and primary human macrophage, whereby the Ca 2+ response to ADP (P2Y receptor agonist) is augmented following anisomycin treatment. In conclusion, we demonstrate a role of ER Ca 2+ leak via the translocon in controlling resting cytoplasmic Ca 2+ in model macrophage and receptor-mediated Ca 2+ signalling in model macrophage and primary macrophage. Copyright © 2017 Elsevier Inc. All rights reserved.

Estrogen receptor status in CHEK2-positive breast cancers: implications for chemoprevention.

PubMed

Cybulski, C; Huzarski, T; Byrski, T; Gronwald, J; Debniak, T; Jakubowska, A; Górski, B; Wokołorczyk, D; Masojć, B; Narod, S A; Lubiński, J

2009-01-01

To investigate the relationship between CHEK2 mutation status and estrogen receptor (ER) status in unselected cases of early-onset breast cancer from Poland, we screened 4441 women diagnosed with breast cancer younger than 51 years and 7217 controls for three inherited mutations in CHEK2 (1100delC, IVS2+1G>A, del5395). ER status was compared between CHEK2-positive and CHEK2-negative breast cancer cases. A truncating mutation in CHEK2 was seen in 140 of 4441 cases and in 70 of 7217 controls [odds ratio (OR) = 3.3; 95% CI = 2.5-4.4; p < 0.0001]. ER status was available for 92 of 140 mutation carriers and for 3001 of 4301 non-carriers with breast cancer. The OR was higher for ER-positive cancers (OR = 3.9; 95% CI = 2.7-5.4; p < 0.0001) than for ER-negative cancers (OR = 2.1; 95% CI = 1.3-3.3; p = 0.002). Sixty-six of the 92 breast cancers in carriers of CHEK2 truncating mutations were ER positive compared with 1742 of the 3001 breast cancers in non-carriers (72% vs 58%; p = 0.01). Women with a CHEK2 mutation face a fourfold increase in the risk of ER-positive breast cancer and might be candidates for tamoxifen chemoprevention.

Protein quality control in the early secretory pathway

PubMed Central

Anelli, Tiziana; Sitia, Roberto

2008-01-01

Eukaryotic cells are able to discriminate between native and non-native polypeptides, selectively transporting the former to their final destinations. Secretory proteins are scrutinized at the endoplasmic reticulum (ER)–Golgi interface. Recent findings reveal novel features of the underlying molecular mechanisms, with several chaperone networks cooperating in assisting the maturation of complex proteins and being selectively induced to match changing synthetic demands. ‘Public' and ‘private' chaperones, some of which enriched in specializes subregions, operate for most or selected substrates, respectively. Moreover, sequential checkpoints are distributed along the early secretory pathway, allowing efficiency and fidelity in protein secretion. PMID:18216874

Documentation of the U.S. Geological Survey Oceanographic Time-Series Measurement Database

USGS Publications Warehouse

Montgomery, Ellyn T.; Martini, Marinna A.; Lightsom, Frances L.; Butman, Bradford

2008-01-02

This report describes the instrumentation and platforms used to make the measurements; the methods used to process, apply quality-control criteria, and archive the data; the data storage format, and how the data are released and distributed. The report also includes instructions on how to access the data from the online database at http://stellwagen.er.usgs.gov/. As of 2016, the database contains about 5,000 files, which may include observations of current velocity, wave statistics, ocean temperature, conductivity, pressure, and light transmission at one or more depths over some duration of time.

Resonantly diode-pumped Er:YAG laser: 1470-nm versus 1530-nm CW pumping case

NASA Astrophysics Data System (ADS)

Kudryashov, Igor; Ter-Gabrielyan, Nikolai; Dubinskii, Mark

2009-05-01

Growing interest to high power lasers in the eye-safe spectral domain initiated a new wave of activity in developing solid-state lasers based on bulk Er3+-doped materials. The resonant pumping of SSL allows for shifting significant part of thermal load from gain medium itself to the pump diodes, thus greatly reducing gain medium thermal distortions deleterious to SSL power scaling with high beam quality. The two major resonant pumping bands in Er:YAG are centered around 1470 and 1532 nm. Pumping into each of these bands has its pros and contras. The best approach to resonant pumping of Er:YAG active media in terms of pump wavelength is yet to be determined. We report the investigation results of high power diode-pumped Er:YAG laser aimed at direct comparison of resonant pumping at 1470 and 1532 nm. Two sources used for pumping were: 1530-nm 10-diode bar stack (>300 W CW) and 1470-nm 10-diode bar stack (>650 W CW). Both pumps were spectrally narrowed by external volume Bragg gratings. The obtained spectral width of less than 1 nm allowed for 'in-line' pumping of Er3+ in either band. The obtained CW power of over 87 W is, to the best of our knowledge, the record high power reported for resonantly pumped Er:YAG DPSSL at room temperature.

[Estrogen receptor alpha in obesity and diabetes].

PubMed

Cahua-Pablo, José Ángel; Flores-Alfaro, Eugenia; Cruz, Miguel

2016-01-01

Estradiol (E2) is an important hormone in reproductive physiology, cardiovascular, skeletal and in the central nervous system (CNS). In human and rodents, E2 and its receptors are involved in the control of energy and glucose metabolism in health and metabolic diseases. The estrogen receptor (ER) belongs to the superfamily of nuclear receptors (NR), which are transcription factors that regulate gene expression. Three ER, ER-alpha, ER-beta and the G protein-coupled ER (GPER; also called GPR30) in tissues are involved in glucose and lipid homeostasis. Also, it may have important implications for risk factors associated with metabolic syndrome (MS), insulin resistance (IR), obesity and type 2 diabetes (T2D).

Endoplasmic reticulum stress is induced in the human placenta during labour

PubMed Central

Veerbeek, J.H.W.; Tissot Van Patot, M.C.; Burton, G.J.; Yung, H.W.

2015-01-01

Placental endoplasmic reticulum (ER) stress has been postulated in the pathophysiology of pre-eclampsia (PE) and intrauterine growth restriction (IUGR), but its activation remains elusive. Oxidative stress induced by ischaemia/hypoxia-reoxygenation activates ER stress in vitro. Here, we explored whether exposure to labour represents an in vivo model for the study of acute placental ER stress. ER stress markers, GRP78, P-eIF2α and XBP-1, were significantly higher in laboured placentas than in Caesarean-delivered controls localised mainly in the syncytiotrophoblast. The similarities to changes observed in PE/IUGR placentas suggest exposure to labour can be used to investigate induction of ER stress in pathological placentas. PMID:25434970

Aging induced endoplasmic reticulum stress alters sleep and sleep homeostasis.

PubMed

Brown, Marishka K; Chan, May T; Zimmerman, John E; Pack, Allan I; Jackson, Nicholas E; Naidoo, Nirinjini

2014-06-01

Alterations in the quality, quantity, and architecture of baseline and recovery sleep have been shown to occur during aging. Sleep deprivation induces endoplasmic reticular (ER) stress and upregulates a protective signaling pathway termed the unfolded protein response. The effectiveness of the adaptive unfolded protein response is diminished by age. Previously, we showed that endogenous chaperone levels altered recovery sleep in Drosophila melanogaster. We now report that acute administration of the chemical chaperone sodium 4-phenylbutyrate (PBA) reduces ER stress and ameliorates age-associated sleep changes in Drosophila. PBA consolidates both baseline and recovery sleep in aging flies. The behavioral modifications of PBA are linked to its suppression of ER stress. PBA decreased splicing of X-box binding protein 1 and upregulation of phosphorylated elongation initiation factor 2 α, in flies that were subjected to sleep deprivation. We also demonstrate that directly activating ER stress in young flies fragments baseline sleep and alters recovery sleep. Alleviating prolonged or sustained ER stress during aging contributes to sleep consolidation and improves recovery sleep or sleep debt discharge. Copyright © 2014 Elsevier Inc. All rights reserved.

Enhanced frequency upconversion in Er3+-Yb3+ codoped heavy metal oxides based tellurite glasses.

PubMed

Azam, Mohd; Rai, Vineet Kumar

2018-01-24

The spectroscopic investigations on the Er 3+ /Yb 3+ ions doped/codoped TeO 2 -ZnO (TZ), TeO 2 -ZnO-WO 3 (TZW) and TeO 2 -ZnO-WO 3 -TiO 2 (TZWTi) heavy metal oxide (HMO) glasses have been made. The absorption, photoluminescence, decay curve and Judd-Ofelt analysis have been performed to optimise the optical properties of the Er 3+ /Yb 3+ ions. The effect of incorporation of HMOs like WO 3 and TiO 2 in the Er 3+ /Yb 3+ doped/codoped TZ glass on its optical properties have been investigated. The enhancement in upconversion emission intensity has been explained on the basis of efficient energy transfer and inhomogeneous local field generation around the rare earth ions. The spectroscopic quality factor, absorption and stimulated emission cross-sections, optical gain, quantum efficiency (∼17.53%), energy transfer efficiency (∼61.64%), colour purity (∼94.7%) and ionic nature of the bonding have been determined. The Er 3+ -Yb 3+ -TZWTi glass can be used in visible lasers, yellowish green optical devices and home appliances.

Conductivity versus Dielectric Mechanisms for Electrorheology

NASA Astrophysics Data System (ADS)

Davis, L. C.

1997-03-01

Electrorheological (ER) fluids are continuously and rapidly controllable by an electric field. Controllability of these materials permits the construction of novel intelligent systems such as semiactively controlled shock absorbers and vibration dampers, tunable composite beams and panels, and even reconfigurable Braille arrays. The eventual success of these applications depends in part on developing improved ER fluids, which requires a fundamental understanding of the physics and chemistry of these materials. ER fluids generally consist of highly polarizable colloidal particles suspended in an insulating oil. Particles are typically 1-10 microns in diameter and can be of a wide variety of materials including zeolites, barium titanate, conducting polymers, and oxide-coated metals. Electric fields of magnitude 1-5 kV/mm induce particle chaining and concomitant shear stresses of order 1 kPa. Recent experiments (J. M. Ginder and S. L. Ceccio, J. Rheol. 39, 211 (1995)) using square-wave electric-field excitation have helped to elucidate the mechanisms of ER activity. Immediately after a step-function increase of electric field, chaining occurs due to particle-particle forces arising from dielectric polarization (dipoles and higher multipoles), i.e., it is controlled by the dielectric mismatch between particles and fluid. On a longer time scale, currents flow in the fluid and in the particles so that the forces are eventually dominated by the conductivity mismatch. Characteristic times for the transition between the two regimes are 10-50 ms. Likewise, in the frequency domain, conductivity mismatch dominates the dc response of ER fluids whereas dielectric effects dominate for high frequencies. A theory of ER fluids is given including a model for non-linear effects at high electric fields.

Calreticulin is required for calcium homeostasis and proper pollen tube tip growth in Petunia.

PubMed

Suwińska, Anna; Wasąg, Piotr; Zakrzewski, Przemysław; Lenartowska, Marta; Lenartowski, Robert

2017-05-01

Calreticulin is involved in stabilization of the tip-focused Ca 2+ gradient and the actin cytoskeleton arrangement and function that is required for several key processes driving Petunia pollen tube tip growth. Although the precise mechanism is unclear, stabilization of a tip-focused calcium (Ca 2+ ) gradient seems to be critical for pollen germination and pollen tube growth. We hypothesize that calreticulin (CRT), a Ca 2+ -binding/buffering chaperone typically residing in the lumen of the endoplasmic reticulum (ER) of eukaryotic cells, is an excellent candidate to fulfill this role. We previously showed that in Petunia pollen tubes growing in vitro, CRT is translated on ER membrane-bound ribosomes that are abundant in the subapical zone of the tube, where CRT's Ca 2+ -buffering and chaperone activities might be particularly required. Here, we sought to determine the function of CRT using small interfering RNA (siRNA) to, for the first time in pollen tubes growing in vitro, knockdown expression of a gene. We demonstrate that siRNA-mediated post-transcriptional silencing of Petunia hybrida CRT gene (PhCRT) expression strongly impairs pollen tube growth, cytoplasmic zonation, actin cytoskeleton organization, and the tip-focused Ca 2+ gradient. Moreover, reduction of CRT alters the localization and disturbs the structure of the ER in abnormally elongating pollen tubes. Finally, cytoplasmic streaming is inhibited, and most of the pollen tubes rupture. Our data clearly show an interplay between CRT, Ca 2+ gradient, actin-dependent cytoplasmic streaming, organelle positioning, and vesicle trafficking during pollen tube elongation. Thus, we suggest that CRT functions in Petunia pollen tube growth by stabilizing Ca 2+ homeostasis and acting as a chaperone to assure quality control of glycoproteins passing through the ER.

Ubiquitin and Parkinson's disease through the looking glass of genetics.

PubMed

Walden, Helen; Muqit, Miratul M K

2017-04-13

Biochemical alterations found in the brains of Parkinson's disease (PD) patients indicate that cellular stress is a major driver of dopaminergic neuronal loss. Oxidative stress, mitochondrial dysfunction, and ER stress lead to impairment of the homeostatic regulation of protein quality control pathways with a consequent increase in protein misfolding and aggregation and failure of the protein degradation machinery. Ubiquitin signalling plays a central role in protein quality control; however, prior to genetic advances, the detailed mechanisms of how impairment in the ubiquitin system was linked to PD remained mysterious. The discovery of mutations in the α-synuclein gene, which encodes the main protein misfolded in PD aggregates, together with mutations in genes encoding ubiquitin regulatory molecules, including PTEN-induced kinase 1 (PINK1), Parkin, and FBX07, has provided an opportunity to dissect out the molecular basis of ubiquitin signalling disruption in PD, and this knowledge will be critical for developing novel therapeutic strategies in PD that target the ubiquitin system. © 2017 The Author(s).

Monitoring asthma in childhood: symptoms, exacerbations and quality of life.

PubMed

Brand, Paul L P; Mäkelä, Mika J; Szefler, Stanley J; Frischer, Thomas; Price, David

2015-06-01

Monitoring asthma in children in clinical practice is primarily performed by reviewing disease activity (daytime and night-time symptoms, use of reliever medication, exacerbations requiring frequent use of reliever medication and urgent visits to the healthcare professional) and the impact of the disease on children's daily activities, including sports and play, in a clinical interview. In such an interview, most task force members also discuss adherence to maintenance therapy and the patients' (and parents') views and beliefs on the goals of treatment and the amount of treatment required to achieve those goals. Composite asthma control and quality of life measures, although potentially useful in research, have limited value in clinical practice because they have a short recall window and do not cover the entire spectrum of asthma control. Telemonitoring of children with asthma cannot replace face-to-face follow-up and monitoring because there is no evidence that it is associated with improved health outcomes. Copyright ©ERS 2015.

Final Disposition and Quality Auditing of the Rehabilitation Process in Wild Raptors Admitted to a Wildlife Rehabilitation Centre in Catalonia, Spain, during a Twelve Year Period (1995–2007)

PubMed Central

Molina-López, Rafael A.; Casal, Jordi; Darwich, Laila

2013-01-01

Background Variability in reporting and classification methods in previous published data of the final dispositions in the rehabilitation of wild raptors makes use of this data limited in trying to audit the quality of the rehabilitation process. Crude as well as stratified disposition rates are needed if quality auditing of the rehabilitation process is to be adequately performed. Methodology Final dispositions of 6221 hospitalized wild raptors admitted at a wildlife rehabilitation centre (WRC) of Catalonia during 1995–2007 were analyzed. These dispositions were calculated as the euthanasia (Er), unassisted mortality (Mr), release (Rr) and captivity rates (Cr)., time to death (Td) for dead and euthanized raptors, and length of stay for released (Tr) raptors was estimated. Stratified analyses by main causes of admission and clinical signs were performed. Results The disposition for the total population were: Er  = 30.6%, Mr = 19.1%, Rr  = 47.2%, and Cr  = 3%. By main causes of admission, Er was higher in the trauma category (34.2%), whereas Mr was found similar between trauma (37.4%) and non-trauma categories (34.8%). The highest Rr was observed for the orphaned group (77.9%). Furthermore, Cr was low in all the categories (<4%). By clinical signs, the highest Er was found in animals suffering musculoskeletal (37.9%) or skin (32.3%) lesions; Mr was high in infectious/parasitic diseases (66.7%) and in case of neurological symptoms (64.5%). The euthanized birds had a median Td  = 1 day (P10 = 0-P90 = 59) for both trauma and non-trauma categories, and Td  = 36 days for the orphaned young group (P10 = 0; P90 = 596). The median Td in the unassisted dead birds was 2 days for all the categories (P10 = 0-P90 = 31). Finally, the median Tr in the centre was variable among categories. Conclusions/Significance Reporting of final dispositions in wildlife rehabilitation should include the crude and stratified rates (Er, Mr, Rr, and Cr), by causes and clinical presentation, as well as Td and Tr, to allow meaningful auditing of the rehabilitation process quality. PMID:23613722

Quality of pathology reporting is crucial for cancer care and registration: a baseline assessment for breast cancers diagnosed in Belgium in 2008.

PubMed

De Schutter, H; Van Damme, N; Colpaert, C; Galant, C; Lambein, K; Cornelis, A; Neven, P; Van Eycken, E

2015-04-01

Given the crucial role of pathology reporting in the management of breast cancers, we aimed to investigate the quality and variability of breast cancer pathology reporting in Belgium. Detailed information on non-molecular and molecular parameters was retrieved from the pathology protocols available at the Belgian Cancer Registry for 10,007 breast cancers diagnosed in Belgium in 2008. Substantial underreporting was shown for several clinically relevant non-molecular parameters, such as lymphovascular invasion. High-volume laboratories performed only slightly better than others, and analyses at the individual laboratory level showed clear inter-laboratory variability in reporting for all volume categories. Information on ER/PR and HER2 IHC was mentioned in respectively 91.7% and 90.8% of evaluative cases. HER2 ISH data were available for 78.5% of the cases judged to be 2+ for HER2 IHC. For cases with different specimens analysed, discordance between these specimens was highest for HER2, followed by PR. For HER2, results obtained from different laboratories were even less concordant. In addition, inter-laboratory differences were noted in the used ER/PR scoring systems, the proportion of ER-/PR+ cases, and the relation between histological grade and ER/PR positivity. Data on Ki67 were only available for 43.8% of the investigated cases, and showed inconsistent use of cut-off values. Breast pathology reporting in Belgium in 2008 was suboptimal and showed considerable inter-laboratory variability. Synoptic reporting has been proposed as a facilitator towards increased reporting quality and harmonization, but the lack of aligned informatics remains a major hurdle in its concrete implementation. Copyright © 2014 Elsevier Ltd. All rights reserved.

Insulin-induced Gene Protein (INSIG)-dependent Sterol Regulation of Hmg2 Endoplasmic Reticulum-associated Degradation (ERAD) in Yeast*

PubMed Central

Theesfeld, Chandra L.; Hampton, Randolph Y.

2013-01-01

Insulin-induced gene proteins (INSIGs) function in control of cellular cholesterol. Mammalian INSIGs exert control by directly interacting with proteins containing sterol-sensing domains (SSDs) when sterol levels are elevated. Mammalian 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase (HMGR) undergoes sterol-dependent, endoplasmic-reticulum (ER)-associated degradation (ERAD) that is mediated by INSIG interaction with the HMGR SSD. The yeast HMGR isozyme Hmg2 also undergoes feedback-regulated ERAD in response to the early pathway-derived isoprene gernanylgeranyl pyrophosphate (GGPP). Hmg2 has an SSD, and its degradation is controlled by the INSIG homologue Nsg1. However, yeast Nsg1 promotes Hmg2 stabilization by inhibiting GGPP-stimulated ERAD. We have proposed that the seemingly disparate INSIG functions can be unified by viewing INSIGs as sterol-dependent chaperones of SSD clients. Accordingly, we tested the role of sterols in the Nsg1 regulation of Hmg2. We found that both Nsg1-mediated stabilization of Hmg2 and the Nsg1-Hmg2 interaction required the early sterol lanosterol. Lowering lanosterol in the cell allowed GGPP-stimulated Hmg2 ERAD. Thus, Hmg2-regulated degradation is controlled by a two-signal logic; GGPP promotes degradation, and lanosterol inhibits degradation. These data reveal that the sterol dependence of INSIG-client interaction has been preserved for over 1 billion years. We propose that the INSIGs are a class of sterol-dependent chaperones that bind to SSD clients, thus harnessing ER quality control in the homeostasis of sterols. PMID:23306196

Criticality safety strategy and analysis summary for the fuel cycle facility electrorefiner at Argonne National Laboratory West

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

Mariani, R.D.; Benedict, R.W.; Lell, R.M.

1996-05-01

As part of the termination activities of Experimental Breeder Reactor II (EBR-II) at Argonne National Laboratory (ANL) West, the spent metallic fuel from EBR-II will be treated in the fuel cycle facility (FCF). A key component of the spent-fuel treatment process in the FCF is the electrorefiner (ER) in which the actinide metals are separated from the active metal fission products and the reactive bond sodium. In the electrorefining process, the metal fuel is anodically dissolved into a high-temperature molten salt, and refined uranium or uranium/plutonium products are deposited at cathodes. The criticality safety strategy and analysis for the ANLmore » West FCF ER is summarized. The FCF ER operations and processes formed the basis for evaluating criticality safety and control during actinide metal fuel refining. To show criticality safety for the FCF ER, the reference operating conditions for the ER had to be defined. Normal operating envelopes (NOEs) were then defined to bracket the important operating conditions. To keep the operating conditions within their NOEs, process controls were identified that can be used to regulate the actinide forms and content within the ER. A series of operational checks were developed for each operation that will verify the extent or success of an operation. The criticality analysis considered the ER operating conditions at their NOE values as the point of departure for credible and incredible failure modes. As a result of the analysis, FCF ER operations were found to be safe with respect to criticality.« less

European Union Standards for Tuberculosis Care

PubMed Central

Migliori, G.B.; Zellweger, J.P.; Abubakar, I.; Ibraim, E.; Caminero, J.A.; De Vries, G.; D'Ambrosio, L.; Centis, R.; Sotgiu, G.; Menegale, O.; Kliiman, K.; Aksamit, T.; Cirillo, D.M.; Danilovits, M.; Dara, M.; Dheda, K.; Dinh-Xuan, A.T.; Kluge, H.; Lange, C.; Leimane, V.; Loddenkemper, R.; Nicod, L.P.; Raviglione, M.C.; Spanevello, A.; Thomsen, V.Ø.; Villar, M.; Wanlin, M.; Wedzicha, J.A.; Zumla, A.; Blasi, F.; Huitric, E.; Sandgren, A.; Manissero, D.

2012-01-01

The European Centre for Disease Prevention and Control (ECDC) and the European Respiratory Society (ERS) jointly developed European Union Standards for Tuberculosis Care (ESTC) aimed at providing European Union (EU)-tailored standards for the diagnosis, treatment and prevention of tuberculosis (TB). The International Standards for TB Care (ISTC) were developed in the global context and are not always adapted to the EU setting and practices. The majority of EU countries have the resources and capacity to implement higher standards to further secure quality TB diagnosis, treatment and prevention. On this basis, the ESTC were developed as standards specifically tailored to the EU setting. A panel of 30 international experts, led by a writing group and the ERS and ECDC, identified and developed the 21 ESTC in the areas of diagnosis, treatment, HIV and comorbid conditions, and public health and prevention. The ISTCs formed the basis for the 21 standards, upon which additional EU adaptations and supplements were developed. These patient-centred standards are targeted to clinicians and public health workers, providing an easy-to-use resource, guiding through all required activities to ensure optimal diagnosis, treatment and prevention of TB. These will support EU health programmes to identify and develop optimal procedures for TB care, control and elimination. PMID:22467723

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

The Scatterometer Instrument Competence Centre (SCIRoCCo): Project's Activities and First Achievements

NASA Astrophysics Data System (ADS)

Crapolicchio, R.; Bigazzi, A.; De Chiara, G.; Neyt, X.; Stoffelen, A.; Belmonte, M.; Wagner, W.; Reimer, C.

2016-08-01

The Scatterometer Instrument Competence Centre (SCIRoCCo, http://scirocco.sp.serco.eu) is a project established by the European Space Agency (ESA) in 2014 as an interdisciplinary cooperation of international scatterometry experts aimed at promoting the continuing exploitation of ESA's unique 20 years' worth of ERS Scatterometer data (ESCAT) at medium (25Km, 50 Km) spatial resolution, and improving the quality of available and future scatterometry data.SCIRoCCo aims at consolidating current methodologies for Scatterometer data processing and calibration. SCIRoCCo provides ERS-1/ERS-2 sensors inter- calibration, sensor characterization and data validation. Data analysis and processing software, academic and technical publications in support of calibration and many diverse applications and research in Land (e.g. Soil Moisture), Oceanography (Ocean Winds, Sea, Ice), Climatology are also provided through the web portal, which also serves as the entry point to SCIRoCCo's educational network, funded through Grants and aimed at fostering the next-generation scatterometry experts. SCIRoCCo thus targets the needs of meteorological agencies, meteorological operations centers and the broader Researchers' and Users' communities for consistent and high quality Scatterometer data processing.

The Coordinated P53 and Estrogen Receptor Cis-Regulation at an FLT1 Promoter SNP Is Specific to Genotoxic Stress and Estrogenic Compound

PubMed Central

Langen, Jan-Stephan; Schoenfelder, Gilbert; Resnick, Michael A.; Inga, Alberto

2010-01-01

Background Recently, we established that a C>T single nucleotide polymorphism (SNP) in the promoter of the VEGF receptor FLT1 gene generates a ½ site p53 response element (RE-T) that results in p53 responsiveness of the promoter. The transcriptional control required an estrogen receptor (ER) ½ site response element (ERE1) 225 nt upstream to the RE-T. Methodology/Principal Findings Here we report the identification of a second ER ½ site (ERE2) located 145 bp downstream of the RE-T and establish that both EREs can impact p53-mediated transactivation of FLT1-T in a manner that is cell type and ER level dependent. Gene reporter assays and ChIP experiments conducted in the breast cancer-derived MCF7 cells revealed that the ERE2 site was sufficient for p53-mediated ERα recruitment and transactivation of the FLT1-T promoter/reporter construct. Surprisingly, unlike the case for other p53 target promoters, p53-mediated transactivation of FLT1-T constructs or expression of the endogenous FLT1 gene, as well as binding of p53 and ER at the promoter constructs, was inducible by doxorubicin but not by 5-fluorouracil. Furthermore, ER activity at FLT1-T was differentially affected by ER ligands, compared to a control TFF1/pS2 ER target promoter. The p53-related transcription factors (TFs) p73 and p63 had no effect on FLT1 transactivation. Conclusions/Significance We establish a new dimension to the p53 master regulatory network where p53-mediated transcription from a ½ site RE can be determined by ER binding at one or more cis-acting EREs in manner that is dependent on level of ER protein, the type of ER ligand and the specific p53-inducing agent. PMID:20422012

Patient satisfaction with the use of an enhanced recovery programme for primary arthroplasty.

PubMed

Machin, J T; Phillips, S; Parker, M; Carrannante, J; Hearth, M W

2013-11-01

Enhanced recovery programmes (ErPs) are increasingly being used for arthroplasty. One of the core aims of an ErP is to improve the quality of patient experience. However, there is currently no published evaluation of patient satisfaction in relation to this new programme of care within orthopaedic surgery. The aim of this study was to compare the ErP against the standard care programme (SCP) at one centre. A satisfaction survey addressing patient opinions on the key objectives of the ErP was conducted by telephone, using a set script. Of the 226 patients contacted, 143 (63.3%) responded (69 from the ErP and 74 from the SCP). Of the respondents, 71 received a total hip arthroplasty and 72 a total knee arthroplasty. Patients were contacted at a mean time from operation to survey of 27.2 weeks. They were asked to rate satisfaction on a five-point scale and complete the EQ-5D™ health questionnaire (EuroQol, rotterdam, Netherlands) to measure healthcare outcomes. The mean patient satisfaction score of 4.07 for speed of recovery in the ErP group was significantly higher than the SCP group's score of 3.68 (p=0.037). Adjusting for the preoperative health score, the postoperative health score was higher for ErP patients at 74.1 compared with 64.7 for SCP patients (p=0.0029). Furthermore, the percentage of patients who had a better than expected recovery was significantly greater in the ErP group at 85.5% compared with 58.1% (p=0.0004) in the SCP group. We believe that the previously established reduction in length of hospital stay delivered by ErPs is not achieved at the expense of the patient's experience.

[Dietary patterns in patients with attention deficit hyperactivity disorder].

PubMed

Durá Travé, T; Diez Bayona, V; Yoldi Petri, M E; Aguilera Albesa, S

2014-04-01

To evaluate the dietary patterns in a group of patients diagnosed with attention deficit hyperactivity disorder (ADHD) and under treatment with extended-release methylphenidate (MPH-ER). A nutrition survey (food intake recall for three consecutive days) was carried out on 100 patients diagnosed with ADHD and under treatment with MPH-ER, and in 150 healthy children (control group). Calorie and nutrient intake, as well as nutrition status, were evaluated and compared in both groups. The mean MPH-ER dose was 1.02 mg/kg/day. Nutritional status in the ADHD group was significantly lower (P < .05) than in control group. The consumption of cereals, meat, pulses and fruits in the control group was significantly higher (P < .05) than in ADHD group. Calorie intake in the mid-morning snack, lunch and afternoon snack was significantly higher (P < .05) in the control group. Calorie intake at supper was significantly higher (P < .05) in the ADHD group. Total calorie intake, as well as protein, carbohydrates, fat, fibre, calcium, iron, magnesium, zinc, selenium and phosphorous, thiamine, niacin, vitamin B6 and folate intake in the control group was significantly higher than in ADHD group. Treatment with MPH-ER substantially modifies the percentage distribution of calorie intake of the different meals. The daily calorie and nutrients intake in patients under treatment with MPH-ER is, generally, lower than in the healthy population of a similar age. Nutrition education should be provided, along with multimodal treatment, to the patients and/or their families. Copyright © 2013 Asociación Española de Pediatría. Published by Elsevier Espana. All rights reserved.

Endoplasmic reticulum calcium release potentiates the ER stress and cell death caused by an oxidative stress in MCF-7 cells.

PubMed

Dejeans, Nicolas; Tajeddine, Nicolas; Beck, Raphaël; Verrax, Julien; Taper, Henryk; Gailly, Philippe; Calderon, Pedro Buc

2010-05-01

Increase in cytosolic calcium concentration ([Ca2+](c)), release of endoplasmic reticulum (ER) calcium ([Ca2+](er)) and ER stress have been proposed to be involved in oxidative toxicity. Nevertheless, their relative involvements in the processes leading to cell death are not well defined. In this study, we investigated whether oxidative stress generated during ascorbate-driven menadione redox cycling (Asc/Men) could trigger these three events, and, if so, whether they contributed to Asc/Men cytoxicity in MCF-7 cells. Using microspectrofluorimetry, we demonstrated that Asc/Men-generated oxidative stress was associated with a slow and moderate increase in [Ca2+](c), largely preceding permeation of propidium iodide, and thus cell death. Asc/Men treatment was shown to partially deplete ER calcium stores after 90 min (decrease by 45% compared to control). This event was associated with ER stress activation, as shown by analysis of eIF2 phosphorylation and expression of the molecular chaperone GRP94. Thapsigargin (TG) was then used to study the effect of complete [Ca2+](er) emptying during the oxidative stress generated by Asc/Men. Surprisingly, the combination of TG and Asc/Men increased ER stress to a level considerably higher than that observed for either treatment alone, suggesting that [Ca2+](er) release alone is not sufficient to explain ER stress activation during oxidative stress. Finally, TG-mediated [Ca2+](er) release largely potentiated ER stress, DNA fragmentation and cell death caused by Asc/Men, supporting a role of ER stress in the process of Asc/Men cytotoxicity. Taken together, our results highlight the involvement of ER stress and [Ca2+](er) decrease in the process of oxidative stress-induced cell death in MCF-7 cells. 2009 Elsevier Inc. All rights reserved.

Endoplasmic reticulum membrane potassium channel dysfunction in high fat diet induced stress in rat hepatocytes

PubMed Central

Khodaee, Naser; Ghasemi, Maedeh; Saghiri, Reza; Eliassi, Afsaneh

2014-01-01

In a previous study we reported the presence of a large conductance K+ channel in the membrane of endoplasmic reticulum (ER) from rat hepatocytes. The channel open probability (Po) appeared voltage dependent and reached to a minimum 0.2 at +50 mV. Channel activity in this case was found to be totally inhibited at ATP concentration 2.5 mM, glibenclamide 100 µM and tolbutamide 400 µM. Existing evidence indicates an impairment of endoplasmic reticulum functions in ER stress condition. Because ER potassium channels have been involved in several ER functions including cytoprotection, apoptosis and calcium homeostasis, a study was carried out to consider whether the ER potassium channel function is altered in a high fat diet model of ER stress. Male Wistar rats were made ER stress for 2 weeks with a high fat diet. Ion channel incorporation of ER stress model into the bilayer lipid membrane allowed the characterization of K+ channel. Our results indicate that the channel Po was significantly increased at voltages above +30 mV. Interestingly, addition of ATP 7.5 mM, glibenclamide 400 µM and tolbutamide 2400 µM totally inhibited the channel activities, 3-fold, 4-fold and 6-fold higher than that in the control groups, respectively. Our results thus demonstrate a modification in the ER K+ channel gating properties and decreased sensitivity to drugs in membrane preparations coming from ER high fat model of ER stress, an effect potentially linked to a change in ER K+ channel subunits in ER stress condition. Our results may provide new insights into the cellular mechanisms underlying ER dysfunctions in ER stress. PMID:26417322

Effects of Simulated Mobile Phone Electromagnetic Radiation on Fertilization and Embryo Development.

PubMed

Chen, Hong; Qu, Zaiqing; Liu, Wenhui

2017-04-01

This study investigated the effects of 935-MHz electromagnetic radiation (ER) on fertilization and subsequent embryonic development in mice. Ovulating mice were irradiated at three ER intensities for 4 h/day (d) or 2 h/d for three consecutive days; the ova were then harvested for in vitro fertilization to observe the 6-h fertilization rate (6-FR), 72-h morula rate (72-MR), and 110-h blastula rate (110-BR). Compared with the control group, the 6-FR, 72-MR, and 110-BR were decreased in the low ER intensity group, but the differences were not significant; in the mid- and high-intensity ER groups, 72-MR and 110-BR in the 4 h/d and 2 h/d subgroups were decreased, showing significant differences compared with the control group. Moreover, the comparison between 4 h/d and 2 h/d subgroups showed significant differences. Mid- and high-intensity ER at 935 MHz can reduce the fertilization rate in mice, and reduce the blastulation rate, thus reducing the possibility of embryo implantation.

Proteomic analysis of endoplasmic reticulum stress responses in rice seeds.

PubMed

Qian, Dandan; Tian, Lihong; Qu, Leqing

2015-09-23

The defects in storage proteins secretion in the endosperm of transgenic rice seeds often leads to endoplasmic reticulum (ER) stress, which produces floury and shrunken seeds, but the mechanism of this response remains unclear. We used an iTRAQ-based proteomics analysis of ER-stressed rice seeds due to the endosperm-specific suppression of OsSar1 to identify changes in the protein levels in response to ER stress. ER stress changed the expression of 405 proteins in rice seed by >2.0- fold compared with the wild-type control. Of these proteins, 140 were upregulated and 265 were downregulated. The upregulated proteins were mainly involved in protein modification, transport and degradation, and the downregulated proteins were mainly involved in metabolism and stress/defense responses. A KOBAS analysis revealed that protein-processing in the ER and degradation-related proteasome were the predominant upregulated pathways in the rice endosperm in response to ER stress. Trans-Golgi protein transport was also involved in the ER stress response. Combined with bioinformatic and molecular biology analyses, our proteomic data will facilitate our understanding of the systemic responses to ER stress in rice seeds.

Videogames for Emotion Regulation: A Systematic Review.

PubMed

Villani, Daniela; Carissoli, Claudia; Triberti, Stefano; Marchetti, Antonella; Gilli, Gabriella; Riva, Giuseppe

2018-04-01

Emotion regulation (ER) supports multiple individual functions and promotes mental health and wellbeing. Among the tools that may be used to help people in managing their affective states, videogames are reaching attention and are showing positive effects. Yet, little is known about their effectiveness. This study aims to assess the amount and quality of studies investigating the effects and modalities of the use of videogames for ER. A systematic literature search according to PRISMA guidelines was performed. Subsequently, according to expert advice other few studies have been added. Twenty-three studies met the inclusion criteria and were included in the review; they can be categorized into three groups, namely (1) cross-sectional and qualitative studies, (2) experimental studies investigating the effects of videogame experience on ER and (3) ER intervention with serious games. Discussion of the reviewed studies highlights that frequent gaming with commercial games offers more opportunities for ER improvement (related to gameplay and enjoyment of fictional properties) than limited-time experiences, such as those supported by bespoke serious games. This research area is still in its infancy and findings need to be interpreted with caution; furthermore, future reviews are encouraged to include clinical populations. Videogames offer several opportunities for ER and a challenge for educational and psychological interventions.

A Large and Intact Viral Particle Penetrates the Endoplasmic Reticulum Membrane to Reach the Cytosol

PubMed Central

Inoue, Takamasa; Tsai, Billy

2011-01-01

Non-enveloped viruses penetrate host membranes to infect cells. A cell-based assay was used to probe the endoplasmic reticulum (ER)-to-cytosol membrane transport of the non-enveloped SV40. We found that, upon ER arrival, SV40 is released into the lumen and undergoes sequential disulfide bond disruptions to reach the cytosol. However, despite these ER-dependent conformational changes, SV40 crosses the ER membrane as a large and intact particle consisting of the VP1 coat, the internal components VP2, VP3, and the genome. This large particle subsequently disassembles in the cytosol. Mutant virus and inhibitor studies demonstrate VP3 and likely the viral genome, as well as cellular proteasome, control ER-to-cytosol transport. Our results identify the sequence of events, as well as virus and host components, that regulate ER membrane penetration. They also suggest that the ER membrane supports passage of a large particle, potentially through either a sizeable protein-conducting channel or the lipid bilayer. PMID:21589906

Cloning and expression of N-glycosylation-related mannosidase from Glaciozyma antarctica for the production of a mannosynthase

NASA Astrophysics Data System (ADS)

Elangovan, Dharshini; Kamaruddin, Shazilah; Hashim, Noor Haza Fazlin; Bakar, Farah Diba Abu; Murad, Abd. Munir Abd.; Mahadi, Nor Muhammad; Allman, Sarah Ann; Mackeen, Mukram Mohamed

2016-11-01

The controlled synthesis of oligosaccharides is of growing interest due to the important roles of oligosaccharides in various biological processes. Enzymatic synthesis enables regio- and stereo-selective control during synthesis which still remains a challenge using total chemical synthesis. In this study, endoplasmic reticulum 1,2-α-mannosidase from Glaciozyma antractica was recombinantly expressed in Pichia pastoris. The gene sequence for ER mannosidase was obtained from the Glaciozyma antractica database. The BLAST (Basic Local Alignment Search Tool) results from bioinformatics screening showed that ER mannosidase had 41 % identity with the equivalent mannosidases from Sacchromyces cerevesiae. ER mannosidase from G. antartica was then cloned into the pPICZαC expression vector and used to transform in the host Pichia pastoris X33 cells. The ER mannosidase (MW˜58 kDa) was successfully expressed at 25 °C with 1.0 % methanol induction.

