Targeting the UPR transcription factor XBP1 protects against Huntington's disease through the regulation of FoxO1 and autophagy

PubMed Central

Vidal, Rene L.; Figueroa, Alicia; Court, Felipe A.; Thielen, Peter; Molina, Claudia; Wirth, Craig; Caballero, Benjamin; Kiffin, Roberta; Segura-Aguilar, Juan; Cuervo, Ana Maria; Glimcher, Laurie H.; Hetz, Claudio

2012-01-01

Mutations leading to expansion of a poly-glutamine track in Huntingtin (Htt) cause Huntington's disease (HD). Signs of endoplasmic reticulum (ER) stress have been recently reported in animal models of HD, associated with the activation of the unfolded protein response (UPR). Here we have investigated the functional contribution of ER stress to HD by targeting the expression of two main UPR transcription factors, XBP1 and ATF4 (activating transcription factor 4), in full-length mutant Huntingtin (mHtt) transgenic mice. XBP1-deficient mice were more resistant to developing disease features, associated with improved neuronal survival and motor performance, and a drastic decrease in mHtt levels. The protective effects of XBP1 deficiency were associated with enhanced macroautophagy in both cellular and animal models of HD. In contrast, ATF4 deficiency did not alter mHtt levels. Although, XBP1 mRNA splicing was observed in the striatum of HD transgenic brains, no changes in the levels of classical ER stress markers were detected in symptomatic animals. At the mechanistic level, we observed that XBP1 deficiency led to augmented expression of Forkhead box O1 (FoxO1), a key transcription factor regulating autophagy in neurons. In agreement with this finding, ectopic expression of FoxO1 enhanced autophagy and mHtt clearance in vitro. Our results provide strong evidence supporting an involvement of XBP1 in HD pathogenesis probably due to an ER stress-independent mechanism involving the control of FoxO1 and autophagy levels. PMID:22337954

Expression of XBP1s in fibroblasts is critical for TiAl6 V4 particle-induced RANKL expression and osteolysis.

PubMed

Wang, Zhenheng; Liu, Naicheng; Zhou, Gang; Shi, Tongguo; Wang, Zhenzhen; Gan, Jingjing; Wang, Rui; Qian, Hongbo; Bao, Nirong; Guo, Ting; Zhao, Jianning

2017-04-01

Wear particle-induced osteolysis is a major cause of aseptic loosening, which is one of the most common reasons for total hip arthroplasty (THA) failure. Previous studies have shown that the expression of Receptor activation of nuclear factor (NF)-kB (RANKL) by fibroblasts in periprosthetic membrane played a crucial role in wear particle-induced osteolysis. However, the underlying mechanism of RANKL expression remains largely unknown. In the present study, we investigated the effect of TiAl 6 V 4 particle (TiPs)-induced XBP1s (spliced form of X-box binding protein 1) on RANKL expression and osteoclastogenesis both in vitro and in vivo. The levels of XBP1s in peri-implant membrane, animal models, and TiPs-stimulated fibroblasts were determined by western blots. To assess the effect of XBP1s on RANKL expression, fibroblasts were treated with both a small interfering RNA (siRNA) and an inhibitor of XBP1 prior to exposure to TiPs. The effect of XBP1s on osteoclasts formation was determined by tartrate-resistant acid phosphatase (TRAP) staining in vitro osteoclastogenesis assay and in animal models. The resorption of bone was assessed by micro-computed tomography (micro-CT) with three-dimensional reconstruction. Our results demonstrated that XBP1s was activated in periprosthetic membrane, mouse calvaria models, and TiPs-stimulated human synovial fibroblasts. Further, inhibition of XBP1s decreased the expression of RANKL and osteoclasts formation in vitro. In mouse calvaria models, both of the osteoclastogenesis and osteolysis were inhibited XBP1s inhibitor. Our results suggested that XBP1s mediated TiPs-induced of RANKL expression in fibroblasts, and down regulating XBP1s may represent a potential therapy for wear particle-induced osteolysis. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:752-759, 2017. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

RACK1 upregulation induces neuroprotection by activating the IRE1-XBP1 signaling pathway following traumatic brain injury in rats.

PubMed

Ni, Haibo; Rui, Qin; Xu, Yitian; Zhu, Jun; Gao, Fan; Dang, Baoqi; Li, Di; Gao, Rong; Chen, Gang

2018-06-01

Receptor for activated protein kinase C 1 (RACK1) is a multifaceted scaffolding protein known to be involved in the regulation of signaling events required for neuronal protection. In the present study, we investigated the role of RACK1 in secondary brain injury in a rat traumatic brain injury (TBI) model. A weight-drop TBI model was established in Sprague Dawley rats, and RACK1 in vivo knockdown and overexpression were performed 24 h before TBI insult. The IRE1 inhibitor 3,5-dibromosalicylaldehyde (DBSA) was administered by intracerebroventricular injection 1 h after TBI insult. Real-time PCR, Western blotting, immunofluorescence, neuronal apoptosis, brain water content, and neurological scores were evaluated. Our results revealed that TBI induced increased expression of endogenous RACK1, phosphorylated inositol-requiring enzyme 1 (p-IRE1), X-box binding protein-1 (XBP1) and glucose-regulated protein 78 (GRP78) in neurons. RACK1 overexpression significantly ameliorated neuronal apoptosis, blood-brain barrier disruption, brain edema and neurological deficits at 48 h after TBI, which was concomitant with upregulation of p-IRE1, XBP1 and GRP78 expression, while its knockdown induced the opposite effects. Furthermore, DBSA administration reversed the protective effects of RACK1 overexpression against brain injury and decreased the expression of p-IRE1, XBP1 and GRP78. In summary, the upregulation of RACK1 following brain contusion exerted neuroprotective effects against secondary brain injury, which were probably mediated by activation of the IRE1-XBP1 pathway. Copyright © 2018. Published by Elsevier Inc.

Control of dopaminergic neuron survival by the unfolded protein response transcription factor XBP1

PubMed Central

Valdés, Pamela; Mercado, Gabriela; Vidal, Rene L.; Molina, Claudia; Parsons, Geoffrey; Court, Felipe A.; Martinez, Alexis; Galleguillos, Danny; Armentano, Donna; Schneider, Bernard L.; Hetz, Claudio

2014-01-01

Parkinson disease (PD) is characterized by the selective loss of dopaminergic neurons of the substantia nigra pars compacta (SNpc). Although growing evidence indicates that endoplasmic reticulum (ER) stress is a hallmark of PD, its exact contribution to the disease process is not well understood. Here we report that developmental ablation of X-Box binding protein 1 (XBP1) in the nervous system, a key regulator of the unfolded protein response (UPR), protects dopaminergic neurons against a PD-inducing neurotoxin. This survival effect was associated with a preconditioning condition that resulted from induction of an adaptive ER stress response in dopaminergic neurons of the SNpc, but not in other brain regions. In contrast, silencing XBP1 in adult animals triggered chronic ER stress and dopaminergic neuron degeneration. Supporting this finding, gene therapy to deliver an active form of XBP1 provided neuroprotection and reduced striatal denervation in animals injected with 6-hydroxydopamine. Our results reveal a physiological role of the UPR in the maintenance of protein homeostasis in dopaminergic neurons that may help explain the differential neuronal vulnerability observed in PD. PMID:24753614

Genetic targeting of the active transcription factor XBP1s to dendritic cells potentiates vaccine-induced prophylactic and therapeutic antitumor immunity.

PubMed

Tian, Shenghe; Liu, Zuqiang; Donahue, Cara; Falo, Louis D; You, Zhaoyang

2012-02-01

In vivo dendritic cells (DC) targeting is an attractive approach with potential advantages in vaccine efficacy, cost, and availability. Identification of molecular adjuvants to in vivo "modulate " DC to coordinately render improved Th1 and CD8 T cell immunity, and attenuated deleterious Treg effects, is a critical challenge. Here, we report that in vivo genetic targeting of the active transcription factor XBP1s to DC (XBP1s/DC) potentiated vaccine-induced prophylactic and therapeutic antitumor immunity in multiple tumor models. This immunization strategy is based on a genetic vaccine encoding both cytomegalovirus (CMV)-driven vaccine Aghsp70 and DC-specific CD11c-driven XBP1s. The novel targeted vaccine induced durable Th1 and CD8 T cell responses to poorly immunogenic self/tumor antigen (Ag) and attenuated tumor-associated Treg suppressive function. Bone marrow (BM)-derived DC genetically modified to simultaneously overexpress XBP1s and express Aghsp70 upregulated CD40, CD70, CD86, interleukin (IL)-15, IL-15Rα, and CCR7 expression, and increased IL-6, IL-12, and tumor necrosis factor (TNF)-α production in vitro. XBP1s/DC elevated functional DEC205(+)CD8α(+)DC in the draining lymph nodes (DLN). The data suggest a novel role for XBP1s in modulating DC to potentiate tumor vaccine efficacy via overcoming two major obstacles to tumor vaccines (i.e., T cell hyporesponsiveness against poorly immunologic self/tumor Ag and tumor-associated Treg-mediated suppression) and improving DEC205(+)CD8α(+)DC.

Transcriptional Regulation of X-Box-binding Protein One (XBP1) by Hepatocyte Nuclear Factor 4α (HNF4Α) Is Vital to Beta-cell Function.