Endoplasmic reticulum stress is induced in the human placenta during labour.

PubMed

Veerbeek, J H W; Tissot Van Patot, M C; Burton, G J; Yung, H W

2015-01-01

Placental endoplasmic reticulum (ER) stress has been postulated in the pathophysiology of pre-eclampsia (PE) and intrauterine growth restriction (IUGR), but its activation remains elusive. Oxidative stress induced by ischaemia/hypoxia-reoxygenation activates ER stress in vitro. Here, we explored whether exposure to labour represents an in vivo model for the study of acute placental ER stress. ER stress markers, GRP78, P-eIF2α and XBP-1, were significantly higher in laboured placentas than in Caesarean-delivered controls localised mainly in the syncytiotrophoblast. The similarities to changes observed in PE/IUGR placentas suggest exposure to labour can be used to investigate induction of ER stress in pathological placentas. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

Highly-efficient mid-infrared CW laser operation in a lightly-doped 3 at.% Er:SrF2 single crystal.

PubMed

Su, Liangbi; Guo, Xinsheng; Jiang, Dapeng; Wu, Qinghui; Qin, Zhipeng; Xie, Guoqiang

2018-03-05

3 at.% Er:SrF 2 laser crystals with high optical quality were successfully grown using the temperature gradient technique (TGT). The intense mid-infrared emission was observed around 2.7 μm with excitation by a 970 nm LD. Based on the Judd-Ofelt theory, the emission cross-sections of the 4 I 13/2 - 4 I 11/2 transition were calculated by using the Fuchtbauer-Ladenburg (FL) method. Efficient continuous-wave laser operation at 2.8 µm was achieved with the lightly-doped 3 at.% Er:SrF 2 crystal pumped by a 970 nm laser diode. The laser output power reached up to 1.06 W with a maximum slope efficiency of 26%.

CO2 and Er:YAG laser interaction with grass tissues

NASA Astrophysics Data System (ADS)

Kim, Jaehun; Ki, Hyungson

2013-01-01

Plant leaves are multi-component optical materials consisting of water, pigments, and dry matter, among which water is the predominant constituent. In this article, we investigate laser interaction with grass using CO2 and Er:YAG lasers theoretically and experimentally, especially targeting water in grass tissues. We have first studied the optical properties of light absorbing constituents of grass theoretically, and then have identified interaction regimes and constructed interaction maps through a systematic experiment. Using the interaction maps, we have studied how interaction regimes change as process parameters are varied. This study reveals some interesting findings concerning carbonization and ablation mechanisms, the effect of laser beam diameter, and the ablation efficiency and quality of CO2 and Er:YAG lasers.

Quality of life, activity impairment, and healthcare resource utilization associated with atrial fibrillation in the US National Health and Wellness Survey.

PubMed

Goren, Amir; Liu, Xianchen; Gupta, Shaloo; Simon, Teresa A; Phatak, Hemant

2013-01-01

This study builds upon current studies of atrial fibrillation (AF) and health outcomes by examining more comprehensively the humanistic burden of illness (quality of life, activity impairment, and healthcare resource utilization) among adult patients with AF, using a large, nationally representative sample and matched controls. Data were analyzed from the Internet-based 2009 US National Health and Wellness Survey. Outcomes were Mental and Physical Component Summary (MCS and PCS) and health utility scores from the SF-12, activity impairment, hospitalizations, and healthcare provider and emergency room (ER) visits. Patients with self-reported diagnosis of AF were matched randomly on age and gender with an equal number of respondents without AF. Generalized linear models examined outcomes as a function of AF vs. non-AF status, controlling for CHADS2 score, comorbidity counts, demographics, and clinical variables. Exploratory structural equation modeling assessed the above in an integrated model of humanistic burden. Mean age of AF patients (1,296 from a total sample of 75,000) was 64.9 years and 65.1% were male. Adjusting for covariates, compared with non-AF patients, AF patients had lower MCS, PCS, and utility scores, greater activity impairment (rate ratio = 1.26), more traditional provider visits (rate ratio = 1.43), and increased odds of ER visits (OR = 2.53) and hospitalizations (OR = 2.71). Exploratory structural equation modeling analyses revealed that persons with AF experienced a significantly higher overall humanistic burden. This study highlights and clarifies the substantial burden of AF and its implications for preparing efficacious AF management plans to address the imminent rise in prevalence.

Potential emerging treatment in vitiligo using Er:YAG in combination with 5FU and clobetasol.

PubMed

Mokhtari, Fatemeh; Bostakian, Anis; Shahmoradi, Zabihollah; Jafari-Koshki, Tohid; Iraji, Fariba; Faghihi, Gita; Hosseini, Sayed Mohsen; Bafandeh, Behzad

2018-04-01

Vitiligo is a pigmentary disorder of skin affecting at least 1% of the world population of all races in both sexes. Its importance is mainly due to subsequent social and psychological problems rather than clinical complications. Various treatment choices are available for vitiligo; however, laser-based courses have shown to give more acceptable results. The aim of this trial was to evaluate the efficacy of Er:YAG laser as a supplementary medicine to topical 5FU and clobetasol in vitiligo patients. Two comparable vitiligo patches from 38 eligible patients were randomized to receive topical 5FU and clobetasol in control group and additional Er:YAG laser in intervention group. Major outcomes of interest were the size of patch and pigmentation score at randomization and 2 and 4 months after therapy. Final sample included 18 (47%) male patients and age of 35.66±8.04. The performance Er:YAG group was superior in all sites. Reduction in the size of patches was greater in Er:YAG group (p-value=.004). Also, this group showed a higher pigmentation scores in the trial period than control group (p-value<.001). Greater reduction in the size and increase in pigmentation score was seen in Er:YAG group especially for short periods after therapy and repeating laser sessions may help improving final outcomes. Er:AYG could help in reducing complications of long-term topical treatments, achieving faster response, and improving patient adherence. © 2017 Wiley Periodicals, Inc.

A multifunctional β-CD-modified Fe3O4@ZnO:Er(3+),Yb(3+) nanocarrier for antitumor drug delivery and microwave-triggered drug release.

PubMed

Peng, Hongxia; Cui, Bin; Li, Guangming; Wang, Yingsai; Li, Nini; Chang, Zhuguo; Wang, Yaoyu

2015-01-01

We constructed a novel core-shell structured Fe3O4@ZnO:Er(3+),Yb(3+)@(β-CD) nanoparticles used as drug carrier to investigate the loading and controllable release properties of the chemotherapeutic drug etoposide (VP-16). The cavity of β-cyclodextrin is chemically inert, it can store etoposide molecules by means of hydrophobic interactions. The Fe3O4 core and ZnO:Er(3+),Yb(3+) shell functioned successfully for magnetic targeting and up-conversion fluorescence imaging, respectively. In addition, the ZnO:Er(3+),Yb(3+) shell acts as a good microwave absorber with excellent microwave thermal response property for microwave triggered drug release (the VP-16 release of 18% under microwave irradiation for 15 min outclass the 2% within 6h without microwave irradiation release). The release profile could be controlled by the duration and number of cycles of microwave application. This material therefore promises to be a useful noninvasive, externally controlled drug-delivery system in cancer therapy. Copyright © 2014 Elsevier B.V. All rights reserved.

GABAB receptor cell surface export is controlled by an endoplasmic reticulum gatekeeper

PubMed Central

Doly, Stéphane; Shirvani, Hamasseh; Gäta, Gabriel; Meye, Frank; Emerit, Michel-Boris; Enslen, Hervé; Achour, Lamia; Pardo-Lopez, Liliana; Kwon, Yang Seung; Armand, Vincent; Gardette, Robert; Giros, Bruno; Gassmann, Martin; Bettler, Bernhard; Mameli, Manuel; Darmon, Michèle; Marullo, Stefano

2016-01-01

Summary Endoplasmic reticulum (ER) release and cell surface export of many G protein-coupled receptors (GPCRs), are tightly regulated. For GABAB receptors of GABA, the major mammalian inhibitory neurotransmitter, the ligand-binding GB1 subunit is maintained in the ER by unknown mechanisms in the absence of hetero-dimerization with the GB2 subunit. We report that GB1 retention is regulated by a specific gatekeeper, PRAF2. This ER resident transmembrane protein binds to GB1, preventing its progression in the biosynthetic pathway. GB1 release occurs upon competitive displacement from PRAF2 by GB2. PRAF2 concentration, relative to that of GB1 and GB2, tightly controls cell surface receptor density and controls GABAB function in neurons. Experimental perturbation of PRAF2 levels in vivo caused marked hyperactivity disorders in mice. These data reveal an unanticipated major impact of specific ER gate-keepers on GPCR function and identify PRAF2 as a new molecular target with therapeutic potential for psychiatric and neurological diseases involving GABAB function. PMID:26033241

Sigma-1 receptor chaperones in neurodegenerative and psychiatric disorders

PubMed Central

Pokrass, Michael J; Klauer, Neal R; De Credico, Nicole E

2017-01-01

Introduction Sigma-1 receptors (Sig-1Rs) are molecular chaperones that reside mainly in the endoplasmic reticulum (ER) but exist also in the proximity of the plasma membrane. Sig-1Rs are highly expressed in the CNS and are involved in many cellular processes including cell differentiation, neuritogenesis, microglia activation, protein quality control, calcium-mediated ER stress and ion channel modulation. Disturbance in any of the above cellular processes can accelerate the progression of many neurological disorders; therefore, the Sig-1R has been implicated in several neurological diseases. Areas covered This review broadly covers the functions of Sig-1Rs including several neurodegenerative disorders in humans and drug addiction-associated neurological disturbance in the case of HIV infection. We discuss how several Sig-1R ligands could be utilized in therapeutic approaches to treat those disorders. Expert opinion Emerging understanding of the cellular functions of this unique transmembrane chaperone may lead to the use of new agents or broaden the use of certain available ligands as therapeutic targets in those neurological disorders. PMID:25331742

Use of Web-based training for quality improvement between a field immunohistochemistry laboratory in Nigeria and its United States-based partner institution.

PubMed

Oluwasola, Abideen O; Malaka, David; Khramtsov, Andrey Ilyich; Ikpatt, Offiong Francis; Odetunde, Abayomi; Adeyanju, Oyinlolu Olorunsogo; Sveen, Walmy Elisabeth; Falusi, Adeyinka Gloria; Huo, Dezheng; Olopade, Olufunmilayo Ibironke

2013-12-01

The importance of hormone receptor status in assigning treatment and the potential use of human epidermal growth factor receptor 2 (HER2)-targeted therapy have made it beneficial for laboratories to improve detection techniques. Because interlaboratory variability in immunohistochemistry (IHC) tests may also affect studies of breast cancer subtypes in different countries, we undertook a Web-based quality improvement training and a comparative study of accuracy of immunohistochemical tests of breast cancer biomarkers between a well-established laboratory in the United States (University of Chicago) and a field laboratory in Ibadan, Nigeria. Two hundred and thirty-two breast tumor blocks were evaluated for estrogen receptors (ERs), progesterone receptors (PRs), and HER2 status at both laboratories using tissue microarray technique. Initially, concordance analysis revealed κ scores of 0.42 (moderate agreement) for ER, 0.41 (moderate agreement) for PR, and 0.39 (fair agreement) for HER2 between the 2 laboratories. Antigen retrieval techniques and scoring methods were identified as important reasons for discrepancy. Web-based conferences using Web conferencing tools such as Skype and WebEx were then held periodically to discuss IHC staining protocols and standard scoring systems and to resolve discrepant cases. After quality assurance and training, the agreement improved to 0.64 (substantial agreement) for ER, 0.60 (moderate agreement) for PR, and 0.75 (substantial agreement) for HER2. We found Web-based conferences and digital microscopy useful and cost-effective tools for quality assurance of IHC, consultation, and collaboration between distant laboratories. Quality improvement exercises in testing of tumor biomarkers will reduce misclassification in epidemiologic studies of breast cancer subtypes and provide much needed capacity building in resource-poor countries. © 2013.

Association of Hormone-Related Characteristics and Breast Cancer Risk by Estrogen Receptor/Progesterone Receptor Status in the Shanghai Breast Cancer Study

PubMed Central

Bao, Ping-Ping; Shu, Xiao Ou; Gao, Yu-Tang; Zheng, Ying; Cai, Hui; Deming, Sandra L.; Ruan, Zhi-Xian; Gu, Kai; Lu, Wei; Zheng, Wei

2011-01-01

Etiologic differences between subtypes of breast cancer defined by estrogen receptor (ER) and progesterone receptor (PR) status are not well understood. The authors evaluated associations of hormone-related factors with breast cancer subtypes in a population-based case-control study involving 1,409 ER-positive (ER+)/PR-positive (PR+) cases, 712 ER-negative (ER−)/PR-negative (PR−) cases, 301 ER+/PR− cases, 254 ER−/PR+ cases, and 3,474 controls aged 20–70 years in Shanghai, China (phase I, 1996–1998; phase II, 2002–2005). Polytomous logistic regression and Wald tests for heterogeneity across subtypes were conducted. Breast cancer risks associated with age at menarche, age at menopause, breastfeeding, age at first livebirth, waist-to-hip ratio, and oral contraceptive use did not differ by hormone receptor status. Among postmenopausal women, higher parity (≥2 children vs. 1) was associated with reduced risk (odds ratio (OR) = 0.69, 95% confidence interval (CI): 0.52, 0.91) and higher body mass index (BMI; weight (kg)/height (m)2) with increased risk (highest quartile: OR = 2.40, 95% CI: 1.65, 3.47) of the ER+/PR+ subtype but was unrelated to the ER−/PR− subtype (for parity, Pheterogeneity = 0.02; for BMI, Pheterogeneity < 0.01). Hormone replacement therapy (OR = 2.25, 95% CI: 1.40, 3.62) and alcohol consumption (OR = 1.59, 95% CI: 1.01, 2.51) appeared to be preferentially associated with the ER+/PR− subtype. These findings indicate that BMI, parity, hormone replacement therapy, and alcohol consumption may play different roles in subtypes of breast cancer. More research is needed to better understand the etiology of 2 relatively rare subtypes, ER+/PR− tumors and ER−/PR+ tumors. PMID:21768404

Criticality safety strategy for the Fuel Cycle Facility electrorefiner at Argonne National Laboratory, West

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

Mariani, R.D.; Benedict, R.W.; Lell, R.M.

1993-09-01

The Integral Fast Reactor being developed by Argonne National Laboratory (ANL) combines the advantages of metal-fueled, liquid-metal-cooled reactors and a closed fuel cycle. Presently, the Fuel Cycle Facility (FCF) at ANL-West in Idaho Falls, Idaho is being modified to recycle spent metallic fuel from Experimental Breeder Reactor II as part of a demonstration project sponsored by the Department of Energy. A key component of the FCF is the electrorefiner (ER) in which the actinides are separated from the fission products. In the electrorefining process, the metal fuel is anodically dissolved into a high-temperature molten salt and refined uranium or uranium/plutoniummore » products are deposited at cathodes. In this report, the criticality safety strategy for the FCF ER is summarized. FCF ER operations and processes formed the basis for evaluating criticality safety and control during actinide metal fuel refining. In order to show criticality safety for the FCF ER, the reference operating conditions for the ER had to be defined. Normal operating envelopes (NOES) were then defined to bracket the important operating conditions. To keep the operating conditions within their NOES, process controls were identified that can be used to regulate the actinide forms and content within the ER. A series of operational checks were developed for each operation that wig verify the extent or success of an operation. The criticality analysis considered the ER operating conditions at their NOE values as the point of departure for credible and incredible failure modes. As a result of the analysis, FCF ER operations were found to be safe with respect to criticality.« less

In vitro activity of an ear rinse containing tromethamine, EDTA, benzyl alcohol and 0.1% ketoconazole on Malassezia organisms from dogs with otitis externa.

PubMed

Cole, Lynette K; Luu, Dao H; Rajala-Schultz, Paivi J; Meadows, Cheyney; Torres, Audrey H

2007-04-01

The purpose of this study was to evaluate the in vitro activity of an ear rinse containing tromethamine, EDTA, benzyl alcohol and 0.1% ketoconazole in purified water on Malassezia organisms from dogs with otitis externa. Malassezia organisms were collected from ear swab samples from the external ear canal of 19 dogs with otitis externa plus one control strain of Malassezia pachydermatis. Three test solutions were evaluated: ER (EDTA, tromethamine, benzyl alcohol), ER + keto (EDTA, tromethamine, benzyl alcohol, ketoconazole), and H2O (purified water). Ten-millilitre aliquots of each test solution was transferred into 20 tubes and inoculated with one of the isolates (1 tube per isolate: 19 clinical and 1 control strain). Samples were retrieved from each tube at five time points (0, 15, 30, 45 and 60 min), transferred to Petri dishes, mixed with Sabouraud dextrose agar supplemented with 0.5% Tween 80 and incubated. Following incubation, the plates were examined for growth and colonies counted as colony-forming units per millilitre. The data were analysed using a repeated measures analysis, with pair-wise comparisons of solution-time combinations. There was a significant reduction in Malassezia growth in ER + keto at all time points (P < 0.0001) compared to time zero. Neither ER nor H2O had any effect on the growth of Malassezia. ER + keto was significantly more effective in reducing Malassezia growth (P < 0.0001) at all time points compared to both ER and H2O. ER + keto may be useful in the treatment of Malassezia otitis externa. Future studies should be performed to evaluate the in vivo efficacy of ER + keto as treatment for otic infections caused by Malassezia.

Inhibition of ER stress and unfolding protein response pathways causes skeletal muscle wasting during cancer cachexia.

PubMed

Bohnert, Kyle R; Gallot, Yann S; Sato, Shuichi; Xiong, Guangyan; Hindi, Sajedah M; Kumar, Ashok

2016-09-01

Cachexia is a devastating syndrome that causes morbidity and mortality in a large number of patients with cancer. However, the mechanisms of cancer cachexia remain poorly understood. Accumulation of misfolded proteins in the endoplasmic reticulum (ER) causes stress. The ER responds to this stress through activating certain pathways commonly known as the unfolding protein response (UPR). The main function of UPR is to restore homeostasis, but excessive or prolonged activation of UPR can lead to pathologic conditions. In this study, we examined the role of ER stress and UPR in regulation of skeletal muscle mass in naïve conditions and during cancer cachexia. Our results demonstrate that multiple markers of ER stress are highly activated in skeletal muscle of Lewis lung carcinoma (LLC) and Apc(Min/+) mouse models of cancer cachexia. Treatment of mice with 4-phenylbutyrate (4-PBA), a chemical chaperon and a potent inhibitor of ER stress, significantly reduced skeletal muscle strength and mass in both control and LLC-bearing mice. Blocking the UPR also increased the proportion of fast-type fibers in soleus muscle of both control and LLC-bearing mice. Inhibition of UPR reduced the activity of Akt/mTOR pathway and increased the expression of the components of the ubiquitin-proteasome system and autophagy in LLC-bearing mice. Moreover, we found that the inhibition of UPR causes severe atrophy in cultured myotubes. Our study provides initial evidence that ER stress and UPR pathways are essential for maintaining skeletal muscle mass and strength and for protection against cancer cachexia.-Bohnert, K. R., Gallot, Y. S., Sato, S., Xiong, G., Hindi, S. M., Kumar, A. Inhibition of ER stress and unfolding protein response pathways causes skeletal muscle wasting during cancer cachexia. © FASEB.

The Ca(2+) status of the endoplasmic reticulum is altered by induction of calreticulin expression in transgenic plants

NASA Technical Reports Server (NTRS)

Persson, S.; Wyatt, S. E.; Love, J.; Thompson, W. F.; Robertson, D.; Boss, W. F.; Brown, C. S. (Principal Investigator)

2001-01-01

To investigate the endoplasmic reticulum (ER) Ca(2+) stores in plant cells, we generated tobacco (Nicotiana tabacum; NT1) suspension cells and Arabidopsis plants with altered levels of calreticulin (CRT), an ER-localized Ca(2+)-binding protein. NT1 cells and Arabidopsis plants were transformed with a maize (Zea mays) CRT gene in both sense and antisense orientations under the control of an Arabidopsis heat shock promoter. ER-enriched membrane fractions from NT1 cells were used to examine how altered expression of CRT affects Ca(2+) uptake and release. We found that a 2.5-fold increase in CRT led to a 2-fold increase in ATP-dependent (45)Ca(2+) accumulation in the ER-enriched fraction compared with heat-shocked wild-type controls. Furthermore, after treatment with the Ca(2+) ionophore ionomycin, ER microsomes from NT1 cells overproducing CRT showed a 2-fold increase in the amount of (45)Ca(2+) released, and a 2- to 3-fold increase in the amount of (45)Ca(2+) retained compared with wild type. These data indicate that altering the production of CRT affects the ER Ca(2+) pool. In addition, CRT transgenic Arabidopsis plants were used to determine if altered CRT levels had any physiological effects. We found that the level of CRT in heat shock-induced CRT transgenic plants correlated positively with the retention of chlorophyll when the plants were transferred from Ca(2+)-containing medium to Ca(2+)-depleted medium. Together these data are consistent with the hypothesis that increasing CRT in the ER increases the ER Ca(2+) stores and thereby enhances the survival of plants grown in low Ca(2+) medium.

The Ca(2+) status of the endoplasmic reticulum is altered by induction of calreticulin expression in transgenic plants.

PubMed

Persson, S; Wyatt, S E; Love, J; Thompson, W F; Robertson, D; Boss, W F

2001-07-01

To investigate the endoplasmic reticulum (ER) Ca(2+) stores in plant cells, we generated tobacco (Nicotiana tabacum; NT1) suspension cells and Arabidopsis plants with altered levels of calreticulin (CRT), an ER-localized Ca(2+)-binding protein. NT1 cells and Arabidopsis plants were transformed with a maize (Zea mays) CRT gene in both sense and antisense orientations under the control of an Arabidopsis heat shock promoter. ER-enriched membrane fractions from NT1 cells were used to examine how altered expression of CRT affects Ca(2+) uptake and release. We found that a 2.5-fold increase in CRT led to a 2-fold increase in ATP-dependent (45)Ca(2+) accumulation in the ER-enriched fraction compared with heat-shocked wild-type controls. Furthermore, after treatment with the Ca(2+) ionophore ionomycin, ER microsomes from NT1 cells overproducing CRT showed a 2-fold increase in the amount of (45)Ca(2+) released, and a 2- to 3-fold increase in the amount of (45)Ca(2+) retained compared with wild type. These data indicate that altering the production of CRT affects the ER Ca(2+) pool. In addition, CRT transgenic Arabidopsis plants were used to determine if altered CRT levels had any physiological effects. We found that the level of CRT in heat shock-induced CRT transgenic plants correlated positively with the retention of chlorophyll when the plants were transferred from Ca(2+)-containing medium to Ca(2+)-depleted medium. Together these data are consistent with the hypothesis that increasing CRT in the ER increases the ER Ca(2+) stores and thereby enhances the survival of plants grown in low Ca(2+) medium.

The Ca2+ Status of the Endoplasmic Reticulum Is Altered by Induction of Calreticulin Expression in Transgenic Plants1

PubMed Central

Persson, Staffan; Wyatt, Sarah E.; Love, John; Thompson, William F.; Robertson, Dominique; Boss, Wendy F.

2001-01-01

To investigate the endoplasmic reticulum (ER) Ca2+ stores in plant cells, we generated tobacco (Nicotiana tabacum; NT1) suspension cells and Arabidopsis plants with altered levels of calreticulin (CRT), an ER-localized Ca2+-binding protein. NT1 cells and Arabidopsis plants were transformed with a maize (Zea mays) CRT gene in both sense and antisense orientations under the control of an Arabidopsis heat shock promoter. ER-enriched membrane fractions from NT1 cells were used to examine how altered expression of CRT affects Ca2+ uptake and release. We found that a 2.5-fold increase in CRT led to a 2-fold increase in ATP-dependent 45Ca2+ accumulation in the ER-enriched fraction compared with heat-shocked wild-type controls. Furthermore, after treatment with the Ca2+ ionophore ionomycin, ER microsomes from NT1 cells overproducing CRT showed a 2-fold increase in the amount of 45Ca2+ released, and a 2- to 3-fold increase in the amount of 45Ca2+ retained compared with wild type. These data indicate that altering the production of CRT affects the ER Ca2+ pool. In addition, CRT transgenic Arabidopsis plants were used to determine if altered CRT levels had any physiological effects. We found that the level of CRT in heat shock-induced CRT transgenic plants correlated positively with the retention of chlorophyll when the plants were transferred from Ca2+-containing medium to Ca2+-depleted medium. Together these data are consistent with the hypothesis that increasing CRT in the ER increases the ER Ca2+ stores and thereby enhances the survival of plants grown in low Ca2+ medium. PMID:11457960

Modeling the economic and health consequences of managing chronic osteoarthritis pain with opioids in Germany: comparison of extended-release oxycodone and OROS hydromorphone.

PubMed

Ward, Alexandra; Bozkaya, Duygu; Fleischmann, Jochen; Dubois, Dominique; Sabatowski, Rainer; Caro, J Jaime

2007-10-01

The Osmotic controlled-Release Oral delivery System (OROS) hydromorphone ensures continuous release of hydromorphone over 24 hours. It is anticipated that this will facilitate optimal pain relief, improve quality of sleep and compliance. This simulation compared managing chronic osteoarthritis pain with once-daily OROS hydromorphone with an equianalgesic dose of extended-release (ER) oxycodone administered two or three times a day. This discrete event simulation follows patients for a year after initiating opioid treatment. Pairs of identical patients are created; one receives OROS hydromorphone the other ER oxycodone; undergo dose adjustments and after titration can be dissatisfied or satisfied, suffer adverse events, pain recurrence, or discontinue the opioid. Each is assigned an initial sleep problems score, and an improved score from a treatment dependent distribution at the end of titration; these are translated to a utility value. Utilities are assigned pre-treatment, updated until the patient reaches the optimal dose or is non-compliant or dissatisfied. The OROS hydromorphone and ER oxycodone doses are converted to equianalgesic morphine doses using the following ratios: hydromorphone to morphine ratio; 1:5, oxycodone to morphine ratio; 1:2. Sensitivity analyses explored uncertainty in the conversion ratios and other key parameters. Direct medical costs are in 2005 euros. Over 1 year on a mean daily morphine-equivalent dose of 90 mg, 14% were estimated to be dissatisfied with each opioid. OROS hydromorphone was predicted to yield 0.017 additional quality-adjusted life years (QALYs)/patient for a small additional annual cost (E141/patient), yielding an incremental cost-effectiveness ratio (ICER) of E8343/QALY gained. Changing the assumed conversion ratio for oxycodone:morphine to 1:1.5 led to lower net costs of E68 per patient, E3979/QALY, and for hydromorphone to 1:7.5 to savings. Based on these analyses, OROS hydromorphone is expected to yield health benefits at reasonable cost in Germany.

Vegetarian Diets and Weight Reduction: a Meta-Analysis of Randomized Controlled Trials.

PubMed

Huang, Ru-Yi; Huang, Chuan-Chin; Hu, Frank B; Chavarro, Jorge E

2016-01-01

Vegetarian diets may promote weight loss, but evidence remains inconclusive. PubMed, EMBASE and UpToDate databases were searched through September 22, 2014, and investigators extracted data regarding study characteristics and assessed study quality among selected randomized clinical trials. Population size, demographic (i.e., gender and age) and anthropometric (i.e., body mass index) characteristics, types of interventions, follow-up periods, and trial quality (Jadad score) were recorded. The net changes in body weight of subjects were analyzed and pooled after assessing heterogeneity with a random effects model. Subgroup analysis was performed based on type of vegetarian diet, type of energy restriction, study population, and follow-up period. Twelve randomized controlled trials were included, involving a total of 1151 subjects who received the intervention over a median duration of 18 weeks. Overall, individuals assigned to the vegetarian diet groups lost significantly more weight than those assigned to the non-vegetarian diet groups (weighted mean difference, -2.02 kg; 95 % confidence interval [CI]: -2.80 to -1.23). Subgroup analysis detected significant weight reduction in subjects consuming a vegan diet (-2.52 kg; 95 % CI: -3.02 to -1.98) and, to a lesser extent, in those given lacto-ovo-vegetarian diets (-1.48 kg; 95 % CI: -3.43 to 0.47). Studies on subjects consuming vegetarian diets with energy restriction (ER) revealed a significantly greater weight reduction (-2.21 kg; 95 % CI: -3.31 to -1.12) than those without ER (-1.66 kg; 95 % CI: -2.85 to -0.48). The weight loss for subjects with follow-up of <1 year was greater (-2.05 kg; 95 % CI: -2.85 to -1.25) than those with follow-up of ≥1 year (-1.13 kg; 95 % CI: -2.04 to -0.21). Vegetarian diets appeared to have significant benefits on weight reduction compared to non-vegetarian diets. Further long-term trials are needed to investigate the effects of vegetarian diets on body weight control.

Variability in Non-Target Terrestrial Plant Studies Should Inform Endpoint Selection.

PubMed

Staveley, J P; Green, J W; Nusz, J; Edwards, D; Henry, K; Kern, M; Deines, A M; Brain, R; Glenn, B; Ehresman, N; Kung, T; Ralston-Hooper, K; Kee, F; McMaster, S

2018-05-04

Inherent variability in Non-Target Terrestrial Plant (NTTP) testing of pesticides creates challenges for using and interpreting these data for risk assessment. Standardized NTTP testing protocols were initially designed to calculate the application rate causing a 25% effect (ER25, used in the U.S.) or a 50% effect (ER50, used in Europe) for various measures based on the observed dose-response. More recently, the requirement to generate a no-observed-effect rate (NOER), or, in the absence of a NOER, the rate causing a 5% effect (ER05), has raised questions about the inherent variability in, and statistical detectability of, these tests. Statistically significant differences observed between test and control groups may be a product of this inherent variability and may not represent biological relevance. Attempting to derive an ER05 and the associated risk assessment conclusions drawn from these values can overestimate risk. To address these concerns, we evaluated historical data from approximately 100 seedling emergence and vegetative vigor guideline studies on pesticides to assess the variability of control results across studies for each plant species, examined potential causes for the variation in control results, and defined the minimum percent effect that can be reliably detected. The results indicate that with current test design and implementation, the ER05 cannot be reliably estimated. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Non-contact profilometry of eroded and abraded enamel irradiated with an Er:YAG laser

PubMed Central

Scatolin, Renata Siqueira; Colucci, Vivian; Lepri, Taísa Penazzo; de Alexandria, Adílis Kalina; Maia, Lucianne Cople; Galo, Rodrigo; Borsatto, Maria Cristina; Corona, Silmara Aparecida Milori

2018-01-01

Abstract Literature has reported positive results regarding the use of lasers in the control of erosive lesions; however, evaluating whether they are effective in the control of the progression of erosive/abrasive lesions is important. Objectives This study aimed to evaluate the effect of the Er:YAG laser irradiation in controlling the progression of erosion associated with abrasive lesions in enamel. Material and methods Bovine incisors were sectioned, flattened and polished. Forty-eight enamel slabs were subjected to treatment in an intraoral phase. Twelve volunteers used an intraoral appliance containing one slab that was irradiated with an Er:YAG laser (5.2 J/cm2, 85 mJ, 2 Hz) and another non-irradiated slab on each side of the appliance, during one phase of 5 d, under a split-mouth design. Devices were subjected to erosive challenges (1% citric acid, 5 min, 3 times a day) and abrasive challenges one h after (brushing force of 1.5 N for 15 s) randomly and independently on each side of the device. Measurements of enamel loss were performed via 3D optical profilometry (μm). We analyzed data using the Kruskal-Wallis and Mann-Whitney tests and morphological characteristics via scanning electron microscopy. Results Following erosive and abrasive challenges, the group that was irradiated with the Er:YAG laser presented less loss of structure than the non-irradiated group. The group that underwent erosion and irradiation did not exhibit a significant difference from the non-irradiated group. Conclusion Irradiation with the Er:YAG laser did not control the loss of structure of enamel subjected to erosion but did control abrasion after erosion. PMID:29742259

Non-contact profilometry of eroded and abraded enamel irradiated with an Er:YAG laser.

PubMed

Scatolin, Renata Siqueira; Colucci, Vivian; Lepri, Taísa Penazzo; Alexandria, Adílis Kalina de; Maia, Lucianne Cople; Galo, Rodrigo; Borsatto, Maria Cristina; Corona, Silmara Aparecida Milori

2018-01-01

Literature has reported positive results regarding the use of lasers in the control of erosive lesions; however, evaluating whether they are effective in the control of the progression of erosive/abrasive lesions is important. Objectives This study aimed to evaluate the effect of the Er:YAG laser irradiation in controlling the progression of erosion associated with abrasive lesions in enamel. Material and methods Bovine incisors were sectioned, flattened and polished. Forty-eight enamel slabs were subjected to treatment in an intraoral phase. Twelve volunteers used an intraoral appliance containing one slab that was irradiated with an Er:YAG laser (5.2 J/cm2, 85 mJ, 2 Hz) and another non-irradiated slab on each side of the appliance, during one phase of 5 d, under a split-mouth design. Devices were subjected to erosive challenges (1% citric acid, 5 min, 3 times a day) and abrasive challenges one h after (brushing force of 1.5 N for 15 s) randomly and independently on each side of the device. Measurements of enamel loss were performed via 3D optical profilometry (μm). We analyzed data using the Kruskal-Wallis and Mann-Whitney tests and morphological characteristics via scanning electron microscopy. Results Following erosive and abrasive challenges, the group that was irradiated with the Er:YAG laser presented less loss of structure than the non-irradiated group. The group that underwent erosion and irradiation did not exhibit a significant difference from the non-irradiated group. Conclusion Irradiation with the Er:YAG laser did not control the loss of structure of enamel subjected to erosion but did control abrasion after erosion.

Visible cathodoluminescence of Er ions in β-Ga(2)O(3) nanowires and microwires.

PubMed

Nogales, E; Méndez, B; Piqueras, J

2008-01-23

Erbium doped β-Ga(2)O(3) nanowires and microwires have been obtained by a vapour-solid process from an initial mixture of Ga(2)O(3) and Er(2)O(3) powders. X-ray diffraction (XRD) analysis reveals the presence of erbium gallium garnet as well as β-Ga(2)O(3) phases in the microwires. Scanning electron microscopy (SEM) images show that the larger microwires have a nearly rectangular cross-section. Transmission electron microscopy (TEM) and high-resolution TEM (HRTEM) analysis show good crystal quality of the β-Ga(2)O(3) nanowires. The nanostructures have been studied by means of the cathodoluminescence technique in the scanning electron microscope. Er intraionic blue, green and red emission lines are observed in luminescence spectra even at room temperature, which confirms the optical activity of the rare earth ions in the grown structures. Mapping of the main 555 nm emission intensity shows a non-homogeneous distribution of Er ions in the microstructures.

Influence of oxygen partial pressure on the microstructural and magnetic properties of Er-doped ZnO thin films

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

Chen, Wei-Bin; Li, Fei; Chen, Hong-Ming

2015-06-15

Er-doped ZnO thin films have been prepared by using inductively coupled plasma enhanced physical vapor deposition at different O{sub 2}:Ar gas flow ratio (R = 0:30, 1:30, 1:15, 1:10 and 1:6). The influence of oxygen partial pressure on the structural, optical and magnetic properties was studied. It is found that an appropriate oxygen partial pressure (R=1:10) can produce the best crystalline quality with a maximum grain size. The internal strain, estimated by fitting the X-ray diffraction peaks, varied with oxygen partial pressure during growth. PL measurements show that plenty of defects, especially zinc vacancy, exist in Er-doped ZnO films. Allmore » the samples show room-temperature ferromagnetism. Importantly, the saturation magnetization exhibits similar dependency on oxygen partial pressure with the internal strain, which indicates that internal strain has an important effect on the magnetic properties of Er-doped ZnO thin films.« less

75 FR 65500 - Agency Information Collection Activities: Form I-360, Extension of a Currently Approved...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-10-25

...(er), or Special Immigrant; OMB Control No. 1615-0020. The Department of Homeland Security, U.S.../Collection: Petition for Amerasian, Widow(er), or Special Immigrant. (3) Agency form number, if any, and the...

Liganded and unliganded activation of estrogen receptor and hormone replacement therapies

PubMed Central

Maggi, Adriana

2011-01-01

Over the past two decades, our understanding of estrogen receptor physiology in mammals widened considerably as we acquired a deeper appreciation of the roles of estrogen receptor alpha and beta (ERα and ERβ) in reproduction as well as in bone and metabolic homeostasis, depression, vascular disorders, neurodegenerative diseases and cancer. In addition, our insights on ER transcriptional functions in cells increased considerably with the demonstration that ER activity is not strictly dependent on ligand availability. Indeed, unliganded ERs may be transcriptionally active and post-translational modifications play a major role in this context. The finding that several intracellular transduction molecules may regulate ER transcriptional programs indicates that ERs may act as a hub where several molecular pathways converge: this allows to maintain ER transcriptional activity in tune with all cell functions. Likely, the biological relevant role of ER was favored by evolution as a mean of integration between reproductive and metabolic functions. We here review the post-translational modifications modulating ER transcriptional activity in the presence or in the absence of estrogens and underline their potential role for ER tissue-specific activities. In our opinion, a better comprehension of the variety of molecular events that control ER activity in reproductive and non-reproductive organs is the foundation for the design of safer and more efficacious hormone-based therapies, particularly for menopause. PMID:21605666

Regulation of plant vascular stem cells by endodermis-derived EPFL-family peptide hormones and phloem-expressed ERECTA-family receptor kinases.

PubMed

Uchida, Naoyuki; Tasaka, Masao

2013-12-01

Plant vasculatures are complex tissues consisting of (pro)cambium, phloem, and xylem. The (pro)cambium serves as vascular stem cells that produce all vascular cells. The Arabidopsis ERECTA (ER) receptor kinase is known to regulate the architecture of inflorescence stems. It was recently reported that the er mutation enhances a vascular phenotype induced by a mutation of TDR/PXY, which plays a significant role in procambial proliferation, suggesting that ER participates in vascular development. However, detailed molecular mechanisms of the ER-dependent vascular regulation are largely unknown. Here, this work found that ER and its paralogue, ER-LIKE1, were redundantly involved in procambial development of inflorescence stems. Interestingly, their activity in the phloem was sufficient for vascular regulation. Furthermore, two endodermis-derived peptide hormones, EPFL4 and EPFL6, were redundantly involved in such regulation. It has been previously reported that EPFL4 and EPFL6 act as ligands of phloem-expressed ER for stem elongation. Therefore, these findings indicate that cell-cell communication between the endodermis and the phloem plays an important role in procambial development as well as stem elongation. Interestingly, similar EPFL-ER modules control two distinct developmental events by slightly changing their components: the EPFL4/6-ER module for stem elongation and the EPFL4/6-ER/ERL1 module for vascular development.

Stacking InAs quantum dots over ErAs semimetal nanoparticles on GaAs (0 0 1) using molecular beam epitaxy

NASA Astrophysics Data System (ADS)

Zhang, Yuanchang; Eyink, Kurt G.; Grazulis, Lawrence; Hill, Madelyn; Peoples, Joseph; Mahalingam, Krishnamurthy

2017-11-01

Hybrid nanostructures are known to elicit an enhanced optical response. We study the directed alignment of ErAs metal nanoparticle (NP) and InAs quantum dot (QD) using molecular beam eptaxy (MBE) in a GaAs matrix. Due to high surface free energy caused by the crystal structure difference, overgrowth of an ErAs NP with GaAs forms a depression that condenses subsequent InAs adatoms to form an inverted QD self-aligned to the underlying ErAs NP. The ErAs NP growth, GaAs overgrowth, and InAs QD deposition were carefully controlled and studied with transmission electron microscopy (TEM) and atomic force microscopy (AFM) to investigate their effects on the QD-NP alignment.

Lifetime moderate-to-vigorous physical activity and ER/PR/HER-defined post-menopausal breast cancer risk.

PubMed

Shi, Joy; Kobayashi, Lindsay C; Grundy, Anne; Richardson, Harriet; SenGupta, Sandip K; Lohrisch, Caroline A; Spinelli, John J; Aronson, Kristan J

2017-08-01

To assess the relationship of moderate-to-vigorous physical activity (MVPA) in leisure-time, household, and occupational domains across the total lifetime and in four age periods with breast cancer risk, as defined by estrogen receptor (ER)/progesterone receptor (PR) status and ER/PR/human epidermal growth factor-2 (HER2) status, among post-menopausal women. Data were from 692 women with incident breast cancer and 644 controls in the Canadian Breast Cancer Study, a case-control study of women aged 40-80 years in British Columbia and Ontario. Mean metabolic equivalent (MET)-hours/week for questionnaire-assessed leisure-time, household, and occupational MVPA were calculated for the total lifetime and four age periods (12-17, 18-34, 45-49, and ≥50 years). Odds ratios (ORs) for the relationships between domain-specific MVPA at each lifetime period and risks of ER/PR-defined and ER/PR/HER2-defined breast cancers were estimated using polytomous logistic regression. Trend tests for dose-response relationships were calculated for the ORs across increasing tertiles of mean MET-hours/week of MVPA. Total lifetime leisure-time MVPA was associated with reduced risk of ER-/PR- breast cancer in a dose-response fashion (p trend  = 0.014). In contrast, total lifetime household MVPA was associated with reduced risk of ER+ and/or PR+ breast cancer (p trend  < 0.001). When further stratified by HER2 status, the effect of leisure-time MVPA appeared confined to HER2- breast cancers, and the effect of household MVPA did not differ according to HER2 status. Similar trends were observed when stratified by age period. Lifetime leisure-time MVPA appeared to be associated with reduced risk of ER-/PR-/HER2- breast cancers and lifetime household MVPA was associated with reduced risk of ER+ and/or PR+ breast cancer, regardless of HER2 status.

Engineered Resistant-Starch (ERS) Diet Shapes Colon Microbiota Profile in Parallel with the Retardation of Tumor Growth in In Vitro and In Vivo Pancreatic Cancer Models.

PubMed

Panebianco, Concetta; Adamberg, Kaarel; Adamberg, Signe; Saracino, Chiara; Jaagura, Madis; Kolk, Kaia; Di Chio, Anna Grazia; Graziano, Paolo; Vilu, Raivo; Pazienza, Valerio

2017-03-27

Pancreatic cancer (PC) is ranked as the fourth leading cause of cancer-related deaths worldwide. Despite recent advances in treatment options, a modest impact on the outcome of the disease is observed so far. We have previously demonstrated that short-term fasting cycles have the potential to improve the efficacy of chemotherapy against PC. The aim of this study was to assess the effect of an engineered resistant-starch (ERS) mimicking diet on the growth of cancer cell lines in vitro, on the composition of fecal microbiota, and on tumor growth in an in vivo pancreatic cancer mouse xenograft model. BxPC-3, MIA PaCa-2 and PANC-1 cells were cultured in the control, and in the ERS-mimicking diet culturing condition, to evaluate tumor growth and proliferation pathways. Pancreatic cancer xenograft mice were subjected to an ERS diet to assess tumor volume and weight as compared to mice fed with a control diet. The composition and activity of fecal microbiota were further analyzed in growth experiments by isothermal microcalorimetry. Pancreatic cancer cells cultured in an ERS diet-mimicking medium showed decreased levels of phospho-ERK1/2 (extracellular signal-regulated kinase proteins) and phospho-mTOR (mammalian target of rapamycin) levels, as compared to those cultured in standard medium. Consistently, xenograft pancreatic cancer mice subjected to an ERS diet displayed significant retardation in tumor growth. In in vitro growth experiments, the fecal microbial cultures from mice fed with an ERS diet showed enhanced growth on residual substrates, higher production of formate and lactate, and decreased amounts of propionate, compared to fecal microbiota from mice fed with the control diet. A positive effect of the ERS diet on composition and metabolism of mouse fecal microbiota shown in vitro is associated with the decrease of tumor progression in the in vivo PC xenograft mouse model. These results suggest that engineered dietary interventions could be supportive as a synergistic approach to enhance the efficacy of existing cancer treatments in pancreatic cancer patients.

Engineered Resistant-Starch (ERS) Diet Shapes Colon Microbiota Profile in Parallel with the Retardation of Tumor Growth in In Vitro and In Vivo Pancreatic Cancer Models

PubMed Central

Panebianco, Concetta; Adamberg, Kaarel; Adamberg, Signe; Saracino, Chiara; Jaagura, Madis; Kolk, Kaia; Di Chio, Anna Grazia; Graziano, Paolo; Vilu, Raivo; Pazienza, Valerio

2017-01-01

Background/aims: Pancreatic cancer (PC) is ranked as the fourth leading cause of cancer-related deaths worldwide. Despite recent advances in treatment options, a modest impact on the outcome of the disease is observed so far. We have previously demonstrated that short-term fasting cycles have the potential to improve the efficacy of chemotherapy against PC. The aim of this study was to assess the effect of an engineered resistant-starch (ERS) mimicking diet on the growth of cancer cell lines in vitro, on the composition of fecal microbiota, and on tumor growth in an in vivo pancreatic cancer mouse xenograft model. Materials and Methods: BxPC-3, MIA PaCa-2 and PANC-1 cells were cultured in the control, and in the ERS-mimicking diet culturing condition, to evaluate tumor growth and proliferation pathways. Pancreatic cancer xenograft mice were subjected to an ERS diet to assess tumor volume and weight as compared to mice fed with a control diet. The composition and activity of fecal microbiota were further analyzed in growth experiments by isothermal microcalorimetry. Results: Pancreatic cancer cells cultured in an ERS diet-mimicking medium showed decreased levels of phospho-ERK1/2 (extracellular signal-regulated kinase proteins) and phospho-mTOR (mammalian target of rapamycin) levels, as compared to those cultured in standard medium. Consistently, xenograft pancreatic cancer mice subjected to an ERS diet displayed significant retardation in tumor growth. In in vitro growth experiments, the fecal microbial cultures from mice fed with an ERS diet showed enhanced growth on residual substrates, higher production of formate and lactate, and decreased amounts of propionate, compared to fecal microbiota from mice fed with the control diet. Conclusion: A positive effect of the ERS diet on composition and metabolism of mouse fecal microbiota shown in vitro is associated with the decrease of tumor progression in the in vivo PC xenograft mouse model. These results suggest that engineered dietary interventions could be supportive as a synergistic approach to enhance the efficacy of existing cancer treatments in pancreatic cancer patients. PMID:28346394

Endoplasmic Reticulum - Plasma Membrane Crosstalk Mediated by the Extended Synaptotagmins.

PubMed

Saheki, Yasunori

2017-01-01

The endoplasmic reticulum (ER) possesses multiplicity of functions including protein synthesis, membrane lipid biogenesis, and Ca 2+ storage and has broad localization throughout the cell. While the ER and most other membranous organelles are highly interconnected via vesicular traffic that relies on membrane budding and fusion reactions, the ER forms direct contacts with virtually all other membranous organelles, including the plasma membrane (PM), without membrane fusion. Growing evidence suggests that these contacts play major roles in cellular physiology, including the regulation of Ca 2+ homeostasis and signaling and control of cellular lipid homeostasis. Extended synaptotagmins (E-Syts) are evolutionarily conserved family of ER-anchored proteins that tether the ER to the PM in PM PI(4,5)P 2 -dependent and cytosolic Ca 2+ -regulated manner. In addition, E-Syts possess a cytosolically exposed lipid-harboring module that confers the ability to transfer/exchange glycerolipids between the ER and the PM at E-Syts-mediated ER-PM contacts. In this chapter, the functions of ER-PM contacts and their role in non-vesicular lipid transport with special emphasis on the crosstalk between the two bilayers mediated by E-Syts will be discussed.

Harvard ER-2 OH laser-induced fluorescence instrument

NASA Technical Reports Server (NTRS)

Wennberg, Paul O.; Anderson, James G.

1994-01-01

The Harvard ER-2 OH instrument is scheduled to be integrated into the NASA ER-2 high altitude aircraft ozone payload in August 1992. Design and fabrication is presently underway. This experiment is a descendant of a balloon borne instrument designed and built in the mid-1980s. The ER-2 instrument is being designed to measure OH and HO2 as part of the NASA ozone payload for the investigation of processes controlling the concentration of stratospheric ozone. Although not specifically designed to do so, it is hoped that valid measurements of OH and HO2 can be made in the remote free troposphere with this instrument.

Emotion regulation mediates the relationship between personality and sleep quality.

PubMed

Vantieghem, Iris; Marcoen, Nele; Mairesse, Olivier; Vandekerckhove, Marie

2016-09-01

Despite a long history of interest in personality as well as in the mechanisms that regulate sleep, the relationship between personality and sleep is not yet well understood. The purpose of this study was to explore how personality affects sleep. The present cross-sectional study, based on a sample of 1291 participants with a mean age of 31.16 years (SD = 12.77), investigates the impact of personality styles, assessed by the Personality Adjectives Checklist (PACL), on subjective sleep quality, as well as the possible mediation of this relationship by dispositional emotion regulation (ER) styles. The dispositional use of suppression was a quite consistent predictor of poor subjective sleep quality for individuals scoring high on Confident, Cooperative or Introversive personality traits, but low on Respectful personality traits. Although a positive relationship between reappraisal and subjective sleep quality was found, there was only little evidence for a relationship between the assessed personality styles and the use of cognitive reappraisal. The present results indicate that in the evaluation of subjective sleep, the impact of personality and ER processes, such as emotion suppression, should be taken into account.

Genetic variants of estrogen beta and leptin receptors may cause gynecomastia in adolescent.

PubMed

Eren, Erdal; Edgunlu, Tuba; Korkmaz, Huseyin Anil; Cakir, Esra Deniz Papatya; Demir, Korcan; Cetin, Esin Sakalli; Celik, Sevim Karakas

2014-05-15

Gynecomastia is a benign breast enlargement in males that affects approximately one-third of adolescents. The exact mechanism is not fully understood; however, it has been proposed that estrogen receptors and aromatase enzyme activity may play important roles in the pathogenesis of gynecomastia. While many studies have reported that aromatase enzyme (CYP19) gene polymorphism is associated with gynecomastia, only one study has shown a relationship between estrogen receptor (ER) alpha and beta gene polymorphism and gynecomastia. Thus, the aim of this study was to evaluate the relationships between CYP19 (rs2414096), ER alpha (rs2234693), ER beta (rs4986938), leptin (rs7799039), and leptin receptor (rs1137101) gene polymorphisms and gynecomastia. This study included 107 male adolescents with gynecomastia and 97 controls. Total serum testosterone (T) and estradiol (E2) levels were measured, and DNA was extracted from whole blood using the PCR-RFLP technique. The polymorphic distributions of CYP19, ER alpha, ER beta, leptin and leptin receptor genes were compared. The median E2 level was 12.41 (5.00-65.40) pg/ml in the control group and 16.86 (2.58-78.47) pg/ml in the study group (p<0.001). The median T level was 2.19 (0.04-7.04) ng/ml in the control group and 1.46 (0.13-12.02) ng/ml in the study group (p=0.714). There was a significant relationship between gynecomastia and leptin receptor rs1137101 (p=0.002) and ER beta receptor rs4986938 gene polymorphisms (p=0.002). According to our results, increased E2 level and ER beta gene rs4986938 polymorphism might explain why some adolescents have gynecomastia. Leptin receptor gene rs1137101 polymorphism might affect susceptibility to gynecomastia. Copyright © 2014 Elsevier B.V. All rights reserved.

Wireless Sensor Network Quality of Service Improvement on Flooding Attack Condition

NASA Astrophysics Data System (ADS)

Hartono, R.; Widyawan; Wibowo, S. B.; Purnomo, A.; Hartatik

2018-03-01

There are two methods of building communication using wireless media. The first method is building a base infrastructure as an intermediary between users. Problems that arise on this type of network infrastructure is limited space to build any network physical infrastructure and also the cost factor. The second method is to build an ad hoc network between users who will communicate. On ad hoc network, each user must be willing to send data from source to destination for the occurrence of a communication. One of network protocol in Ad Hoc, Ad hoc on demand Distance Vector (AODV), has the smallest overhead value, easier to adapt to dynamic network and has small control message. One AODV protocol’s drawback is route finding process’ security for sending the data. In this research, AODV protocol is optimized by determining Expanding Ring Search (ERS) best value. Random topology is used with variation in the number of nodes: 25, 50, 75, 100, 125 and 150 with node’s speed of 10m/s in the area of 1000m x 1000m on flooding network condition. Parameters measured are Throughput, Packet Delivery Ratio, Average Delay and Normalized Routing Load. From the test results of AODV protocol optimization with best value of Expanding Ring Search (ERS), throughput increased by 5.67%, packet delivery ratio increased by 5.73%, and as for Normalized Routing Load decreased by 4.66%. ERS optimal value for each node’s condition depending on the number of nodes on the network.

Study of Isospin Correlation in High Energy Heavy Ion Interactions with the RHIC PHENIX. Final Report

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

Takahashi, Y.

This report describes the research work performed under the support of the DOE research grant E-FG02-97ER4108. The work is composed of three parts: (1) Visual analysis and quality control of the Micro Vertex Detector (MVD) of the PHENIX experiments carried out of Brookhaven National Laboratory. (2) Continuation of the data analysis of the EMU05/09/16 experiments for the study of the inclusive particle production spectra and multi-particle correlation. (3) Exploration of a new statistical means to study very high-multiplicity of nuclear-particle ensembles and its perspectives to apply to the higher energy experiments.

Impact of scavenging hydrogen peroxide in the endoplasmic reticulum for β cell function.

PubMed

Lortz, S; Lenzen, S; Mehmeti, I

2015-08-01

Oxidative folding of nascent proteins in the endoplasmic reticulum (ER), catalysed by one or more members of the protein disulfide isomerase family and the sulfhydryl oxidase ER oxidoreductin 1 (ERO1), is accompanied by generation of hydrogen peroxide (H2O2). Because of the high rate of insulin biosynthesis and the low expression of H2O2-inactivating enzymes in pancreatic β cells, it has been proposed that the luminal H2O2 concentration might be very high. As the role of this H2O2 in ER stress and proinsulin processing is still unsolved, an ER-targeted and luminal-active catalase variant, ER-Catalase N244, was expressed in insulin-secreting INS-1E cells. In these cells, the influence of ER-specific H2O2 removal on cytokine-mediated cytotoxicity and ER stress, insulin gene expression, insulin content and secretion was analysed. The expression of ER-Catalase N244 reduced the toxicity of exogenously added H2O2 significantly with a threefold increase of the EC50 value for H2O2. However, the expression of cytokine-induced ER stress genes and viability after incubation with β cell toxic cytokines (IL1β alone or together with TNFα+IFNγ) was not affected by ER-Catalase N244. In control and ER-Catalase N244 expressing cells, insulin secretion and proinsulin content was identical, while removal of luminal H2O2 reduced insulin gene expression and insulin content in ER-Catalase N244 expressing cells. These data show that ER-Catalase N244 reduced H2O2 toxicity but did not provide protection against pro-inflammatory cytokine-mediated toxicity and ER stress. Insulin secretion was not affected by decreasing H2O2 in the ER in spite of a reduced insulin transcription and processing. © 2015 Society for Endocrinology.

Cutting and coagulation during intraoral soft tissue surgery using Er: YAG laser.

PubMed

Onisor, I; Pecie, R; Chaskelis, I; Krejci, I

2013-06-01

To find the optimal techniques and parameters that enables Er:YAG laser to be used successfully for small intraoral soft tissue interventions, in respect to its cutting and coagulation abilities. In vitro pre-tests: 4 different Er:YAG laser units and one CO2 unit as the control were used for incision and coagulation on porcine lower jaws and optimal parameters were established for each type of intervention and each laser unit: energy, frequency, type, pulse duration and distance. 3 different types of intervention using Er:YAG units are presented: crown lengthening, gingivoplasty and maxillary labial frenectomy with parameters found in the in vitro pre-tests. The results showed a great decrease of the EMG activity of masseter and anterior temporalis muscles. Moreover, the height and width of the chewing cycles in the frontal plane increased after therapy. Er:YAG is able to provide good cutting and coagulation effects on soft tissues. Specific parameters have to be defined for each laser unit in order to obtain the desired effect. Reduced or absent water spray, defocused light beam, local anaesthesia and the most effective use of long pulses are methods to obtain optimal coagulation and bleeding control.

Optical switching and photoluminescence in erbium-implanted vanadium dioxide thin films

NASA Astrophysics Data System (ADS)

Lim, Herianto; Stavrias, Nikolas; Johnson, Brett C.; Marvel, Robert E.; Haglund, Richard F.; McCallum, Jeffrey C.

2014-03-01

Vanadium dioxide (VO2) is under intensive consideration for optical switching due to its reversible phase transition, which features a drastic and rapid shift in infrared reflectivity. Classified as an insulator-to-metal transition, the phase transition in VO2 can be induced thermally, electrically, and optically. When induced optically, the transition can occur on sub-picosecond time scales. It is interesting to dope VO2 with erbium ions (Er3+) and observe their combined properties. The first excited-state luminescence of Er3+ lies within the wavelength window of minimal transmission-loss in silicon and has been widely utilized for signal amplification and generation in silicon photonics. The incorporation of Er3+ into VO2 could therefore result in a novel photonic material capable of simultaneous optical switching and amplification. In this work, we investigate the optical switching and photoluminescence in Er-implanted VO2 thin films. Thermally driven optical switching is demonstrated in the Er-implanted VO2 by infrared reflectometry. Photoluminescence is observed in the thin films annealed at ˜800 °C or above. In addition, Raman spectroscopy and a statistical analysis of switching hysteresis are carried out to assess the effects of the ion implantation on the VO2 thin films. We conclude that Er-implanted VO2 can function as an optical switch and amplifier, but with reduced switching quality compared to pure VO2.

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

PubMed

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

2018-01-18

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

Adjuvant Trastuzumab in HER2-Positive Early Breast Cancer by Age and Hormone Receptor Status: A Cost-Utility Analysis.

PubMed

Leung, William; Kvizhinadze, Giorgi; Nair, Nisha; Blakely, Tony

2016-08-01

The anti-human epidermal growth factor receptor 2 (HER2) monoclonal antibody trastuzumab improves outcomes in patients with node-positive HER2+ early breast cancer. Given trastuzumab's high cost, we aimed to estimate its cost-effectiveness by heterogeneity in age and estrogen receptor (ER) and progesterone receptor (PR) status, which has previously been unexplored, to assist prioritisation. A cost-utility analysis was performed using a Markov macro-simulation model, with a lifetime horizon, comparing a 12-mo regimen of trastuzumab with chemotherapy alone using the latest (2014) effectiveness measures from landmark randomised trials. A New Zealand (NZ) health system perspective was adopted, employing high-quality national administrative data. Incremental quality-adjusted life-years for trastuzumab versus chemotherapy alone are two times higher (2.33 times for the age group 50-54 y; 95% CI 2.29-2.37) for the worst prognosis (ER-/PR-) subtype compared to the best prognosis (ER+/PR+) subtype, causing incremental cost-effectiveness ratios (ICERs) for the former to be less than half those of the latter for the age groups from 25-29 to 90-94 y (0.44 times for the age group 50-54 y; 95% CI 0.43-0.45). If we were to strictly apply an arbitrary cost-effectiveness threshold equal to the NZ gross domestic product per capita (2011 purchasing power parity [PPP]-adjusted: US$30,300; €23,700; £21,200), our study suggests that trastuzumab (2011 PPP-adjusted US$45,400/€35,900/£21,900 for 1 y at formulary prices) may not be cost-effective for ER+ (which are 61% of all) node-positive HER2+ early breast cancer patients but cost-effective for ER-/PR- subtypes (37% of all cases) to age 69 y. Market entry of trastuzumab biosimilars will likely reduce the ICER to below this threshold for premenopausal ER+/PR- cancer but not for ER+/PR+ cancer. Sensitivity analysis using the best-case effectiveness measure for ER+ cancer had the same result. A key limitation was a lack of treatment-effect data by hormone receptor subtype. Heterogeneity was restricted to age and hormone receptor status; tumour size/grade heterogeneity could be explored in future work. This study highlights how cost-effectiveness can vary greatly by heterogeneity in age and hormone receptor subtype. Resource allocation and licensing of subsidised therapies such as trastuzumab should consider demographic and clinical heterogeneity; there is currently a profound disconnect between how funding decisions are made (largely agnostic to heterogeneity) and the principles of personalised medicine.

Immediate bonding properties of universal adhesives to dentine.

PubMed

Muñoz, Miguel Angel; Luque, Issis; Hass, Viviane; Reis, Alessandra; Loguercio, Alessandro Dourado; Bombarda, Nara Hellen Campanha

2013-05-01

To evaluate the dentine microtensile bond strength (μTBS), nanoleakage (NL), degree of conversion (DC) within the hybrid layer for etch-and-rinse and self-etch strategies of universal simplified adhesive systems. forty caries free extracted third molars were divided into 8 groups for μTBS (n=5), according to the adhesive and etching strategy: Clearfil SE Bond [CSE] and Adper Single Bond 2 [SB], as controls; Peak Universal Adhesive System, self-etch [PkSe] and etch-and-rinse [PkEr]; Scotchbond Universal Adhesive, self-etch [ScSe] and etch-and-rinse [ScEr]; All Bond Universal, self-etch [AlSe] and etch-and-rinse [AlEr]. After restorations were constructed, specimens were stored in water (37°C/24h) and then resin-dentine sticks were prepared (0.8mm(2)). The sticks were tested under tension at 0.5mm/min. Some sticks from each tooth group were used for DC determination by micro-Raman spectroscopy or nanoleakage evaluation (NL). The pH for each solution was evaluated using a pH metre. Data were analyzed with one-way ANOVA and Tukey's test (α=0.05). For μTBS, only PkSe and PkEr were similar to the respective control groups (p>0.05). AlSe showed the lowest μTBS mean (p<0.05). For NL, ScEr, ScSe, AlSe, and AlEr showed the lowest NL similar to control groups (p<0.05). For DC, only ScSe showed lower DC than the other materials (p<0.05). Performance of universal adhesives was shown to be material-dependent. The results indicate that this new category of universal adhesives used on dentine as either etch-and-rinse or self-etch strategies were inferior as regards at least one of the properties evaluated (μTBS, NL and DC) in comparison with the control adhesives (CSE for self-etch and SB for etch-and-rinse). Copyright © 2013 Elsevier Ltd. All rights reserved.

Comparative Study of the Shear Bond Strength of Flowable Composite in Permanent Teeth Treated with Conventional Bur and Contact or Non-Contact Er:YAG Laser

PubMed Central

Parhami, Parisa; Pourhashemi, Seyed Jalal; Ghandehari, Mehdi; Mighani, Ghasem; Chiniforush, Nasim

2014-01-01

Introduction: The aim of this study was to evaluate and compare the in vitro effect of the Erbium-Doped Yttrium Aluminum Garnet (Er:YAG) laser with different radiation distances and high-speed rotary treatment on the shear bond strength of flowable composite to enamel of human permanent posterior teeth. Methods: freshly extracted human molar teeth with no caries or other surface defects were used in this study (n=45). The teeth were randomly divided into 3 groups. Group 1: treated with non-contact Er:YAG Laser and etched with Er:YAG laser, Group 2: treated with contact Er:YAG Laser and etched with Er:YAG laser, Group 3 (control): treated with diamond fissure bur and etched with acid phosphoric 37%. Then the adhesive was applied on the surafces of the teeth and polymerized using a curing light appliance. Resin cylinders were fabricated from flowable composite. Shear bond strength was tested at a crosshead speed of 0.5 mm/min. Results: The amount of Shear Bond Strength (SBS) in the 3 treatment groups was not the same (P<0.05).The group in which enamel surfaces were treated with diamond fissure bur and etched with acid (conrtol group) had the highest mean shear bond strength (19.92±4.76) and the group in which the enamel surfaces were treated with contact Er:YAG laser and etched with Er:YAG laser had the lowest mean shear bond strength (10.89±2.89). Mann-whitney test with adjusted P-value detected significant difference in shear bond strength between the control group and the other 2 groups (P < 0.05). Conclusion: It was concluded that both contact and non-contact Er:YAG laser treatment reduced shear bond strength of flowable resin composite to enamel in comparison with conventional treatment with high speed rotary. Different Er:YAG laser distance irradiations did not influence the shear bond strength of flowable composite to enamel. PMID:25653813

Suppression of endoplasmic reticulum stress improves endothelium-dependent contractile responses in aorta of the spontaneously hypertensive rat

PubMed Central

Matsumoto, Takayuki; Webb, R. Clinton

2013-01-01

A contributing factor to increased peripheral resistance seen during hypertension is an increased production of endothelium-derived contractile factors (EDCFs). The main EDCFs are vasoconstrictor prostanoids, metabolites of arachidonic acid (AA) produced by Ca2+-dependent cytosolic phospholipase A2 (cPLA2) following phosphorylation (at Ser505) mediated by extracellular signal-regulated kinase (ERK1/2) and cyclooxygenase (COX) activations. Although endoplasmic reticulum (ER) stress has been shown to contribute to pathophysiological alterations in cardiovascular diseases, the relationship between ER stress and EDCF-mediated responses remains unclear. We tested the hypothesis that ER stress plays a role in EDCF-mediated responses via activation of the cPLA2/COX pathway in the aorta of the spontaneously hypertensive rat (SHR). Male SHR and Wistar-Kyoto rats (WKY) were treated with ER stress inhibitor, tauroursodeoxycholic acid or 4-phenlybutyric acid (TUDCA or PBA, respectively, 100 mg·kg−1·day−1 ip) or PBS (control, 300 μl/day ip) for 1 wk. There was a decrease in systolic blood pressure in SHR treated with TUDCA or PBA compared with control SHR (176 ± 3 or 181 ± 5, respectively vs. 200 ± 2 mmHg). In the SHR, treatment with TUDCA or PBA normalized aortic (vs. control SHR) 1) contractions to acetylcholine (ACh), AA, and tert-butyl hydroperoxide, 2) ACh-stimulated releases of prostanoids (thromboxane A2, PGF2α, and prostacyclin), 3) expression of COX-1, 4) phosphorylation of cPLA2 and ERK1/2, and 5) production of H2O2. Our findings demonstrate a novel interplay between ER stress and EDCF-mediated responses in the aorta of the SHR. Moreover, ER stress inhibition normalizes such responses by suppressing the cPLA2/COX pathway. PMID:23709602

Effects of environmental risks and polygenic loading for schizophrenia on cortical thickness.

PubMed

Neilson, Emma; Bois, Catherine; Gibson, Jude; Duff, Barbara; Watson, Andrew; Roberts, Neil; Brandon, Nicholas J; Dunlop, John; Hall, Jeremy; McIntosh, Andrew M; Whalley, Heather C; Lawrie, Stephen M

2017-06-01

There are established differences in cortical thickness (CT) in schizophrenia (SCZ) and bipolar (BD) patients when compared to healthy controls (HC). However, it is unknown to what extent environmental or genetic risk factors impact on CT in these populations. We have investigated the effect of Environmental Risk Scores (ERS) and Polygenic Risk Scores for SCZ (PGRS-SCZ) on CT. Structural MRI scans were acquired at 3T for patients with SCZ or BD (n=57) and controls (n=41). Cortical reconstructions were generated in FreeSurfer (v5.3). The ERS was created by determining exposure to cannabis use, childhood adverse events, migration, urbanicity and obstetric complications. The PGRS-SCZ were generated, for a subset of the sample (Patients=43, HC=32), based on the latest PGC GWAS findings. ANCOVAs were used to test the hypotheses that ERS and PGRS-SCZ relate to CT globally, and in frontal and temporal lobes. An increase in ERS was negatively associated with CT within temporal lobe for patients. A higher PGRS-SCZ was also related to global cortical thinning for patients. ERS effects remained significant when including PGRS-SCZ as a fixed effect. No relationship which survived FDR correction was found for ERS and PGRS-SCZ in controls. Environmental risk for SCZ was related to localised cortical thinning in patients with SCZ and BD, while increased PGRS-SCZ was associated with global cortical thinning. Genetic and environmental risk factors for SCZ appear therefore to have differential effects. This provides a mechanistic means by which different risk factors may contribute to the development of SCZ and BD. Copyright © 2016 Elsevier B.V. All rights reserved.

In vitro bioanalysis of drinking water from source to tap.

PubMed

Rosenmai, Anna Kjerstine; Lundqvist, Johan; le Godec, Théo; Ohlsson, Åsa; Tröger, Rikard; Hellman, Björn; Oskarsson, Agneta

2018-08-01

The presence of chemical pollutants in sources of drinking water is a key environmental problem threatening public health. Efficient removal of pollutants in drinking water treatment plants (DWTPs) is needed as well as methods for assessment of the total impact of all present chemicals on water quality. In the present study we have analyzed the bioactivity of water samples from source to tap, including effects of various water treatments in a DWTP, using a battery of cell-based bioassays, covering health-relevant endpoints. Reporter gene assays were used to analyze receptor activity of the aryl hydrocarbon receptor (AhR), estrogen receptor (ER), androgen receptor (AR), peroxisome proliferator-activated receptor alpha (PPARα) and induction of oxidative stress by the nuclear factor erythroid 2-related factor 2 (Nrf2). DNA damage was determined by Comet assay. Grab water samples were concentrated by HLB or ENV solid phase extraction and the water samples assayed at a relative enrichment factor of 50. The enrichment procedure did not induce any bioactivity. No bioactivity was detected in Milli-Q water or drinking water control samples. Induction of AhR, ER and Nrf2 activities was revealed in source to tap water samples. No cytotoxicity, PPARα or AR antagonist activity, or DNA damage were observed in any of the water samples. A low AR agonist activity was detected in a few samples of surface water, but not in the samples from the DWTP. The treatment steps at the DWTP, coagulation, granulated activated carbon filtration, UV disinfection and NH 2 Cl dosing had little or no effect on the AhR, Nrf2 and ER bioactivity. However, nanofiltration and passage through the distribution network drastically decreased AhR activity, while the effect on Nrf2 activity was more modest and no apparent effect was observed on ER activity. The present results suggest that bioassays are useful tools for evaluation of the efficiency of different treatment steps in DWTPs in reducing toxic activities. Bioassays of AhR and Nrf2 are useful for screening of effects of a broad range of chemicals in drinking water and ER activity can be monitored with a high sensitivity. Copyright © 2018 Elsevier Ltd. All rights reserved.

Interactive effects of fire, soil climate, and moss on CO2 fluxes in black spruce ecosystems of interior Alaska

USGS Publications Warehouse

O'Donnell, J. A.; Turetsky, M.R.; Harden, J.W.; Manies, K.L.; Pruett, L.E.; Shetler, G.; Neff, J.C.

2009-01-01

Fire is an important control on the carbon (C) balance of the boreal forest region. Here, we present findings from two complementary studies that examine how fire modifies soil organic matter properties, and how these modifications influence rates of decomposition and C exchange in black spruce (Picea mariana) ecosystems of interior Alaska. First, we used laboratory incubations to explore soil temperature, moisture, and vegetation effects on CO2 and DOC production rates in burned and unburned soils from three study regions in interior Alaska. Second, at one of the study regions used in the incubation experiments, we conducted intensive field measurements of net ecosystem exchange (NEE) and ecosystem respiration (ER) across an unreplicated factorial design of burning (2 year post-fire versus unburned sites) and drainage class (upland forest versus peatland sites). Our laboratory study showed that burning reduced the sensitivity of decomposition to increased temperature, most likely by inducing moisture or substrate quality limitations on decomposition rates. Burning also reduced the decomposability of Sphagnum-derived organic matter, increased the hydrophobicity of feather moss-derived organic matter, and increased the ratio of dissolved organic carbon (DOC) to total dissolved nitrogen (TDN) in both the upland and peatland sites. At the ecosystem scale, our field measurements indicate that the surface organic soil was generally wetter in burned than in unburned sites, whereas soil temperature was not different between the burned and unburned sites. Analysis of variance results showed that ER varied with soil drainage class but not by burn status, averaging 0.9 ?? 0.1 and 1.4 ?? 0.1 g C m-2d-1 in the upland and peatland sites, respectively. However, a more complex general linear model showed that ER was controlled by an interaction between soil temperature, moisture, and burn status, and in general was less variable over time in the burned than in the unburned sites. Together, findings from these studies across different spatial scales suggest that although fire can create some soil climate conditions more conducive to rapid decomposition, rates of C release from soils may be constrained following fire by changes in moisture and/or substrate quality that impede rates of decomposition. ?? 2008 Springer Science+Business Media, LLC.

Interactive effects of fire, soil climate, and moss on CO2 fluxes in black spruce ecosystems of interior Alaska

USGS Publications Warehouse

O'Donnell, Jonathan A.; Turetsky, Merritt R.; Harden, Jennifer W.; Manies, Kristen L.; Pruett, L.E.; Shetler, Gordon; Neff, Jason C.

2009-01-01

Fire is an important control on the carbon (C) balance of the boreal forest region. Here, we present findings from two complementary studies that examine how fire modifies soil organic matter properties, and how these modifications influence rates of decomposition and C exchange in black spruce (Picea mariana) ecosystems of interior Alaska. First, we used laboratory incubations to explore soil temperature, moisture, and vegetation effects on CO2 and DOC production rates in burned and unburned soils from three study regions in interior Alaska. Second, at one of the study regions used in the incubation experiments, we conducted intensive field measurements of net ecosystem exchange (NEE) and ecosystem respiration (ER) across an unreplicated factorial design of burning (2 year post-fire versus unburned sites) and drainage class (upland forest versus peatland sites). Our laboratory study showed that burning reduced the sensitivity of decomposition to increased temperature, most likely by inducing moisture or substrate quality limitations on decomposition rates. Burning also reduced the decomposability of Sphagnum-derived organic matter, increased the hydrophobicity of feather moss-derived organic matter, and increased the ratio of dissolved organic carbon (DOC) to total dissolved nitrogen (TDN) in both the upland and peatland sites. At the ecosystem scale, our field measurements indicate that the surface organic soil was generally wetter in burned than in unburned sites, whereas soil temperature was not different between the burned and unburned sites. Analysis of variance results showed that ER varied with soil drainage class but not by burn status, averaging 0.9 ± 0.1 and 1.4 ± 0.1 g C m−2 d−1 in the upland and peatland sites, respectively. However, a more complex general linear model showed that ER was controlled by an interaction between soil temperature, moisture, and burn status, and in general was less variable over time in the burned than in the unburned sites. Together, findings from these studies across different spatial scales suggest that although fire can create some soil climate conditions more conducive to rapid decomposition, rates of C release from soils may be constrained following fire by changes in moisture and/or substrate quality that impede rates of decomposition.

Formation of size controlled Ge nanocrystals in Er-doped ZnO matrix and their enhancement effect in 1.54 μm photoluminescence

NASA Astrophysics Data System (ADS)

Fan, Ranran; Lu, Fei; Li, Kaikai; Liu, Kaijing

2018-06-01

This paper investigated the controllable growth of Ge nanocrystal (nc-Ge) in (Ge, Er) co-doped ZnO film, and the relationship between the size of nc-Ge and the enhancement of Er3+ related 1.54 μm photoluminescence (PL). It was found that nc-Ge with size of ∼5 nm was formed by annealing treatment at 600 °C. The intensity of 1.54 μm was significantly enhanced due to the existence of nc-Ge and showed an obvious dependence on nanocrystal size. The size of nc-Ge increased with the increase of the annealing temperature, and the nanocrystal with size of ∼5 nm made the most obvious contribution to PL enhancement. Prolonging annealing time could improve the crystalline structure of ZnO matrix but had no effect on PL intensity. The experimental results showed that the PL enhancement was mainly achieved by transferring the energy to Er through the resonance absorption of nc-Ge.

Effect of Er,Cr:YSGG laser irradiation on eruption of rat mandibular incisor after disturbance of the enamel organ in the pulp.