PubMed

Moore, Benjamin D; Jin, Ramon U; Lo, Heiyong; Jung, Min; Wang, Haiyan; Battle, Michele A; Wollheim, Claes B; Urano, Fumihiko; Mills, Jason C

2016-03-18

The transcription factor, X-box-binding protein-1 (XBP1), controls the development and maintenance of the endoplasmic reticulum (ER) in multiple secretory cell lineages. We show here that Hepatocyte Nuclear Factor 4α (HNF4α) directly induces XBP1 expression. Mutations in HNF4α cause Mature-Onset Diabetes of the Young I (MODYI), a subset of diabetes characterized by diminished GSIS. In mouse models, cell lines, and ex vivo islets, using dominant negative and human- disease-allele point mutants or knock-out and knockdown models, we show that disruption of HNF4α caused decreased expression of XBP1 and reduced cellular ER networks. GSIS depends on ER Ca(2+) signaling; we show that diminished XBP1 and/or HNF4α in β-cells led to impaired ER Ca(2+) homeostasis. Restoring XBP1 expression was sufficient to completely rescue GSIS in HNF4α-deficient β-cells. Our findings uncover a transcriptional relationship between HNF4α and Xbp1 with potentially broader implications about MODYI and the importance of transcription factor signaling in the regulation of secretion. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

The fibroblast expression of RANKL in CoCrMo-particle-induced osteolysis is mediated by ER stress and XBP1s.

PubMed

Wang, Zhenheng; Huang, Zhen; Gan, Jingjing; Liu, Naicheng; Zhou, Gang; Shi, Tongguo; Wang, Zhenzhen; Wang, Rui; Bao, Nirong; Guo, Ting; Chen, Jiangning; Zhang, Junfeng; Dong, Lei; Zhao, Jianning

2015-09-01

Particle-induced osteolysis is a major cause of aseptic loosening, which is the most common reason for total hip arthroplasty (THA) failure and revision surgery. Although existing studies suggest that synovial fibroblasts present in the interfacial membrane are important targets of wear particles during bone resorption, the interaction mechanisms between the particles and fibroblasts remains elusive. In the present study, we investigated the effect of ER stress induced by CoCrMo particles (CoPs) in fibroblasts, calvarial resorption animal models and aseptic loosening clinical samples and its role in the stimulation of the RANKL expression. Our study further demonstrated that CoPs could induce significant ER stress in fibroblasts. Blocking ER stress with a specific inhibitor dramatically reduced the particle-induced expression of RANKL in vitro and in vivo. Furthermore, in fibroblasts, downregulation of the expression of XBP1s, a signaling molecule of ER stress, significantly reduced the expression of RANKL induced by wear particles. Moreover, inhibition of ER stress or XBP1s both ameliorated the CoPs-induced osteolysis in animal models. Collectively, these results suggested that in particle-induced osteolysis, CoPs could stimulate fibroblasts to secret RANKL through ER stress and the signaling molecule XBP1s. Therefore, downregulating ER stress or the signaling molecule XBP1s of fibroblasts represents a potential therapeutic approach for treating particle-induced peri-implant osteolysis. For the first time, our study demonstrated that ER stress mediated the induction of RANKL expression by CoPs in fibroblasts and promoted particle-induced osteolysis. Furthermore, the upregulation of RANKL by CoPs in fibroblasts was mediated by the ER stress signaling molecule XBP1s. Both blocking ER stress and inhibiting the protein XBP1s by specific inhibitors resulted in downregulation of the expression of RANKL and amelioration of osteolysis induced by the implanted particles

Loss of p53 enhances the function of the endoplasmic reticulum through activation of the IRE1α/XBP1 pathway.

PubMed

Namba, Takushi; Chu, Kiki; Kodama, Rika; Byun, Sanguine; Yoon, Kyoung Wan; Hiraki, Masatsugu; Mandinova, Anna; Lee, Sam W

2015-08-21

Altered regulation of ER stress response has been implicated in a variety of human diseases, such as cancer and metabolic diseases. Excessive ER function contributes to malignant phenotypes, such as chemoresistance and metastasis. Here we report that the tumor suppressor p53 regulates ER function in response to stress. We found that loss of p53 function activates the IRE1α/XBP1 pathway to enhance protein folding and secretion through upregulation of IRE1α and subsequent activation of its target XBP1. We also show that wild-type p53 interacts with synoviolin (SYVN1)/HRD1/DER3, a transmembrane E3 ubiquitin ligase localized to ER during ER stress and removes unfolded proteins by reversing transport to the cytosol from the ER, and its interaction stimulates IRE1α degradation. Moreover, IRE1α inhibitor suppressed protein secretion, induced cell death in p53-deficient cells, and strongly suppressed the formation of tumors by p53-deficient human tumor cells in vivo compared with those that expressed wild-type p53. Therefore, our data imply that the IRE1α/XBP1 pathway serves as a target for therapy of chemoresistant tumors that express mutant p53.

Loss of p53 enhances the function of the endoplasmic reticulum through activation of the IRE1α/XBP1 pathway

PubMed Central

Kodama, Rika; Byun, Sanguine; Yoon, Kyoung Wan; Hiraki, Masatsugu; Mandinova, Anna; Lee, Sam W.

2015-01-01

Altered regulation of ER stress response has been implicated in a variety of human diseases, such as cancer and metabolic diseases. Excessive ER function contributes to malignant phenotypes, such as chemoresistance and metastasis. Here we report that the tumor suppressor p53 regulates ER function in response to stress. We found that loss of p53 function activates the IRE1α/XBP1 pathway to enhance protein folding and secretion through upregulation of IRE1α and subsequent activation of its target XBP1. We also show that wild-type p53 interacts with synoviolin (SYVN1)/HRD1/DER3, a transmembrane E3 ubiquitin ligase localized to ER during ER stress and removes unfolded proteins by reversing transport to the cytosol from the ER, and its interaction stimulates IRE1α degradation. Moreover, IRE1α inhibitor suppressed protein secretion, induced cell death in p53-deficient cells, and strongly suppressed the formation of tumors by p53-deficient human tumor cells in vivo compared with those that expressed wild-type p53. Therefore, our data imply that the IRE1α/XBP1 pathway serves as a target for therapy of chemoresistant tumors that express mutant p53. PMID:26254280

Xbp1s in Pomc neurons connects ER stress with energy balance and glucose homeostasis

USDA-ARS?s Scientific Manuscript database

The molecular mechanisms underlying neuronal leptin and insulin resistance in obesity and diabetes remain unclear. Here we show that induction ofthe unfolded protein response transcription factor spliced X-box binding protein 1(Xbp1s) in pro-opio-melanocortin (Pomc) neurons alone is sufficient to pr...

AAV-mediated delivery of the transcription factor XBP1s into the striatum reduces mutant Huntingtin aggregation in a mouse model of Huntington's disease

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

Zuleta, Amparo; Center for Molecular Studies of the Cell, Institute of Biomedical Sciences, University of Chile, Santiago; Vidal, Rene L.

2012-04-13

Highlights: Black-Right-Pointing-Pointer The contribution of ER stress to HD has not been directly addressed. Black-Right-Pointing-Pointer Expression of XBP1s using AAVs decreases Huntingtin aggregation in vivo. Black-Right-Pointing-Pointer We describe a new in vivo model of HD based on the expression of a large fragment of mHtt-RFP. -- Abstract: Huntington's disease (HD) is caused by mutations that expand a polyglutamine region in the amino-terminal domain of Huntingtin (Htt), leading to the accumulation of intracellular inclusions and progressive neurodegeneration. Recent reports indicate the engagement of endoplasmic reticulum (ER) stress responses in human HD post mortem samples and animal models of the disease. Adaptationmore » to ER stress is mediated by the activation of the unfolded protein response (UPR), an integrated signal transduction pathway that attenuates protein folding stress by controlling the expression of distinct transcription factors including X-Box binding protein 1 (XBP1). Here we targeted the expression of XBP1 on a novel viral-based model of HD. We delivered an active form of XBP1 locally into the striatum of adult mice using adeno-associated vectors (AAVs) and co-expressed this factor with a large fragment of mutant Htt as a fusion protein with RFP (Htt588{sup Q95}-mRFP) to directly visualize the accumulation of Htt inclusions in the brain. Using this approach, we observed a significant reduction in the accumulation of Htt588{sup Q95}-mRFP intracellular inclusion when XBP1 was co-expressed in the striatum. These results contrast with recent findings indicating a protective effect of XBP1 deficiency in neurodegeneration using knockout mice, and suggest a potential use of gene therapy strategies to manipulate the UPR in the context of HD.« less

XBP1 (X-Box-Binding Protein-1)-Dependent O-GlcNAcylation Is Neuroprotective in Ischemic Stroke in Young Mice and Its Impairment in Aged Mice Is Rescued by Thiamet-G.

PubMed

Jiang, Meng; Yu, Shu; Yu, Zhui; Sheng, Huaxin; Li, Ying; Liu, Shuai; Warner, David S; Paschen, Wulf; Yang, Wei

2017-06-01

Impaired protein homeostasis induced by endoplasmic reticulum dysfunction is a key feature of a variety of age-related brain diseases including stroke. To restore endoplasmic reticulum function impaired by stress, the unfolded protein response is activated. A key unfolded protein response prosurvival pathway is controlled by the endoplasmic reticulum stress sensor (inositol-requiring enzyme-1), XBP1 (downstream X-box-binding protein-1), and O-GlcNAc (O-linked β-N-acetylglucosamine) modification of proteins (O-GlcNAcylation). Stroke impairs endoplasmic reticulum function, which activates unfolded protein response. The rationale of this study was to explore the potentials of the IRE1/XBP1/O-GlcNAc axis as a target for neuroprotection in ischemic stroke. Mice with Xbp1 loss and gain of function in neurons were generated. Stroke was induced by transient or permanent occlusion of the middle cerebral artery in young and aged mice. Thiamet-G was used to increase O-GlcNAcylation. Deletion of Xbp1 worsened outcome after transient and permanent middle cerebral artery occlusion. After stroke, O-GlcNAcylation was activated in neurons of the stroke penumbra in young mice, which was largely Xbp1 dependent. This activation of O-GlcNAcylation was impaired in aged mice. Pharmacological increase of O-GlcNAcylation before or after stroke improved outcome in both young and aged mice. Our study indicates a critical role for the IRE1/XBP1 unfolded protein response branch in stroke outcome. O-GlcNAcylation is a prosurvival pathway that is activated in the stroke penumbra in young mice but impaired in aged mice. Boosting prosurvival pathways to counterbalance the age-related decline in the brain's self-healing capacity could be a promising strategy to improve ischemic stroke outcome in aged brains. © 2017 American Heart Association, Inc.