PubMed

Masuda, Yoshiko Murakami; Hossain, Mozammal; Wang, Xiaogu; Matsuoka, Emi; Okano, Tomohiro; Matsumoto, Koukichi

2006-09-01

To investigate the efficacy of Er,Cr:YSGG (erbium,chromium:yttrium scandium gallium garnet) laser irradiation in root canal preparation and to evaluate its effect on eruption of rat incisors after disturbance of the enamel organ in the pulp, 20 canals of lower left incisor teeth were prepared by K-files followed by Er,Cr:YSGG laser irradiation, and 20 canals of right incisors were subjected to K-files only (control). At 1 week after irradiation, both sides of incisors erupted at the same level from the gingival margin. Histological findings showed that laser irradiation produced a slightly larger damage in the pulp than that of control. Scanning electron microscope observation revealed that laser-treated surface revealed a rough, irregular, and very clean surface; there was almost no evidence of debris or smear layer, and dentinal tubules were opened. Adequate power of Er,Cr:YSGG laser irradiation is effective in root canal preparation without disturbance of the eruption.

An ER-peroxisome tether exerts peroxisome population control in yeast

PubMed Central

Knoblach, Barbara; Sun, Xuejun; Coquelle, Nicolas; Fagarasanu, Andrei; Poirier, Richard L; Rachubinski, Richard A

2013-01-01

Eukaryotic cells compartmentalize biochemical reactions into membrane-enclosed organelles that must be faithfully propagated from one cell generation to the next. Transport and retention processes balance the partitioning of organelles between mother and daughter cells. Here we report the identification of an ER-peroxisome tether that links peroxisomes to the ER and ensures peroxisome population control in the yeast Saccharomyces cerevisiae. The tether consists of the peroxisome biogenic protein, Pex3p, and the peroxisome inheritance factor, Inp1p. Inp1p bridges the two compartments by acting as a molecular hinge between ER-bound Pex3p and peroxisomal Pex3p. Asymmetric peroxisome division leads to the formation of Inp1p-containing anchored peroxisomes and Inp1p-deficient mobile peroxisomes that segregate to the bud. While peroxisomes in mother cells are not released from tethering, de novo formation of tethers in the bud assists in the directionality of peroxisome transfer. Peroxisomes are thus stably maintained over generations of cells through their continued interaction with tethers. PMID:23900285

Alpha-mangostin attenuates diabetic nephropathy in association with suppression of acid sphingomyelianse and endoplasmic reticulum stress.

PubMed

Liu, Tingting; Duan, Wang; Nizigiyimana, Paul; Gao, Lin; Liao, Zhouning; Xu, Boya; Liu, Lerong; Lei, Minxiang

2018-02-05

Diabetic nephropathy is a common complication of diabetes, but there are currently few treatment options. The aim of this study was to gain insight into the effect of alpha-mangostin on diabetic nephropathy and possible related mechanisms. Goto-Kakizaki rats were used as a diabetic model and received alpha-mangostin or desipramine treatment with normal saline as a control. Ten age-matched Sprague Dawley rats were used as normal controls and treated with normal saline. At week 12, blood glucose, albuminuria, apoptosis and renal pathologic changes were assessed. Protein levels for acid sphingomyelinase, glucose-regulated protein 78, phosphorylated PKR-like ER-resident kinase, activated transcription factor 4, CCAAT/enhancer-binding protein, homologous protein), and cleaved-caspase12 were measured. The level of acid sphingomyelinase was significantly increased, and ER stress was activated in diabetic rat kidneys when compared to the control animals. When acid sphingomyelinase was inhibited by alpha-mangostin, the expression of ER stress-related proteins was down-regulated in association with decreased levels of diabetic kidney injury. Alpha-mangostin, an acid sphingomyelinase inhibitor plays a protective role in diabetic neuropathy by relieving ER stress induced-renal cell apoptosis. Copyright © 2018 Elsevier Inc. All rights reserved.

Self- and Co-regulation of Anger and Fear in Preschoolers with Autism Spectrum Disorders: The Role of Maternal Parenting Style and Temperament.

PubMed

Hirschler-Guttenberg, Yael; Feldman, Ruth; Ostfeld-Etzion, Sharon; Laor, Nathaniel; Golan, Ofer

2015-09-01

Emotion regulation (ER) difficulties are a major concern in children with autism spectrum disorder (ASD). Maternal temperament and parenting style have significant effects on children's ER. However, these effects have not been studied in children with ASD. Forty preschoolers with ASD and their mothers and forty matched controls engaged in fear and anger ER paradigms, micro-coded for child self- and co-regulatory behaviors and parent's regulation-facilitation. Mothers' parenting style and temperament were self-reported. In the ASD group only, maternal authoritarian style predicted higher self-regulation and lower co-regulation of anger and maternal authoritative style predicted higher self-regulation of fear. Maternal temperament did not predict child's ER. Findings emphasize the importance of maternal flexible parenting style in facilitating ER among children with ASD.

ER-2: Flying Laboratory for Earth Science Studies

NASA Technical Reports Server (NTRS)

Navarro, Robert

2007-01-01

The National Aeronautics and Space Administration (NASA) Dryden Flight Research Center (DFRC), (Edwards, California, USA) has two Lockheed Martin Corporation (Bethesda, Maryland) Earth Research-2 (ER-2) aircraft that serve as high-altitude and long-range flying laboratories. The ER-2 has been utilized to conduct scientific studies of stratospheric and tropospheric chemistry, land-use mapping, disaster assessment, preliminary testing and calibration and validation of satellite sensors. The ER-2 aircraft provides experimenters with a wide array of payload accommodation areas with suitable environment control with required electrical and mechanical interfaces. Missions may be flown out of DFRC or from remote bases worldwide. The NASA ER-2 is utilized by a variety of customers, including U.S. Government agencies, civilian organizations, universities, and state governments. The combination of the ER-2 s range, endurance, altitude, payload power, payload volume and payload weight capabilities complemented by a trained maintenance and operations team provides an excellent and unique platform system to the science community.

ER-mitochondria contacts control surface glycan expression and sensitivity to killer lymphocytes in glioma stem-like cells.

PubMed

Bassoy, Esen Yonca; Kasahara, Atsuko; Chiusolo, Valentina; Jacquemin, Guillaume; Boydell, Emma; Zamorano, Sebastian; Riccadonna, Cristina; Pellegatta, Serena; Hulo, Nicolas; Dutoit, Valérie; Derouazi, Madiha; Dietrich, Pierre Yves; Walker, Paul R; Martinvalet, Denis

2017-06-01

Glioblastoma is a highly heterogeneous aggressive primary brain tumor, with the glioma stem-like cells (GSC) being more sensitive to cytotoxic lymphocyte-mediated killing than glioma differentiated cells (GDC). However, the mechanism behind this higher sensitivity is unclear. Here, we found that the mitochondrial morphology of GSCs modulates the ER-mitochondria contacts that regulate the surface expression of sialylated glycans and their recognition by cytotoxic T lymphocytes and natural killer cells. GSCs displayed diminished ER-mitochondria contacts compared to GDCs. Forced ER-mitochondria contacts in GSCs increased their cell surface expression of sialylated glycans and reduced their susceptibility to cytotoxic lymphocytes. Therefore, mitochondrial morphology and dynamism dictate the ER-mitochondria contacts in order to regulate the surface expression of certain glycans and thus play a role in GSC recognition and elimination by immune effector cells. Targeting the mitochondrial morphology, dynamism, and contacts with the ER could be an innovative strategy to deplete the cancer stem cell compartment to successfully treat glioblastoma. © 2017 The Authors.

Synthesis of novel branched β-NaLuF4: Yb/Er upconversion luminescence material and investigation of its optical properties

NASA Astrophysics Data System (ADS)

Ding, Yanli; Yang, Tonghui; Yin, Naiqiang; Shu, Fangjie; Zhao, Ying; Zhang, Xiaodan

2018-05-01

Branched β-NaLuF4: Yb/Er was synthesized using a simple hydrothermal method by controlling the NaF/Ln molar ratio. In contrast to the β-NaYF4: Yb/Er hexagonal disks, the branched β-NaLuF4: Yb/Er has stronger emission intensity. The integrated intensities of green and red emission bands were as 6.2 and 3.3 times as that of NaYF4, respectively. The branched β-NaLuF4: Yb/Er has the smaller unit cell volume, the higher absorption intensity around 980 nm and the lower crystal field symmetry than NaYF4, which made a significant contribution to the stronger upconversion (UC) fluorescence emissions. The results indicate that the branched β-NaLuF4: Yb/Er is an excellent UC luminescence material. The current research has a great potential in improving near-infrared conversion efficiency of solar cells.

Galantamine-ER for the treatment of mild-to-moderate Alzheimer’s disease

PubMed Central

Seltzer, Ben

2010-01-01

An extended release form of the cholinesterase inhibitor (ChEI) drug galantamine (galantamine-ER) was developed, chiefly to increase adherence to medication regimes in patients with mild-to-moderate Alzheimer’s disease (AD). Except for predicted differences in (Cmax) and tmax, comparable doses of once daily galantamine-ER and regular, immediate release galantamine, (galantamine-IR), are pharmacologically equivalent. A 24-week randomized, double-blind, placebo-and active-controlled, multicenter phase III trial, which compared galantamine-IR, galantamine-ER and placebo in subjects with mild to moderate AD (mini-mental state examination [MMSE] score range, 10 to 24) showed that both formulations of galantamine were significantly better than placebo in terms of cognition, although not with regard to global change. There was no difference in drug-related adverse events between galantamine-ER and galantamine-IR. Since its release onto the market galantamine-ER has enjoyed wide popularity and a recent surveillance study suggests that it has the highest 1-year persistence rate of all the ChEIs. PMID:20169037

STIM proteins and the endoplasmic reticulum-plasma membrane junctions.

PubMed

Carrasco, Silvia; Meyer, Tobias

2011-01-01

Eukaryotic organelles can interact with each other through stable junctions where the two membranes are kept in close apposition. The junction that connects the endoplasmic reticulum to the plasma membrane (ER-PM junction) is unique in providing a direct communication link between the ER and the PM. In a recently discovered signaling process, STIM (stromal-interacting molecule) proteins sense a drop in ER Ca(2+) levels and directly activate Orai PM Ca(2+) channels across the junction space. In an inverse process, a voltage-gated PM Ca(2+) channel can directly open ER ryanodine-receptor Ca(2+) channels in striated-muscle cells. Although ER-PM junctions were first described 50 years ago, their broad importance in Ca(2+) signaling, as well as in the regulation of cholesterol and phosphatidylinositol lipid transfer, has only recently been realized. Here, we discuss research from different fields to provide a broad perspective on the structures and unique roles of ER-PM junctions in controlling signaling and metabolic processes.

Self-focused cognitive emotion regulation style as associated with widespread diminished EEG fractal dimension.

PubMed

Bornas, Xavier; Tortella-Feliu, Miquel; Balle, Maria; Llabrés, Jordi

2013-01-01

The cognitive regulation of emotions is important for human adaptation. Self-focused emotion regulation (ER) strategies have been linked to the development and persistence of anxiety and depression. A vast array of research has provided valuable knowledge about the neural correlates of the use of specific self-focused ER strategies; however, the resting neural correlates of cognitive ER styles, which reflect an individual's disposition to engage in different forms of ER in order to manage distress, are largely unknown. In this study, associations between theoretically negative ER style (self-focused or not) and the complexity (fractal dimension, FD) of the resting EEG at frontal, central, parietal, and occipital regions were investigated in 58 healthy volunteers. The Cognitive Emotion Regulation Questionnaire was used as the self-report measure of ER style. Results showed that a diminished FD over the scalp significantly correlated with self-focused ER style scores, even after controlling for negative affect, which has been also considered to influence the use of ER strategies. The lower the EEG FD, the higher were the self-focused ER style scores. Correlational analyses of specific self-focused ER strategies showed that self-blaming and rumination were negatively associated with diminished FD of the EEG, but catastrophizing and blaming others were not. No significant correlations were found for ER strategies more focused on situation or others. Results are discussed within the self-organized criticality theory of brain dynamics: The diminished FD of the EEG may reflect a disposition to engage in self-focused ER strategies as people prone to ruminate and self-blame show a less complex resting EEG activity, which may make it more difficult for them to exit their negative emotional state.

Laser reduction of specific microorganisms in the periodontal pocket using Er:YAG and Nd:YAG lasers: a randomized controlled clinical study.

PubMed

Grzech-Leśniak, K; Sculean, A; Gašpirc, Boris

2018-05-15

The objective of this study was to evaluate the microbiological and clinical outcomes following nonsurgical treatment by either scaling and root planing, combination of Nd:YAG and Er:YAG lasers, or by Er:YAG laser treatment alone. The study involved 60 patients with generalized chronic periodontitis, randomly assigned into one of three treatment groups of 20 patients. The first group received scaling and root planing by hand instruments (SRP group), the second group received Er:YAG laser treatment alone (Er group), and the third group received combined treatment with Nd:YAG and Er:YAG lasers (NdErNd group). Microbiological samples, taken from the periodontal pockets at baseline and 6 months after treatments, were assessed with PET Plus tests. The combined NdErNd laser (93.0%), followed closely by Er:YAG laser (84.9%), treatment resulted in the highest reduction of all bacteria count after 6 months, whereas SRP (46.2%) failed to reduce Treponema denticola, Peptostreptococcus micros, and Capnocytophaga gingivalis. Full-mouth plaque and bleeding on probing scores dropped after 6 months and were the lowest in both laser groups. The combination of NdErNd resulted in higher probing pocket depth reduction and gain of clinical attachment level (1.99 ± 0.23 mm) compared to SRP (0.86 ± 0.13 mm) or Er:YAG laser alone (0.93 ± 0.20 mm) in 4-6 mm-deep pockets. Within their limits, the present results provide support for the combination of Nd:YAG and Er:YAG lasers to additionally improve the microbiological and clinical outcomes of nonsurgical periodontal therapy in patients with moderate to severe chronic periodontitis.

Estrogen Receptor Expression in Atypical Hyperplasia: Lack of Association with Breast Cancer

PubMed Central

Barr Fritcher, Emily G.; Degnim, Amy C.; Hartmann, Lynn C.; Radisky, Derek C.; Boughey, Judy C.; Anderson, Stephanie S.; Vierkant, Robert A.; Frost, Marlene H.; Visscher, Daniel W.; Reynolds, Carol

2011-01-01

Background Estrogen receptor (ER) is expressed in normal and malignant breast epithelium, and expression levels have been found to increase with age in normal breast epithelium but not in atypical hyperplasia (AH) and carcinoma in situ. Here we assess ER expression in AH and its association with later breast cancer. Methods ER expression was assessed immunohistochemically in archival sections from 246 women with AH who had open benign breast biopsy from 1967–1991. The ACISRIII (Dako, Carpinteria, CA) was utilized to calculate ER expression in all atypical foci. Using multivariate linear regression, we examined associations of ER expression with age at biopsy, indication for biopsy, type of atypia, number of atypical foci, involution status, and family history. Breast cancer risk across levels of ER expression was also assessed compared to the Iowa SEER control population. Results Among 246 women, 87 (35%) had atypical ductal hyperplasia (ADH), 141 (57%) had atypical lobular hyperplasia (ALH), and 18 (7%) had both. Forty-nine (20%) developed breast cancer (median follow-up of 14.4 years). Multivariate analysis indicated that type of atypia and age at diagnosis were significantly associated with ER percent staining and intensity [p<0.05]. ER expression was increased in women with ADH and/or those over age 55. ER expression did not significantly impact breast cancer risk in patients diagnosed with atypia. Conclusion We found increasing ER expression in atypical hyperplasia with increasing age. ER expression in atypical hyperplasia does not further discriminate breast cancer risk in women with atypia. PMID:21209395

Shoulder Dynamic Control Ratio and Rotation Range of Motion in Female Junior Elite Handball Players and Controls.

PubMed

van Cingel, Robert; Habets, Bas; Willemsen, Linn; Staal, Bart

2018-03-01

To compare glenohumeral range of motion and shoulder rotator muscle strength in healthy female junior elite handball players and controls. Cross-sectional case-control study. Sports medical center. Forty elite female handball players and 30 controls active in nonoverhead sports participated in this study. Passive external rotator (ER), internal rotator (IR), and total range of motion (TROM) of the dominant and nondominant arm were examined with a goniometer. An isokinetic dynamometer was used to evaluate concentric and eccentric rotator muscle strength at 60 and 120 degrees/s with dynamic control ratio (DCR = ERecc:IRcon) as the main outcome parameter. Except for the ER range of motion in the nondominant arm, no significant differences were found between groups for IR, ER of the dominant arm, and the TROM. Within the handball group, the side-to-side difference for IR of the dominant arm was -1.4 degrees. The ER and the TROM of the dominant arm were significantly larger, 6.3 and 4.9 degrees, respectively. For both groups, the DCR values were above 1 and no significant differences were found between the dominant and nondominant arm. The DCR values in the handball group were significantly lower than in the control group. Based on the adopted definitions for muscle imbalance, glenohumeral internal range of motion deficit and TROM deficit our elite female handball players seem not at risk for shoulder injuries. Prospective studies are needed to support the belief that a DCR below 1 places the shoulder at risk for injury.

Type-I Insulin-Like Growth Factor Receptor (IGF1R)-Estrogen Receptor (ER) Crosstalk Contributes to Antiestrogen Therapy Resistance in Breast Cancer Cells

DTIC Science & Technology

2013-02-01

penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR...great success in treating estrogen receptor (ER) positive breast cancer. However, both acquired and de novo resistance to this therapy prevents it from...has shown great success in treating estrogen receptor (ER) positive breast tumors. However, both acquired and de novo resistance to this therapy

In vitro antioxidant and in vivo hepatoprotective activity of leave extract of Raphanus sativus in rats using CCL4 model.

PubMed

Syed, Shariq Naeem; Rizvi, Waseem; Kumar, Anil; Khan, Aijaz Ahmad; Moin, Shagufta; Ahsan, Akif

2014-01-01

Raphanus sativus is reported to have a variety of biological activities. This work screened the hepato-protective and antioxidant activity of ethanol (ERS), and aqueous (ARS), extracts of leaves of Raphanus sativus in Carbon tetrachloride (CCl4), model in rats. The extracts were subjected to antioxidant tests (Total reducing power and Total phenolic content), and preliminary phytochemical screening. A pilot study was done on 100 and 300 mg/kg extracts, form which 300 mg was chosen for further experiments. The albino rats (200-250 grams), were divided into 5 groups of 6 animals each (n=6). There were three control groups comprising of normal control (normal saline -1ml/kg), negative control group (CCl4 1ml/kg in olive oil in a ratio of 1:1 v/v), and positive control group (Silymarin 50mg/kg). The Test drugs were given in a dose of 300 mg/kg for both ERS and ARS extract for 7 days. Biochemical parameters (AST, ALT, Alkaline phosphatase, Total Bilirubin), histo-pathological examination of liver and in vivo antioxidant tests [CAT, GSH and MDA] were done. The phytochemical study showed the presence of flavanoids, terpenoids, alkaloids, saponins and sterols. A dose dependent increase in the oxidative potential was observed in both the extracts with total phenolic content 70.1 and 44.4 GAE/g extract for ERS and ARS respectively. ERS 300mg/kg showed a significant (p<0.001) increase in levels of AST, ALT and alkaline phosphatase as compared to negative control (percentage hepatoprotection =45.3%) while ARS 300 mg/kg (p<.01) group showed 30% hepatoprotection. The GSH (p<0.001) and CAT (p<0.05) in ERS and ARS were significantly increased while MDA levels were decreased (P< 0.01), as compared negative control. The findings were confirmed histo-pathological examination. The ethanol and aqueous extract of Raphanus sativus have partial hepatoprotection against CCl4 toxicity.

Liganded and unliganded activation of estrogen receptor and hormone replacement therapies.

PubMed

Maggi, Adriana

2011-08-01

Over the past two decades, our understanding of estrogen receptor physiology in mammals widened considerably as we acquired a deeper appreciation of the roles of estrogen receptor alpha and beta (ERα and ERβ) in reproduction as well as in bone and metabolic homeostasis, depression, vascular disorders, neurodegenerative diseases and cancer. In addition, our insights on ER transcriptional functions in cells increased considerably with the demonstration that ER activity is not strictly dependent on ligand availability. Indeed, unliganded ERs may be transcriptionally active and post-translational modifications play a major role in this context. The finding that several intracellular transduction molecules may regulate ER transcriptional programs indicates that ERs may act as a hub where several molecular pathways converge: this allows to maintain ER transcriptional activity in tune with all cell functions. Likely, the biological relevant role of ER was favored by evolution as a mean of integration between reproductive and metabolic functions. We here review the post-translational modifications modulating ER transcriptional activity in the presence or in the absence of estrogens and underline their potential role for ER tissue-specific activities. In our opinion, a better comprehension of the variety of molecular events that control ER activity in reproductive and non-reproductive organs is the foundation for the design of safer and more efficacious hormone-based therapies, particularly for menopause. This article is part of a Special Issue entitled: Translating Nuclear receptors from health to disease. Copyright © 2011 Elsevier B.V. All rights reserved.

International Validation of Two Human Recombinant Estrogen ...

EPA Pesticide Factsheets

An international validation study has been successfully completed for 2 competitive binding assays using human recombinant ERa. Assays evaluated included the Freyberger-Wilson (FW) assay using a full length human ER, and the Chemical Evaluation and Research Institute (CERI) assay using a ligand-binding domain of the human ER. Twenty three compounds were tested in 6 laboratories for the FW assay and 5 for the CERJ assay, which included three controls (used with every run), 9 uncoded, and 14 coded chemicals across 3 subtasks. The overall goal of this validation study was to demonstrate the ability of each of the two assays to reliably classify the test chemicals as binders or non-binders. Laboratories had little trouble with the ER binders that produced a full binding curve when using either the CERI or FW assays. As is typical with all ER competitive binding assays, the weak binders proved to be more challenging. However, overall results from both the FW and CERI assays were consistent and in agreement with expected classifications regardless of the form of the hrER (i.e., full length ER versus an ER ligand binding domain) or the subtle differences in the protocols for conducting each assay. The reproducibility and accuracy for classification of chemicals as potential ER binders and non- binders using the FW and CERI hrER binding assays were comparable to that of the U.S.EPA’s existing ER binding test guideline OPPTS 890.1250, while providing an improved, highe

The control of ultrasonic transmission by the metamaterials structure of electrorheological fluid and metal foam

NASA Astrophysics Data System (ADS)

Li, Linlin; Wang, Mingzhong; Wang, Jiahui; Zhao, Xiaopeng

2017-11-01

A metamaterial structure formed by foamed metal and starch and oil-based electrorheological (ER) fluid is designed in this paper. Experiments show that the metamaterial structure exhibits a regulation effect on the amplitude and phase of the transmitted waves of 35-80 kHz ultra-wideband ultrasonic waves in water. With the increase of the electric field, the transmission amplitude and phase of the ultrasonic wave increases, whereas the control ability of the same gradient electric field decreases. The amplitude of the transmission controlled by the metamaterial structure and electric field increases at first, and then decreases with the increase in volume fraction of the ER fluid. Thus, it is thought that the interaction between the microstructure produced by the rheological properties of the ER fluid and the porous foam metal affects the propagation of the acoustic wave.

Update on tolterodine extended-release for treatment of overactive bladder

PubMed Central

Omotosho, Tola; Chen, Chi Chiung Grace

2010-01-01

Overactive bladder is a prevalent condition which negatively impacts quality of life and puts a significant economical burden on society. First-line therapy often includes pharmacotherapy with antimuscarinic medications, and numerous research studies have demonstrated that tolterodine extended-release (ER) is an efficacious and tolerable formulation of this class of medication. This review provides an update on the clinical use of tolterodine ER, detailing the current literature on its efficacy, tolerability, adverse effects, and comparability with other commonly prescribed medications for the treatment of overactive bladder. PMID:24198627

From Endoplasmic Reticulum to Mitochondria: Absence of the Arabidopsis ATP Antiporter Endoplasmic Reticulum Adenylate Transporter1 Perturbs Photorespiration[W

PubMed Central

Hoffmann, Christiane; Plocharski, Bartolome; Haferkamp, Ilka; Leroch, Michaela; Ewald, Ralph; Bauwe, Hermann; Riemer, Jan; Herrmann, Johannes M.; Neuhaus, H. Ekkehard

2013-01-01

The carrier Endoplasmic Reticulum Adenylate Transporter1 (ER-ANT1) resides in the endoplasmic reticulum (ER) membrane and acts as an ATP/ADP antiporter. Mutant plants lacking ER-ANT1 exhibit a dwarf phenotype and their seeds contain reduced protein and lipid contents. In this study, we describe a further surprising metabolic peculiarity of the er-ant1 mutants. Interestingly, Gly levels in leaves are immensely enhanced (26×) when compared with that of wild-type plants. Gly accumulation is caused by significantly decreased mitochondrial glycine decarboxylase (GDC) activity. Reduced GDC activity in mutant plants was attributed to oxidative posttranslational protein modification induced by elevated levels of reactive oxygen species (ROS). GDC activity is crucial for photorespiration; accordingly, morphological and physiological defects in er-ant1 plants were nearly completely abolished by application of high environmental CO2 concentrations. The latter observation demonstrates that the absence of ER-ANT1 activity mainly affects photorespiration (maybe solely GDC), whereas basic cellular metabolism remains largely unchanged. Since ER-ANT1 homologs are restricted to higher plants, it is tempting to speculate that this carrier fulfils a plant-specific function directly or indirectly controlling cellular ROS production. The observation that ER-ANT1 activity is associated with cellular ROS levels reveals an unexpected and critical physiological connection between the ER and other organelles in plants. PMID:23860249

The Neural Correlates of Emotion Regulation by Implementation Intentions

PubMed Central

Hallam, Glyn P.; Webb, Thomas L.; Sheeran, Paschal; Miles, Eleanor; Wilkinson, Iain D.; Hunter, Michael D.; Barker, Anthony T.; Woodruff, Peter W. R.; Totterdell, Peter; Lindquist, Kristen A.; Farrow, Tom F. D.

2015-01-01

Several studies have investigated the neural basis of effortful emotion regulation (ER) but the neural basis of automatic ER has been less comprehensively explored. The present study investigated the neural basis of automatic ER supported by ‘implementation intentions’. 40 healthy participants underwent fMRI while viewing emotion-eliciting images and used either a previously-taught effortful ER strategy, in the form of a goal intention (e.g., try to take a detached perspective), or a more automatic ER strategy, in the form of an implementation intention (e.g., “If I see something disgusting, then I will think these are just pixels on the screen!”), to regulate their emotional response. Whereas goal intention ER strategies were associated with activation of brain areas previously reported to be involved in effortful ER (including dorsolateral prefrontal cortex), ER strategies based on an implementation intention strategy were associated with activation of right inferior frontal gyrus and ventro-parietal cortex, which may reflect the attentional control processes automatically captured by the cue for action contained within the implementation intention. Goal intentions were also associated with less effective modulation of left amygdala, supporting the increased efficacy of ER under implementation intention instructions, which showed coupling of orbitofrontal cortex and amygdala. The findings support previous behavioural studies in suggesting that forming an implementation intention enables people to enact goal-directed responses with less effort and more efficiency. PMID:25798822

Sub ablative Er: YAG laser irradiation on surface roughness of eroded dental enamel.

PubMed

Curylofo-Zotti, Fabiana Almeida; Lepri, Taísa Penazzo; Colucci, Vivian; Turssi, Cecília Pedroso; Corona, Silmara Aparecida Milori

2015-11-01

This study evaluated the effects of Er:YAG laser irradiation applied at varying pulse repetition rate on the surface roughness of eroded enamel. Bovine enamel slabs (n = 10) were embedded in polyester resin, ground, and polished. To erosive challenges, specimens were immersed two times per day in 20mL of concentrated orange juice (pH = 3.84) under agitation, during a two-day period. Specimens were randomly assigned to irradiation with the Er:YAG laser (focused mode, pulse energy of 60 mJ and energy density of 3.79 J/cm(2) ) operating at 1, 2, 3, or 4 Hz. The control group was left nonirradiated. Surface roughness measurements were recorded post erosion-like formation and further erosive episodes by a profilometer and observed through atomic force microscopy (AFM). Analysis of variance revealed that the control group showed the lowest surface roughness, while laser-irradiated substrates did not differ from each other following post erosion-like lesion formation. According to analysis of covariance, at further erosive episodes, the control group demonstrated lower surface roughness (P > 0.05), than any of the irradiated groups (P < 0.05). The pulse repetition rate of the Er:YAG laser did not affect roughness of dental enamel eroded. The AFM images showed that the specimens irradiated by the Er:YAG laser at 1 Hz presented a less rough surface than those irradiated at 2, 3, and 4 Hz. © 2015 Wiley Periodicals, Inc.

ApoER2 Controls Not Only Neuronal Migration in the Intermediate Zone But Also Termination of Migration in the Developing Cerebral Cortex.

PubMed

Hirota, Yuki; Kubo, Ken-Ichiro; Fujino, Takahiro; Yamamoto, Tokuo T; Nakajima, Kazunori

2018-01-01

Neuronal migration contributes to the establishment of mammalian brain. The extracellular protein Reelin sends signals to various downstream molecules by binding to its receptors, the apolipoprotein E receptor 2 (ApoER2) and very low-density lipoprotein receptor and exerts essential roles in the neuronal migration and formation of the layered neocortex. However, the cellular and molecular functions of Reelin signaling in the cortical development are not yet fully understood. Here, to gain insight into the role of Reelin signaling during cortical development, we examined the migratory behavior of Apoer2-deficient neurons in the developing brain. Stage-specific labeling of newborn neurons revealed that the neurons ectopically invaded the marginal zone (MZ) and that neuronal migration of both early- and late-born neurons was disrupted in the intermediate zone (IZ) in the Apoer2 KO mice. Rescue experiments showed that ApoER2 functions both in cell-autonomous and noncell-autonomous manners, that Rap1, integrin, and Akt are involved in the termination of migration beneath the MZ, and that Akt also controls neuronal migration in the IZ downstream of ApoER2. These data indicate that ApoER2 controls multiple processes in neuronal migration, including the early stage of radial migration and termination of migration beneath the MZ in the developing neocortex. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Estrogen Receptors and Chronic Venous Disease.

PubMed

Serra, R; Gallelli, L; Perri, P; De Francesco, E M; Rigiracciolo, D C; Mastroroberto, P; Maggiolini, M; de Franciscis, S

2016-07-01

Chronic venous disease (CVD) is a common and relevant problem affecting Western people. The role of estrogens and their receptors in the venous wall seems to support the major prevalence of CVD in women. The effects of the estrogens are mediated by three estrogen receptors (ERs): ERα, ERβ, and G protein-coupled ER (GPER). The expression of ERs in the vessel walls of varicose veins is evaluated. In this prospective study, patients of both sexes, with CVD and varicose veins undergoing open venous surgery procedures, were enrolled in order to obtain vein samples. To obtain control samples of healthy veins, patients of both sexes without CVD undergoing coronary artery bypass grafting with autologous saphenous vein were recruited (control group). Samples were processed in order to evaluate gene expression. Forty patients with CVD (10 men [25%], 30 women [75%], mean age 54.3 years [median 52 years, range 33-74 years]) were enrolled. Five patients without CVD (three men, two women [aged 61-73 years]) were enrolled as the control group. A significant increase of tissue expression of ERα, ERβ and GPER in patients with CVD was recorded (p < .01), which was also related to the severity of venous disease. ERs seem to play a role in CVD; in this study, the expression of ERs correlated with the severity of the disease, and their expression was correlated with the clinical stage. Copyright © 2016 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.

Central and peripheral effects of chronic food restriction and weight restoration in the rat.

PubMed

Kinzig, Kimberly P; Hargrave, Sara L; Tao, Erin E

2009-02-01

Previous studies have demonstrated that some endocrine consequences of long-term caloric restriction persist after weight restoration in human subjects. Here we evaluate effects of chronic food restriction in rats that were restricted to 70% of control kcal for 4 wk and subsequently weight restored. Measures were taken from rats at 80% (chronically restricted; CR), 90% (partially weight restored; PR), 100% (fully weight restored; FR), and after 4 wk at 100% body weight of controls (extended weight restored; ER). Plasma insulin and leptin were decreased, and ghrelin was increased in CR compared with controls. Leptin and ghrelin normalized with weight restoration at PR, FR, and ER; however, baseline insulin was not normalized until the ER state. Hypothalamic mRNA expression levels for proopiomelanocortin (POMC), agouti-related protein (AgRP), and neuropeptide Y (NPY) revealed significantly less POMC mRNA expression in CR and PR rats, and significantly less arcuate NPY mRNA in PR and FR. In the dorsomedial hypothalamus, CR, PR, and FR rats had significantly increased NPY expression that was not normalized until the ER state. In response to a test meal, insulin and ghrelin release patterns were altered through the FR stage, and ghrelin remained affected at ER. Collectively, these data demonstrate that mere weight restoration is not sufficient to normalize hypothalamic gene expression levels and endocrine responses to a meal, and that meal-related ghrelin responses persist despite weight restoration for up to 4 wk.

jsc2017e009735

NASA Image and Video Library

2017-01-26

jsc2017e009735 (01/26/2017) --- Former NFL players on tour of the Johnson Space Center (JSC) as part of the Centers Super Bowl tailgate event gathered together in front of JSC's Mission Control. The former players toured JSC in the week before the Super Bowl game. Kneeling front left: Kerry Henderson (NY Jets), Joe Wesley (49ers, Jaguars), First standing row, left: Ronald Humphrey (IN Colts), James Williams (Saints, Jag, 49ers, Browns), Emanuel McNeil (NY Jets), Sammy Davis (Chargers, 49ers, Buccaneers), Daryl Gaines (KC Chiefs, Cris Calloway (Giants, Steelers, Falcons, Patriots), Lemanual Stinson (Bears & Falcons). Back row left: Ginger Kerrrick (JSC Staff), Jermaine Fazonde (Chargers), Michael Holmes (49ers), Kevin Williams (Vikings, Seahawks, Saints). NASA PHOTOGRAPHER: Lauren Harnett

Controlled spontaneous emission in erbium-doped microphotonic materials

NASA Astrophysics Data System (ADS)

Kalkman, Jeroen

2005-03-01

Erbium is a rare-earth metal that, when incorporated in a solid, can emit light at a wavelength of 1.5 μm. It plays a key role in current day telecommunication technology as the principle ingredient of optical fiber amplifiers. In this thesis the control of the Er spontaneous emission in three different types of microphotonic materials is described. Part I of this thesis focuses on the effect of a metallo-dielectric interface on the spontaneous emission of optical emitters in silica glass. It is shown that Er ions near a Ag interface can couple to surface plasmons (SPs) via a near-field interaction. By coupling SPs out into the far field, large changes in the Er photoluminescence emission distribution, spectra, and polarization can be observed. The excitation of SPs also results in an increase of the Er photoluminescence decay rate. The observed decay rates are in good agreement with calculations based on a classical dipole oscillator model. From the change in photoluminescence decay rate of Si nanocrystals near a Ag interface it is shown that Si nanocrystals can efficiently excite SPs and have an internal quantum efficiency of 77 %. Part II focuses on the effect of a microcavity on the spontaneous emission of Er and describes how ion implantation can be used to dope dielectric microresonators with optically active Er ions. The fabrication and characterization of an Er ion-implanted silica microsphere resonator is described that shows lasing at 1.5 μm when pumped above its lasing threshold. Ion implantation is also used to dope toroidal microcavities on a Si chip with Er. The microtoroids are doped by either pre-implantation into the SiO2 base material, or by post-implantation in a fully fabricated microtoroid. The optical activation of Er ions in the microtoroid is investigated and Er lasing at 1.5 μm is observed for both types of microcavities with the lowest threshold (4.5 μW) for the pre-implanted microtoroids. Part III describes the fabrication of an Er-doped Si-inverse opal photonic crystal. These photonic crystals can potentially have a photonic bandgap that can fully inhibit the spontaneous emission of on optical emitter. Fabrication criteria are derived for such a photonic crystal, based on the lattice parameter, filling fraction, and Si refractive index. In the opal photonic crystal composed of both Si and SiO2 we show that Er ions can be selectively excited in both the Si and SiO2 part of the photonic crystal by changing the excitation wavelength and/or the measurement temperature.

Nonsense-Mediated Decay in Genetic Disease: Friend or Foe?

PubMed Central

Miller, Jake N.; Pearce, David A.

2014-01-01

Eukaryotic cells utilize various RNA quality control mechanisms to ensure high fidelity of gene expression, thus protecting against the accumulation of nonfunctional RNA and the subsequent production of abnormal peptides. Messenger RNAs (mRNAs) are largely responsible for protein production, and mRNA quality control is particularly important for protecting the cell against the downstream effects of genetic mutations. Nonsense-mediated decay (NMD) is an evolutionarily conserved mRNA quality control system in all eukaryotes that degrades transcripts containing premature termination codons (PTCs). By degrading these aberrant transcripts, NMD acts to prevent the production of truncated proteins that could otherwise harm the cell through various insults, such as dominant negative effects or the ER stress response. Although NMD functions to protect the cell against the deleterious effects of aberrant mRNA, there is a growing body of evidence that mutation-, codon-, gene-, cell-, and tissue-specific differences in NMD efficiency can alter the underlying pathology of genetic disease. In addition, the protective role that NMD plays in genetic disease can undermine current therapeutic strategies aimed at increasing the production of full-length functional protein from genes harboring nonsense mutations. Here, we review the normal function of this RNA surveillance pathway and how it is regulated, provide current evidence for the role that it plays in modulating genetic disease phenotypes, and how NMD can be used as a therapeutic target. PMID:25485595

Er:YAG laser in the treatment of periodontal sites with recurring chronic inflammation: a 12-month randomized, controlled clinical trial.

PubMed

Krohn-Dale, Ivar; Bøe, Olav E; Enersen, Morten; Leknes, Knut N

2012-08-01

The objective of this randomized, controlled clinical trial was to compare the clinical and microbiological effects of pocket debridement using erbium-doped: yttrium, aluminium and garnet (Er:YAG) laser with conventional debridement in maintenance patients. Fifteen patients, all smokers, having at least four teeth with residual probing depth (PD) ≥ 5 mm were recruited. Two pockets in two jaw quadrants were randomly assigned to subgingival debridement using an Er:YAG laser (test) or ultrasonic scaler/curette (control) at 3-month intervals. Relative attachment level (RAL), PD, bleeding on probing and dental plaque were recorded at baseline and at 6 and 12 months. Microbiological subgingival samples were taken at the same time points and analysed using a checkerboard DNA-DNA hybridization technique. A significant decrease in PD took place in both treatments from baseline to 12 months (p < 0.01). In the control, the mean initial PD decreased from 5.4 to 4.0 mm at 12 months. For the test, a similar decrease occurred. No significant between-treatment differences were shown at any time point. The mean RAL showed no overall significant inter- or intra-treatment differences (p > 0.05). No significant between-treatment differences were observed in subgingival microbiological composition or total pathogens. The results failed to support that an Er:YAG laser may be superior to conventional debridement in the treatment of smokers with recurring chronic inflammation. This appears to be the first time that repeated Er-YAG laser instrumentation has been compared with mechanical instrumentation of periodontal sites with recurring chronic inflammation over a clinically relevant time period. © 2012 John Wiley & Sons A/S.

Breast cancer and exposure to aircraft, road, and railway-noise: a case-control study based on health insurance records.

PubMed

Hegewald, Janice; Schubert, Melanie; Wagner, Mandy; Dröge, Patrik; Prote, Ursel; Swart, Enno; Möhler, Ulrich; Zeeb, Hajo; Seidler, Andreas

2017-11-01

Objectives Aircraft, road, and rail traffic noise can cause sleep disturbances. Since night work and shorter sleep durations have been linked to increased risks of breast cancer, we examined if 24-hour, or day- or night-time traffic noise exposure may also increase the risk of breast cancer. Methods To investigate the noise-related risks of breast cancer, the pseudonymized insurance records of three large statutory health companies (2005-2010) for women aged ≥40 years living in the region surrounding the Frankfurt international airport were analyzed with address-specific acoustic data representing aircraft, road, and rail-traffic noise. Noise exposure among women with incident breast cancer (N=6643) were compared with that of control subjects (N=471 596) using logistic regression and adjusting for age, hormone replacement therapy, education and occupation (only available for 27.9%), and a regional proportion of persons receiving long-term unemployment benefits as an ecological indicator of socioeconomic level. Analyses were also stratified according to estrogen receptor (ER) status. Results An increased odds ratio (OR) was observed for ER negative (ER-) tumors at 24-hour aircraft noise levels 55-59 dB [OR 55-59 dB 1.41, 95% confidence interval (CI) 1.04-1.90] but not for ER positive (ER+) breast cancers (OR 55-59 dB 0.95, 95% CI 0.75-1.20). Clear associations between road and rail traffic noise were not observed. Conclusions The results indicate increased aircraft noise may be an etiologic factor for ER- breast cancers. However, information regarding potential confounding factors was largely unattainable. Further research is required to understand how environmental noise may be involved in the pathogenesis of ER- breast cancers.

Joint relative risks for estrogen receptor-positive breast cancer from a clinical model, polygenic risk score, and sex hormones.

PubMed

Shieh, Yiwey; Hu, Donglei; Ma, Lin; Huntsman, Scott; Gard, Charlotte C; Leung, Jessica W T; Tice, Jeffrey A; Ziv, Elad; Kerlikowske, Karla; Cummings, Steven R

2017-11-01

Models that predict the risk of estrogen receptor (ER)-positive breast cancers may improve our ability to target chemoprevention. We investigated the contributions of sex hormones to the discrimination of the Breast Cancer Surveillance Consortium (BCSC) risk model and a polygenic risk score comprised of 83 single nucleotide polymorphisms. We conducted a nested case-control study of 110 women with ER-positive breast cancers and 214 matched controls within a mammography screening cohort. Participants were postmenopausal and not on hormonal therapy. The associations of estradiol, estrone, testosterone, and sex hormone binding globulin with ER-positive breast cancer were evaluated using conditional logistic regression. We assessed the individual and combined discrimination of estradiol, the BCSC risk score, and polygenic risk score using the area under the receiver operating characteristic curve (AUROC). Of the sex hormones assessed, estradiol (OR 3.64, 95% CI 1.64-8.06 for top vs bottom quartile), and to a lesser degree estrone, was most strongly associated with ER-positive breast cancer in unadjusted analysis. The BCSC risk score (OR 1.32, 95% CI 1.00-1.75 per 1% increase) and polygenic risk score (OR 1.58, 95% CI 1.06-2.36 per standard deviation) were also associated with ER-positive cancers. A model containing the BCSC risk score, polygenic risk score, and estradiol levels showed good discrimination for ER-positive cancers (AUROC 0.72, 95% CI 0.65-0.79), representing a significant improvement over the BCSC risk score (AUROC 0.58, 95% CI 0.50-0.65). Adding estradiol and a polygenic risk score to a clinical risk model improves discrimination for postmenopausal ER-positive breast cancers.

Fracture Forces of Dentin after Surface Treatment with High Speed Drill Compared to Er:YAG and Er,Cr:YSGG Laser Irradiation

PubMed Central

Franzen, Rene; Kianimanesh, Nasrin; Marx, Rudolf; Ahmed, Asma; Gutknecht, Norbert

2016-01-01

Dental tooth restorative procedures may weaken the structural integrity of the tooth, with the possibility of leading to fracture. In this study we present findings of coronal dentin strength after different techniques of surface modification. The fracture strength of dentin beams after superficial material removal with a fine diamond bur high speed drill hand piece, Er:YAG (2.94 μm, 8 J/cm2), and Er,Cr:YSGG (2.78 μm, 7.8 J/cm2) laser irradiation slightly above the ablation threshold was measured by a four-point bending apparatus. Untreated dentin beams served as a control. A total of 58 dentin beams were manufactured from sterilized human extracted molars using the coronal part of the available dentin. Mean values of fracture strength were calculated as 82.0 ± 27.3 MPa for the control group (n = 10), 104.5 ± 26.3 MPa for high speed drill treatment (n = 10), 96.1 ± 28.1 MPa for Er,Cr:YSGG laser irradiation (n = 20), and 89.1 ± 36.3 MPa for Er:YAG laser irradiation (n = 18). Independent Student's t-tests showed no significant difference between each two groups (p > 0.05). Within the parameter settings and the limits of the experimental setup used in this study, both lasers systems as well as the high speed drill do not significantly weaken coronal dentin after surface treatment. PMID:26962473

[Association of estrogen receptor gene polymorphism with cerebral infarction, a case-control study].

PubMed

Zhang, Yan; Xie, Ruping; Wang, Yinhua; Chen, Dafang; Wang, Guoying; Xu, Xiping

2002-11-10

To explore the association between estrogen receptor (ER) gene PvuII and XbaI polymorphisms and cerebral infarction among Chinese Han people. Samples of peripheral blood white cell were extracted among 234 patients with cerebral infarction, aged 63.9 +/- 10.3, and 259 controls without cerebrovascular disease, aged 59.2 +/- 9.2, all of Chinese Han nationality. PCR-RFLP and genotyping of ER PvuII and XbaI polymorphisms were performed. Multiple Logistic regression analysis was made to explore the risk factors for cerebral infarction. After adjustment for major confounders including age, gender, smoking, alcohol drinking, education, history of hypertension, diabetes mellitus, coronary artery disease and hyperlipoidemia, multiple Logistic regression analysis showed that: (1) The Pp genotype of ER PvuII polymorphism increased the risk of cerebral infarction significantly (OR = 1.97, 95% CI: 1.21 - 3.21); (2) The ER XbaI polymorphism was not in association with cerebral infarction significantly; (3) The PPXx/Ppxx genotypes increased the risk of cerebral infarction significantly (OR = 1.67, 2.52 and 2.18 respectively, P < 0.05) before or after all subjects were stratified by the history of hypertension or hyperlipoidemia; and (4) The positive interaction between the ER PvuII polymorphism and the presence of hypertension or diabetes or hyperlipoidemia could increase the risk of cerebral infarction significantly. ER gene may be one of the genetic candidate genes for cerebral infarction among Chinese Han population.

Brainstem Regions Involved in the Expiration Reflex. A c-fos Study in Anesthetized Cats

PubMed Central

Poliacek, Ivan; Halasova, Erika; Jakus, Jan; Murin, Peter; Barani, Helena; Stransky, Albert; Bolser, Donald C

2009-01-01

Expression of the immediate-early gene c-fos, a marker of neuronal activation, was employed to localize brainstem neuronal populations functionally related to the expiration reflex (ER). Twelve spontaneously breathing, non-decerebrate, pentobarbital anesthetized cats were used. The level of Fos-like immunoreactivity (FLI) in 6 animals with repetitive ERs mechanically induced from the glottis (296±9 ERs) was compared to FLI in 6 control non-stimulated cats. Respiratory rate, arterial blood pressure, and end tidal CO2 concentration remained stable during the experiment. In the medulla, increased FLI was found in the region of nucleus tractus solitarii (p<0.001), in the ventrolateral medulla along with the lateral tegmental field (p<0.01), and in the vestibular nuclei (p<0.01). In the pons, increased FLI was detected in the caudal extensions of the lateral parabrachial and Kölliker-Fuse nuclei (p<0.05). Within the rostral mesencephalon FLI was enhanced in the midline area (p<0.05). A lower level of ER-related FLI compared to control animals was detected in the pontine raphe region (p<0.05) and the lateral division of mesencephalic periaqueductal gray (p<0.05). The results suggest that the ER is coordinated by a complex long loop of medullary-pontine-mesencephalic neuronal circuits, some of which may differ from those of other respiratory reflexes. The FLI related to the expulsive behavior ER differs from that induced by laryngeal stimulation and laryngeal adductor responses, particularly in ventrolateral medulla and mesencephalon. PMID:17964550

Endoscopic resection is cost-effective compared with laparoscopic resection in the management of complex colon polyps: an economic analysis.

PubMed

Law, Ryan; Das, Ananya; Gregory, Dyanna; Komanduri, Srinadh; Muthusamy, Raman; Rastogi, Amit; Vargo, John; Wallace, Michael B; Raju, G S; Mounzer, Rawad; Klapman, Jason; Shah, Janak; Watson, Rabindra; Wilson, Robert; Edmundowicz, Steven A; Wani, Sachin

2016-06-01

Endoscopic resection (ER) is an efficacious treatment for complex colon polyps (CCPs). Many patients are referred for surgical resection because of concerns over procedural safety, incomplete polyp resection, and adenoma recurrence after ER. Efficacy data for both resection strategies are widely available, but a paucity of data exist on the cost-effectiveness of each modality. The aim of this study was to perform an economic analysis comparing ER and laparoscopic resection (LR) strategies in patients with CCP. A decision analysis tree was constructed using decision analysis software. The 2 strategies (ER vs LR) were evaluated in a hypothetical cohort of patients with CCPs. A hybrid Markov model with a 10-year time horizon was used. Patients entered the model after colonoscopic diagnosis at age 50. Under Strategy I, patients underwent ER followed by surveillance colonoscopy at 3 to 6 months and 12 months. Patients with failed ER and residual adenoma at 12 months were referred for LR. Under Strategy II, patients underwent LR as primary treatment. Patients with invasive cancer were excluded. Estimates regarding ER performance characteristics were obtained from a systematic review of published literature. The Centers for Medicare & Medicaid Services (2012-2013) and the 2012 Healthcare Cost and Utilization Project databases were used to determine the costs and loss of utility. We assumed that all procedures were performed with anesthesia support, and patients with adverse events in both strategies required inpatient hospitalization. Baseline estimates and costs were varied by using a sensitivity analysis through the ranges. LR was found to be more costly and yielded fewer quality-adjusted life-years (QALYs) compared with ER. The cost of ER of a CCP was $5570 per patient and yielded 9.640 QALYs. LR of a CCP cost $18,717 per patient and yielded fewer QALYs (9.577). For LR to be more cost-effective, the thresholds of 1-way sensitivity analyses were (1) technical success of ER for complete resection in <75.8% of cases, (2) adverse event rates for ER > 12%, and (3) LR cost of <$14,000. Our data suggest that ER is a cost-effective strategy for removal of CCPs. The effectiveness is driven by high technical success and low adverse event rates associated with ER, in addition to the increased cost of LR. Copyright © 2016 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.

Multiscale Measurement of Extreme Response Style

ERIC Educational Resources Information Center

Bolt, Daniel M.; Newton, Joseph R.

2011-01-01

This article extends a methodological approach considered by Bolt and Johnson for the measurement and control of extreme response style (ERS) to the analysis of rating data from multiple scales. Specifically, it is shown how the simultaneous analysis of item responses across scales allows for more accurate identification of ERS, and more effective…

Single-longitudinal-mode Er:GGG microchip laser operating at 2.7  μm.

PubMed

You, Zhenyu; Wang, Yan; Xu, Jinlong; Zhu, Zhaojie; Li, Jianfu; Wang, Hongyan; Tu, Chaoyang

2015-08-15

We reported on a diode-end-pumped single-longitudinal-mode microchip laser using a 600-μm-thick Er:GGG crystal at ∼2.7  μm, generating a maximum output power of 50.8 mW and the maximum pulsed energy of 0.306 mJ, with repetition rates of pumping light of 300, 200, and 100 Hz, respectively. The maximum slope efficiency of the laser was 20.1%. The laser was operated in a single-longitudinal mode centered at about 2704 nm with a FWHM of 0.42 nm. The laser had a fundamental beam profile and the beam quality parameter M(2) was measured as 1.46. These results indicate that the Er:GGG microchip laser is a potential compact mid-infrared laser source.

A Comparison of Daily Average Consumption Of Oxycodone Controlled Release (OxyContin CR) And Oxymorphone Extended Release (Opana ER) In Patients With Low Back Pain.

PubMed

Berner, Todd; Thomson, Heather; Hartry, Ann; Puenpatom, R Amy; Ben-Joseph, Rami; Szeinbach, Sheryl L

2011-03-01

Our goal was to examine the daily average consumption (DACON) of oxycodone controlled-release tablets (OxyContin CR)and oxymorphone extended-release tablets (Opana ER) in patients with low back pain. An observational, retrospective cohort study enrolled patients with multiple prescriptions for oxycodone CR or oxymorphone ER tablets. These patients also had International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes for low back pain. Pharmacy prescription medication claims data were obtained from a large commercially insured health plan in the U.S. Mean daily consumption was calculated for a 90-day period. We used descriptive statistics to evaluate patient demographics and health plan characteristics. Univariate analyses were used to examine the data as observed. A generalized linear model with a gamma distribution and log-link function provided a sensitivity measure, adjusting for heterogeneity among patients and the skewed nature of the DACON variable. A total of 4,023 patients received oxycodone CR, and 374 patients received oxymorphone ER. The mean age of patients (standard deviation, SD) was 49.0 (11.6) years for oxycodone CR and 47.3 (10.6) years for oxymorphone ER. DACON of oxycodone CR was 3.2 tablets per day, and DACON of oxymorphone ER was 2.7 tablets per day (P < 0.01). Utilization of maximum-strength tablets of oxycodone CR 80 mg was 3.9 tablets per day, which was significantly higher, by one tablet per day, than the utilization of equipotent oxymorphone ER maximum-strength tablets of 40 mg at 2.9 tablets per day (P < 0.01). The use of oxycodone CR, measured as mean daily consumption over a 90-day period, was significantly higher than that for oxymorphone ER in these patients, a finding that could have financial implications for health care systems.

Engineered Plants as Biosensors

DTIC Science & Technology

2003-05-28

GFP fluorescence was detectable in the lower leaves and especially in the roots of one transgenic plant compared to negative and positive control...mgfp5-er gene, lane 5 contains cDNA from a 35s-mgfp5-er transgenic plant , lanes 6-10 contain cDNAs from gn1/gfp plants. RNA extraction was performed 7...contains transgenic plant sprayed with water (negative control). Lanes 5-12 are independent gn1/gfp transgenic events sprayed with 5 mM BTH. Lanes

Progesterone receptors identified in vascular malformations of the head and neck.

PubMed

Duyka, Landon J; Fan, Chun Y; Coviello-Malle, Jean M; Buckmiller, Lisa; Suen, James Y

2009-10-01

To identify hormone receptors within vascular malformations (arteriovenous malformations [AVMs], venous malformations [VMs], and lymphatic malformations [LMs]) of the head and neck. Immunohistochemical staining for estrogen receptor (ER) and progesterone receptor (PR) was performed on archival vascular malformation tissue collected from both pediatric and adult patients. Tertiary referral center from 2006 to 2008. Twelve AVM, 10 VM, and eight LM specimens were stained for both ER and PR. Ten breast carcinoma specimens were used as controls, with the carcinoma cells serving as positive controls, and the endothelium and smooth muscle cells of the blood vessels serving as negative controls. Five normal supraglottic mucosal samples served as head and neck controls. The Fisher exact test was used for statistical analysis. Ten of the 12 (83%) AVM specimens stained diffusely positive for PR within the nuclei of the endothelium and smooth muscle of the malformed vessels (P < 0.0001). Five of the 10 (50%) VM specimens stained positive for PR (2 [20%] focal, 3 [30%] diffuse) within the nuclei of the endothelium and smooth muscle of the malformed vessels (P = 0.0325). Four of the eight (50%) LM specimens stained focally positive for PR within the nuclei of the endothelium of the malformed vessels (P = 0.0229). None of the vascular malformation specimens stained positive for ER. Our data suggest that PR, but not ER, is expressed in AVMs, VMs, and LMs of the head and neck.

Red shifts of the Eg(1) Raman mode of nanocrystalline TiO2:Er monoliths grown by sol-gel process

NASA Astrophysics Data System (ADS)

Palomino-Merino, R.; Trejo-Garcia, P.; Portillo-Moreno, O.; Jiménez-Sandoval, S.; Tomás, S. A.; Zelaya-Angel, O.; Lozada-Morales, R.; Castaño, V. M.

2015-08-01

Nanocrystalline monoliths of Er doped TiO2 were prepared by the sol-gel technique, by controlling the Er-doping levels into the TiO2 precursor solution. As-prepared and annealed in air samples showed the anatase TiO2 phase. The average diameter of the nanoparticles ranged from 19 to 2.6 nm as the nominal concentration of Er varies from 0% to 7%, as revealed by EDS analysis in an electron microscope. Photo Acoustic Spectroscopy (PAS) allowed calculate the forbidden band gap, evidencing an absorption edge at around 300 nm, attributed to TiO2 and evidence of electronic transitions or Er3+. The Raman spectra, corresponding to the anatase phase, show the main phonon mode Eg(1) band position at 144 cm-1 with a red shift for the annealing samples.

The roles of membranes and associated cytoskeleton in plant virus replication and cell-to-cell movement.

PubMed

Pitzalis, Nicolas; Heinlein, Manfred

2017-12-18

The infection of plants by viruses depends on cellular mechanisms that support the replication of the viral genomes, and the cell-to-cell and systemic movement of the virus via plasmodesmata (PD) and the connected phloem. While the propagation of some viruses requires the conventional endoplasmic reticulum (ER)-Golgi pathway, others replicate and spread between cells in association with the ER and are independent of this pathway. Using selected viruses as examples, this review re-examines the involvement of membranes and the cytoskeleton during virus infection and proposes potential roles of class VIII myosins and membrane-tethering proteins in controlling viral functions at specific ER subdomains, such as cortical microtubule-associated ER sites, ER-plasma membrane contact sites, and PD. © The Author(s) 2017. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Robustness of magnetic and electric domains against charge carrier doping in multiferroic hexagonal ErMnO 3

DOE PAGES

Hassanpour, E.; Wegmayr, V.; Schaab, J.; ...

2016-04-12

We investigate the effect of chemical doping on the electric and magnetic domain pattern in multiferroic hexagonal ErMnO 3 . Hole- and electron doping are achieved through the growth of Er 1-x Ca x MnO 3 and Er 1-x Zr x MnO 3 single crystals, which allows for a controlled introduction of divalent and tetravalent ions, respectively. Using conductance measurements, piezoresponse force microscopy and nonlinear optics we study doping-related variations in the electronic transport and image the corrsponding ferroelectric and antiferromagnetic domains. We find that moderate doping levels allow for adjusting the electronic conduction properties of ErMnO 3 without destroyingmore » its characteristic domain patterns. Our findings demonstrate the feasibility of chemical doping for nonperturbative property-engineering of intrinsic domain states in this important class of multiferroics.« less

Reducing Inpatient Hospital and Emergency Room Utilization Among Nursing Home Residents.

PubMed

Haber, Susan G; Wensky, Suzanne G; McCall, Nancy T

2017-04-01

To examine the association among nursing home residents between strength of relationship with a primary care provider (PCP) and inpatient hospital and emergency room (ER) utilization. Medicare administrative data for beneficiaries residing in a nursing home between July 2007 and June 2009 were used in multivariate analyses controlling for beneficiary, nursing home, and market characteristics to assess the association between two measures-percentage of months with a PCP visit and whether the patient maintained the same usual source of care after nursing home admission-and hospital admissions and ER visits for all causes and for ambulatory care sensitive conditions (ACSCs). Both measures of strength of patient-provider relationships were associated with fewer inpatient admissions and ER visits, except regularity of PCP visits and ACSC ER visits. Policy makers should consider increasing the strength of nursing home resident and PCP relationships as one strategy for reducing inpatient and ER utilization.

Genome-wide screen identifies a novel p97/CDC-48-dependent pathway regulating ER-stress-induced gene transcription

PubMed Central

Marza, Esther; Taouji, Saïd; Barroso, Kim; Raymond, Anne-Aurélie; Guignard, Léo; Bonneu, Marc; Pallares-Lupon, Néstor; Dupuy, Jean-William; Fernandez-Zapico, Martin E; Rosenbaum, Jean; Palladino, Francesca; Dupuy, Denis; Chevet, Eric

2015-01-01

The accumulation of misfolded proteins in the endoplasmic reticulum (ER) activates the Unfolded Protein Response (UPRER) to restore ER homeostasis. The AAA+ ATPase p97/CDC-48 plays key roles in ER stress by promoting both ER protein degradation and transcription of UPRER genes. Although the mechanisms associated with protein degradation are now well established, the molecular events involved in the regulation of gene transcription by p97/CDC-48 remain unclear. Using a reporter-based genome-wide RNAi screen in combination with quantitative proteomic analysis in Caenorhabditis elegans, we have identified RUVB-2, a AAA+ ATPase, as a novel repressor of a subset of UPRER genes. We show that degradation of RUVB-2 by CDC-48 enhances expression of ER stress response genes through an XBP1-dependent mechanism. The functional interplay between CDC-48 and RUVB-2 in controlling transcription of select UPRER genes appears conserved in human cells. Together, these results describe a novel role for p97/CDC-48, whereby its role in protein degradation is integrated with its role in regulating expression of ER stress response genes. PMID:25652260

Pravastatin chitosan nanogels-loaded erythrocytes as a new delivery strategy for targeting liver cancer.

PubMed

Harisa, Gamaleldin I; Badran, Mohamed M; AlQahtani, Saeed A; Alanazi, Fars K; Attia, Sabry M

2016-01-01

Chitosan nanogels (CNG) are developed as one of the most promising carriers for cancer targeting. However, these carriers are rapidly eliminated from circulation by reticuloendothelial system (RES), which limits their application. Therefore, erythrocytes (ER) loaded CNG as multifunctional carrier may overcome the massive elimination of nanocarriers by RES. In this study, erythrocytes loaded pravastatin-chitosan nanogels (PR-CNG-ER) were utilized as a novel drug carrier to target liver cancer. Thus, PR-CNG formula was developed in nanosize, with good entrapment efficiency, drug loading and sustained release over 48 h. Then, PR-CNG loaded into ER were prepared by hypotonic preswelling technique. The resulting PR-CNG-ER showed 36.85% of entrapment efficiency, 66.82% of cell recovery and release consistent to that of hemoglobin over 48 h. Moreover, PR-CNG-ER exhibited negative zeta potential, increasing of hemolysis percent, marked phosphatidylserine exposure and stomatocytes shape compared to control unloaded erythrocytes. PR-CNG-ER reduced cells viability of HepG2 cells line by 28% compared to unloaded erythrocytes (UER). These results concluded that PR-CNG-ER are promising drug carriers to target liver cancer.

Pravastatin chitosan nanogels-loaded erythrocytes as a new delivery strategy for targeting liver cancer

PubMed Central

Harisa, Gamaleldin I.; Badran, Mohamed M.; AlQahtani, Saeed A.; Alanazi, Fars K.; Attia, Sabry M.

2015-01-01

Chitosan nanogels (CNG) are developed as one of the most promising carriers for cancer targeting. However, these carriers are rapidly eliminated from circulation by reticuloendothelial system (RES), which limits their application. Therefore, erythrocytes (ER) loaded CNG as multifunctional carrier may overcome the massive elimination of nanocarriers by RES. In this study, erythrocytes loaded pravastatin–chitosan nanogels (PR–CNG–ER) were utilized as a novel drug carrier to target liver cancer. Thus, PR–CNG formula was developed in nanosize, with good entrapment efficiency, drug loading and sustained release over 48 h. Then, PR–CNG loaded into ER were prepared by hypotonic preswelling technique. The resulting PR–CNG–ER showed 36.85% of entrapment efficiency, 66.82% of cell recovery and release consistent to that of hemoglobin over 48 h. Moreover, PR–CNG–ER exhibited negative zeta potential, increasing of hemolysis percent, marked phosphatidylserine exposure and stomatocytes shape compared to control unloaded erythrocytes. PR–CNG–ER reduced cells viability of HepG2 cells line by 28% compared to unloaded erythrocytes (UER). These results concluded that PR–CNG–ER are promising drug carriers to target liver cancer. PMID:26903771

The role of endoplasmic reticulum stress and insulin resistance in the occurrence of goose fatty liver.

PubMed

Geng, Tuoyu; Xia, Lili; Li, Fuyuan; Xia, Jing; Zhang, Yihui; Wang, Qianqian; Yang, Biao; Montgomery, Sean; Cui, Hengmi; Gong, Daoqing

2015-09-11

In mammals, insulin resistance (IR) is required for the occurrence of non-alcoholic fatty liver disease, and endoplasmic reticulum stress (ERS) contributes to IR. As geese have physiological and metabolic characteristics different from mammals, it is unclear whether these mechanisms also underlie the occurrence of goose fatty liver. To address this, 70-day-old geese were treated with an ERS inducer or overfed, and variables associated with ERS or IR were subsequently determined. The data indicated that the group of geese treated with the ERS inducer for 20d appeared to be more intolerant to blood glucose than the control group, and their livers showed features of hepatic steatosis, suggesting ERS can induce IR and hepatic steatosis in geese. In contrast, overfeeding did not induce ERS, probably due to the upregulated expression of fatty acid desaturases, but induced higher fasting/postprandial blood glucose as well as glucose intolerance in geese, which was accompanied by a dramatic increase of liver weight. Taken together, these findings delineated the role of ERS and IR in the occurrence of goose fatty liver. Copyright © 2015 Elsevier Inc. All rights reserved.

Abuse and Diversion of Immediate Release Opioid Analgesics as Compared to Extended Release Formulations in the United States

PubMed Central

Iwanicki, Janetta L.; Severtson, S. Geoff; McDaniel, Heather; Rosenblum, Andrew; Fong, Chunki; Cicero, Theodore J.; Ellis, Matthew S.; Kurtz, Steven P.; Buttram, Mance E.; Dart, Richard C.

2016-01-01

Background Therapeutic use and abuse of prescription opioids in the United States increased substantially between 1990 and 2010. The Centers for Disease Control estimated deaths related to pharmaceutical opioids reached nearly 19,000 in 2014. Of prescription opioids sold, 10% are extended release (ER) and 90% immediate release (IR). However, most regulations and interventions have focused on decreasing ER abuse. Our objective was to compare rates of abuse and diversion of ER and IR opioid analgesics over time using multiple surveillance programs. Methods Rates of abuse and diversion of ER and IR opioid formulations were compared using data from four surveillance programs in the Researched Abuse, Diversion and Addiction Related Surveillance (RADARS®) System. Data were evaluated from 2009 through 2015, and Poisson regression used to compare IR and ER opioid cases over time. Results From 2009 to 2015, IR opioids were prescribed at a rate 12 to 16 times higher than ER. In the Poison Center Program, population-adjusted rates of Intentional Abuse for IR were 4.6 fold higher than ER opioids (p<0.001). In the Drug Diversion Program, population-adjusted rates of diversion were 6.1 fold higher for IR than ER opioids (p<0.001). In the Opioid Treatment Program, population-adjusted rates of endorsements for abuse were 1.6 fold higher for IR opioids than ER (p = 0.002). In the Survey of Key Informants' Patients Program, population-adjusted rates of endorsements for abuse were 1.5 fold higher for IR opioids than ER (p<0.001). Conclusions Between 2009 and 2015, IR opioids were prescribed at a much higher rate than ER opioids. Results from four surveillance programs show population-adjusted rates of prescription opioid abuse were markedly higher for IR than ER medications. For the greatest public health benefit, future interventions to decrease prescription opioid abuse should focus on both IR and ER formulations. PMID:27936038

Abuse and Diversion of Immediate Release Opioid Analgesics as Compared to Extended Release Formulations in the United States.

PubMed

Iwanicki, Janetta L; Severtson, S Geoff; McDaniel, Heather; Rosenblum, Andrew; Fong, Chunki; Cicero, Theodore J; Ellis, Matthew S; Kurtz, Steven P; Buttram, Mance E; Dart, Richard C

2016-01-01

Therapeutic use and abuse of prescription opioids in the United States increased substantially between 1990 and 2010. The Centers for Disease Control estimated deaths related to pharmaceutical opioids reached nearly 19,000 in 2014. Of prescription opioids sold, 10% are extended release (ER) and 90% immediate release (IR). However, most regulations and interventions have focused on decreasing ER abuse. Our objective was to compare rates of abuse and diversion of ER and IR opioid analgesics over time using multiple surveillance programs. Rates of abuse and diversion of ER and IR opioid formulations were compared using data from four surveillance programs in the Researched Abuse, Diversion and Addiction Related Surveillance (RADARS®) System. Data were evaluated from 2009 through 2015, and Poisson regression used to compare IR and ER opioid cases over time. From 2009 to 2015, IR opioids were prescribed at a rate 12 to 16 times higher than ER. In the Poison Center Program, population-adjusted rates of Intentional Abuse for IR were 4.6 fold higher than ER opioids (p<0.001). In the Drug Diversion Program, population-adjusted rates of diversion were 6.1 fold higher for IR than ER opioids (p<0.001). In the Opioid Treatment Program, population-adjusted rates of endorsements for abuse were 1.6 fold higher for IR opioids than ER (p = 0.002). In the Survey of Key Informants' Patients Program, population-adjusted rates of endorsements for abuse were 1.5 fold higher for IR opioids than ER (p<0.001). Between 2009 and 2015, IR opioids were prescribed at a much higher rate than ER opioids. Results from four surveillance programs show population-adjusted rates of prescription opioid abuse were markedly higher for IR than ER medications. For the greatest public health benefit, future interventions to decrease prescription opioid abuse should focus on both IR and ER formulations.

Disruption of Protein Processing in the Endoplasmic Reticulum of DYT1 Knock-in Mice Implicates Novel Pathways in Dystonia Pathogenesis.

PubMed

Beauvais, Genevieve; Bode, Nicole M; Watson, Jaime L; Wen, Hsiang; Glenn, Kevin A; Kawano, Hiroyuki; Harata, N Charles; Ehrlich, Michelle E; Gonzalez-Alegre, Pedro

2016-10-05

Dystonia type 1 (DYT1) is a dominantly inherited neurological disease caused by mutations in TOR1A, the gene encoding the endoplasmic reticulum (ER)-resident protein torsinA. Previous work mostly completed in cell-based systems suggests that mutant torsinA alters protein processing in the secretory pathway. We hypothesized that inducing ER stress in the mammalian brain in vivo would trigger or exacerbate mutant torsinA-induced dysfunction. To test this hypothesis, we crossed DYT1 knock-in with p58(IPK)-null mice. The ER co-chaperone p58(IPK) interacts with BiP and assists in protein maturation by helping to fold ER cargo. Its deletion increases the cellular sensitivity to ER stress. We found a lower generation of DYT1 knock-in/p58 knock-out mice than expected from this cross, suggesting a developmental interaction that influences viability. However, surviving animals did not exhibit abnormal motor function. Analysis of brain tissue uncovered dysregulation of eiF2α and Akt/mTOR translational control pathways in the DYT1 brain, a finding confirmed in a second rodent model and in human brain. Finally, an unbiased proteomic analysis identified relevant changes in the neuronal protein landscape suggesting abnormal ER protein metabolism and calcium dysregulation. Functional studies confirmed the interaction between the DYT1 genotype and neuronal calcium dynamics. Overall, these findings advance our knowledge on dystonia, linking translational control pathways and calcium physiology to dystonia pathogenesis and identifying potential new pharmacological targets. Dystonia type 1 (DYT1) is one of the different forms of inherited dystonia, a neurological disorder characterized by involuntary, disabling movements. DYT1 is caused by mutations in the gene that encodes the endoplasmic reticulum (ER)-resident protein torsinA. How mutant torsinA causes neuronal dysfunction remains unknown. Here, we show the behavioral and molecular consequences of stressing the ER in DYT1 mice by increasing the amount of misfolded proteins. This resulted in the generation of a reduced number of animals, evidence of abnormal ER protein processing and dysregulation of translational control pathways. The work described here proposes a shared mechanism for different forms of dystonia, links for the first time known biological pathways to dystonia pathogenesis, and uncovers potential pharmacological targets for its treatment. Copyright © 2016 the authors 0270-6474/16/3610245-12$15.00/0.

Emotion regulation choice in female patients with borderline personality disorder: Findings from self-reports and experimental measures.

PubMed

Sauer, Christina; Sheppes, Gal; Lackner, Helmut Karl; Arens, Elisabeth A; Tarrasch, Ricardo; Barnow, Sven

2016-08-30

Emotion dysregulation is a core feature of borderline personality disorder (BPD). So far, many studies have tested the consequences of the implementation of certain emotion regulation (ER) strategies, but there have been no investigations about ER choices in BPD. Thus, the aim of this study was to investigate habitual ER choices by self-report questionnaires and experimentally by testing the preference to select between distraction and reappraisal when facing different emotional intensities (high vs. low) and contents (borderline-specific vs. unspecific negative) in patients with BPD (n=24) compared with clinical controls (patients with major depression, n=19) and a healthy control group (n=32). Additionally, heart rate (HR) responses were continuously assessed. Main results revealed that both patient groups showed maladaptive self-reported ER choice profiles compared with HC. We found, however, no differences between the groups in the choice of distraction and reappraisal on the behavioral level and in HR responses. In BPD, within-group analyses revealed a positive correlation between symptom severity and the preference for distraction under high-intensity borderline-specific stimuli. Our findings provide preliminary evidence of ER choices in BPD and show the robustness of the choice effect in patients with affective disorders. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Estrogen and Thyroid Hormone Receptor Activation by Medicinal Plants from Bahia, Brazil

PubMed Central

da Silva, Magnus Régios Dias; Costa, Silvia Lima; Velozo, Eudes da Silva

2018-01-01

Background: A number of medicinal plants are traditionally used for metabolic disorders in Bahia state, Brazil. The aim of this study was to evaluate the estrogen receptor (ER) and thyroid receptor (TR) activation of crude extracts prepared from 20 plants. Methods: Species were extracted and assayed for receptor activation through both ER and TR gene-reporter assays, using 17β-estradiol and triiodothyronine (T3), respectively, as the positive controls. Results: Cajanus cajan (Fabaceae), Abarema cochliacarpus (Fabaceae), and Borreria verticillata (Rubiaceae) were able to activate ER as much as the positive control (17β-estradiol). These three plant species were also assayed for TR activation. At the concentration of 50 µg/mL, C. cajans exerted the highest positive modulation on TR, causing an activation of 59.9%, while B. verticillata and A. cochliacarpus caused 30.8% and 23.3%, respectively. Conclusions: Our results contribute towards the validation of the traditional use of C. cajans, B. verticillata, and A. cochliacarpus in the treatment of metabolic disorders related to ER and TR functions. The gene-reporter assay was proven effective in screening crude plant extracts for ER/TR activation, endorsing this methodology as an important tool for future bioprospection studies focused on identifying novel starting molecules for the development of estrogen and thyroid agonists. PMID:29342924

Important Role of Menarche in Development of Estrogen Receptor-Negative Breast Cancer in African American Women.

PubMed

Ambrosone, Christine B; Zirpoli, Gary; Hong, Chi-Chen; Yao, Song; Troester, Melissa A; Bandera, Elisa V; Schedin, Pepper; Bethea, Traci N; Borges, Virginia; Park, Song-Yi; Chandra, Dhyan; Rosenberg, Lynn; Kolonel, Laurence N; Olshan, Andrew F; Palmer, Julie R

2015-09-01

Menarche is a critical time point for diverging fates of mammary cells of origin. African American women have young age at menarche, which could be associated with their high rates of estrogen receptor-negative (ER-) breast cancer. In the AMBER Consortium, using harmonized data from 4426 African American women with breast cancer and 17 474 controls, we used polytomous logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for ages at menarche and first live birth (FLB), and the interval between, in relation to ER+ and ER- breast cancer. All statistical tests were two-sided. Risk of ER- breast cancer was reduced with later age at menarche among both parous and nulliparous women (≥15 vs <11 years OR = 0.62, 95% CI = 0.48 to 0.81 and OR = 0.56, 95% CI = 0.29 to 1.10, respectively), with no effect of age at FLB. For ER+ breast cancer, the inverse association was weaker among nulliparous women. While longer intervals between menarche and FLB were associated with increased risk of ER+ breast cancer in a dose-response fashion (OR for 20 year interval = 1.39, 95% CI = 1.08 to 1.79, P trend = .003), ER- risk was only increased for intervals up to 14 years and not beyond (P trend = .33). While ER- breast cancer risk was markedly reduced in women with a late age at menarche, there was not a clear pattern of increased risk with longer interval between menarche and FLB, as was observed for ER+ breast cancer. These findings indicate that etiologic pathways involving adolescence and pregnancy may differ for ER- and ER+ breast cancer. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Controls on ecosystem and root respiration across a permafrost and wetland gradient in interior Alaska

USGS Publications Warehouse

McConnell, Nicole A.; Turetsky, Merritt R.; McGuire, A. David; Kane, Evan S.; Waldrop, Mark P.; Harden, Jennifer W.