X box binding protein XBP-1s transactivates the Kaposi's sarcoma-associated herpesvirus (KSHV) ORF50 promoter, linking plasma cell differentiation to KSHV reactivation from latency.

PubMed

Wilson, Sam J; Tsao, Edward H; Webb, Benjamin L J; Ye, Hongtao; Dalton-Griffin, Lucy; Tsantoulas, Christoforos; Gale, Catherine V; Du, Ming-Qing; Whitehouse, Adrian; Kellam, Paul

2007-12-01

Reactivation of lytic replication from viral latency is a defining property of all herpesviruses. Despite this, the authentic physiological cues for the latent-lytic switch are unclear. Such cues should ensure that viral lytic replication occurs under physiological conditions, predominantly in sites which facilitate transmission to permissive uninfected cells and new susceptible hosts. Kaposi's sarcoma-associated herpesvirus (KSHV) is associated with the B-cell neoplasm primary effusion lymphoma (PEL), in which the virus remains latent. We have previously shown that PEL cells have the gene expression profile and immunophenotype of cycling preplasma cells (plasmablasts). Here, we show that the highly active spliced isoform of plasma cell transcription factor X box binding protein 1 (XBP-1s) is a lytic switch for KSHV. XBP-1s is normally absent in PEL, but the induction of endoplasmic reticulum stress leads to XBP-1s generation, plasma cell-like differentiation, and lytic reactivation of KSHV. XBP-1s binds to and activates the KSHV immediate-early gene ORF50 and synergizes with the ORF50 gene product RTA to induce a full lytic cycle. These data suggest that KSHV remains latent until B-cell terminal differentiation into plasma cells, the transcriptional environment of which provides the physiological "lytic switch" through XBP-1s. This links B-cell terminal differentiation to KSHV lytic reactivation.

Palmitate induces cisternal ER expansion via the activation of XBP-1/CCTα-mediated phospholipid accumulation in RAW 264.7 cells.

PubMed

Kim, Seong Keun; Oh, Eunhye; Yun, Mihee; Lee, Seong-Beom; Chae, Gue Tae

2015-07-16

Endoplasmic reticulum (ER) stress induces ER expansion. The expansion of the intracisternal space of the ER was found in macrophages associated with human atherosclerotic lesions. We also previously reported that palmitate induces cisternal ER expansion and necrosis in RAW 264.7 cells. In this study, we report on an investigation of the likely mechanism responsible for this palmitate-induced cisternal ER expansion in a mouse macrophage cell line, RAW 264.7 cells. RAW 264.7 cells were pre-treated with the designated inhibitor or siRNA, followed by treatment with palmitate. Changes in the ER structure were examined by transmission electron microscopy. The induction of ER stress was confirmed by an increase in the extent of phosphorylation of PERK, the expression of BiP and CHOP, and the splicing of XBP-1 mRNA. Phospholipid staining was performed with the LipidTOX Red phospholipidosis detection reagent. Related gene expressions were detected by quantitative real time-RT-PCR or RT-PCR. Palmitate was found to induce ER stress and cisternal ER expansion. In addition, palmitate-induced cisternal ER expansion was attenuated by ER stress inhibitors, such as 4-phenylbutyric acid (4-PBA) and tauroursodeoxycholic acid (TUDCA). The findings also show that palmitate induced-mRNA expression of CCTα, which increases phospholipid synthesis, was attenuated by the down-regulation of XBP-1, a part of ER stress. Furthermore, palmitate-induced phospholipid accumulation and cisternal ER expansion were attenuated by the down-regulation of XBP-1 or CCTα. The findings reported herein indicate that palmitate-induced cisternal ER expansion is dependent on the activation of XBP-1/CCTα-mediated phospholipid accumulation in RAW 264.7 cells.

Identification of eQTLs for Hepatic Xbp1s and Socs3 Gene Expression in Mice Fed a High-Fat, High-Caloric Diet

PubMed Central

Pasricha, Sarina; Kenney-Hunt, Jane; Anderson, Kristy; Jafari, Nadereh; Hall, Rabea A.; Lammert, Frank; Cheverud, James; Green, Richard M.

2015-01-01

Nonalcoholic fatty liver disease (NAFLD) is a highly prevalent form of human hepatic disease and feeding mice a high-fat, high-caloric (HFHC) diet is a standard model of NAFLD. To better understand the genetic basis of NAFLD, we conducted an expression quantitative trait locus (eQTL) analysis of mice fed a HFHC diet. Two-hundred sixty-five (A/J × C57BL/6J) F2 male mice were fed a HFHC diet for 8 wk. eQTL analysis was utilized to identify genomic regions that regulate hepatic gene expression of Xbp1s and Socs3. We identified two overlapping loci for Xbp1s and Socs3 on Chr 1 (164.0–185.4 Mb and 174.4–190.5 Mb, respectively) and Chr 11 (41.1–73.1 Mb and 44.0–68.6 Mb, respectively), and an additional locus for Socs3 on Chr 12 (109.9–117.4 Mb). C57BL/6J-Chr 11A/J/ NaJ mice fed a HFHC diet manifested the A/J phenotype of increased Xbp1s and Socs3 gene expression (P < 0.05), whereas C57BL/6J-Chr 1A/J/ NaJ mice retained the C57BL/6J phenotype. In addition, we replicated the eQTLs on Chr 1 and Chr 12 (LOD scores ≥3.5) using mice from the BXD murine reference panel challenged with CCl4 to induce chronic liver injury and fibrosis. We have identified overlapping eQTLs for Xbp1 and Socs3 on Chr 1 and Chr 11, and consomic mice confirmed that replacing the C57BL/6J Chr 11 with the A/J Chr 11 resulted in an A/J phenotype for Xbp1 and Socs3 gene expression. Identification of the genes for these eQTLs will lead to a better understanding of the genetic factors responsible for NAFLD and potentially other hepatic diseases. PMID:25617409

In vivo intratumoral Epstein-Barr virus replication is associated with XBP1 activation and early-onset post-transplant lymphoproliferative disorders with prognostic implications.

PubMed

Gonzalez-Farre, Blanca; Rovira, Jordina; Martinez, Daniel; Valera, Alexandra; Garcia-Herrera, Adriana; Marcos, Maria Angeles; Sole, Carla; Roue, Gael; Colomer, Dolors; Gonzalvo, Elena; Ribera-Cortada, Imma; Araya, Monica; Lloreta, Josep; Colomo, Luis; Campo, Elias; Lopez-Guillermo, Armando; Martinez, Antonio

2014-12-01

Post-transplant lymphoproliferative disorders are life-threatening complications following hematopoietic or solid organ transplantation. They represent a spectrum of mostly EBV-driven lymphoplasmacytic proliferations. While the oncogenic effect of EBV is related to latent infection, lytic infection also has a role in lymphomagenesis. In vitro, EBV replication is linked to plasma cell differentiation and XBP1 activation, although this phenomenon has never been addressed in vivo. We analyzed for the first time latent and lytic intratumoral EBV infection in a series of 35 adult patients with a diagnosis of post-transplant lymphoproliferative disorder (26M/9F, median age 54 years). A complete EBV study was performed including the analysis of the latent EBER, latent membrane protein-11, and EBV nuclear antigens as well as the immediate-early BZLF1/ZEBRA and early BMRF1/EADE31 lytic genes. XBP1 activation was assessed by nuclear protein expression. EBV infection was observed in 28 (80%) cases being latency II and III the most frequently observed 22 (79%). Intratumoral EBV replication was detected in 17 (60%) cases. Among these, XBP1 activation was observed in 11/12 evaluable cases associated with strong cytoplasmic immunoglobulin expression consistent with plasma cell differentiation. Intriguingly, the combination of latency III infection and EBV replication identified a high-risk subgroup of patients with significantly shorter survival (overall survival at 1 year 18% vs 48%) and early-onset (median of 7 vs 26 months) post-transplant lymphoproliferative disorder. Moreover, these patients appear to be more heavily immunosuppressed, so they exhibit lower rates of rejection and graft vs host disease but higher rates of cytomegalovirus reactivation. In conclusion, EBV replication is associated with plasma cell differentiation and XBP1 activation with prognostic implications. Both latency III and lytic EBV infection are related to aggressive and early-onset post

l-Glutamine Attenuates Apoptosis Induced by Endoplasmic Reticulum Stress by Activating the IRE1α-XBP1 Axis in IPEC-J2: A Novel Mechanism of l-Glutamine in Promoting Intestinal Health

PubMed Central

Chen, Jiashun; Liu, Shaojuan; Yao, Kang; Yin, Yulong

2017-01-01

Intestinal absorption and barrier malfunctions are associated with endoplasmic reticulum stress (ERS) in the intestine. We induced ERS by exposing the intestinal porcine epithelial cell line J2 (IPEC-J2) to tunicamycin (TUNI) to explore the potential of l-glutamine to reduce ERS-induced apoptosis. Our experiments demonstrated that exposing cells to TUNI results in spontaneous ERS and encourages the upregulation of glucose-regulated protein 78 (GRP78). Prolonged TUNI-induced ERS was found to increase apoptosis mediated by C/enhancer binding protein homologous protein (CHOP), accompanied by GRP78 downregulation. Treatment with l-glutamine was found to promote cell proliferation within the growth medium but to have little effect in basic Dulbecco’s modified Eagle medium. Finally, in the milieu of TUNI-induced ERS, l-glutamine was found to maintain a high level of GRP78, alleviate CHOP-mediated apoptosis and activate the inositol requiring enzyme 1α (IRE1α)-X-box binding protein 1 (XBP1) axis. A specific inhibitor of the IRE1α-XBP1 axis reversed the protective effect of l-glutamine by blocking the expression of IRE1α/XBP1s. We propose that the functional effect of l-glutamine on intestinal health may be partly due to its modulation of ERS and CHOP-mediated apoptosis. PMID:29206200

Synthesis and Structure-Activity Relationships of N-Dihydrocoptisine-8-ylidene Aromatic Amines and N-Dihydrocoptisine-8-ylidene Aliphatic Amides as Antiulcerative Colitis Agents Targeting XBP1.