2013-01-01

Permafrost is common to many northern wetlands given the insulation of thick organic soil layers, although soil saturation in wetlands can lead to warmer soils and increased thaw depth. We analyzed five years of soil CO2 fluxes along a wetland gradient that varied in permafrost and soil moisture conditions. We predicted that communities with permafrost would have reduced ecosystem respiration (ER) but greater temperature sensitivity than communities without permafrost. These predictions were partially supported. The colder communities underlain by shallow permafrost had lower ecosystem respiration (ER) than communities with greater active layer thickness. However, the apparent Q10 of monthly averaged ER was similar in most of the vegetation communities except the rich fen, which had smaller Q10 values. Across the gradient there was a negative relationship between water table position and apparent Q10, showing that ER was more temperature sensitive under drier soil conditions. We explored whether root respiration could account for differences in ER between two adjacent communities (sedge marsh and rich fen), which corresponded to the highest and lowest ER, respectively. Despite differences in root respiration rates, roots contributed equally (~40%) to ER in both communities. Also, despite similar plant biomass, ER in the rich fen was positively related to root biomass, while ER in the sedge marsh appeared to be related more to vascular green area. Our results suggest that ER across this wetland gradient was temperature-limited, until conditions became so wet that respiration became oxygen-limited and influenced less by temperature. But even in sites with similar hydrology and thaw depth, ER varied significantly likely based on factors such as soil redox status and vegetation composition.

Volumetric laser endomicroscopy in Barrett's esophagus: a feasibility study on histological correlation.

PubMed

Swager, A; Boerwinkel, D F; de Bruin, D M; Weusten, B L; Faber, D J; Meijer, S L; van Leeuwen, T G; Curvers, W L; Bergman, J J

2016-08-01

Volumetric laser endomicroscopy (VLE) is a novel balloon-based optical coherence tomography (OCT) imaging technique that may improve detection of early neoplasia in Barrett's esophagus (BE). Most OCT studies lack a direct correlation between histology and OCT images. The aim is to investigate the optimal approach for achieving one-to-one correlation of ex-vivo VLE images of endoscopic resection (ER) specimens with histology. BE patients with and without early neoplasia underwent ER after delineating areas with electrocoagulation markers (ECM). After ER, specimens underwent additional ex-vivo marking with several different markers (ink, pin, Gold Probe) followed by ex-vivo VLE scanning. ER specimens were carefully sectioned into tissue blocks guided by the markers. Histology and VLE slides were considered a match if ≥ 2 markers were visible on both modalities and mucosal patterns aside from these markers matched on both histology and VLE. From 16 ER specimens 120 tissue blocks were sectioned of which 23 contained multiple markers. Fourteen histology-VLE matches were identified. ECMs and ink markers proved to be the most effective combination for matching. The last 6/16 ER specimens yielded 9/14 matches, demonstrating a learning curve due to methodological improvements in marker placement and tissue block sectioning. One-to-one correlation of VLE and histology is complex but feasible. The groundwork laid in this study will provide high-quality histology-VLE correlations that will allow further research on VLE features of early neoplasia in BE. © 2015 International Society for Diseases of the Esophagus.

The AVIRIS Low Altitude Option-An Approach to Increase Geometric Resolution and Improve Operational Flexibility Simultaneously

NASA Technical Reports Server (NTRS)

Sarture, Charles M.; Chovit, Christopher J.; Chrien, Thomas G.; Eastwood, Michael L.; Green, Robert O.; Kurzwell, Charles G.

1998-01-01

From 1987 through 1997 the Airborne Visible-InfraRed Imaging Spectrometer has matured into a remote sensing instrument capable of producing prodigious amounts of high quality data. Using the NASA/Ames ER-2 high altitude aircraft platform, flight operations have become very reliable as well. Being exclusively dependent on the ER-2, however, has limitations: the ER-2 has a narrow cruise envelope which fixes the AVIRIS ground pixel at 20 meters; it requires a significant support infrastructure; and it has a very limited number of bases it can operate from. In the coming years, the ER-2 will also become less available for AVIRIS flights as NASA Earth Observing System satellite underflights increase. Adapting AVIRIS to lower altitude, less specialized aircraft will create a much broader envelope for data acquisition, i.e., higher ground geometric resolution while maintaining nearly the ideal spatial sampling. This approach will also greatly enhance flexibility while decreasing the overall cost of flight operations and field support. Successful adaptation is expected to culminate with a one-month period of demonstration flights.

Frequency and reliability of oestrogen receptor, progesterone receptor and HER2 in breast carcinoma determined by immunohistochemistry in Australasia: results of the RCPA Quality Assurance Program

PubMed Central

Francis, Glenn D; Dimech, Margaret; Giles, Leanne; Hopkins, Alison

2007-01-01

Background and Aims Immunohistochemistry (IHC) has replaced radioligand binding assay for the determination of oestrogen receptor (ER) status in breast carcinoma. IHC is also used for assessment of progesterone receptor (PR) and HER2. The Royal College of Pathologists of Australasia (RCPA) Quality Assurance Program (QAP) introduced a breast markers module in 2003 to evaluate the performance of laboratories with IHC for ER, PR and HER2. Methods An audit of laboratories reporting breast carcinomas was performed in 2005 and 2006 to evaluate in‐house results. Laboratories were asked to submit the hormone receptor and HER2 status on each invasive breast carcinoma for the previous 6 month period up to a maximum of 100 cases. The time periods were 1 July 2004 to 31 December 2004, and 1 July 2005 to 31 December 2005. A total of 55 laboratories returned information for 2004 and 67 for 2005. Results Complete data on 8128 patients was returned for both surveys, 3353 cases for 2004 and 4775 for 2005. The results were similar for both surveys. Of the 8128 cases, 59.0% were ER+/PR+, 15.9% ER+/PR−, 2.4% ER−/PR+ and 22.7% ER−/PR−. HER2 data were submitted for a total of 6512 patients (excludes 52 patients with incomplete data sets); 17.1% were reported as 3+ positive on IHC, 12.5% as 2+ and 70.4% as negative. Conclusions A laboratory audit was introduced into the RCPA QAP for breast markers due to concerns raised by participating laboratories about technical differences in supplied tissues for testing. This audit indicates that overall the results for ER, PR and HER2 fall inside established parameters. However, a number of individual laboratories do not meet the target values and variation in results would impact on patient treatment decisions. PMID:17259294

Plasma carotenoids, vitamin C, tocopherols, and retinol and the risk of breast cancer in the European Prospective Investigation into Cancer and Nutrition cohort.

PubMed

Bakker, Marije F; Peeters, Petra Hm; Klaasen, Veronique M; Bueno-de-Mesquita, H Bas; Jansen, Eugene Hjm; Ros, Martine M; Travier, Noémie; Olsen, Anja; Tjønneland, Anne; Overvad, Kim; Rinaldi, Sabina; Romieu, Isabelle; Brennan, Paul; Boutron-Ruault, Marie-Christine; Perquier, Florence; Cadeau, Claire; Boeing, Heiner; Aleksandrova, Krasimira; Kaaks, Rudolf; Kühn, Tilman; Trichopoulou, Antonia; Lagiou, Pagona; Trichopoulos, Dimitrios; Vineis, Paolo; Krogh, Vittorio; Panico, Salvatore; Masala, Giovanna; Tumino, Rosario; Weiderpass, Elisabete; Skeie, Guri; Lund, Eiliv; Quirós, J Ramón; Ardanaz, Eva; Navarro, Carmen; Amiano, Pilar; Sánchez, María-José; Buckland, Genevieve; Ericson, Ulrika; Sonestedt, Emily; Johansson, Matthias; Sund, Malin; Travis, Ruth C; Key, Timothy J; Khaw, Kay-Tee; Wareham, Nick; Riboli, Elio; van Gils, Carla H

2016-02-01

Carotenoids and vitamin C are thought to be associated with reduced cancer risk because of their antioxidative capacity. This study evaluated the associations of plasma carotenoid, retinol, tocopherol, and vitamin C concentrations and risk of breast cancer. In a nested case-control study within the European Prospective Investigation into Cancer and Nutrition cohort, 1502 female incident breast cancer cases were included, with an oversampling of premenopausal (n = 582) and estrogen receptor-negative (ER-) cases (n = 462). Controls (n = 1502) were individually matched to cases by using incidence density sampling. Prediagnostic samples were analyzed for α-carotene, β-carotene, lycopene, lutein, zeaxanthin, β-cryptoxanthin, retinol, α-tocopherol, γ-tocopherol, and vitamin C. Breast cancer risk was computed according to hormone receptor status and age at diagnosis (proxy for menopausal status) by using conditional logistic regression and was further stratified by smoking status, alcohol consumption, and body mass index (BMI). All statistical tests were 2-sided. In quintile 5 compared with quintile 1, α-carotene (OR: 0.61; 95% CI: 0.39, 0.98) and β-carotene (OR: 0.41; 95% CI: 0.26, 0.65) were inversely associated with risk of ER- breast tumors. The other analytes were not statistically associated with ER- breast cancer. For estrogen receptor-positive (ER+) tumors, no statistically significant associations were found. The test for heterogeneity between ER- and ER+ tumors was statistically significant only for β-carotene (P-heterogeneity = 0.03). A higher risk of breast cancer was found for retinol in relation to ER-/progesterone receptor-negative tumors (OR: 2.37; 95% CI: 1.20, 4.67; P-heterogeneity with ER+/progesterone receptor positive = 0.06). We observed no statistically significant interaction between smoking, alcohol, or BMI and all investigated plasma analytes (based on tertile distribution). Our results indicate that higher concentrations of plasma β-carotene and α-carotene are associated with lower breast cancer risk of ER- tumors. © 2016 American Society for Nutrition.

Lung cancer and diesel exhaust: an updated critical review of the occupational epidemiology literature.

PubMed

Gamble, John F; Nicolich, Mark J; Boffetta, Paolo

2012-08-01

A recent review concluded that the evidence from epidemiology studies was indeterminate and that additional studies were required to support the diesel exhaust-lung cancer hypothesis. This updated review includes seven recent studies. Two population-based studies concluded that significant exposure-response (E-R) trends between cumulative diesel exhaust and lung cancer were unlikely to be entirely explained by bias or confounding. Those studies have quality data on life-style risk factors, but do not allow definitive conclusions because of inconsistent E-R trends, qualitative exposure estimates and exposure misclassification (insufficient latency based on job title), and selection bias from low participation rates. Non-definitive results are consistent with the larger body of population studies. An NCI/NIOSH cohort mortality and nested case-control study of non-metal miners have some surrogate-based quantitative diesel exposure estimates (including highest exposure measured as respirable elemental carbon (REC) in the workplace) and smoking histories. The authors concluded that diesel exhaust may cause lung cancer. Nonetheless, the results are non-definitive because the conclusions are based on E-R patterns where high exposures were deleted to achieve significant results, where a posteriori adjustments were made to augment results, and where inappropriate adjustments were made for the "negative confounding" effects of smoking even though current smoking was not associated with diesel exposure and therefore could not be a confounder. Three cohort studies of bus drivers and truck drivers are in effect air pollution studies without estimates of diesel exhaust exposure and so are not sufficient for assessing the lung cancer-diesel exhaust hypothesis. Results from all occupational cohort studies with quantitative estimates of exposure have limitations, including weak and inconsistent E-R associations that could be explained by bias, confounding or chance, exposure misclassification, and often inadequate latency. In sum, the weight of evidence is considered inadequate to confirm the diesel-lung cancer hypothesis.

Defective cellular trafficking of the bone morphogenetic protein receptor type II by mutations underlying familial pulmonary arterial hypertension.

PubMed

John, Anne; Kizhakkedath, Praseetha; Al-Gazali, Lihadh; Ali, Bassam R

2015-04-25

Familial pulmonary arterial hypertension (FPAH) is a relatively rare but fatal disorder characterized by elevated arterial pressure caused by abnormal proliferation of endothelial cells of the arteries, which eventually leads to heart failure and death. FPAH is inherited as an autosomal dominant trait and is caused by heterozygous mutations in the BMPR2 gene encoding the bone morphogenetic protein type II receptor (BMPR2). BMPR2 belongs to the TGF β/BMP super-family of receptors involved in a signal transduction cascade via the SMAD signaling pathway. The BMPR2 polypeptide is composed of 1038 amino acids and consists of a ligand binding domain, a kinase domain and a cytoplasmic tail. To investigate the cellular and functional consequence of BMPR2 mutations, C-terminally FLAG-tagged constructs of eighteen pathogenic BMPR2 missense mutants were generated by site directed mutagenesis and expressed in HeLa and HEK-293T cell lines. The subcellular localizations of the mutant proteins were investigated using immunostaining and confocal microscopy. Post-translational modifications of the proteins were analyzed by Endoglycosidase H deglycosylation assay. Our results indicated that mutations in the ligand binding domain affecting highly conserved cysteine residues resulted in retention of the mutant proteins in the endoplasmic reticulum (ER), as evident from their co-localization with the ER resident protein calnexin. The kinase domain mutants showed both ER and plasma membrane (PM) distributions, while the cytoplasmic tail domain variants were localized exclusively to the PM. The subcellular localizations of the mutants were further confirmed by their characteristic glycosylation profiles. In conclusion, our results indicate that ER quality control (ERQC) is involved in the pathological mechanism of several BMPR2 receptor missense mutations causing FPAH, which can be explored as a potential therapeutic target in the future. Copyright © 2015. Published by Elsevier B.V.

Role of cleavage at the core-E1 junction of hepatitis C virus polyprotein in viral morphogenesis.

PubMed

Pène, Véronique; Lemasson, Matthieu; Harper, Francis; Pierron, Gérard; Rosenberg, Arielle R

2017-01-01

In hepatitis C virus (HCV) polyprotein sequence, core protein terminates with E1 envelope signal peptide. Cleavage by signal peptidase (SP) separates E1 from the complete form of core protein, anchored in the endoplasmic reticulum (ER) membrane by the signal peptide. Subsequent cleavage of the signal peptide by signal-peptide peptidase (SPP) releases the mature form of core protein, which preferentially relocates to lipid droplets. Both of these cleavages are required for the HCV infectious cycle, supporting the idea that HCV assembly begins at the surface of lipid droplets, yet SPP-catalyzed cleavage is dispensable for initiation of budding in the ER. Here we have addressed at what step(s) of the HCV infectious cycle SP-catalyzed cleavage at the core-E1 junction is required. Taking advantage of the sole system that has allowed visualization of HCV budding events in the ER lumen of mammalian cells, we showed that, unexpectedly, mutations abolishing this cleavage did not prevent but instead tended to promote the initiation of viral budding. Moreover, even though no viral particles were released from Huh-7 cells transfected with a full-length HCV genome bearing these mutations, intracellular viral particles containing core protein protected by a membrane envelope were formed. These were visualized by electron microscopy as capsid-containing particles with a diameter of about 70 nm and 40 nm before and after delipidation, respectively, comparable to intracellular wild-type particle precursors except that they were non-infectious. Thus, our results show that SP-catalyzed cleavage is dispensable for HCV budding per se, but is required for the viral particles to acquire their infectivity and secretion. These data support the idea that HCV assembly occurs in concert with budding at the ER membrane. Furthermore, capsid-containing particles did not accumulate in the absence of SP-catalyzed cleavage, suggesting the quality of newly formed viral particles is controlled before secretion.

Role of cleavage at the core-E1 junction of hepatitis C virus polyprotein in viral morphogenesis

PubMed Central

Pène, Véronique; Lemasson, Matthieu; Harper, Francis; Pierron, Gérard; Rosenberg, Arielle R.

2017-01-01

In hepatitis C virus (HCV) polyprotein sequence, core protein terminates with E1 envelope signal peptide. Cleavage by signal peptidase (SP) separates E1 from the complete form of core protein, anchored in the endoplasmic reticulum (ER) membrane by the signal peptide. Subsequent cleavage of the signal peptide by signal-peptide peptidase (SPP) releases the mature form of core protein, which preferentially relocates to lipid droplets. Both of these cleavages are required for the HCV infectious cycle, supporting the idea that HCV assembly begins at the surface of lipid droplets, yet SPP-catalyzed cleavage is dispensable for initiation of budding in the ER. Here we have addressed at what step(s) of the HCV infectious cycle SP-catalyzed cleavage at the core-E1 junction is required. Taking advantage of the sole system that has allowed visualization of HCV budding events in the ER lumen of mammalian cells, we showed that, unexpectedly, mutations abolishing this cleavage did not prevent but instead tended to promote the initiation of viral budding. Moreover, even though no viral particles were released from Huh-7 cells transfected with a full-length HCV genome bearing these mutations, intracellular viral particles containing core protein protected by a membrane envelope were formed. These were visualized by electron microscopy as capsid-containing particles with a diameter of about 70 nm and 40 nm before and after delipidation, respectively, comparable to intracellular wild-type particle precursors except that they were non-infectious. Thus, our results show that SP-catalyzed cleavage is dispensable for HCV budding per se, but is required for the viral particles to acquire their infectivity and secretion. These data support the idea that HCV assembly occurs in concert with budding at the ER membrane. Furthermore, capsid-containing particles did not accumulate in the absence of SP-catalyzed cleavage, suggesting the quality of newly formed viral particles is controlled before secretion. PMID:28437468

Lung cancer and diesel exhaust: an updated critical review of the occupational epidemiology literature

PubMed Central

Gamble, John F.; Nicolich, Mark J.; Boffetta, Paolo

2012-01-01

A recent review concluded that the evidence from epidemiology studies was indeterminate and that additional studies were required to support the diesel exhaust-lung cancer hypothesis. This updated review includes seven recent studies. Two population-based studies concluded that significant exposure-response (E-R) trends between cumulative diesel exhaust and lung cancer were unlikely to be entirely explained by bias or confounding. Those studies have quality data on life-style risk factors, but do not allow definitive conclusions because of inconsistent E-R trends, qualitative exposure estimates and exposure misclassification (insufficient latency based on job title), and selection bias from low participation rates. Non-definitive results are consistent with the larger body of population studies. An NCI/NIOSH cohort mortality and nested case-control study of non-metal miners have some surrogate-based quantitative diesel exposure estimates (including highest exposure measured as respirable elemental carbon (REC) in the workplace) and smoking histories. The authors concluded that diesel exhaust may cause lung cancer. Nonetheless, the results are non-definitive because the conclusions are based on E-R patterns where high exposures were deleted to achieve significant results, where a posteriori adjustments were made to augment results, and where inappropriate adjustments were made for the “negative confounding” effects of smoking even though current smoking was not associated with diesel exposure and therefore could not be a confounder. Three cohort studies of bus drivers and truck drivers are in effect air pollution studies without estimates of diesel exhaust exposure and so are not sufficient for assessing the lung cancer-diesel exhaust hypothesis. Results from all occupational cohort studies with quantitative estimates of exposure have limitations, including weak and inconsistent E-R associations that could be explained by bias, confounding or chance, exposure misclassification, and often inadequate latency. In sum, the weight of evidence is considered inadequate to confirm the diesel-lung cancer hypothesis. PMID:22656672

Optically-controlled extinction ratio and Q-factor tunable silicon microring resonators based on optical forces

NASA Astrophysics Data System (ADS)

Long, Yun; Wang, Jian

2014-06-01

Tunability is a desirable property of microring resonators to facilitate superior performance. Using light to control light, we present an alternative simple approach to tuning the extinction ratio (ER) and Q-factor of silicon microring resonators based on optical forces. We design an opto-mechanical tunable silicon microring resonator consisting of an add-drop microring resonator and a control-light-carrying waveguide (``controlling'' waveguide). One of the two bus waveguides of the microring resonator is a deformable nanostring put in parallel with the ``controlling'' waveguide. The tuning mechanism relies on the optical force induced deflection of suspended nanostring, leading to the change of coupling coefficient of microring and resultant tuning of ER and Q-factor. Two possible geometries, i.e. double-clamped nanostring and cantilever nanostring, are studied in detail for comparison. The obtained results imply a favorable structure with the microring positioned at the end of the cantilever nanostring. It features a wide tuning range of ER from 5.6 to 39.9 dB and Q-factor from 309 to 639 as changing the control power from 0 to 1.4 mW.

A comparison of two adaptive algorithms for the control of active engine mounts

NASA Astrophysics Data System (ADS)

Hillis, A. J.; Harrison, A. J. L.; Stoten, D. P.

2005-08-01

This paper describes work conducted in order to control automotive active engine mounts, consisting of a conventional passive mount and an internal electromagnetic actuator. Active engine mounts seek to cancel the oscillatory forces generated by the rotation of out-of-balance masses within the engine. The actuator generates a force dependent on a control signal from an algorithm implemented with a real-time DSP. The filtered-x least-mean-square (FXLMS) adaptive filter is used as a benchmark for comparison with a new implementation of the error-driven minimal controller synthesis (Er-MCSI) adaptive controller. Both algorithms are applied to an active mount fitted to a saloon car equipped with a four-cylinder turbo-diesel engine, and have no a priori knowledge of the system dynamics. The steady-state and transient performance of the two algorithms are compared and the relative merits of the two approaches are discussed. The Er-MCSI strategy offers significant computational advantages as it requires no cancellation path modelling. The Er-MCSI controller is found to perform in a fashion similar to the FXLMS filter—typically reducing chassis vibration by 50-90% under normal driving conditions.

Control of an ER haptic master in a virtual slave environment for minimally invasive surgery applications

NASA Astrophysics Data System (ADS)

Han, Young-Min; Choi, Seung-Bok

2008-12-01

This paper presents the control performance of an electrorheological (ER) fluid-based haptic master device connected to a virtual slave environment that can be used for minimally invasive surgery (MIS). An already developed haptic joint featuring controllable ER fluid and a spherical joint mechanism is adopted for the master system. Medical forceps and an angular position measuring device are devised and integrated with the joint to establish the MIS master system. In order to embody a human organ in virtual space, a volumetric deformable object is used. The virtual object is then mathematically formulated by a shape-retaining chain-linked (S-chain) model. After evaluating the reflection force, computation time and compatibility with real-time control, the haptic architecture for MIS is established by incorporating the virtual slave with the master device so that the reflection force for the object of the virtual slave and the desired position for the master operator are transferred to each other. In order to achieve the desired force trajectories, a sliding mode controller is formulated and then experimentally realized. Tracking control performances for various force trajectories are evaluated and presented in the time domain.

The ER membrane insertase Get1/2 is required for efficient mitophagy in yeast.

PubMed

Onishi, Mashun; Nagumo, Sachiyo; Iwashita, Shohei; Okamoto, Koji

2018-05-10

Mitophagy is an evolutionarily conserved autophagy pathway that selectively eliminates mitochondria to control mitochondrial quality and quantity. Although mitophagy is thought to be crucial for cellular homeostasis, how this catabolic process is regulated remains largely unknown. Here we demonstrate that mitophagy during prolonged respiratory growth is strongly impaired in yeast cells lacking Get1/2, a transmembrane complex mediating insertion of tail-anchored (TA) proteins into the endoplasmic reticulum (ER) membrane. Under the same conditions, loss of Get1/2 caused only slight defects in other types of selective and bulk autophagy. In addition, mitophagy and other autophagy-related processes are mostly normal in cells lacking Get3, a cytosolic ATP-driven chaperone that promotes delivery of TA proteins to the Get1/2 complex. We also found that Get1/2-deficient cells exhibited wildtype-like induction and mitochondrial localization of Atg32, a protein essential for mitophagy. Notably, Get1/2 is important for Atg32-independent, ectopically promoted mitophagy. Together, we propose that Get1/2-dependent TA protein(s) and/or the Get1/2 complex itself may act specifically in mitophagy. Copyright © 2018 Elsevier Inc. All rights reserved.

Analysis of ER–mitochondria contacts using correlative fluorescence microscopy and soft X-ray tomography of mammalian cells

PubMed Central

Elgass, Kirstin D.; Smith, Elizabeth A.; LeGros, Mark A.; Larabell, Carolyn A.; Ryan, Michael T.

2015-01-01

ABSTRACT Mitochondrial fission is important for organelle transport, quality control and apoptosis. Changes to the fission process can result in a wide variety of neurological diseases. In mammals, mitochondrial fission is executed by the GTPase dynamin-related protein 1 (Drp1; encoded by DNM1L), which oligomerizes around mitochondria and constricts the organelle. The mitochondrial outer membrane proteins Mff, MiD49 (encoded by MIEF2) and MiD51 (encoded by MIEF1) are involved in mitochondrial fission by recruiting Drp1 from the cytosol to the organelle surface. In addition, endoplasmic reticulum (ER) tubules have been shown to wrap around and constrict mitochondria before a fission event. Up to now, the presence of MiD49 and MiD51 at ER–mitochondrial division foci has not been established. Here, we combine confocal live-cell imaging with correlative cryogenic fluorescence microscopy and soft x-ray tomography to link MiD49 and MiD51 to the involvement of the ER in mitochondrial fission. We gain further insight into this complex process and characterize the 3D structure of ER–mitochondria contact sites. PMID:26101352

Algorithm for automatic forced spirometry quality assessment: technological developments.

PubMed

Melia, Umberto; Burgos, Felip; Vallverdú, Montserrat; Velickovski, Filip; Lluch-Ariet, Magí; Roca, Josep; Caminal, Pere

2014-01-01

We hypothesized that the implementation of automatic real-time assessment of quality of forced spirometry (FS) may significantly enhance the potential for extensive deployment of a FS program in the community. Recent studies have demonstrated that the application of quality criteria defined by the ATS/ERS (American Thoracic Society/European Respiratory Society) in commercially available equipment with automatic quality assessment can be markedly improved. To this end, an algorithm for assessing quality of FS automatically was reported. The current research describes the mathematical developments of the algorithm. An innovative analysis of the shape of the spirometric curve, adding 23 new metrics to the traditional 4 recommended by ATS/ERS, was done. The algorithm was created through a two-step iterative process including: (1) an initial version using the standard FS curves recommended by the ATS; and, (2) a refined version using curves from patients. In each of these steps the results were assessed against one expert's opinion. Finally, an independent set of FS curves from 291 patients was used for validation purposes. The novel mathematical approach to characterize the FS curves led to appropriate FS classification with high specificity (95%) and sensitivity (96%). The results constitute the basis for a successful transfer of FS testing to non-specialized professionals in the community.

Levels of metacaspase1 and chaperones related to protein quality control in alcoholic and nonalcoholic steatohepatitis.

PubMed

Mendoza, Alejandro S; Dorce, Jacques; Peng, Yue; French, Barbara A; Tillman, Brittany; Li, Jun; French, Samuel W

2015-02-01

Efficient management of misfolded or aggregated proteins in ASH and NASH is crucial for continued hepatic viability. Cellular protein quality control systems play an important role in the pathogenesis and progression of ASH and NASH. In a recent study, elevated Mca1 expression counteracted aggregation and accumulation of misfolded proteins and extended the life span of the yeast Saccharomyces cerevisiae (Hill et al, 2014). Mca1 may also associate with Ssa1 and Hsp104 in disaggregation and fragmentation of aggregated proteins and their subsequent degradation through the ER-associated degradation (ERAD) pathway. If degradation is not available, protection of the cellular environment from a misfolded protein is accomplished by its sequestration into two distinct inclusion bodies (Kaganovich et al., 2008) called the JUNQ (JUxta Nuclear Quality control compartment) and the IPOD (Insoluble Protein Deposit). Mca1, Hsp104, Hsp40, Ydj1, Ssa1, VCP/p97, and p62 all play important roles in protein quality control systems. This study aims to measure the expression of Mca1 and related chaperones involved in protein quality control in alcoholic steatohepatitis (ASH), and nonalcoholic steatohepatitis (NASH) compared with normal control liver biopsies. Mca1, Hsp104, Hsp40, Ydj1, Ssa1, VCP/p97, and p62 expressions were measured in three to six formalin-fixed paraffin embedded ASH and NASH liver biopsies and control normal liver specimens by immunofluorescence staining and quantified by immunofluorescence intensity. Mca1, Hsp104, Ydj1 and p62 were significantly upregulated compared to control (p<0.05) in ASH specimens. Hsp40 and VCP/p97 were also uptrending in ASH. In NASH, the only significant difference was the increased expression of Hsp104 compared to control (p<0.05). Ssa1 levels were uptrending in both ASH and NASH specimens. The upregulation of Mca1, Hsp104, Ydj1 and p62 in ASH may be elicited as a response to the chronic exposure of the hepatocytes to the toxicity of alcohol. Recruitment of Mca1, Hsp104, Ydj1 and p62 may indicate that autophagy, the ERAD, JUNQ, and IPOD systems are active in ASH. Whereas in NASH, elevated Hsp104 and uptrending Ssa1 levels may indicate that autophagy and IPOD may be the only active protein quality control systems involved. Published by Elsevier Inc.

Efficacy of single-dose, extended-release naproxen sodium 660 mg in postsurgical dental pain: two double-blind, randomized, placebo-controlled trials.

PubMed

Laurora, Irene; An, Robert

2016-01-01

To evaluate the efficacy of a novel formulation of extended-release/immediate-release (ER) naproxen sodium over 24 h in a dental pain model. Two randomized, double-blind, placebo-controlled trials in moderate to severe pain after extraction of one or two impacted third molars (at least one partial mandibular bony impaction). Treatment comprised oral ER naproxen sodium 660 mg (single dose), placebo (both studies) or immediate-release (IR) naproxen sodium 220 mg tid (study 2). Primary efficacy endpoint: 24-h summed pain intensity difference (SPID). Secondary variables included total pain relief (TOTPAR), use of rescue medication. All treatment-emergent adverse events were recorded. NCT00720057 (study 1), NCT01389284 (study 2). Primary efficacy analyses: pain intensity was significantly lower over 24 h with ER naproxen sodium vs. placebo (p < 0.001), with significant relief from 15 min (study 2). In study 2, ER naproxen sodium was non-inferior to IR naproxen sodium, reducing pain intensity to a comparable extent over 24 h. TOTPAR was significantly greater with ER and IR naproxen sodium vs. placebo at all time points, with generally comparable differences between active treatments. Significantly more placebo patients required rescue medication vs. ER and IR naproxen sodium from 2-24 h post-dose. Once daily ER naproxen sodium was generally safe and well tolerated, with a similar safety profile to IR naproxen sodium tid. The studies were single dose, with limited ability to assess efficacy or safety of multiple doses over time. As the imputed pain score meant that estimated treatment differences may have been biased in favor of ER naproxen sodium, a post hoc analysis evaluated the robustness of the results for pain relief. A single dose of ER naproxen sodium 660 mg significantly reduced moderate to severe dental pain vs. placebo and was comparable to IR naproxen sodium 220 mg tid. Significant pain relief was experienced from 15 min and sustained over 24 h, resulting in a reduced need for rescue medication. ER naproxen sodium 660 mg once daily is a convenient and effective therapy providing 24 h relief of pain.

Next generation Er:YAG fractional ablative laser

NASA Astrophysics Data System (ADS)

Heinrich, A.; Vizhanyo, A.; Krammer, P.; Summer, S.; Gross, S.; Bragagna, T.; Böhler, C.

2011-03-01

Pantec Biosolutions AG presents a portable fractional ablative laser system based on a miniaturized diode pumped Er:YAG laser. The system can operate at repetition rates up to 500 Hz and has an incorporated beam deflection unit. It is smaller, lighter and cost efficient compared to systems based on lamp pumped Er:YAG lasers and incorporates a skin layer detection to guarantee precise control of the microporation process. The pulse parameters enable a variety of applications in dermatology and in general medicine, as demonstrated by first results on transdermal drug delivery of FSH (follicle stimulating hormone).

A systematic review on the neural effects of music on emotion regulation: implications for music therapy practice.

PubMed

Moore, Kimberly Sena

2013-01-01

Emotion regulation (ER) is an internal process through which a person maintains a comfortable state of arousal by modulating one or more aspects of emotion. The neural correlates underlying ER suggest an interplay between cognitive control areas and areas involved in emotional reactivity. Although some studies have suggested that music may be a useful tool in ER, few studies have examined the links between music perception/production and the neural mechanisms that underlie ER and resulting implications for clinical music therapy treatment. Objectives of this systematic review were to explore and synthesize what is known about how music and music experiences impact neural structures implicated in ER, and to consider clinical implications of these findings for structuring music stimuli to facilitate ER. A comprehensive electronic database search resulted in 50 studies that met predetermined inclusion and exclusion criteria. Pertinent data related to the objective were extracted and study outcomes were analyzed and compared for trends and common findings. Results indicated there are certain music characteristics and experiences that produce desired and undesired neural activation patterns implicated in ER. Desired activation patterns occurred when listening to preferred and familiar music, when singing, and (in musicians) when improvising; undesired activation patterns arose when introducing complexity, dissonance, and unexpected musical events. Furthermore, the connection between music-influenced changes in attention and its link to ER was explored. Implications for music therapy practice are discussed and preliminary guidelines for how to use music to facilitate ER are shared.

Emotion regulation deficits in eating disorders: a marker of eating pathology or general psychopathology?

PubMed

Svaldi, Jennifer; Griepenstroh, Julia; Tuschen-Caffier, Brunna; Ehring, Thomas

2012-05-15

Preliminary evidence indicates that individuals with eating disorders (ED) show emotion regulation (ER) difficulties. However, it is yet unclear whether different types of ED differ in their ER profile and whether certain ER difficulties are specific for ED or rather a transdiagnostic factor. Twenty women with anorexia nervosa (AN), 18 with bulimia nervosa (BN), 25 with binge eating disorder (BED), 15 with borderline personality disorder (BPD), 16 with major depressive disorder (MDD) and 42 female healthy controls (HC) were administered the Emotion Regulation Questionnaire, the Inventory of Cognitive Affect Regulation Strategies, the Difficulties in Emotion Regulation Scale and the Affect Intensity Measure. The ED groups reported significantly higher levels of emotion intensity, lower acceptance of emotions, less emotional awareness and clarity, more self-reported ER problems as well as decreased use of functional and increased use of dysfunctional emotion regulation strategies when compared to HC. No significant differences between the ED groups emerged for most ER variables. However, there were indications that the BED group may show a slightly more adaptive pattern of ER than the two other ED groups. As a whole, all clinical groups performed very similar on most ER variables and reported more difficulties regulating their emotions than HC. The findings suggest that ER difficulties are not linked to a particular diagnostic category. Instead, ER difficulties appear to be a transdiagnostic risk and/or maintenance factor rather than being disorder-specific. Copyright © 2012 Elsevier Ltd. All rights reserved.

ER-stress and apoptosis: molecular mechanisms and potential relevance in infection.

PubMed

Häcker, Georg

2014-10-01

During ER-stress, one of the responses a cell can choose is apoptosis. Apoptosis generally is a cell's preferred response when other control mechanisms are overwhelmed. We now have a reasonably clear molecular picture what is happening once the apoptotic apparatus has been started. Unclear however are the majority of the upstream pathways that connect other signalling to apoptosis. During ER-stress, confirmed apoptosis-regulating targets are pro- and anti-apoptotic proteins of the Bcl-2-family, whose concerted action induces apoptosis. I will here discuss how mitochondrial apoptosis is triggered, how this is linked to the ER-stress response and in what way this may be relevant during microbial infections. Copyright © 2014 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.

Variants in the vitamin D pathway, serum levels of vitamin D, and estrogen receptor negative breast cancer among African-American women: a case-control study

PubMed Central

2012-01-01

Introduction American women of African ancestry (AA) are more likely than European Americans (EA) to have estrogen receptor (ER)-negative breast cancer. 25-hydroxyvitamin D (25OHD) is low in AAs, and was associated with ER-negative tumors in EAs. We hypothesized that racial differences in 25OHD levels, as well as in inherited genetic variations, may contribute, in part, to the differences in tumor characteristics. Methods In a case (n = 928)-control (n = 843) study of breast cancer in AA and EA women, we measured serum 25OHD levels in controls and tested associations between risk and tag single nucleotide polymorphisms (SNPs) in VDR, CYP24A1 and CYP27B1, particularly by ER status. Results More AAs had severe vitamin D deficiency (< 10 ng/ml) than EAs (34.3% vs 5.9%), with lowest levels among those with the highest African ancestry. Associations for SNPs differed by race. Among AAs, VDR SNP rs2239186, associated with higher serum levels of 25OHD, decreased risk after correction for multiple testing (OR = 0.53, 95% CI = 0.31-0.79, p by permutation = 0.03), but had no effect in EAs. The majority of associations were for ER-negative breast cancer, with seven differential associations between AA and EA women for CYP24A1 (p for interaction < 0.10). SNP rs27622941 was associated with a > twofold increased risk of ER-negative breast cancer among AAs (OR = 2.62, 95% CI = 1.38-4.98), but had no effect in EAs. rs2209314 decreased risk among EAs (OR = 0.38, 95% CI = 0.20-0.73), with no associations in AAs. The increased risk of ER-negative breast cancer in AAs compared to EAs was reduced and became non-significant (OR = 1.20, 95% CI = 0.80-1.79) after adjusting for these two CYP24A1 SNPs. Conclusions These data suggest that genetic variants in the vitamin D pathway may be related to the higher prevalence of ER-negative breast cancer in AA women. PMID:22480149

SAR operational aspects

NASA Astrophysics Data System (ADS)

Holmdahl, P. E.; Ellis, A. B. E.; Moeller-Olsen, P.; Ringgaard, J. P.

1981-12-01

The basic requirements of the SAR ground segment of ERS-1 are discussed. A system configuration for the real time data acquisition station and the processing and archive facility is depicted. The functions of a typical SAR processing unit (SPU) are specified, and inputs required for near real time and full precision, deferred time processing are described. Inputs and the processing required for provision of these inputs to the SPU are dealt with. Data flow through the systems, and normal and nonnormal operational sequence, are outlined. Prerequisites for maintaining overall performance are identified, emphasizing quality control. The most demanding tasks to be performed by the front end are defined in order to determine types of processors and peripherals which comply with throughput requirements.

Dealing with feeling: Specific emotion regulation skills predict responses to stress in psychosis.

PubMed

Lincoln, Tania M; Hartmann, Maike; Köther, Ulf; Moritz, Steffen

2015-08-15

Elevated negative affect is an established link between minor stressors and psychotic symptoms. Less clear is why people with psychosis fail to regulate distressing emotions effectively. This study tests whether subjective, psychophysiological and symptomatic responses to stress can be predicted by specific emotion regulation (ER) difficulties. Participants with psychotic disorders (n=35) and healthy controls (n=28) were assessed for ER-skills at baseline. They were then exposed to a noise versus no stressor on different days, during which self-reported stress responses, state paranoia and skin conductance levels (SCL) were assessed. Participants with psychosis showed a stronger increase in self-reported stress and SCL in response to the stressor than healthy controls. Stronger increases in self-reported stress were predicted by a reduced ability to be aware of and tolerate distressing emotions, whereas increases in SCL were predicted by a reduced ability to be aware of, tolerate, accept and modify them. Although paranoid symptoms were not significantly affected by the stressors, individual variation in paranoid responses was also predicted by a reduced ability to be aware of and tolerate emotions. Differences in stress responses in the samples were no longer significant after controlling for ER skills. Thus, interventions that improve ER-skills could reduce stress-sensitivity in psychosis. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Estrogen and progesterone receptors in human decidua after RU486 treatment.

PubMed

Shi, W L; Wang, J D; Fu, Y; Zhu, P D

1993-07-01

To examine RU486 action on decidua at the level of cellular estrogen receptor (ER) and P receptor (PR). Controlled basic study for contragestion mechanism of mifepristone. Normal human volunteers in an academic research environment. Sixty women with 6 to 7 weeks of gestation who voluntarily requested termination of pregnancy were recruited and randomly divided into three groups. A single dose of 200 mg RU486 was orally administered to the two treatment groups 12 and 24 hours, respectively, before surgical interruption of pregnancies. Placebo was used for control group. Decidual tissues were collected right after operation. Immunocytochemical reactions of PR and ER in decidua after RU486 treatment were compared with the control subjects. The differences of the reaction in decidual area with or without trophoblast invasion were noted. RU486 treatment increased PR and ER staining in vessel and stroma of decidua without trophoblast invasion (decidua parietalis) but not in decidua with trophoblast invasion (decidua capsularis or basalis). Chi-squared analysis indicated a significant increase in the number of ER-positive samples after RU486 treatment. The decidua parietalis was the primary target site of RU486. The lack of RU486 effect on decidua capsularis implied that trophoblast invasion prevented against antiprogestin impact.

ER phospholipid composition modulates lipogenesis during feeding and in obesity.

PubMed

Rong, Xin; Wang, Bo; Palladino, Elisa Nd; de Aguiar Vallim, Thomas Q; Ford, David A; Tontonoz, Peter

2017-10-02

Sterol regulatory element-binding protein 1c (SREBP-1c) is a central regulator of lipogenesis whose activity is controlled by proteolytic cleavage. The metabolic factors that affect its processing are incompletely understood. Here, we show that dynamic changes in the acyl chain composition of ER phospholipids affect SREBP-1c maturation in physiology and disease. The abundance of polyunsaturated phosphatidylcholine in liver ER is selectively increased in response to feeding and in the setting of obesity-linked insulin resistance. Exogenous delivery of polyunsaturated phosphatidylcholine to ER accelerated SREBP-1c processing through a mechanism that required an intact SREBP cleavage-activating protein (SCAP) pathway. Furthermore, induction of the phospholipid-remodeling enzyme LPCAT3 in response to liver X receptor (LXR) activation promoted SREBP-1c processing by driving the incorporation of polyunsaturated fatty acids into ER. Conversely, LPCAT3 deficiency increased membrane saturation, reduced nuclear SREBP-1c abundance, and blunted the lipogenic response to feeding, LXR agonist treatment, or obesity-linked insulin resistance. Desaturation of the ER membrane may serve as an auxiliary signal of the fed state that promotes lipid synthesis in response to nutrient availability.

Chronic Intermittent Hypobaric Hypoxia Improves Cardiac Function through Inhibition of Endoplasmic Reticulum Stress.

PubMed

Yuan, Fang; Zhang, Li; Li, Yan-Qing; Teng, Xu; Tian, Si-Yu; Wang, Xiao-Ran; Zhang, Yi

2017-08-11

We investigated the role of endoplasmic reticulum stress (ERS) in chronic intermittent hypobaric hypoxia (CIHH)-induced cardiac protection. Adult male Sprague-Dawley rats were exposed to CIHH treatment simulating 5000 m altitude for 28 days, 6 hours per day. The heart was isolated and perfused with Langendorff apparatus and subjected to 30-min ischemia followed by 60-min reperfusion. Cardiac function, infarct size, and lactate dehydrogenase (LDH) activity were assessed. Expression of ERS molecular chaperones (GRP78, CHOP and caspase-12) was assayed by western blot analysis. CIHH treatment improved the recovery of left ventricular function and decreased cardiac infarct size and activity of LDH after I/R compared to control rats. Furthermore, CIHH treatment inhibited over-expression of ERS-related factors including GRP78, CHOP and caspase-12. CIHH-induced cardioprotection and inhibition of ERS were eliminated by application of dithiothreitol, an ERS inducer, and chelerythrine, a protein kinase C (PKC) inhibitor. In conclusion CIHH treatment exerts cardiac protection against I/R injury through inhibition of ERS via PKC signaling pathway.

Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer

PubMed Central

Milne, Roger L; Kuchenbaecker, Karoline B; Michailidou, Kyriaki; Beesley, Jonathan; Kar, Siddhartha; Lindström, Sara; Hui, Shirley; Lemaçon, Audrey; Soucy, Penny; Dennis, Joe; Jiang, Xia; Rostamianfar, Asha; Finucane, Hilary; Bolla, Manjeet K; McGuffog, Lesley; Wang, Qin; Aalfs, Cora M; Adams, Marcia; Adlard, Julian; Agata, Simona; Ahmed, Shahana; Ahsan, Habibul; Aittomäki, Kristiina; Al-Ejeh, Fares; Allen, Jamie; Ambrosone, Christine B; Amos, Christopher I; Andrulis, Irene L; Anton-Culver, Hoda; Antonenkova, Natalia N; Arndt, Volker; Arnold, Norbert; Aronson, Kristan J; Auber, Bernd; Auer, Paul L; Ausems, Margreet G E M; Azzollini, Jacopo; Bacot, François; Balmaña, Judith; Barile, Monica; Barjhoux, Laure; Barkardottir, Rosa B; Barrdahl, Myrto; Barnes, Daniel; Barrowdale, Daniel; Baynes, Caroline; Beckmann, Matthias W; Benitez, Javier; Bermisheva, Marina; Bernstein, Leslie; Bignon, Yves-Jean; Blazer, Kathleen R; Blok, Marinus J; Blomqvist, Carl; Blot, William; Bobolis, Kristie; Boeckx, Bram; Bogdanova, Natalia V; Bojesen, Anders; Bojesen, Stig E; Bonanni, Bernardo; Børresen-Dale, Anne-Lise; Bozsik, Aniko; Bradbury, Angela R; Brand, Judith S; Brauch, Hiltrud; Brenner, Hermann; Bressac-de Paillerets, Brigitte; Brewer, Carole; Brinton, Louise; Broberg, Per; Brooks-Wilson, Angela; Brunet, Joan; Brüning, Thomas; Burwinkel, Barbara; Buys, Saundra S; Byun, Jinyoung; Cai, Qiuyin; Caldés, Trinidad; Caligo, Maria A; Campbell, Ian; Canzian, Federico; Caron, Olivier; Carracedo, Angel; Carter, Brian D; Castelao, J Esteban; Castera, Laurent; Caux-Moncoutier, Virginie; Chan, Salina B; Chang-Claude, Jenny; Chanock, Stephen J; Chen, Xiaoqing; Cheng, Ting-Yuan David; Chiquette, Jocelyne; Christiansen, Hans; Claes, Kathleen B M; Clarke, Christine L; Conner, Thomas; Conroy, Don M; Cook, Jackie; Cordina-Duverger, Emilie; Cornelissen, Sten; Coupier, Isabelle; Cox, Angela; Cox, David G; Cross, Simon S; Cuk, Katarina; Cunningham, Julie M; Czene, Kamila; Daly, Mary B; Damiola, Francesca; Darabi, Hatef; Davidson, Rosemarie; De Leeneer, Kim; Devilee, Peter; Dicks, Ed; Diez, Orland; Ding, Yuan Chun; Ditsch, Nina; Doheny, Kimberly F; Domchek, Susan M; Dorfling, Cecilia M; Dörk, Thilo; dos-Santos-Silva, Isabel; Dubois, Stéphane; Dugué, Pierre-Antoine; Dumont, Martine; Dunning, Alison M; Durcan, Lorraine; Dwek, Miriam; Dworniczak, Bernd; Eccles, Diana; Eeles, Ros; Ehrencrona, Hans; Eilber, Ursula; Ejlertsen, Bent; Ekici, Arif B; Engel, Christoph; Eriksson, Mikael; Fachal, Laura; Faivre, Laurence; Fasching, Peter A; Faust, Ulrike; Figueroa, Jonine; Flesch-Janys, Dieter; Fletcher, Olivia; Flyger, Henrik; Foulkes, William D; Friedman, Eitan; Fritschi, Lin; Frost, Debra; Gabrielson, Marike; Gaddam, Pragna; Gammon, Marilie D; Ganz, Patricia A; Gapstur, Susan M; Garber, Judy; Garcia-Barberan, Vanesa; García-Sáenz, José A; Gaudet, Mia M; Gauthier-Villars, Marion; Gehrig, Andrea; Georgoulias, Vassilios; Gerdes, Anne-Marie; Giles, Graham G; Glendon, Gord; Godwin, Andrew K; Goldberg, Mark S; Goldgar, David E; González-Neira, Anna; Goodfellow, Paul; Greene, Mark H; Grip, Mervi; Gronwald, Jacek; Grundy, Anne; Gschwantler-Kaulich, Daphne; Guénel, Pascal; Guo, Qi; Haeberle, Lothar; Hahnen, Eric; Haiman, Christopher A; Håkansson, Niclas; Hallberg, Emily; Hamann, Ute; Hamel, Nathalie; Hankinson, Susan; Hansen, Thomas V O; Harrington, Patricia; Hart, Steven N; Hartikainen, Jaana M; Healey, Catherine S; Hein, Alexander; Helbig, Sonja; Henderson, Alex; Heyworth, Jane; Hicks, Belynda; Hillemanns, Peter; Hodgson, Shirley; Hogervorst, Frans B; Hollestelle, Antoinette; Hooning, Maartje J; Hoover, Bob; Hopper, John L; Hu, Chunling; Huang, Guanmengqian; Hulick, Peter J; Humphreys, Keith; Hunter, David J; Imyanitov, Evgeny N; Isaacs, Claudine; Iwasaki, Motoki; Izatt, Louise; Jakubowska, Anna; James, Paul; Janavicius, Ramunas; Janni, Wolfgang; Jensen, Uffe Birk; John, Esther M; Johnson, Nichola; Jones, Kristine; Jones, Michael; Jukkola-Vuorinen, Arja; Kaaks, Rudolf; Kabisch, Maria; Kaczmarek, Katarzyna; Kang, Daehee; Kast, Karin; Keeman, Renske; Kerin, Michael J; Kets, Carolien M; Keupers, Machteld; Khan, Sofia; Khusnutdinova, Elza; Kiiski, Johanna I; Kim, Sung-Won; Knight, Julia A; Konstantopoulou, Irene; Kosma, Veli-Matti; Kristensen, Vessela N; Kruse, Torben A; Kwong, Ava; Lænkholm, Anne-Vibeke; Laitman, Yael; Lalloo, Fiona; Lambrechts, Diether; Landsman, Keren; Lasset, Christine; Lazaro, Conxi; Le Marchand, Loic; Lecarpentier, Julie; Lee, Andrew; Lee, Eunjung; Lee, Jong Won; Lee, Min Hyuk; Lejbkowicz, Flavio; Lesueur, Fabienne; Li, Jingmei; Lilyquist, Jenna; Lincoln, Anne; Lindblom, Annika; Lissowska, Jolanta; Lo, Wing-Yee; Loibl, Sibylle; Long, Jirong; Loud, Jennifer T; Lubinski, Jan; Luccarini, Craig; Lush, Michael; MacInnis, Robert J; Maishman, Tom; Makalic, Enes; Kostovska, Ivana Maleva; Malone, Kathleen E; Manoukian, Siranoush; Manson, JoAnn E; Margolin, Sara; Martens, John W M; Martinez, Maria Elena; Matsuo, Keitaro; Mavroudis, Dimitrios; Mazoyer, Sylvie; McLean, Catriona; Meijers-Heijboer, Hanne; Menéndez, Primitiva; Meyer, Jeffery; Miao, Hui; Miller, Austin; Miller, Nicola; Mitchell, Gillian; Montagna, Marco; Muir, Kenneth; Mulligan, Anna Marie; Mulot, Claire; Nadesan, Sue; Nathanson, Katherine L; Neuhausen, Susan L; Nevanlinna, Heli; Nevelsteen, Ines; Niederacher, Dieter; Nielsen, Sune F; Nordestgaard, Børge G; Norman, Aaron; Nussbaum, Robert L; Olah, Edith; Olopade, Olufunmilayo I; Olson, Janet E; Olswold, Curtis; Ong, Kai-ren; Oosterwijk, Jan C; Orr, Nick; Osorio, Ana; Pankratz, V Shane; Papi, Laura; Park-Simon, Tjoung-Won; Paulsson-Karlsson, Ylva; Lloyd, Rachel; Pedersen, Inge Søkilde; Peissel, Bernard; Peixoto, Ana; Perez, Jose I A; Peterlongo, Paolo; Peto, Julian; Pfeiler, Georg; Phelan, Catherine M; Pinchev, Mila; Plaseska-Karanfilska, Dijana; Poppe, Bruce; Porteous, Mary E; Prentice, Ross; Presneau, Nadege; Prokofieva, Darya; Pugh, Elizabeth; Pujana, Miquel Angel; Pylkäs, Katri; Rack, Brigitte; Radice, Paolo; Rahman, Nazneen; Rantala, Johanna; Rappaport-Fuerhauser, Christine; Rennert, Gad; Rennert, Hedy S; Rhenius, Valerie; Rhiem, Kerstin; Richardson, Andrea; Rodriguez, Gustavo C; Romero, Atocha; Romm, Jane; Rookus, Matti A; Rudolph, Anja; Ruediger, Thomas; Saloustros, Emmanouil; Sanders, Joyce; Sandler, Dale P; Sangrajrang, Suleeporn; Sawyer, Elinor J; Schmidt, Daniel F; Schoemaker, Minouk J; Schumacher, Fredrick; Schürmann, Peter; Schwentner, Lukas; Scott, Christopher; Scott, Rodney J; Seal, Sheila; Senter, Leigha; Seynaeve, Caroline; Shah, Mitul; Sharma, Priyanka; Shen, Chen-Yang; Sheng, Xin; Shimelis, Hermela; Shrubsole, Martha J; Shu, Xiao-Ou; Side, Lucy E; Singer, Christian F; Sohn, Christof; Southey, Melissa C; Spinelli, John J; Spurdle, Amanda B; Stegmaier, Christa; Stoppa-Lyonnet, Dominique; Sukiennicki, Grzegorz; Surowy, Harald; Sutter, Christian; Swerdlow, Anthony; Szabo, Csilla I; Tamimi, Rulla M; Tan, Yen Y; Taylor, Jack A; Tejada, Maria-Isabel; Tengström, Maria; Teo, Soo H; Terry, Mary B; Tessier, Daniel C; Teulé, Alex; Thöne, Kathrin; Thull, Darcy L; Tibiletti, Maria Grazia; Tihomirova, Laima; Tischkowitz, Marc; Toland, Amanda E; Tollenaar, Rob A E M; Tomlinson, Ian; Tong, Ling; Torres, Diana; Tranchant, Martine; Truong, Thérèse; Tucker, Kathy; Tung, Nadine; Tyrer, Jonathan; Ulmer, Hans-Ulrich; Vachon, Celine; van Asperen, Christi J; Van Den Berg, David; van den Ouweland, Ans M W; van Rensburg, Elizabeth J; Varesco, Liliana; Varon-Mateeva, Raymonda; Vega, Ana; Viel, Alessandra; Vijai, Joseph; Vincent, Daniel; Vollenweider, Jason; Walker, Lisa; Wang, Zhaoming; Wang-Gohrke, Shan; Wappenschmidt, Barbara; Weinberg, Clarice R; Weitzel, Jeffrey N; Wendt, Camilla; Wesseling, Jelle; Whittemore, Alice S; Wijnen, Juul T; Willett, Walter; Winqvist, Robert; Wolk, Alicja; Wu, Anna H; Xia, Lucy; Yang, Xiaohong R; Yannoukakos, Drakoulis; Zaffaroni, Daniela; Zheng, Wei; Zhu, Bin; Ziogas, Argyrios; Ziv, Elad; Zorn, Kristin K; Gago-Dominguez, Manuela; Mannermaa, Arto; Olsson, Håkan; Teixeira, Manuel R; Stone, Jennifer; Offit, Kenneth; Ottini, Laura; Park, Sue K; Thomassen, Mads; Hall, Per; Meindl, Alfons; Schmutzler, Rita K; Droit, Arnaud; Bader, Gary D; Pharoah, Paul D P; Couch, Fergus J; Easton, Douglas F; Kraft, Peter; Chenevix-Trench, Georgia; García-Closas, Montserrat; Schmidt, Marjanka K; Antoniou, Antonis C; Simard, Jacques

2018-01-01

Most common breast cancer susceptibility variants have been identified through genome-wide association studies (GWAS) of predominantly estrogen receptor (ER)-positive disease1. We conducted a GWAS using 21,468 ER-negative cases and 100,594 controls combined with 18,908 BRCA1 mutation carriers (9,414 with breast cancer), all of European origin. We identified independent associations at P < 5 × 10−8 with ten variants at nine new loci. At P < 0.05, we replicated associations with 10 of 11 variants previously reported in ER-negative disease or BRCA1 mutation carrier GWAS and observed consistent associations with ER-negative disease for 105 susceptibility variants identified by other studies. These 125 variants explain approximately 14% of the familial risk of this breast cancer subtype. There was high genetic correlation (0.72) between risk of ER-negative breast cancer and breast cancer risk for BRCA1 mutation carriers. These findings may lead to improved risk prediction and inform further fine-mapping and functional work to better understand the biological basis of ER-negative breast cancer. PMID:29058716

Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer.

PubMed

Milne, Roger L; Kuchenbaecker, Karoline B; Michailidou, Kyriaki; Beesley, Jonathan; Kar, Siddhartha; Lindström, Sara; Hui, Shirley; Lemaçon, Audrey; Soucy, Penny; Dennis, Joe; Jiang, Xia; Rostamianfar, Asha; Finucane, Hilary; Bolla, Manjeet K; McGuffog, Lesley; Wang, Qin; Aalfs, Cora M; Adams, Marcia; Adlard, Julian; Agata, Simona; Ahmed, Shahana; Ahsan, Habibul; Aittomäki, Kristiina; Al-Ejeh, Fares; Allen, Jamie; Ambrosone, Christine B; Amos, Christopher I; Andrulis, Irene L; Anton-Culver, Hoda; Antonenkova, Natalia N; Arndt, Volker; Arnold, Norbert; Aronson, Kristan J; Auber, Bernd; Auer, Paul L; Ausems, Margreet G E M; Azzollini, Jacopo; Bacot, François; Balmaña, Judith; Barile, Monica; Barjhoux, Laure; Barkardottir, Rosa B; Barrdahl, Myrto; Barnes, Daniel; Barrowdale, Daniel; Baynes, Caroline; Beckmann, Matthias W; Benitez, Javier; Bermisheva, Marina; Bernstein, Leslie; Bignon, Yves-Jean; Blazer, Kathleen R; Blok, Marinus J; Blomqvist, Carl; Blot, William; Bobolis, Kristie; Boeckx, Bram; Bogdanova, Natalia V; Bojesen, Anders; Bojesen, Stig E; Bonanni, Bernardo; Børresen-Dale, Anne-Lise; Bozsik, Aniko; Bradbury, Angela R; Brand, Judith S; Brauch, Hiltrud; Brenner, Hermann; Bressac-de Paillerets, Brigitte; Brewer, Carole; Brinton, Louise; Broberg, Per; Brooks-Wilson, Angela; Brunet, Joan; Brüning, Thomas; Burwinkel, Barbara; Buys, Saundra S; Byun, Jinyoung; Cai, Qiuyin; Caldés, Trinidad; Caligo, Maria A; Campbell, Ian; Canzian, Federico; Caron, Olivier; Carracedo, Angel; Carter, Brian D; Castelao, J Esteban; Castera, Laurent; Caux-Moncoutier, Virginie; Chan, Salina B; Chang-Claude, Jenny; Chanock, Stephen J; Chen, Xiaoqing; Cheng, Ting-Yuan David; Chiquette, Jocelyne; Christiansen, Hans; Claes, Kathleen B M; Clarke, Christine L; Conner, Thomas; Conroy, Don M; Cook, Jackie; Cordina-Duverger, Emilie; Cornelissen, Sten; Coupier, Isabelle; Cox, Angela; Cox, David G; Cross, Simon S; Cuk, Katarina; Cunningham, Julie M; Czene, Kamila; Daly, Mary B; Damiola, Francesca; Darabi, Hatef; Davidson, Rosemarie; De Leeneer, Kim; Devilee, Peter; Dicks, Ed; Diez, Orland; Ding, Yuan Chun; Ditsch, Nina; Doheny, Kimberly F; Domchek, Susan M; Dorfling, Cecilia M; Dörk, Thilo; Dos-Santos-Silva, Isabel; Dubois, Stéphane; Dugué, Pierre-Antoine; Dumont, Martine; Dunning, Alison M; Durcan, Lorraine; Dwek, Miriam; Dworniczak, Bernd; Eccles, Diana; Eeles, Ros; Ehrencrona, Hans; Eilber, Ursula; Ejlertsen, Bent; Ekici, Arif B; Eliassen, A Heather; Engel, Christoph; Eriksson, Mikael; Fachal, Laura; Faivre, Laurence; Fasching, Peter A; Faust, Ulrike; Figueroa, Jonine; Flesch-Janys, Dieter; Fletcher, Olivia; Flyger, Henrik; Foulkes, William D; Friedman, Eitan; Fritschi, Lin; Frost, Debra; Gabrielson, Marike; Gaddam, Pragna; Gammon, Marilie D; Ganz, Patricia A; Gapstur, Susan M; Garber, Judy; Garcia-Barberan, Vanesa; García-Sáenz, José A; Gaudet, Mia M; Gauthier-Villars, Marion; Gehrig, Andrea; Georgoulias, Vassilios; Gerdes, Anne-Marie; Giles, Graham G; Glendon, Gord; Godwin, Andrew K; Goldberg, Mark S; Goldgar, David E; González-Neira, Anna; Goodfellow, Paul; Greene, Mark H; Alnæs, Grethe I Grenaker; Grip, Mervi; Gronwald, Jacek; Grundy, Anne; Gschwantler-Kaulich, Daphne; Guénel, Pascal; Guo, Qi; Haeberle, Lothar; Hahnen, Eric; Haiman, Christopher A; Håkansson, Niclas; Hallberg, Emily; Hamann, Ute; Hamel, Nathalie; Hankinson, Susan; Hansen, Thomas V O; Harrington, Patricia; Hart, Steven N; Hartikainen, Jaana M; Healey, Catherine S; Hein, Alexander; Helbig, Sonja; Henderson, Alex; Heyworth, Jane; Hicks, Belynda; Hillemanns, Peter; Hodgson, Shirley; Hogervorst, Frans B; Hollestelle, Antoinette; Hooning, Maartje J; Hoover, Bob; Hopper, John L; Hu, Chunling; Huang, Guanmengqian; Hulick, Peter J; Humphreys, Keith; Hunter, David J; Imyanitov, Evgeny N; Isaacs, Claudine; Iwasaki, Motoki; Izatt, Louise; Jakubowska, Anna; James, Paul; Janavicius, Ramunas; Janni, Wolfgang; Jensen, Uffe Birk; John, Esther M; Johnson, Nichola; Jones, Kristine; Jones, Michael; Jukkola-Vuorinen, Arja; Kaaks, Rudolf; Kabisch, Maria; Kaczmarek, Katarzyna; Kang, Daehee; Kast, Karin; Keeman, Renske; Kerin, Michael J; Kets, Carolien M; Keupers, Machteld; Khan, Sofia; Khusnutdinova, Elza; Kiiski, Johanna I; Kim, Sung-Won; Knight, Julia A; Konstantopoulou, Irene; Kosma, Veli-Matti; Kristensen, Vessela N; Kruse, Torben A; Kwong, Ava; Lænkholm, Anne-Vibeke; Laitman, Yael; Lalloo, Fiona; Lambrechts, Diether; Landsman, Keren; Lasset, Christine; Lazaro, Conxi; Le Marchand, Loic; Lecarpentier, Julie; Lee, Andrew; Lee, Eunjung; Lee, Jong Won; Lee, Min Hyuk; Lejbkowicz, Flavio; Lesueur, Fabienne; Li, Jingmei; Lilyquist, Jenna; Lincoln, Anne; Lindblom, Annika; Lissowska, Jolanta; Lo, Wing-Yee; Loibl, Sibylle; Long, Jirong; Loud, Jennifer T; Lubinski, Jan; Luccarini, Craig; Lush, Michael; MacInnis, Robert J; Maishman, Tom; Makalic, Enes; Kostovska, Ivana Maleva; Malone, Kathleen E; Manoukian, Siranoush; Manson, JoAnn E; Margolin, Sara; Martens, John W M; Martinez, Maria Elena; Matsuo, Keitaro; Mavroudis, Dimitrios; Mazoyer, Sylvie; McLean, Catriona; Meijers-Heijboer, Hanne; Menéndez, Primitiva; Meyer, Jeffery; Miao, Hui; Miller, Austin; Miller, Nicola; Mitchell, Gillian; Montagna, Marco; Muir, Kenneth; Mulligan, Anna Marie; Mulot, Claire; Nadesan, Sue; Nathanson, Katherine L; Neuhausen, Susan L; Nevanlinna, Heli; Nevelsteen, Ines; Niederacher, Dieter; Nielsen, Sune F; Nordestgaard, Børge G; Norman, Aaron; Nussbaum, Robert L; Olah, Edith; Olopade, Olufunmilayo I; Olson, Janet E; Olswold, Curtis; Ong, Kai-Ren; Oosterwijk, Jan C; Orr, Nick; Osorio, Ana; Pankratz, V Shane; Papi, Laura; Park-Simon, Tjoung-Won; Paulsson-Karlsson, Ylva; Lloyd, Rachel; Pedersen, Inge Søkilde; Peissel, Bernard; Peixoto, Ana; Perez, Jose I A; Peterlongo, Paolo; Peto, Julian; Pfeiler, Georg; Phelan, Catherine M; Pinchev, Mila; Plaseska-Karanfilska, Dijana; Poppe, Bruce; Porteous, Mary E; Prentice, Ross; Presneau, Nadege; Prokofieva, Darya; Pugh, Elizabeth; Pujana, Miquel Angel; Pylkäs, Katri; Rack, Brigitte; Radice, Paolo; Rahman, Nazneen; Rantala, Johanna; Rappaport-Fuerhauser, Christine; Rennert, Gad; Rennert, Hedy S; Rhenius, Valerie; Rhiem, Kerstin; Richardson, Andrea; Rodriguez, Gustavo C; Romero, Atocha; Romm, Jane; Rookus, Matti A; Rudolph, Anja; Ruediger, Thomas; Saloustros, Emmanouil; Sanders, Joyce; Sandler, Dale P; Sangrajrang, Suleeporn; Sawyer, Elinor J; Schmidt, Daniel F; Schoemaker, Minouk J; Schumacher, Fredrick; Schürmann, Peter; Schwentner, Lukas; Scott, Christopher; Scott, Rodney J; Seal, Sheila; Senter, Leigha; Seynaeve, Caroline; Shah, Mitul; Sharma, Priyanka; Shen, Chen-Yang; Sheng, Xin; Shimelis, Hermela; Shrubsole, Martha J; Shu, Xiao-Ou; Side, Lucy E; Singer, Christian F; Sohn, Christof; Southey, Melissa C; Spinelli, John J; Spurdle, Amanda B; Stegmaier, Christa; Stoppa-Lyonnet, Dominique; Sukiennicki, Grzegorz; Surowy, Harald; Sutter, Christian; Swerdlow, Anthony; Szabo, Csilla I; Tamimi, Rulla M; Tan, Yen Y; Taylor, Jack A; Tejada, Maria-Isabel; Tengström, Maria; Teo, Soo H; Terry, Mary B; Tessier, Daniel C; Teulé, Alex; Thöne, Kathrin; Thull, Darcy L; Tibiletti, Maria Grazia; Tihomirova, Laima; Tischkowitz, Marc; Toland, Amanda E; Tollenaar, Rob A E M; Tomlinson, Ian; Tong, Ling; Torres, Diana; Tranchant, Martine; Truong, Thérèse; Tucker, Kathy; Tung, Nadine; Tyrer, Jonathan; Ulmer, Hans-Ulrich; Vachon, Celine; van Asperen, Christi J; Van Den Berg, David; van den Ouweland, Ans M W; van Rensburg, Elizabeth J; Varesco, Liliana; Varon-Mateeva, Raymonda; Vega, Ana; Viel, Alessandra; Vijai, Joseph; Vincent, Daniel; Vollenweider, Jason; Walker, Lisa; Wang, Zhaoming; Wang-Gohrke, Shan; Wappenschmidt, Barbara; Weinberg, Clarice R; Weitzel, Jeffrey N; Wendt, Camilla; Wesseling, Jelle; Whittemore, Alice S; Wijnen, Juul T; Willett, Walter; Winqvist, Robert; Wolk, Alicja; Wu, Anna H; Xia, Lucy; Yang, Xiaohong R; Yannoukakos, Drakoulis; Zaffaroni, Daniela; Zheng, Wei; Zhu, Bin; Ziogas, Argyrios; Ziv, Elad; Zorn, Kristin K; Gago-Dominguez, Manuela; Mannermaa, Arto; Olsson, Håkan; Teixeira, Manuel R; Stone, Jennifer; Offit, Kenneth; Ottini, Laura; Park, Sue K; Thomassen, Mads; Hall, Per; Meindl, Alfons; Schmutzler, Rita K; Droit, Arnaud; Bader, Gary D; Pharoah, Paul D P; Couch, Fergus J; Easton, Douglas F; Kraft, Peter; Chenevix-Trench, Georgia; García-Closas, Montserrat; Schmidt, Marjanka K; Antoniou, Antonis C; Simard, Jacques

2017-12-01

Most common breast cancer susceptibility variants have been identified through genome-wide association studies (GWAS) of predominantly estrogen receptor (ER)-positive disease. We conducted a GWAS using 21,468 ER-negative cases and 100,594 controls combined with 18,908 BRCA1 mutation carriers (9,414 with breast cancer), all of European origin. We identified independent associations at P < 5 × 10 -8 with ten variants at nine new loci. At P < 0.05, we replicated associations with 10 of 11 variants previously reported in ER-negative disease or BRCA1 mutation carrier GWAS and observed consistent associations with ER-negative disease for 105 susceptibility variants identified by other studies. These 125 variants explain approximately 16% of the familial risk of this breast cancer subtype. There was high genetic correlation (0.72) between risk of ER-negative breast cancer and breast cancer risk for BRCA1 mutation carriers. These findings may lead to improved risk prediction and inform further fine-mapping and functional work to better understand the biological basis of ER-negative breast cancer.

Comparison on different repetition rate locking methods in Er-doped fiber laser

NASA Astrophysics Data System (ADS)

Yang, Kangwen; Zhao, Peng; Luo, Jiang; Huang, Kun; Hao, Qiang; Zeng, Heping

2018-05-01

We demonstrate a systematic comparative research on the all-optical, mechanical and opto-mechanical repetition rate control methods in an Er-doped fiber laser. A piece of Yb-doped fiber, a piezoelectric transducer and an electronic polarization controller are simultaneously added in the laser cavity as different cavity length modulators. By measuring the cavity length tuning ranges, the output power fluctuations, the temporal and frequency repetition rate stability, we show that all-optical method introduces the minimal disturbances under current experimental condition.

Changes in the Healthy Beverage Index in Response to an Intervention Targeting a Reduction in Sugar-Sweetened Beverage Consumption as Compared to an Intervention Targeting Improvements in Physical Activity: Results from the Talking Health Trial.

PubMed

Hedrick, Valisa E; Davy, Brenda M; Myers, Emily A; You, Wen; Zoellner, Jamie M

2015-12-04

The recently developed Healthy Beverage Index (HBI) was designed to evaluate overall beverage intake quality (including total fluid consumption and beverage calories), yet no known intervention studies have assessed longitudinal changes to the HBI. The objective of this investigation was to assess changes in HBI scores in response to a sugar-sweetened beverage (SSB) reduction trial as compared to a physical activity comparison group. Participants were enrolled into a six-month, community-based, controlled behavioral trial and randomized into either a SSB reduction group (SIPsmartER) or a physical activity group (MoveMore). Correlations and multilevel mixed-effects linear regression with intention-to-treat analyses are presented. Total HBI score significantly increased for SIPsmartER (n = 149) (mean increase = 7.5 points (5.4, 9.7), p ≤ 0.001) and MoveMore (n = 143) (mean increase = 3.4 points (1.6, 5.2), p ≤ 0.001) participants, with a significant between group effect (p ≤ 0.05), over the six-month intervention. Other significant changes in HBI components for SIPsmartER included increased SSB and total beverage calorie scores, and decreased low-fat milk and diet soda scores. Changes in total HBI scores were significantly correlated with changes in total Healthy Eating Index-2010 scores (r = 0.15, p ≤ 0.01). Our findings suggest that individual HBI component scores, beyond the SSB component, are influenced by intervention strategies that primarily focus on SSB reduction.

Comparative study on morphologic changes and cell attachment of periodontitis-affected root surfaces following conditioning with CO2 and Er:YAG laser irradiations.

PubMed

Belal, Mahmoud Helmy; Watanabe, Hisashi

2014-10-01

Clinical application of lasers in periodontal therapy has continued to expand in last decades; however there are still some controversies. The present study aimed to compare the conditioning effects of the carbon dioxide (CO2) or erbium-doped: yttrium, aluminum and garnet (Er:YAG) laser on periodontally diseased root surfaces following scaling and root planing (SRP) in terms of the alteration of morphologies as well as the attachment of periodontal ligament cells. Forty-five periodontally affected root specimens were prepared and randomly assigned into three groups: I control (untreated diseased), II. SRP+CO2 laser (pulsed, noncontact mode), and III. SRP+Er:YAG laser (slight contact mode). After treatment, five specimens in each group were used for surface topographic examination. The remaining 10 specimens in each group were incubated with human periodontal ligament cell suspension. All the specimens were finally evaluated by scanning electron microscopy. The control specimens showed the lowest number of cultured cells, mostly in oval shape, with no tightly attached cells. The CO2 lased specimens showed a significant increase in the number of attached cells compared with controls, but demonstrated some major thermal alterations on the surfaces. The Er:YAG lased specimens showed the significantly highest number of attached cells, mostly in flat form, and did not show distinct thermal damage. The present study suggests that compared with the CO2 laser, the Er:YAG laser may constitute a more useful conditioning tool for enhancing periodontal cell attachment to periodontally diseased root surfaces, with fewer undesirable thermal side effects.

40 CFR 1065.602 - Statistics.

Code of Federal Regulations, 2014 CFR

2014-07-01

... Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR POLLUTION CONTROLS ENGINE-TESTING...., differences) between each pair of y refi and y i: ER28AP14.011 ER28AP14.012 Table 1 of § 1065.602—Critical t... concentration is measured continuously from the raw exhaust of an engine, its flow-weighted mean concentration...

Endoplasmic reticulum proteostasis impairment in aging.

PubMed

Martínez, Gabriela; Duran-Aniotz, Claudia; Cabral-Miranda, Felipe; Vivar, Juan P; Hetz, Claudio

2017-08-01

Perturbed neuronal proteostasis is a salient feature shared by both aging and protein misfolding disorders. The proteostasis network controls the health of the proteome by integrating pathways involved in protein synthesis, folding, trafficking, secretion, and their degradation. A reduction in the buffering capacity of the proteostasis network during aging may increase the risk to undergo neurodegeneration by enhancing the accumulation of misfolded proteins. As almost one-third of the proteome is synthetized at the endoplasmic reticulum (ER), maintenance of its proper function is fundamental to sustain neuronal function. In fact, ER stress is a common feature of most neurodegenerative diseases. The unfolded protein response (UPR) operates as central player to maintain ER homeostasis or the induction of cell death of chronically damaged cells. Here, we discuss recent evidence placing ER stress as a driver of brain aging, and the emerging impact of neuronal UPR in controlling global proteostasis at the whole organismal level. Finally, we discuss possible therapeutic interventions to improve proteostasis and prevent pathological brain aging. © 2017 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

Selectivity of natural, synthetic and environmental estrogens for zebrafish estrogen receptors

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

Pinto, Caroline; Grimaldi, Marina; Boulahtouf, Abdelhay

2014-10-01

Zebrafish, Danio rerio, is increasingly used as an animal model to study the effects of pharmaceuticals and environmental estrogens. As most of these estrogens have only been tested on human estrogen receptors (ERs), it is necessary to measure their effects on zebrafish ERs. In humans there are two distinct nuclear ERs (hERα and hERβ), whereas the zebrafish genome encodes three ERs, zfERα and two zfERβs (zfERβ1 and zfERβ2). In this study, we established HeLa-based reporter cell lines stably expressing each of the three zfERs. We first reported that estrogens more efficiently activate the zfERs at 28 °C as compared tomore » 37 °C, thus reflecting the physiological temperature of zebrafish in wildlife. We then showed significant differences in the ability of agonist and antagonist estrogens to modulate activation of the three zfER isotypes in comparison to hERs. Environmental compounds (bisphenol A, alkylphenols, mycoestrogens) which are hER panagonists and hERβ selective agonists displayed greater potency for zfERα as compared to zfERβs. Among hERα selective synthetic agonists, PPT did not activate zfERα while 16α-LE2 was the most zfERα selective compound. Altogether, these results confirm that all hER ligands control in a similar manner the transcriptional activity of zfERs although significant differences in selectivity were observed among subtypes. The zfER subtype selective ligands that we identified thus represent new valuable tools to dissect the physiological roles of the different zfERs. Finally, our work also points out that care has to be taken in transposing the results obtained using the zebrafish as a model for human physiopathology. - Highlights: • Zebrafish is increasingly used to study the effects of estrogens. • We assessed the activity of pharmaceutical and environmental estrogens on zfERs. • Environmental estrogens displayed greater potency for zfERα compared to zfERβs. • hERβ selective agonists displayed greater potency for zfERα compared to zfERβs. • The hERα selective agonist 16αL-E2 is the most zfERα selective compound.« less

The Role of Emotion Regulation in Autism Spectrum Disorder RH: Emotion Regulation in ASD

PubMed Central

Mazefsky, Carla A.; Herrington, John; Siegel, Matthew; Scarpa, Angela; Maddox, Brenna B.; Scahill, Lawrence; White, Susan W.