PubMed

Xie, Meng; Zhang, Hai-Jing; Deng, An-Jun; Wu, Lian-Qiu; Zhang, Zhi-Hui; Li, Zhi-Hong; Wang, Wen-Jie; Qin, Hai-Lin

2016-04-22

In this study, natural quaternary coptisine was used as a lead compound to design and synthesize structurally stable and actively potent coptisine analogues. Of the synthesized library, 13 N-dihydrocoptisine-8-ylidene amines/amides were found not only to be noncytotoxic toward intestinal epithelial cells (IECs), but they were also able to activate the transcription of X-box-binding protein 1 (XBP1) targets to varying extents in vitro. Antiulcerative colitis (UC) activity levels were assessed at the in vitro molecular level as well as in vivo in animals using multiple biomarkers as indices. In an in vitro XBP1 transcriptional activity assay, four compounds demonstrated good dose-effect relationships with EC50 values of 0.0708-0.0132 μM. Moreover, two compounds were confirmed to be more potent in vivo than a positive control, demonstrating a curative effect for UC in experimental animals. Thus, the findings of this study suggest that these coptisine analogues are promising candidates for the development of anti-UC drugs.

RITA enhances irradiation-induced apoptosis in p53-defective cervical cancer cells via upregulation of IRE1α/XBP1 signaling.

PubMed

Zhu, Hong; Abulimiti, Muyasha; Liu, Huan; Su, Xiang-Jiang; Liu, Cai-Hong; Pei, Hai-Ping

2015-09-01

Radiation therapy is the most widely used treatment for patients with cervical cancer. Recent studies have shown that endoplasmic reticulum (ER) stress induces apoptosis and sensitizes tumor cells to radiotherapy, which reportedly induces ER stress in cells. Classical key tumor suppressor p53 is involved in the response to a variety of cellular stresses, including those incurred by ionizing irradiation. A recent study demonstrated that small-molecule RITA (reactivation of p53 and induction of tumor cell apoptosis) increased the radiosensitivity of tumor cells expressing mutant p53 (mtp53). In the present study, we explored the effects and the underlying mechanisms of RITA in regards to the radiosensitivity and ER stress in mtp53-expressing human cervix cancer cells. Treatment with 1 µM of RITA for 24 h before irradiation markedly decreased survival and increased apoptosis in C-33A and HT-3 cells; the effects were not significantly altered by knockdown of p53. In the irradiated C-33A and HT-3 cells, RITA significantly increased the expression of IRE1α, the spliced XBP1 mRNA level, as well as apoptosis; the effects were abolished by knockdown of IRE1α. Transcriptional pulse-chase assays revealed that RITA significantly increased the stability of IRE1α mRNA in the irradiated C-33A and HT-3 cells. In contrast, the same RITA treatment did not show any significant effect on sham-irradiated cells. In conclusion, the present study provides initial evidence that RITA upregulates the expression level of IRE1α by increasing the stability of IRE1α mRNA in irradiated mtp53-expressing cervical cancer cells; the effect leads to enhanced IRE1α/XBP1 ER stress signaling and increased apoptosis in the cells. The present study offers novel insight into the pharmacological potential of RITA in the radiotherapy for cervical cancer.

A Multiepitope of XBP1, CD138 and CS1 Peptides Induces Myeloma-Specific Cytotoxic T lymphocytes in T cells of Smoldering Myeloma Patients

PubMed Central

Bae, Jooeun; Prabhala, Rao; Voskertchian, Annie; Brown, Andrew; Maguire, Craig; Richardson, Paul; Dranoff, Glen; Anderson, Kenneth C.; Munshi, Nikhil C.

2014-01-01

We evaluated a cocktail of HLA-A2-specific peptides including heteroclitic XBP1 US184-192 (YISPWILAV), heteroclitic XBP1 SP367-375 (YLFPQLISV), native CD138260-268 (GLVGLIFAV) and native CS1239-247 (SLFVLGLFL), for their ability to elicit multipeptide specific cytotoxic T lymphocytes (MP-CTL) using T cells from smoldering multiple myeloma (SMM) patients. Our results demonstrate that MP-CTL generated from SMM patients’ T cells show effective anti-MM responses including CD137 (4-1BB) upregulation, CTL proliferation, IFN-γ production, and degranulation (CD107a) in an HLA-A2-restricted and peptide-specific manner. Phenotypically, we observed increased total CD3+CD8+ T cells (>80%) and cellular activation (CD69+) within the memory SMM MP-CTL (CD45RO+/CD3+CD8+) subset after repeated multipeptide stimulation. Importantly, SMM patients could be categorized into distinct groups by their level of MP-CTL expansion and anti-tumor activity. In high responders, the effector memory (CCR7-CD45RO+/CD3+CD8+) T cell subset was enriched, while the remaining responders’ CTL contained a higher frequency of the terminal effector (CCR7-CD45RO-/CD3+CD8+) subset. These results suggest that this multipeptide cocktail has the potential to induce effective and durable memory MP-CTL in SMM patients. Therefore, our findings provide the rationale for clinical evaluation of a therapeutic vaccine to prevent or delay progression of SMM to active disease. PMID:24935722

PTGER4 Expression-Modulating Polymorphisms in the 5p13.1 Region Predispose to Crohn's Disease and Affect NF-κB and XBP1 Binding Sites

PubMed Central

Czamara, Darina; Pasciuto, Giulia; Diegelmann, Julia; Wetzke, Martin; Olszak, Torsten; Wolf, Christiane; Müller-Myhsok, Bertram; Balschun, Tobias; Achkar, Jean-Paul; Kamboh, M. Ilyas; Franke, Andre; Duerr, Richard H.; Brand, Stephan

2012-01-01

Background Genome-wide association studies identified a PTGER4 expression-modulating region on chromosome 5p13.1 as Crohn's disease (CD) susceptibility region. The study aim was to test this association in a large cohort of patients with inflammatory bowel disease (IBD) and to elucidate genotypic and phenotypic interactions with other IBD genes. Methodology/Principal Findings A total of 7073 patients and controls were genotyped: 844 CD and 471 patients with ulcerative colitis and 1488 controls were analyzed for the single nucleotide polymorphisms (SNPs) rs4495224 and rs7720838 on chromosome 5p13.1. The study included two replication cohorts of North American (CD: n = 684; controls: n = 1440) and of German origin (CD: n = 1098; controls: n = 1048). Genotype-phenotype, epistasis and transcription factor binding analyses were performed. In the discovery cohort, an association of rs4495224 (p = 4.10×10−5; 0.76 [0.67–0.87]) and of rs7720838 (p = 6.91×10−4; 0.81 [0.71–0.91]) with susceptibility to CD was demonstrated. These associations were confirmed in both replication cohorts. In silico analysis predicted rs4495224 and rs7720838 as essential parts of binding sites for the transcription factors NF-κB and XBP1 with higher binding scores for carriers of the CD risk alleles, providing an explanation of how these SNPs might contribute to increased PTGER4 expression. There was no association of the PTGER4 SNPs with IBD phenotypes. Epistasis detected between 5p13.1 and ATG16L1 for CD susceptibility in the discovery cohort (p = 5.99×10−7 for rs7720838 and rs2241880) could not be replicated in both replication cohorts arguing against a major role of this gene-gene interaction in the susceptibility to CD. Conclusions/Significance We confirmed 5p13.1 as a major CD susceptibility locus and demonstrate by in silico analysis rs4495224 and rs7720838 as part of binding sites for NF-κB and XBP1. Further functional studies are necessary to

PTGER4 expression-modulating polymorphisms in the 5p13.1 region predispose to Crohn's disease and affect NF-κB and XBP1 binding sites.