2013-01-01

Objective Autism spectrum disorder (ASD) is associated with amplified emotional responses and poor emotional control, but little is known about the underlying mechanisms. This paper provides a conceptual and methodological framework for understanding compromised emotion regulation (ER) in ASD. Method After defining ER and related constructs, methods to study ER were reviewed with special consideration on how to apply these approaches to ASD. Against the backdrop of cognitive characteristics in ASD and existing ER theories, available research was examined to identify likely contributors to emotional dysregulation in ASD. Results Little is currently known about ER in youth with ASD. Some mechanisms that contribute to poor ER in ASD may be shared with other clinical populations (e.g., physiological arousal, degree of negative and positive affect, alterations in the amygdala and prefrontal cortex), whereas other mechanisms may be more unique to ASD (e.g., differences in information processing/perception, cognitive factors (e.g., rigidity), less goal-directed behavior and more disorganized emotion in ASD). Conclusions Although assignment of concomitant psychiatric diagnoses is warranted in some cases, poor ER may be inherent in ASD and may provide a more parsimonious conceptualization for the many associated socio-emotional and behavioral problems in this population. Further study of ER in youth with ASD may identify meaningful subgroups of patients and lead to more effective individualized treatments. PMID:23800481

Platelet derived growth factor secretion and bone healing after Er:YAG laser bone irradiation.

PubMed

Kesler, Gavriel; Shvero, Dana Kesler; Tov, Yariv Siman; Romanos, George

2011-03-01

Er:YAG laser irradiation has been reported to enhance wound healing. However, no studies have evaluated the synthesis of growth factors after laser irradiation. The present study investigated the effects of laser irradiation on the amount of secretion of platelet derived growth factor (PDGF) in the wound, clarifying the effects of the Er:YAG laser on the bone healing. Osteotomies were prepared in the tibiae of 28 rats using an Er:YAG laser (test group). Maximum power of 8 watts, energy per pulse of 700 mJ, and frequency up to 50 Hz were used. The laser was used with external water irrigation, a spot size of 2 mm, energy per pulse of 500 to 1000 mJ/pulse, and energy density of 32 J/cm(2). Twenty eight additional rats served as a control group and their osteotomies were prepared with a drill 1.3 mm in diameter at 1000 rpm, with simultaneous saline irrigation. Two rats from the tested group and 2 from the control group were sacrificed on each day following surgery (1-14 days), and the tissue specimens were prepared for histologic evaluation. Immunohistochemical staining with anti-PDGF was performed after histologic examination. The difference between the PDGF staining intensities of the 2 treatment groups was analyzed using a multivariate logistic regression test. A significant rise in PDGF staining occurred in both groups 2-3 days following surgery. However, while high PDGF counts remained for the 2-week experimental period in the laser group, PDGF levels in the control group returned to baseline levels 8 days post surgery. The 2 groups (laser and control) were found to be different throughout the experiment, and the rat type was found to be a significant predictor (P  =  .000011). The present study demonstrated that Er:YAG laser irradiation seems to stimulate the secretion of PDGF in osteotomy sites in a rat model. It is possible that the high levels of PDGF are part of the mechanism that Er:YAG irradiation enhances and improves the healing of osteotomy sites.

Supplementing dietary sugar promotes endoplasmic reticulum stress-independent insulin resistance and fatty liver in goose.

PubMed

Geng, Tuoyu; Zhao, Xing; Xia, Lili; Liu, Long; Li, Fuyuan; Yang, Biao; Wang, Qianqian; Montgomery, Sean; Cui, Hengmi; Gong, Daoqing

2016-08-05

It is known that endoplasmic reticulum stress (ERS) contributes to insulin resistance (IR) and non-alcoholic fatty liver disease (NAFLD) in mammals. However, we recently demonstrated that overfeeding with a traditional diet (mainly consisting of cooked maize) does not induce ERS in goose. As cellular studies show that high glucose and palmitate can trigger ERS in mammalian cells, we hypothesized that supplementing sugar to the traditional diet could induce ERS, thus promoting insulin resistance and fatty liver. To test the hypothesis, we first treated goose primary hepatocytes with high glucose (25 mM and 50 mM) and palmitate (0.5 mM) supplemented with or without 0.25 mM oleate. Data indicated that, as in mammalian cells, high glucose and palmitate indeed induced ERS in goose primary hepatocytes, and palmitate-induced ERS was suppressed by supplemental 0.25 mM oleate. We then tested the hypothesis with an in vivo study, in which Landes geese overfed with traditional or novel diets (i.e., the traditional diet supplemented with sugar) were compared with control geese (normally fed with cooked maize) for ERS, IR and fatty liver. The differences in glucose tolerance, insulin tolerance and postprandial blood glucose between the geese overfed with traditional and novel diets suggested that supplementing dietary sugar promoted IR. This promotion was accompanied with an increasing trend of liver weight and abdominal fat weight relative to body weight. Surprisingly, compared to overfeeding with the traditional diet, overfeeding with the novel diet did not induce ERS, even further suppressed ERS in goose fatty liver. Together, our findings suggest that supplementing dietary sugar promotes ERS-independent IR and fatty liver in goose. It is intriguing to discover the factor(s) protecting goose liver from ERS as well as the non-ERS mechanism underlying IR. Copyright © 2016 Elsevier Inc. All rights reserved.

Effects of a behavioral and health literacy intervention to reduce sugar-sweetened beverages: a randomized-controlled trial.

PubMed

Zoellner, Jamie M; Hedrick, Valisa E; You, Wen; Chen, Yvonnes; Davy, Brenda M; Porter, Kathleen J; Bailey, Angela; Lane, Hannah; Alexander, Ramine; Estabrooks, Paul A

2016-03-22

Despite excessive consumption of sugar-sweetened beverages (SSB), little is known about behavioral interventions to reduce SSB intake among adults, particularly in medically-underserved rural communities. This type 1 effectiveness-implementation hybrid RCT, conducted in 2012-2014, applied the RE-AIM framework and was designed to assess the effectiveness of a behavioral intervention targeting SSB consumption (SIPsmartER) when compared to an intervention targeting physical activity (MoveMore) and to determine if health literacy influenced retention, engagement or outcomes. Guided by the Theory of Planned Behavior and health literacy strategies, the 6 month multi-component intervention for both conditions included three small-group classes, one live teach-back call, and 11 interactive voice response calls. Validated measures were used to assess SSB consumption (primary outcome) and all secondary outcomes including physical activity behaviors, theory-based constructs, quality of life, media literacy, anthropometric, and biological outcomes. Targeting a medically-underserved rural region in southwest Virginia, 1056 adult participants were screened, 620 (59%) eligible, 301 (49%) enrolled and randomized, and 296 included in these 2015 analyses. Participants were 93% Caucasian, 81% female, 31 % ≤ high-school educated, 43% < $14,999 household income, and 33% low health literate. Retention rates (74%) and program engagement was not statistically different between conditions. Compared to MoveMore, SIPsmartER participants significantly decreased SSB kcals and BMI at 6 months. SIPsmartER participants significantly decreased SSB intake by 227 (95% CI = -326,-127, p < 0.001) kcals/day from baseline to 6 months when compared to the decrease of 53 (95% CI = -88,-17, p < 0.01) kcals/day among MoveMore participants (p < 0.001). SIPsmartER participants decreased BMI by 0.21 (95% CI = -0.35,-0.06; p < 0.01) kg/m(2) from baseline to 6 months when compared to the non-significant 0.10 (95 % CI = -0.23, 0.43; NS) kg/m(2) gain among MoveMore participants (p < 0.05). Significant 0-6 month effects were observed for about half of the theory-based constructs, but for no biological outcomes. Health literacy status did not influence retention rates, engagement or outcomes. SIPsmartER is an effective intervention to decrease SSB consumption among adults and is promising for translation into practice settings. SIPsmartER also yielded small, yet significant, improvements in BMI. By using health literacy-focused strategies, the intervention was robust in achieving reductions for participants of varying health literacy status. Clinicaltrials.gov; ID: NCT02193009 .

Receptor-Defined Subtypes of Breast Cancer in Indigenous Populations in Africa: A Systematic Review and Meta-Analysis

PubMed Central

Eng, Amanda; McCormack, Valerie; dos-Santos-Silva, Isabel

2014-01-01

Background Breast cancer is the most common female cancer in Africa. Receptor-defined subtypes are a major determinant of treatment options and disease outcomes but there is considerable uncertainty regarding the frequency of poor prognosis estrogen receptor (ER) negative subtypes in Africa. We systematically reviewed publications reporting on the frequency of breast cancer receptor-defined subtypes in indigenous populations in Africa. Methods and Findings Medline, Embase, and Global Health were searched for studies published between 1st January 1980 and 15th April 2014. Reported proportions of ER positive (ER+), progesterone receptor positive (PR+), and human epidermal growth factor receptor-2 positive (HER2+) disease were extracted and 95% CI calculated. Random effects meta-analyses were used to pool estimates. Fifty-four studies from North Africa (n = 12,284 women with breast cancer) and 26 from sub-Saharan Africa (n = 4,737) were eligible. There was marked between-study heterogeneity in the ER+ estimates in both regions (I2>90%), with the majority reporting proportions between 0.40 and 0.80 in North Africa and between 0.20 and 0.70 in sub-Saharan Africa. Similarly, large between-study heterogeneity was observed for PR+ and HER2+ estimates (I2>80%, in all instances). Meta-regression analyses showed that the proportion of ER+ disease was 10% (4%–17%) lower for studies based on archived tumor blocks rather than prospectively collected specimens, and 9% (2%–17%) lower for those with ≥40% versus those with <40% grade 3 tumors. For prospectively collected samples, the pooled proportions for ER+ and triple negative tumors were 0.59 (0.56–0.62) and 0.21 (0.17–0.25), respectively, regardless of region. Limitations of the study include the lack of standardized procedures across the various studies; the low methodological quality of many studies in terms of the representativeness of their case series and the quality of the procedures for collection, fixation, and receptor testing; and the possibility that women with breast cancer may have contributed to more than one study. Conclusions The published data from the more appropriate prospectively measured specimens are consistent with the majority of breast cancers in Africa being ER+. As no single subtype dominates in the continent availability of receptor testing should be a priority, especially for young women with early stage disease where appropriate receptor-specific treatment modalities offer the greatest potential for reducing years of life lost. Please see later in the article for the Editors' Summary PMID:25202974

Ethanol metabolism, oxidative stress, and endoplasmic reticulum stress responses in the lungs of hepatic alcohol dehydrogenase deficient deer mice after chronic ethanol feeding

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

Kaphalia, Lata; Boroumand, Nahal; Hyunsu, Ju

Consumption and over-consumption of alcoholic beverages are well-recognized contributors to a variety of pulmonary disorders, even in the absence of intoxication. The mechanisms by which alcohol (ethanol) may produce disease include oxidative stress and prolonged endoplasmic reticulum (ER) stress. Many aspects of these processes remain incompletely understood due to a lack of a suitable animal model. Chronic alcohol over-consumption reduces hepatic alcohol dehydrogenase (ADH), the principal canonical metabolic pathway of ethanol oxidation. We therefore modeled this situation using hepatic ADH-deficient deer mice fed 3.5% ethanol daily for 3 months. Blood ethanol concentration was 180 mg% in ethanol fed mice, comparedmore » to < 1.0% in the controls. Acetaldehyde (oxidative metabolite of ethanol) was minimally, but significantly increased in ethanol-fed vs. pair-fed control mice. Total fatty acid ethyl esters (FAEEs, nonoxidative metabolites of ethanol) were 47.6 μg/g in the lungs of ethanol-fed mice as compared to 1.5 μg/g in pair-fed controls. Histological and immunohistological evaluation showed perivascular and peribronchiolar lymphocytic infiltration, and significant oxidative injury, in the lungs of ethanol-fed mice compared to pair-fed controls. Several fold increases for cytochrome P450 2E1, caspase 8 and caspase 3 found in the lungs of ethanol-fed mice as compared to pair-fed controls suggest role of oxidative stress in ethanol-induced lung injury. ER stress and unfolded protein response signaling were also significantly increased in the lungs of ethanol-fed mice. Surprisingly, no significant activation of inositol-requiring enzyme-1α and spliced XBP1 was observed indicating a lack of activation of corrective mechanisms to reinstate ER homeostasis. The data suggest that oxidative stress and prolonged ER stress, coupled with formation and accumulation of cytotoxic FAEEs may contribute to the pathogenesis of alcoholic lung disease. - Highlights: • Chronic ethanol feeding causes oxidative stress, ER stress and inflammation in lungs of ADH– deer mice. • Chronic ethanol feeding generates FAEEs (nonoxidative metabolites of ethanol) in lungs of ADH– deer mice. • Chronic ethanol feeding induces CYP2E1 in the lungs of ADH– deer mice. • Lack of ER homeostasis due to a prolonged ethanol feeding could trigger inflammation.« less

Research and Development for Health and Environmental Hazard Assessment. Task Order 1. Development of Data Base Requirements for Human Health Based Water Quality Criteria for Military Recycle/Reuse Applications.

DTIC Science & Technology

1980-06-01

Environmental Hazard Assessment -. .’.’ASK ORDER I j EVELOPMENT OF DATA BASE REQUIREMENTS I . .oR HUMAN HEALTH BASED WATER QUALITY CRITERIA | COR MILITARY...Requirements for Human Sep a -1979- June 89 Health Based Water Quality Criteria for Military -%4,o ER Reevcle/ Reuse Applications Is 8_ 3.7𔃾__=1_...KEY WORDS (Continue on reverse aide If neceseary and Identify by block number) Water Reuse, Water Recycle, Water Quality Criteria, Human Health

Surgical treatments for esophageal cancers

PubMed Central

Allum, William H.; Bonavina, Luigi; Cassivi, Stephen D.; Cuesta, Miguel A.; Dong, Zhao Ming; Felix, Valter Nilton; Figueredo, Edgar; Gatenby, Piers A.C.; Haverkamp, Leonie; Ibraev, Maksat A.; Krasna, Mark J.; Lambert, René; Langer, Rupert; Lewis, Michael P.N.; Nason, Katie S.; Parry, Kevin; Preston, Shaun R.; Ruurda, Jelle P.; Schaheen, Lara W.; Tatum, Roger P.; Turkin, Igor N.; van der Horst, Sylvia; van der Peet, Donald L.; van der Sluis, Peter C.; van Hillegersberg, Richard; Wormald, Justin C.R.; Wu, Peter C.; Zonderhuis, Barbara M.

2015-01-01

The following, from the 12th OESO World Conference: Cancers of the Esophagus, includes commentaries on the role of the nurse in preparation of esophageal resection (ER); the management of patients who develop high-grade dysplasia after having undergone Nissen fundoplication; the trajectory of care for the patient with esophageal cancer; the influence of the site of tumor in the choice of treatment; the best location for esophagogastrostomy; management of chylous leak after esophagectomy; the optimal approach to manage thoracic esophageal leak after esophagectomy; the choice for operational approach in surgery of cardioesophageal crossing; the advantages of robot esophagectomy; the place of open esophagectomy; the advantages of esophagectomy compared to definitive chemoradiotherapy; the pathologist report in the resected specimen; the best way to manage patients with unsuspected positive microscopic margin after ER; enhanced recovery after surgery for ER: expedited care protocols; and long-term quality of life in patients following esophagectomy. PMID:25266029

Architecture and permeability of post-cytokinesis plasmodesmata lacking cytoplasmic sleeves.

PubMed

Nicolas, William J; Grison, Magali S; Trépout, Sylvain; Gaston, Amélia; Fouché, Mathieu; Cordelières, Fabrice P; Oparka, Karl; Tilsner, Jens; Brocard, Lysiane; Bayer, Emmanuelle M

2017-06-12

Plasmodesmata are remarkable cellular machines responsible for the controlled exchange of proteins, small RNAs and signalling molecules between cells. They are lined by the plasma membrane (PM), contain a strand of tubular endoplasmic reticulum (ER), and the space between these two membranes is thought to control plasmodesmata permeability. Here, we have reconstructed plasmodesmata three-dimensional (3D) ultrastructure with an unprecedented level of 3D information using electron tomography. We show that within plasmodesmata, ER-PM contact sites undergo substantial remodelling events during cell differentiation. Instead of being open pores, post-cytokinesis plasmodesmata present such intimate ER-PM contact along the entire length of the pores that no intermembrane gap is visible. Later on, during cell expansion, the plasmodesmata pore widens and the two membranes separate, leaving a cytosolic sleeve spanned by tethers whose presence correlates with the appearance of the intermembrane gap. Surprisingly, the post-cytokinesis plasmodesmata allow diffusion of macromolecules despite the apparent lack of an open cytoplasmic sleeve, forcing the reassessment of the mechanisms that control plant cell-cell communication.

Hospitalizations for asthma: impact of a program for the control of asthma and allergic rhinitis in Feira de Santana, Brazil.

PubMed

Brandão, Heli Vieira; Cruz, Constança Margarida Sampaio; Santos, Ivan da Silva; Ponte, Eduardo Vieira; Guimarães, Armênio; Augusto Filho, Alvaro

2009-08-01

To evaluate the impact of the Programa de Controle da Asma e Rinite Alérgica em Feira de Santana (ProAR-FS, Program for the Control of Asthma and Allergic Rhinitis in Feira de Santana) on the frequency of hospitalizations for asthma in patients monitored at a referral center for one year. This was a historical control study involving 253 consecutive patients with asthma, ages ranging from 4 to 76 years. We compared the frequency of hospital admissions and visits to the emergency room (ER) in the 12 months prior to and after their admission to the ProAR-FS. During the program, patients received free treatment, including inhaled medications and education on asthma. Demographic and socioeconomic aspects were also assessed. There was a significant reduction in the number of hospitalizations (465 vs. 21) and of visits to the ER (2,473 vs. 184) after their admission to ProAR-FS (p < 0.001 for both). Of the 253 patients who had been hospitalized and had had ER visits within the year prior to the admission to ProAR-FS, only 16 were hospitalized and 92 visited the ER during the follow-up year, representing a reduction of 94% and 64%, respectively. Implementing a referral center for the treatment of asthma and rhinitis in the Unified Health Care System, with the free distribution of inhaled corticosteroids and the support of an education program, is a highly effective strategy for the control of asthma.

Impact of ER520, a candidate of selective estrogen receptor modulators, on in vitro cell growth, migration, invasion, angiogenesis and in vivo tumor xenograft of human breast cancer cells.

PubMed

Wang, Lijun; Wang, Ying; Du, Huaqing; Jiang, Yao; Tang, Zhichao; Liu, Hongyi; Xiang, Hua; Xiao, Hong

2015-12-01

ER520, a derivative of indenoisoquinoline, is a patented compound. This study was designed to screen its biological properties and to evaluate its antineoplastic and antiangiogenic effect. Western blot was employed to monitor the ERα and ERβ protein expression in human breast cancer MCF-7 cells and endometrial carcinoma Ishikawa cells. MTT assay was employed to determine cell proliferation. Cell adhesion, scratch and Transwell assay were utilized to estimate the ability of cellular adhesion, migration and invasion. ELISA kit was applied to detect the VEGF products in culture medium. In addition, the inhibitory effect of ER520 on the vessel-like construction of HUVEC cells and the angiogenesis of chicken embryos was investigated. The efficiency of ER520 on tumor growth in nude mice was also assessed. ER520 inhibited the expression of ERα in MCF-7 and Ishikawa cells, while it increased ERβ protein level. ER520 also suppressed the proliferation of MCF-7 and Ishikawa cells. Due to its remarkably negative role in cell adhesion, migration and invasion, ER520 showed a potential ability of inhibiting tumor metastasis. Meanwhile, ER520 reduced the VEGF secretion of MCF-7 and Ishikawa cells, prevented the formation of VEGF-stimulated tubular structure and the cell migration of HUVEC cells, and inhibited the angiogenesis of chicken chorioallantoic membrane. Animal experiment also demonstrated that ER520 could frustrate the in vivo tumor growth and the inhibitory ratio was 48.5 % compared with control group. Our findings indicate that ER520 possesses the competence to be a candidate against breast cancer and angiogenesis.

4-PBA improves lithium-induced nephrogenic diabetes insipidus by attenuating ER stress.

PubMed

Zheng, Peili; Lin, Yu; Wang, Feifei; Luo, Renfei; Zhang, Tiezheng; Hu, Shan; Feng, Pinning; Liang, Xinling; Li, Chunling; Wang, Weidong

2016-10-01

Endoplasmic reticulum (ER) stress has been implicated in some types of glomerular and tubular disorders. The objectives of this study were to elucidate the role of ER stress in lithium-induced nephrogenic diabetes insipidus (NDI) and to investigate whether attenuation of ER stress by 4-phenylbutyric acid (4-PBA) improves urinary concentrating defect in lithium-treated rats. Wistar rats received lithium (40 mmol/kg food), 4-PBA (320 mg/kg body wt by gavage every day), or no treatment (control) for 2 wk, and they were dehydrated for 24 h before euthanasia. Lithium treatment resulted in increased urine output and decreased urinary osmolality, which was significantly improved by 4-PBA. 4-PBA also prevented reduced protein expression of aquaporin-2 (AQP2), pS256-AQP2, and pS261-AQP2 in the inner medulla of kidneys from lithium-treated rats after 24-h dehydration. Lithium treatment resulted in increased expression of ER stress markers in the inner medulla, which was associated with dilated cisternae and expansion of ER in the inner medullary collecting duct (IMCD) principal cells. Confocal immunofluorescence studies showed colocalization of a molecular chaperone, binding IgG protein (BiP), with AQP2 in principal cells. Immunohistochemistry demonstrated increased intracellular expression of BiP and decreased AQP2 expression in IMCD principal cells of kidneys from lithium-treated rats. 4-PBA attenuated expression of ER stress markers and recovered ER morphology. In IMCD suspensions isolated from lithium-treated rats, 4-PBA incubation was also associated with increased AQP2 expression and ameliorated ER stress. In conclusion, in experimental lithium-induced NDI, 4-PBA improved the urinary concentrating defect and increased AQP2 expression, likely via attenuating ER stress in IMCD principal cells. Copyright © 2016 the American Physiological Society.

Lace plant ethylene receptors, AmERS1a and AmERS1c, regulate ethylene-induced programmed cell death during leaf morphogenesis.

PubMed

Rantong, Gaolathe; Evans, Rodger; Gunawardena, Arunika H L A N

2015-10-01

The lace plant, Aponogeton madagascariensis, is an aquatic monocot that forms perforations in its leaves as part of normal leaf development. Perforation formation occurs through developmentally regulated programmed cell death (PCD). The molecular basis of PCD regulation in the lace plant is unknown, however ethylene has been shown to play a significant role. In this study, we examined the role of ethylene receptors during perforation formation. We isolated three lace plant ethylene receptors AmERS1a, AmERS1b and AmERS1c. Using quantitative PCR, we examined their transcript levels at seven stages of leaf development. Through laser-capture microscopy, transcript levels were also determined in cells undergoing PCD and cells not undergoing PCD (NPCD cells). AmERS1a transcript levels were significantly lower in window stage leaves (in which perforation formation and PCD are occurring) as compared to all other leaf developmental stages. AmERS1a and AmERS1c (the most abundant among the three receptors) had the highest transcript levels in mature stage leaves, where PCD is not occurring. Their transcript levels decreased significantly during senescence-associated PCD. AmERS1c had significantly higher transcript levels in NPCD compared to PCD cells. Despite being significantly low in window stage leaves, AmERS1a transcripts were not differentially expressed between PCD and NPCD cells. The results suggested that ethylene receptors negatively regulate ethylene-controlled PCD in the lace plant. A combination of ethylene and receptor levels determines cell fate during perforation formation and leaf senescence. A new model for ethylene emission and receptor expression during lace plant perforation formation and senescence is proposed.

The NASA Earth Research-2 (ER-2) Aircraft: A Flying Laboratory for Earth Science Studies

NASA Technical Reports Server (NTRS)

Navarro, Robert

2007-01-01

The National Aeronautics and Space Administration Dryden Flight Research Center, Edwards, California, has two Lockheed Martin Corporation (Bethesda, Maryland) Earth Research-2 (ER2) aircraft that serve as high-altitude and long-range flying laboratories. The ER-2 aircraft has been successfully utilized to conduct scientific studies of stratospheric and tropospheric chemistry, land-use mapping, disaster assessment, preliminary testing and calibration and validation of satellite sensors. The research missions for the ER-2 aircraft are planned, implemented, and managed by the Dryden Flight Research Center Science Mission Directorate. Maintenance and instrument payload integration is conducted by Dryden personnel. The ER-2 aircraft provides experimenters with a wide array of payload accommodations areas with suitable environment control with required electrical and mechanical interfaces. Missions may be flown out of Dryden or from remote bases worldwide, according to research requirements. The NASA ER-2 aircraft is utilized by a variety of customers, including U.S. Government agencies, civilian organizations, universities, and state governments. The combination of the ER-2 aircraft s range, endurance, altitude, payload power, payload volume and payload weight capabilities complemented by a trained maintenance and operations team provides an excellent and unique platform system to the science community and other customers.

ER residency of the ceramide phosphoethanolamine synthase SMSr relies on homotypic oligomerization mediated by its SAM domain.

PubMed

Cabukusta, Birol; Kol, Matthijs; Kneller, Laura; Hilderink, Angelika; Bickert, Andreas; Mina, John G M; Korneev, Sergei; Holthuis, Joost C M

2017-01-25

SMSr/SAMD8 is an ER-resident ceramide phosphoethanolamine synthase with a critical role in controlling ER ceramides and suppressing ceramide-induced apoptosis in cultured cells. SMSr-mediated ceramide homeostasis relies on the enzyme's catalytic activity as well as on its N-terminal sterile α-motif or SAM domain. Here we report that SMSr-SAM is structurally and functionally related to the SAM domain of diacylglycerol kinase DGKδ, a central regulator of lipid signaling at the plasma membrane. Native gel electrophoresis indicates that both SAM domains form homotypic oligomers. Chemical crosslinking studies show that SMSr self-associates into ER-resident trimers and hexamers that resemble the helical oligomers formed by DGKδ-SAM. Residues critical for DGKδ-SAM oligomerization are conserved in SMSr-SAM and their substitution causes a dissociation of SMSr oligomers as well as a partial redistribution of the enzyme to the Golgi. Conversely, treatment of cells with curcumin, a drug disrupting ceramide and Ca 2+ homeostasis in the ER, stabilizes SMSr oligomers and promotes retention of the enzyme in the ER. Our data provide first demonstration of a multi-pass membrane protein that undergoes homotypic oligomerization via its SAM domain and indicate that SAM-mediated self-assembly of SMSr is required for efficient retention of the enzyme in the ER.

Cross-lagged relations among parenting, children's emotion regulation, and psychosocial adjustment in early adolescence.

PubMed

Otterpohl, Nantje; Wild, Elke

2015-01-01

Numerous studies have reported substantive correlations between indicators of parenting, children's emotion regulation (ER), and children's psychosocial adjustment. However, studies on underlying mechanisms are scarce. Particularly in early adolescence, it is still unclear whether relations between parenting and ER are caused by adolescent behavior, by parent behavior, or by reciprocal processes. Moreover, it is unclear whether ER can be seen as an antecedent or a consequence of psychosocial adjustment. The aim of this study was to examine predictive relations among parenting and adolescents' ER, and adolescents' ER and psychosocial adjustment, respectively. We collected longitudinal, multiple informant data at two measurement occasions (Grade 6, Grade 7). All told, 1,100 adolescents (10-14 years) and their parents filled out questionnaires assessing responsiveness and psychological control, adolescents' anger regulation, and adolescents' problem and prosocial behavior. Cross-lagged analyses revealed reciprocal effects between parenting, ER, and adjustment for the parent and boys', but not for the girls', report. Moreover, relations were different for adolescents with versus without clinically elevated symptoms of psychopathology. Our findings support the assumption that reciprocal relations between parenting, ER, and psychosocial adjustment are likely to persist until early adolescence. Nevertheless, the moderating role of gender and psychopathology should be taken into account. Possible reasons for the different findings, and practical implications, are discussed.

Fine Mapping of a Gene (ER4.1) that Causes Epidermal Reticulation of Tomato Fruit and Characterization of the Associated Transcriptome

PubMed Central

Cui, Lipeng; Qiu, Zhengkun; Wang, Zhirong; Gao, Jianchang; Guo, Yanmei; Huang, Zejun; Du, Yongchen; Wang, Xiaoxuan

2017-01-01

The hydrophobic cuticle that covers the surface of tomato (Solanum lycopersicum) fruit plays key roles in development and protection against biotic and abiotic stresses, including water loss, mechanical damage, UV radiation, pathogens, and pests. However, many details of the genes and regulatory mechanisms involved in cuticle biosynthesis in fleshy fruits are not well understood. In this study, we describe a novel tomato fruit phenotype, characterized by epidermal reticulation (ER) of green fruit and a higher water loss rate than wild type (WT) fruit. The ER phenotype is controlled by a single gene, ER4.1, derived from an introgressed chromosomal segment from the wild tomato species S. pennellii (LA0716). We performed fine mapping of the single dominant gene to an ~300 kb region and identified Solyc04g082540, Solyc04g082950, Solyc04g082630, and Solyc04g082910as potential candidate genes for the ER4.1 locus, based on comparative RNA-seq analysis of ER and WT fruit peels. In addition, the transcriptome analysis revealed that the expression levels of genes involved in cutin, wax and flavonoid biosynthesis were altered in the ER fruit compared with WT. This study provides new insights into the regulatory mechanisms and metabolism of the fruit cuticle. PMID:28798753

Analysis of Shear Bond Strength and Morphology of Er:YAG Laser-Recycled Ceramic Orthodontic Brackets.

PubMed

Han, Ruo-qiao; Yang, Kai; Ji, Ling-fei; Ling, Chen

2016-01-01

The aim of this study was to compare the recycling of deboned ceramic brackets via an Er:YAG laser or via the traditional chairside processing methods of flaming and sandblasting; shear bond strength and morphological changes were evaluated in recycled brackets versus new brackets. 3M Clarity Self-Ligating Ceramic Brackets with a microcrystalline base were divided into groups subjected to flaming, sandblasting, or exposure to an Er:YAG laser. New ceramic brackets served as a control group. Shear bond strengths were determined with an Electroforce test machine and tested for statistical significance through analysis of variance. Morphological examinations of the recycled ceramic bracket bases were conducted with scanning electron microscopy and confocal laser scanning microscopy. Residue on the bracket base was analyzed with Raman spectroscopy. Faded, dark adhesive was left on recycled bracket bases processed via flaming. Adhesive was thoroughly removed by both sandblasting and exposure to an Er:YAG laser. Compared with new brackets, shear bond strength was lower after sandblasting (p < 0.05), but not after exposure to an Er:YAG laser. The Er:YAG laser caused no damage to the bracket. Er:YAG lasers effectively remove adhesive from the bases of ceramic brackets without damaging them; thus, this method may be preferred over other recycling methods.

Parkin regulation of CHOP modulates susceptibility to cardiac endoplasmic reticulum stress.

PubMed

Han, Kim; Hassanzadeh, Shahin; Singh, Komudi; Menazza, Sara; Nguyen, Tiffany T; Stevens, Mark V; Nguyen, An; San, Hong; Anderson, Stasia A; Lin, Yongshun; Zou, Jizhong; Murphy, Elizabeth; Sack, Michael N

2017-05-18

The regulatory control of cardiac endoplasmic reticulum (ER) stress is incompletely characterized. As ER stress signaling upregulates the E3-ubiquitin ligase Parkin, we investigated the role of Parkin in cardiac ER stress. Parkin knockout mice exposed to aortic constriction-induced cardiac pressure-overload or in response to systemic tunicamycin (TM) developed adverse ventricular remodeling with excessive levels of the ER regulatory C/EBP homologous protein CHOP. CHOP was identified as a Parkin substrate and its turnover was Parkin-dose and proteasome-dependent. Parkin depletion in cardiac HL-1 cells increased CHOP levels and enhanced susceptibility to TM-induced cell death. Parkin reconstitution rescued this phenotype and the contribution of excess CHOP to this ER stress injury was confirmed by reduction in TM-induced cell death when CHOP was depleted in Parkin knockdown cardiomyocytes. Isogenic Parkin mutant iPSC-derived cardiomyocytes showed exaggerated ER stress induced CHOP and apoptotic signatures and myocardium from subjects with dilated cardiomyopathy showed excessive Parkin and CHOP induction. This study identifies that Parkin functions to blunt excessive CHOP to prevent maladaptive ER stress-induced cell death and adverse cardiac ventricular remodeling. Additionally, Parkin is identified as a novel post-translational regulatory moderator of CHOP stability and uncovers an additional stress-modifying function of this E3-ubiquitin ligase.

Meeting Total Fat Requirements for School Lunches: Influence of School Policies and Characteristics. ERS Report Summary

ERIC Educational Resources Information Center

Newman, Constance; Guthrie, Joanne; Mancino, Lisa; Ralston, Katherine; Musiker, Melissa

2009-01-01

Concerns about child obesity have raised questions about the quality of meals served in the National School Lunch Program (NSLP). Local, State, and Federal policymakers responded to these concerns beginning in the mid-1990s by instituting a range of policies and standards to improve the quality of USDA-subsidized meals. While most of USDA's…

Optimal control of Formula One car energy recovery systems

NASA Astrophysics Data System (ADS)

Limebeer, D. J. N.; Perantoni, G.; Rao, A. V.

2014-10-01

The utility of orthogonal collocation methods in the solution of optimal control problems relating to Formula One racing is demonstrated. These methods can be used to optimise driver controls such as the steering, braking and throttle usage, and to optimise vehicle parameters such as the aerodynamic down force and mass distributions. Of particular interest is the optimal usage of energy recovery systems (ERSs). Contemporary kinetic energy recovery systems are studied and compared with future hybrid kinetic and thermal/heat ERSs known as ERS-K and ERS-H, respectively. It is demonstrated that these systems, when properly controlled, can produce contemporary lap time using approximately two-thirds of the fuel required by earlier generation (2013 and prior) vehicles.

Leisure-time physical activity and breast cancer risk by hormone receptor status: effective life periods and exercise intensity.

PubMed

Suzuki, Reiko; Iwasaki, Motoki; Kasuga, Yoshio; Yokoyama, Shiro; Onuma, Hiroshi; Nishimura, Hideki; Kusama, Ritsu; Shimazu, Taichi; Tsugane, Shoichiro

2010-11-01

Physical activity may decrease breast cancer risk. However, it is unclear what intensity of exercise and during which life periods this effect on decreasing risk is efficiently expressed, and whether the associations differ by the estrogen-/progesterone- receptor (ER/PR) status of tumors. We investigated associations between age- and intensity-specific leisure-time physical activity and ER/PR-defined breast cancer risk. We conducted a hospital-based case-control study in Nagano, Japan. Subjects were 405 cases newly diagnosed (>99% known ER/PR) from 2001 to 2005, who were age-/area-matched with 405 controls. Activity was assessed with a self-reported questionnaire which considered intensity level (moderate and/or strenuous) at different ages (at 12 and 20 years, and in the previous 5 years). Odds ratios (ORs) and 95% confidence intervals were calculated using logistic regression. Strenuous but not moderate physical activity at age 12 was inversely associated with pre- and postmenopausal breast cancer risk across ER/PR subtypes [overall OR(≥ 5 days/week vs. none) = 0.24 (0.14-0.43)]. Moderate physical activity in the previous 5 years was significantly associated with a decrease in risk for postmenopausal ER + PR + tumors only [OR(≥ 1 day/week vs. none) = 0.35 (0.18-0.67)]. Strenuous activity in teens and moderate activity after menopause may contribute to a reduction in breast cancer risk.

An N-Terminal ER Export Signal Facilitates the Plasma Membrane Targeting of HCN1 Channels in Photoreceptors.

PubMed

Pan, Yuan; Laird, Joseph G; Yamaguchi, David M; Baker, Sheila A

2015-06-01

Hyperpolarization-activated cyclic nucleotide-gated 1 (HCN1) channels are widely expressed in the retina. In photoreceptors, the hyperpolarization-activated current (Ih) carried by HCN1 is important for shaping the light response. It has been shown in multiple systems that trafficking HCN1 channels to specific compartments is key to their function. The localization of HCN1 in photoreceptors is concentrated in the plasma membrane of the inner segment (IS). The mechanisms controlling this localization are not understood. We previously identified a di-arginine endoplasmic reticulum (ER) retention motif that negatively regulates the surface targeting of HCN1. In this study, we sought to identify a forward trafficking signal that could counter the function of the ER retention signal. We studied trafficking of HCN1 and several mutants by imaging their subcellular localization in transgenic X. laevis photoreceptors. Velocity sedimentation was used to assay the assembly state of HCN1 channels. We found the HCN1 N-terminus can redirect a membrane reporter from outer segments (OS) to the plasma membrane of the IS. The sequence necessary for this behavior was mapped to a 20 amino acid region containing a leucine-based ER export motif. The ER export signal is necessary for forward trafficking but not channel oligomerization. Moreover, this ER export signal alone counteracted the di-arginine ER retention signal. We identified an ER export signal in HCN1 that functions with the ER retention signal to maintain equilibrium of HCN1 between the endomembrane system and the plasma membrane.

An N-Terminal ER Export Signal Facilitates the Plasma Membrane Targeting of HCN1 Channels in Photoreceptors

PubMed Central

Pan, Yuan; Laird, Joseph G.; Yamaguchi, David M.; Baker, Sheila A.

2015-01-01

Purpose. Hyperpolarization-activated cyclic nucleotide-gated 1 (HCN1) channels are widely expressed in the retina. In photoreceptors, the hyperpolarization-activated current (Ih) carried by HCN1 is important for shaping the light response. It has been shown in multiple systems that trafficking HCN1 channels to specific compartments is key to their function. The localization of HCN1 in photoreceptors is concentrated in the plasma membrane of the inner segment (IS). The mechanisms controlling this localization are not understood. We previously identified a di-arginine endoplasmic reticulum (ER) retention motif that negatively regulates the surface targeting of HCN1. In this study, we sought to identify a forward trafficking signal that could counter the function of the ER retention signal. Methods. We studied trafficking of HCN1 and several mutants by imaging their subcellular localization in transgenic X. laevis photoreceptors. Velocity sedimentation was used to assay the assembly state of HCN1 channels. Results. We found the HCN1 N-terminus can redirect a membrane reporter from outer segments (OS) to the plasma membrane of the IS. The sequence necessary for this behavior was mapped to a 20 amino acid region containing a leucine-based ER export motif. The ER export signal is necessary for forward trafficking but not channel oligomerization. Moreover, this ER export signal alone counteracted the di-arginine ER retention signal. Conclusions. We identified an ER export signal in HCN1 that functions with the ER retention signal to maintain equilibrium of HCN1 between the endomembrane system and the plasma membrane. PMID:26030105