PubMed

Glas, Jürgen; Seiderer, Julia; Czamara, Darina; Pasciuto, Giulia; Diegelmann, Julia; Wetzke, Martin; Olszak, Torsten; Wolf, Christiane; Müller-Myhsok, Bertram; Balschun, Tobias; Achkar, Jean-Paul; Kamboh, M Ilyas; Franke, Andre; Duerr, Richard H; Brand, Stephan

2012-01-01

Genome-wide association studies identified a PTGER4 expression-modulating region on chromosome 5p13.1 as Crohn's disease (CD) susceptibility region. The study aim was to test this association in a large cohort of patients with inflammatory bowel disease (IBD) and to elucidate genotypic and phenotypic interactions with other IBD genes. A total of 7073 patients and controls were genotyped: 844 CD and 471 patients with ulcerative colitis and 1488 controls were analyzed for the single nucleotide polymorphisms (SNPs) rs4495224 and rs7720838 on chromosome 5p13.1. The study included two replication cohorts of North American (CD: n = 684; controls: n = 1440) and of German origin (CD: n = 1098; controls: n = 1048). Genotype-phenotype, epistasis and transcription factor binding analyses were performed. In the discovery cohort, an association of rs4495224 (p = 4.10×10⁻⁵; 0.76 [0.67-0.87]) and of rs7720838 (p = 6.91×10⁻⁴; 0.81 [0.71-0.91]) with susceptibility to CD was demonstrated. These associations were confirmed in both replication cohorts. In silico analysis predicted rs4495224 and rs7720838 as essential parts of binding sites for the transcription factors NF-κB and XBP1 with higher binding scores for carriers of the CD risk alleles, providing an explanation of how these SNPs might contribute to increased PTGER4 expression. There was no association of the PTGER4 SNPs with IBD phenotypes. Epistasis detected between 5p13.1 and ATG16L1 for CD susceptibility in the discovery cohort (p = 5.99×10⁻⁷ for rs7720838 and rs2241880) could not be replicated in both replication cohorts arguing against a major role of this gene-gene interaction in the susceptibility to CD. We confirmed 5p13.1 as a major CD susceptibility locus and demonstrate by in silico analysis rs4495224 and rs7720838 as part of binding sites for NF-κB and XBP1. Further functional studies are necessary to confirm the results of our in silico analysis and to analyze if

Insulin/IGF-1 signaling mutants reprogram ER stress response regulators to promote longevity.

PubMed

Henis-Korenblit, Sivan; Zhang, Peichuan; Hansen, Malene; McCormick, Mark; Lee, Seung-Jae; Cary, Michael; Kenyon, Cynthia

2010-05-25

When unfolded proteins accumulate in the endoplasmic reticulum (ER), the unfolded protein response is activated. This ER stress response restores ER homeostasis by coordinating processes that decrease translation, degrade misfolded proteins, and increase the levels of ER-resident chaperones. Ribonuclease inositol-requiring protein-1 (IRE-1), an endoribonuclease that mediates unconventional splicing, and its target, the XBP-1 transcription factor, are key mediators of the unfolded protein response. In this study, we show that in Caenorhabditis elegans insulin/IGF-1 pathway mutants, IRE-1 and XBP-1 promote lifespan extension and enhance resistance to ER stress. We show that these effects are not achieved simply by increasing the level of spliced xbp-1 mRNA and expression of XBP-1's normal target genes. Instead, in insulin/IGF-1 pathway mutants, XBP-1 collaborates with DAF-16, a FOXO-transcription factor that is activated in these mutants, to enhance ER stress resistance and to activate new genes that promote longevity.

Activation of the Endoplasmic Reticulum Stress-Associated Transcription Factor X Box-Binding Protein-1 Occurs in a Subset of Normal Germinal-Center B Cells and in Aggressive B-Cell Lymphomas with Prognostic Implications

PubMed Central

Balague, Olga; Mozos, Ana; Martinez, Daniel; Hernandez, Luis; Colomo, Lluis; Mate, Jose Luis; Teruya-Feldstein, Julie; Lin, Oscar; Campo, Elias; Lopez-Guillermo, Armando; Martinez, Antonio

2009-01-01

X box-binding protein 1 (Xbp-1) is a transcription factor that is required for the terminal differentiation of B lymphocytes into plasma cells. The Xbp-1 gene is activated in response to endoplasmic reticulum stress signals, which generate a 50-kDa nuclear protein that acts as a potent transactivator and regulates the expression of genes related to the unfolded protein response. Activated Xbp-1 is essential for cell survival in plasma-cell tumors but its role in B-cell lymphomas is unknown. We analyzed the expression of activated Xbp-1 in reactive lymphoid tissues, 411 lymphomas and plasma-cell neoplasms, and 24 B-cell lines. In reactive tissues, Xbp-1 was only found in nuclear extracts. Nuclear expression of Xbp-1 was observed in occasional reactive plasma cells and in a subpopulation of Irf-4+/Bcl-6−/Pax-5− B cells in the light zones of reactive germinal centers, probably representing cells committed to plasma-cell differentiation. None of the low-grade lymphomas showed evidence of Xbp-1 activation; however, Xbp-1 activation was found in 28% of diffuse large B-cell lymphomas, independent of germinal or postgerminal center phenotype, as well as in 48% of plasmablastic lymphomas and 69% of plasma-cell neoplasms. Diffuse large B-cell lymphomas with nuclear Xbp-1 expression had a significantly worse response to therapy and shorter overall survival compared with negative tumors. These findings suggest that Xbp-1 activation may play a role in the pathogenesis of aggressive B-cell lymphomas. PMID:19389935

IRE-1α promotes viral infection by conferring resistance to apoptosis

PubMed Central

Fink, Susan L.; Jayewickreme, Teshika R.; Molony, Ryan D.; Iwawaki, Takao; Landis, Charles S.; Lindenbach, Brett D.; Iwasaki, Akiko

2017-01-01

The unfolded protein response (UPR) is an ancient cellular pathway that detects and alleviates protein-folding stresses. The UPR components X-box binding protein 1 (XBP1) and inositol-requiring enzyme 1α (IRE1α) promote type I interferon (IFN) responses. Here, we found that Xbp1-deficient mouse embryonic fibroblasts and macrophages had impaired antiviral resistance. Unexpectedly, this was not because of a defect in type I IFN responses, but rather an inability of Xbp1-deficient cells to undergo viral-induced apoptosis. The ability to undergo apoptosis directly limited infection in WT cells. Xbp1-deficient cells were generally resistant to the intrinsic pathway of apoptosis through an indirect mechanism involving activation of the nuclease IRE1α. We observed an IRE1α-dependent reduction in the abundance of the pro-apoptotic microRNA miR-125a, and a corresponding increase in the amounts of the members of the anti-apoptotic Bcl2 family. The activation of IRE1α by the hepatitis C virus (HCV) protein NS4B in Xbp1-proficient cells also conferred apoptosis resistance and promoted viral replication. Furthermore, we found evidence of IRE1α activation and decreased miR-125a abundance in liver biopsies from patients infected with HCV compared to those in the livers of healthy controls. Our results reveal a pro-survival role for IRE1α in virally infected cells, and suggest a possible target for IFN-independent antiviral therapy. PMID:28588082

Factors associated with late stage at diagnosis among Puerto Rico's government health plan colorectal cancer patients: a cross-sectional study.

PubMed

Ortiz-Ortiz, Karen J; Ríos-Motta, Ruth; Marín-Centeno, Heriberto; Cruz-Correa, Marcia; Ortiz, Ana Patricia

2016-08-03

Late stage at diagnosis of cancer is considered a key predictor factor for a lower survival rate. Knowing and understanding the barriers to an early diagnosis of colorectal cancer is critical in the fight to reduce the social and economic burden caused by cancer in Puerto Rico. This study evaluates factors associated to colorectal cancer stage at diagnosis among Puerto Rico's Government Health Plan (GHP) patients. We conducted a cross-sectional study based on a secondary data analysis using information from the Puerto Rico Central Cancer Registry (PRCCR) and the Puerto Rico Health Insurance Administration (PRHIA). Logistic regression models were used to estimate the unadjusted odds ratio (ORs) and adjusted odds ratio (AORs), and their 95 % confidence intervals (CIs). Colorectal cancer cases diagnosed between January 1, 2012 and December 31, 2012, among persons 50 to 64 years of age, participants of the GHP and with a cancer diagnosis reported to the PRCCR were included in the study. There were 68 (35.79 %) colorectal cancer patients diagnosed at early stage while 122 (64.21 %) where diagnosed at late stage. In the multivariate analysis having a diagnostic delay of more than 59 days (AOR 2.94, 95 % CI: 1.32 to 6.52) and having the first visit through the emergency room (AOR 3.48, 95 % CI: 1.60 to 7.60) were strong predictors of being diagnosed with colorectal cancer at a late stage. These results are relevant to understand the factors that influence the outcomes of colorectal cancer patients in the GHP. Therefore, it is important to continue developing studies to understand the Government Health Plan patient's pathways to a cancer diagnosis, in order to promote assertive decisions to improve patient outcomes.

Lateness: A Recurrent Problem among Secondary School Students in Akoko South East Local Government Area of Ondo State Nigeria, Implications for Counselling

ERIC Educational Resources Information Center

Onoyase, Anna

2017-01-01

The study investigated lateness as a recurrent problem among secondary school students in Akoko South East Local Government Area of Ondo State. Four hypotheses were formulated and an instrument titled "Cause of Lateness to School Questionnaire" (COLTSQ) used to gather data for the study. The instrument had a reliability coefficient of…

Intestinal IRE1 Is Required for Increased Triglyceride Metabolism and Longer Lifespan under Dietary Restriction.

PubMed

Luis, Nuno Miguel; Wang, Lifen; Ortega, Mauricio; Deng, Hansong; Katewa, Subhash D; Li, Patrick Wai-Lun; Karpac, Jason; Jasper, Heinrich; Kapahi, Pankaj

2016-10-25

Dietary restriction (DR) is one of the most robust lifespan-extending interventions in animals. The beneficial effects of DR involve a metabolic adaptation toward increased triglyceride usage. The regulatory mechanism and the tissue specificity of this metabolic switch remain unclear. Here, we show that the IRE1/XBP1 endoplasmic reticulum (ER) stress signaling module mediates metabolic adaptation upon DR in flies by promoting triglyceride synthesis and accumulation in enterocytes (ECs) of the Drosophila midgut. Consistently, IRE1/XBP1 function in ECs is required for increased longevity upon DR. We further identify sugarbabe, a Gli-like zinc-finger transcription factor, as a key mediator of the IRE1/XBP1-regulated induction of de novo lipogenesis in ECs. Overexpression of sugarbabe rescues metabolic and lifespan phenotypes of IRE1 loss-of-function conditions. Our study highlights the critical role of metabolic adaptation of the intestinal epithelium for DR-induced lifespan extension and explores the IRE1/XBP1 signaling pathway regulating this adaptation and influencing lifespan. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

Spliced X-box Binding Protein 1 Couples the Unfolded Protein Response to Hexosamine Biosynthetic Pathway

PubMed Central

Wang, Zhao V.; Deng, Yingfeng; Gao, Ningguo; Pedrozo, Zully; Li, Dan L.; Morales, Cyndi R.; Criollo, Alfredo; Luo, Xiang; Tan, Wei; Jiang, Nan; Lehrman, Mark A.; Rothermel, Beverly A.; Lee, Ann-Hwee; Lavandero, Sergio; Mammen, Pradeep P.A.; Ferdous, Anwarul; Gillette, Thomas G.; Scherer, Philipp E.; Hill, Joseph A.

2014-01-01

SUMMARY The hexosamine biosynthetic pathway (HBP) generates UDP-GlcNAc (uridine diphosphate N-acetylglucosamine) for glycan synthesis and O-linked GlcNAc (O-GlcNAc) protein modifications. Despite the established role of the HBP in metabolism and multiple diseases, regulation of the HBP remains largely undefined. Here, we show that spliced X-box binding protein 1 (Xbp1s), the most conserved signal transducer of the unfolded protein response (UPR), is a direct transcriptional activator of the HBP. We demonstrate that the UPR triggers HBP activation via Xbp1s-dependent transcription of genes coding for key, rate-limiting enzymes. We further establish that this previously unrecognized UPR-HBP axis is triggered in a variety of stress conditions. Finally, we demonstrate a physiologic role for the UPR-HBP axis, by showing that acute stimulation of Xbp1s in heart by ischemia/reperfusion confers robust cardioprotection in part through induction of the HBP. Collectively, these studies reveal that Xbp1s couples the UPR to the HBP to protect cells under stress. PMID:24630721

Spliced X-box binding protein 1 couples the unfolded protein response to hexosamine biosynthetic pathway.

PubMed

Wang, Zhao V; Deng, Yingfeng; Gao, Ningguo; Pedrozo, Zully; Li, Dan L; Morales, Cyndi R; Criollo, Alfredo; Luo, Xiang; Tan, Wei; Jiang, Nan; Lehrman, Mark A; Rothermel, Beverly A; Lee, Ann-Hwee; Lavandero, Sergio; Mammen, Pradeep P A; Ferdous, Anwarul; Gillette, Thomas G; Scherer, Philipp E; Hill, Joseph A

2014-03-13

The hexosamine biosynthetic pathway (HBP) generates uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) for glycan synthesis and O-linked GlcNAc (O-GlcNAc) protein modifications. Despite the established role of the HBP in metabolism and multiple diseases, regulation of the HBP remains largely undefined. Here, we show that spliced X-box binding protein 1 (Xbp1s), the most conserved signal transducer of the unfolded protein response (UPR), is a direct transcriptional activator of the HBP. We demonstrate that the UPR triggers HBP activation via Xbp1s-dependent transcription of genes coding for key, rate-limiting enzymes. We further establish that this previously unrecognized UPR-HBP axis is triggered in a variety of stress conditions. Finally, we demonstrate a physiologic role for the UPR-HBP axis by showing that acute stimulation of Xbp1s in heart by ischemia/reperfusion confers robust cardioprotection in part through induction of the HBP. Collectively, these studies reveal that Xbp1s couples the UPR to the HBP to protect cells under stress. Copyright © 2014 Elsevier Inc. All rights reserved.

39 CFR 259.1 - Government.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 39 Postal Service 1 2012-07-01 2012-07-01 false Government. 259.1 Section 259.1 Postal Service....1 Government. (a) Policy. The Postal Service cooperates with Federal Agencies whenever the overall costs to Government will be reduced. Assistance in a number of special projects and programs is provided...

39 CFR 259.1 - Government.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 39 Postal Service 1 2013-07-01 2013-07-01 false Government. 259.1 Section 259.1 Postal Service....1 Government. (a) Policy. The Postal Service cooperates with Federal Agencies whenever the overall costs to Government will be reduced. Assistance in a number of special projects and programs is provided...

39 CFR 259.1 - Government.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 39 Postal Service 1 2011-07-01 2011-07-01 false Government. 259.1 Section 259.1 Postal Service....1 Government. (a) Policy. The Postal Service cooperates with Federal Agencies whenever the overall costs to Government will be reduced. Assistance in a number of special projects and programs is provided...

39 CFR 259.1 - Government.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 39 Postal Service 1 2010-07-01 2010-07-01 false Government. 259.1 Section 259.1 Postal Service....1 Government. (a) Policy. The Postal Service cooperates with Federal Agencies whenever the overall costs to Government will be reduced. Assistance in a number of special projects and programs is provided...

39 CFR 259.1 - Government.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 39 Postal Service 1 2014-07-01 2014-07-01 false Government. 259.1 Section 259.1 Postal Service....1 Government. (a) Policy. The Postal Service cooperates with Federal Agencies whenever the overall costs to Government will be reduced. Assistance in a number of special projects and programs is provided...

The integrated endoplasmic reticulum stress response in Leishmania amazonensis macrophage infection: the role of X-box binding protein 1 transcription factor.

PubMed

Dias-Teixeira, Karina Luiza; Calegari-Silva, Teresa Cristina; dos Santos, Guilherme R R M; Vitorino Dos Santos, José; Lima, Carolina; Medina, Jorge Mansur; Aktas, Bertal Huseyin; Lopes, Ulisses G

2016-04-01

Endoplasmic reticulum (ER) stress triggers the integrated ER-stress response (IERSR) that ensures cellular survival of ER stress and represents a primordial form of innate immunity. We investigated the role of IERSR duringLeishmania amazonensisinfection. Treatment of RAW 264.7 infected macrophages with the ER stress-inducing agent thapsigargin (TG; 1 μM) increasedL. amazonensisinfectivity in an IFN1-α receptor (IFNAR)-dependent manner. In Western blot assays, we showed thatL. amazonensisactivates the inositol-requiring enzyme (IRE1)/ X-box binding protein (XBP)-1-splicing arms of the IERSR in host cells. In chromatin immunoprecipitation (ChIP) assays, we showed an increased occupancy of enhancer and promoter sequences for theIfnbgene by XBP1 in infected RAW 264.7 cells. Knocking down XBP1 expression by transducing RAW 264.7 cells with the short hairpin XBP1 lentiviral vector significantly reduced the parasite proliferation associated with impaired translocation of phosphorylated IFN regulatory transcription factor (IRF)-3 to the nucleus and a decrease in IFN1-β expression. Knocking down XBP1 expression also increased NO concentration, as determined by Griess reaction and reduced the expression of antioxidant genes, such as heme oxygenase (HO)-1, that protect parasites from oxidative stress. We conclude thatL. amazonensisactivation of XBP1 plays a critical role in infection by protecting the parasites from oxidative stress and increasing IFN1-β expression.-Dias-Teixeira, K. L., Calegari-Silva, T. C., Dos Santos, G. R. R. M., Vitorino dos Santos, J., Lima, C., Medina, J. M., Aktas, B. H., Lopes, U. G. The integrated endoplasmic reticulum stress response inLeishmania amazonensismacrophage infection: the role of X-box binding protein 1 transcription factor. © FASEB.

ER stress triggers MCP-1 expression through SET7/9-induced histone methylation in the kidneys of db/db mice.

PubMed

Chen, Jigang; Guo, Yanhong; Zeng, Wei; Huang, Li; Pang, Qi; Nie, Ling; Mu, Jiao; Yuan, Fahuan; Feng, Bing

2014-04-15

Epigenetics plays a key role in the pathogenesis of diabetic nephropathy (DN), although the precise regulatory mechanism is still unclear. Here, we examined the role of endoplasmic reticulum (ER) stress in histone H3 lysine 4 (H3K4) methyltransferase SET7/9-induced monocyte chemoattractant protein-1 (MCP-1) expression in the kidneys of db/db mice. Our results indicate that the expression of MCP-1 significantly increased in the kidneys of db/db mice in a time-dependent manner. An increased chromatin mark associated with an active gene (H3K4me1) at MCP-1 promoters accompanied this change in expression. The expression of SET7/9 and the recruitment to these promoters were also elevated. SET7/9 gene silencing with small interfering (si) RNAs significantly attenuated the expression of H3K4me1 and MCP-1. Furthermore, expression of signaling regulator glucose-regulated protein 78 (GRP78), a monitor of ER stress, significantly increased in the kidneys of db/db mice. The expression of spliced X-box binding protein 1 (XBP1s), an ER stress-inducible transcription factor, and recruitment to the SET7/9 promoters were also increased. XBP1s gene silencing with siRNAs significantly attenuated the expression of SET7/9, H3K4me1, and MCP-1. The chaperone betaine not only effectively downregulated the GRP78 and XBP1s expression levels but also markedly decreased the SET7/9, H3K4me1, and MCP-1 levels. Luciferase reporter assay demonstrated that XBP1s participated in ER stress-induced SET7/9 transcription, Taken together, these results reveal that ER stress can trigger the expression of MCP-1, in part through the XBP1s-mediated induction of SET7/9.

Late-L2 Increased Reliance on L1 Neurocognitive Substrates: A Comment on Babcock, Stowe, Maloof, Brovetto & Ullman (2012)

ERIC Educational Resources Information Center

Paradis, Michel

2013-01-01

Babcok et al. (2012) claim that Paradis (1994, 2004, 2009) argues that the reliance of late L2 learners on L1 neurocognitive mechanisms increases over time across both lexical and grammatical functions, namely for lexical items as well as rule-governed grammatical procedures, when in fact one can find repeated statements to the contrary in the…

31 CFR 352.1 - Governing regulations.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 31 Money and Finance: Treasury 2 2010-07-01 2010-07-01 false Governing regulations. 352.1 Section 352.1 Money and Finance: Treasury Regulations Relating to Money and Finance (Continued) FISCAL SERVICE....1 Governing regulations. Series HH bonds are subject to the regulations of the Department of the...

31 CFR 352.1 - Governing regulations.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 31 Money and Finance:Treasury 2 2011-07-01 2011-07-01 false Governing regulations. 352.1 Section 352.1 Money and Finance: Treasury Regulations Relating to Money and Finance (Continued) FISCAL SERVICE....1 Governing regulations. Series HH bonds are subject to the regulations of the Department of the...

4 CFR 25.1 - Applicability and governing laws.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 4 Accounts 1 2012-01-01 2012-01-01 false Applicability and governing laws. 25.1 Section 25.1... OFFICE BUILDING AND ON ITS GROUNDS § 25.1 Applicability and governing laws. These rules and regulations, and the laws of the United States and the District of Columbia, apply to the Government Accountability...

4 CFR 25.1 - Applicability and governing laws.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 4 Accounts 1 2013-01-01 2013-01-01 false Applicability and governing laws. 25.1 Section 25.1... OFFICE BUILDING AND ON ITS GROUNDS § 25.1 Applicability and governing laws. These rules and regulations, and the laws of the United States and the District of Columbia, apply to the Government Accountability...

4 CFR 25.1 - Applicability and governing laws.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 4 Accounts 1 2010-01-01 2010-01-01 false Applicability and governing laws. 25.1 Section 25.1... OFFICE BUILDING AND ON ITS GROUNDS § 25.1 Applicability and governing laws. These rules and regulations, and the laws of the United States and the District of Columbia, apply to the Government Accountability...

Forces from the Portal Govern the Late-Stage DNA Transport in a Viral DNA Packaging Nanomotor.

PubMed

Jing, Peng; Burris, Benjamin; Zhang, Rong

2016-07-12

In the Phi29 bacteriophage, the DNA packaging nanomotor packs its double-stranded DNA genome into the virus capsid. At the late stage of DNA packaging, the negatively charged genome is increasingly compacted at a higher density in the capsid with a higher internal pressure. During the process, two Donnan effects, osmotic pressure and Donnan equilibrium potentials, are significantly amplified, which, in turn, affect the channel activity of the portal protein, GP10, embedded in the semipermeable capsid shell. In the research, planar lipid bilayer experiments were used to study the channel activities of the viral protein. The Donnan effect on the conformational changes of the viral protein was discovered, indicating GP10 may not be a static channel at the late stage of DNA packaging. Due to the conformational changes, GP10 may generate electrostatic forces that govern the DNA transport. For the section of the genome DNA that remains outside of the connector channel, a strong repulsive force from the viral protein would be generated against the DNA entry; however, for the section of the genome DNA within the channel, the portal protein would become a Brownian motor, which adopts the flash Brownian ratchet mechanism to pump the DNA against the increasingly built-up internal pressure (up to 20 atm) in the capsid. Therefore, the DNA transport in the nanoscale viral channel at the late stage of DNA packaging could be a consequence of Brownian movement of the genomic DNA, which would be rectified and harnessed by the forces from the interior wall of the viral channel under the influence of the Donnan effect. Copyright © 2016 Biophysical Society. Published by Elsevier Inc. All rights reserved.

Government Regulation of Higher Education.

ERIC Educational Resources Information Center

Hobbs, Walter C., Ed.

Only lately has government regulation developed with great force among colleges and universities. A collection of essays examines that development from the perspectives of the legal scholar, the university president, the university lawyer, the government lawyer, the university's affirmative action officer, the professional association's government…

48 CFR 49.402-1 - The Government's right.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 48 Federal Acquisition Regulations System 1 2010-10-01 2010-10-01 false The Government's right. 49... MANAGEMENT TERMINATION OF CONTRACTS Termination for Default 49.402-1 The Government's right. Under contracts containing the Default clause at 52.249-8, the Government has the right, subject to the notice requirements...

48 CFR 49.402-1 - The Government's right.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 48 Federal Acquisition Regulations System 1 2014-10-01 2014-10-01 false The Government's right. 49... MANAGEMENT TERMINATION OF CONTRACTS Termination for Default 49.402-1 The Government's right. Under contracts containing the Default clause at 52.249-8, the Government has the right, subject to the notice requirements...

48 CFR 52.251-1 - Government Supply Sources.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 48 Federal Acquisition Regulations System 2 2014-10-01 2014-10-01 false Government Supply Sources....251-1 Government Supply Sources. As prescribed in 51.107, insert the following clause: Government... Government supply sources in the performance of this contract. Title to all property acquired by the...

48 CFR 52.251-1 - Government Supply Sources.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 48 Federal Acquisition Regulations System 2 2013-10-01 2013-10-01 false Government Supply Sources....251-1 Government Supply Sources. As prescribed in 51.107, insert the following clause: Government... Government supply sources in the performance of this contract. Title to all property acquired by the...

41 CFR 60-1.10 - Foreign government practices.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 41 Public Contracts and Property Management 1 2011-07-01 2009-07-01 true Foreign government practices. 60-1.10 Section 60-1.10 Public Contracts and Property Management Other Provisions Relating to... Clause; Compliance Reports § 60-1.10 Foreign government practices. Contractors shall not discriminate on...

A xylose-stimulated xylanase-xylose binding protein chimera created by random nonhomologous recombination.

PubMed

Ribeiro, Lucas Ferreira; Tullman, Jennifer; Nicholes, Nathan; Silva, Sérgio Ruschi Bergamachi; Vieira, Davi Serradella; Ostermeier, Marc; Ward, Richard John

2016-01-01

Saccharification of lignocellulosic material by xylanases and other glycoside hydrolases is generally conducted at high concentrations of the final reaction products, which frequently inhibit the enzymes used in the saccharification process. Using a random nonhomologous recombination strategy, we have fused the GH11 xylanase from Bacillus subtilis (XynA) with the xylose binding protein from Escherichia coli (XBP) to produce an enzyme that is allosterically stimulated by xylose. The pT7T3GFP_XBP plasmid containing the XBP coding sequence was randomly linearized with DNase I, and ligated with the XynA coding sequence to create a random XynA-XBP insertion library, which was used to transform E. coli strain JW3538-1 lacking the XBP gene. Screening for active XBP was based on the expression of GFP from the pT7T3GFP_XBP plasmid under the control of a xylose inducible promoter. In the presence of xylose, cells harboring a functional XBP domain in the fusion protein (XBP+) showed increased GFP fluorescence and were selected using FACS. The XBP+ cells were further screened for xylanase activity by halo formation around xylanase producing colonies (XynA+) on LB-agar-xylan media after staining with Congo red. The xylanase activity ratio with xylose/without xylose in supernatants from the XBP+/XynA+ clones was measured against remazol brilliant blue xylan. A clone showing an activity ratio higher than 1.3 was selected where the XynA was inserted after the asparagine 271 in the XBP, and this chimera was denominated as XynA-XBP271. The XynA-XBP271 was more stable than XynA at 55 °C, and in the presence of xylose the catalytic efficiency was ~3-fold greater than the parental xylanase. Molecular dynamics simulations predicted the formation of an extended protein-protein interface with coupled movements between the XynA and XBP domains. In the XynA-XBP271 with xylose bound to the XBP domain, the mobility of a β-loop in the XynA domain results in an increased access to the

48 CFR 47.104-1 - Government rate tender procedures.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 48 Federal Acquisition Regulations System 1 2010-10-01 2010-10-01 false Government rate tender... CONTRACT MANAGEMENT TRANSPORTATION General 47.104-1 Government rate tender procedures. (a) 49 U.S.C. 10721 and 13712 rates are published in Government rate tenders and apply to shipments moving for the account...

48 CFR 47.104-1 - Government rate tender procedures.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 48 Federal Acquisition Regulations System 1 2014-10-01 2014-10-01 false Government rate tender... CONTRACT MANAGEMENT TRANSPORTATION General 47.104-1 Government rate tender procedures. (a) 49 U.S.C. 10721 and 13712 rates are published in Government rate tenders and apply to shipments moving for the account...

1 CFR 12.3 - The United States Government Manual.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 1 General Provisions 1 2011-01-01 2011-01-01 false The United States Government Manual. 12.3... States Government Manual. (a) Copies of The United States Government Manual shall be made available to... legislative courts of the United States will be provided with one copy based on a written request from the...

1 CFR 12.3 - The United States Government Manual.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 1 General Provisions 1 2010-01-01 2010-01-01 false The United States Government Manual. 12.3... States Government Manual. (a) Copies of The United States Government Manual shall be made available to... legislative courts of the United States will be provided with one copy based on a written request from the...

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

PubMed Central

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

2018-01-01

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

Induction of endoplasmic reticulum stress under endotoxin tolerance increases inflammatory responses and decreases Pseudomonas aeruginosa pneumonia.

PubMed

Kim, Sena; Joe, Yeonsoo; Park, Se-Ung; Jeong, Sun Oh; Kim, Jin-Kyung; Park, Seong Hoon; Pae, Hyun-Ock; Surh, Young-Joon; Shin, Jaekyoon; Chung, Hun Taeg

2018-06-20

Endotoxin tolerance develops in the late phase of sepsis to protect cells from an early hyperinflammatory response. Nonetheless, because it induces an immunosuppressive environment, patients with sepsis in its late phase are affected by secondary infections, particularly bacterial pneumonia. Here, we showed that induction of endoplasmic reticulum (ER) stress leads to activation of glycogen synthase kinase 3β (GSK-3β) and X-box-binding protein 1 (XBP-1) in an inositol-requiring enzyme 1α (IRE1α)-mediated manner, which in turn restores the inflammatory response in endotoxin-tolerant macrophages. Animal and in vitro models of endotoxin tolerance were studied along with a model of LPS-induced endotoxin tolerance and a model of cecal ligation and puncture (CLP)-induced endotoxin tolerance. To detect the suppressed inflammatory response during endotoxin tolerance, inflammatory-cytokine expression levels were measured by quantitative real-time PCR and an ELISA. Our research revealed that induction of ER stress alleviated lung injury in a septic host infected with Pseudomonas aeruginosa via the activation of GSK-3β and XBP-1 in an IRE1α-mediated manner. Consequently, in the lungs of the septic host infected with P. aeruginosa, symptoms of pneumonia improved and the infecting bacteria were cleared. Thus, for septic patients, determination of immune status may guide the selection of appropriate immunomodulation, and ER stress can be a novel therapeutic strategy restoring the immune response in patients with endotoxin tolerance. ©2018 Society for Leukocyte Biology.

XBP1, Unfolded Protein Response, and Endocrine Responsiveness

DTIC Science & Technology

2009-05-01

through regu- lation of large-scale chromatin unfolding. Biochem Biophys Res Commun 2004, 323(1): 269-74. 59. Vaupel, P., Kelleher, D.K. and Hockel...stage 2 (M2)” or “ crisis ” [64]. 2.6. Endocrine-induced cell death in breast cancer Precisely how breast cancer cells die following estrogen with- drawal...2005) 2747–2757. [17] R.C. Coombes , E. Hall, L.J. Gibson, R. Paridaens, J. Jassem, T. Delozier, S.E. Jones, I. Alvarez, G. Bertelli, O. Ortmann, A.S

Sigmar1 regulates endoplasmic reticulum stress-induced C/EBP-homologous protein expression in cardiomyocytes.

PubMed

Alam, Shafiul; Abdullah, Chowdhury S; Aishwarya, Richa; Orr, A Wayne; Traylor, James; Miriyala, Sumitra; Panchatcharam, Manikandan; Pattillo, Christopher B; Bhuiyan, Md Shenuarin

2017-08-31

C/EBP-homologous protein (CHOP) is a ubiquitously expressed stress-inducible transcription factor robustly induced by maladaptive endoplasmic reticulum (ER) stresses in a wide variety of cells. Here, we examined a novel function of Sigma 1 receptor (Sigmar1) in regulating CHOP expression under ER stress in cardiomyocytes. We also defined Sigmar1-dependent activation of the adaptive ER-stress pathway in regulating CHOP expression. We used adenovirus-mediated Sigmar1 overexpression as well as Sigmar1 knockdown by siRNA in neonatal rat ventricular cardiomyocytes (NRCs); to induce ER stress, cardiomyocytes were treated with tunicamycin. Sigmar1-siRNA knockdown significantly increased the expression of CHOP and significantly induced cellular toxicity by sustained activation of ER stress in cardiomyocytes. Sigmar1 overexpression decreased the expression of CHOP and significantly decreased cellular toxicity in cells. Using biochemical and immunocytochemical experiments, we also defined the specific ER-stress pathway associated with Sigmar1-dependent regulation of CHOP expression and cellular toxicity. We found that Sigmar1 overexpression significantly increased inositol requiring kinase 1α (IRE1α) phosphorylation and increased spliced X-box-binding proteins (XBP1s) expression as well as nuclear localization. In contrast, Sigmar1 knockdown significantly decreased IRE1α phosphorylation and decreased XBP1s expression as well as nuclear transport. Taken together, these results indicate that Sigmar1-dependent activation of IRE1α-XBP1s ER-stress response pathways are associated with inhibition of CHOP expression and suppression of cellular toxicity. Hence, Sigmar1 is an essential component of the adaptive ER-stress response pathways eliciting cellular protection in cardiomyocytes. © 2017 The Author(s).

Sigmar1 regulates endoplasmic reticulum stress-induced C/EBP-homologous protein expression in cardiomyocytes

PubMed Central

Alam, Shafiul; Abdullah, Chowdhury S.; Aishwarya, Richa; Orr, A. Wayne; Traylor, James; Miriyala, Sumitra; Panchatcharam, Manikandan; Pattillo, Christopher B.

2017-01-01

C/EBP-homologous protein (CHOP) is a ubiquitously expressed stress-inducible transcription factor robustly induced by maladaptive endoplasmic reticulum (ER) stresses in a wide variety of cells. Here, we examined a novel function of Sigma 1 receptor (Sigmar1) in regulating CHOP expression under ER stress in cardiomyocytes. We also defined Sigmar1-dependent activation of the adaptive ER-stress pathway in regulating CHOP expression. We used adenovirus-mediated Sigmar1 overexpression as well as Sigmar1 knockdown by siRNA in neonatal rat ventricular cardiomyocytes (NRCs); to induce ER stress, cardiomyocytes were treated with tunicamycin. Sigmar1-siRNA knockdown significantly increased the expression of CHOP and significantly induced cellular toxicity by sustained activation of ER stress in cardiomyocytes. Sigmar1 overexpression decreased the expression of CHOP and significantly decreased cellular toxicity in cells. Using biochemical and immunocytochemical experiments, we also defined the specific ER-stress pathway associated with Sigmar1-dependent regulation of CHOP expression and cellular toxicity. We found that Sigmar1 overexpression significantly increased inositol requiring kinase 1α (IRE1α) phosphorylation and increased spliced X-box-binding proteins (XBP1s) expression as well as nuclear localization. In contrast, Sigmar1 knockdown significantly decreased IRE1α phosphorylation and decreased XBP1s expression as well as nuclear transport. Taken together, these results indicate that Sigmar1-dependent activation of IRE1α-XBP1s ER-stress response pathways are associated with inhibition of CHOP expression and suppression of cellular toxicity. Hence, Sigmar1 is an essential component of the adaptive ER-stress response pathways eliciting cellular protection in cardiomyocytes. PMID:28667101

48 CFR 970.5236-1 - Government facility subcontract approval.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 48 Federal Acquisition Regulations System 5 2011-10-01 2011-10-01 false Government facility... and Contract Clauses for Management and Operating Contracts 970.5236-1 Government facility subcontract approval. As prescribed at 48 CFR 970.3605-2, insert the following clause: Government Facility Subcontract...

48 CFR 970.5236-1 - Government facility subcontract approval.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 48 Federal Acquisition Regulations System 5 2014-10-01 2014-10-01 false Government facility... and Contract Clauses for Management and Operating Contracts 970.5236-1 Government facility subcontract approval. As prescribed at 48 CFR 970.3605-2, insert the following clause: Government Facility Subcontract...

48 CFR 970.5236-1 - Government facility subcontract approval.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 48 Federal Acquisition Regulations System 5 2012-10-01 2012-10-01 false Government facility... and Contract Clauses for Management and Operating Contracts 970.5236-1 Government facility subcontract approval. As prescribed at 48 CFR 970.3605-2, insert the following clause: Government Facility Subcontract...

Blimp-1 controls plasma cell function through the regulation of immunoglobulin secretion and the unfolded protein response.

PubMed

Tellier, Julie; Shi, Wei; Minnich, Martina; Liao, Yang; Crawford, Simon; Smyth, Gordon K; Kallies, Axel; Busslinger, Meinrad; Nutt, Stephen L

2016-03-01

Plasma cell differentiation requires silencing of B cell transcription, while it establishes antibody-secretory function and long-term survival. The transcription factors Blimp-1 and IRF4 are essential for the generation of plasma cells; however, their function in mature plasma cells has remained elusive. We found that while IRF4 was essential for the survival of plasma cells, Blimp-1 was dispensable for this. Blimp-1-deficient plasma cells retained their transcriptional identity but lost the ability to secrete antibody. Blimp-1 regulated many components of the unfolded protein response (UPR), including XBP-1 and ATF6. The overlap in the functions of Blimp-1 and XBP-1 was restricted to that response, with Blimp-1 uniquely regulating activity of the kinase mTOR and the size of plasma cells. Thus, Blimp-1 was required for the unique physiological ability of plasma cells that enables the secretion of protective antibody.

41 CFR 101-28.203-1 - Government storage activity.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 41 Public Contracts and Property Management 2 2013-07-01 2012-07-01 true Government storage... DISTRIBUTION 28.2-Interagency Cross-Servicing in Storage Activities § 101-28.203-1 Government storage activity. A Government activity or facility utilized for the receipt, storage, and issue of supplies...

41 CFR 101-28.203-1 - Government storage activity.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 41 Public Contracts and Property Management 2 2012-07-01 2012-07-01 false Government storage... DISTRIBUTION 28.2-Interagency Cross-Servicing in Storage Activities § 101-28.203-1 Government storage activity. A Government activity or facility utilized for the receipt, storage, and issue of supplies...

Dengue Virus Modulates the Unfolded Protein Response in a Time-dependent Manner*

PubMed Central

Peña, José; Harris, Eva

2011-01-01

Flaviviruses, such as dengue virus (DENV), depend on the host endoplasmic reticulum for translation, replication, and packaging of their genomes. Here we report that DENV-2 infection modulates the unfolded protein response in a time-dependent manner. We show that early DENV-2 infection triggers and then suppresses PERK-mediated eIF2α phosphorylation and that in mid and late DENV-2 infection, the IRE1-XBP1 and ATF6 pathways are activated, respectively. Activation of IRE1-XBP1 correlated with induction of downstream targets GRP78, CHOP, and GADD34. Furthermore, induction of CHOP did not induce apoptotic markers, such as suppression of anti-apoptotic protein Bcl-2, activation of caspase-9 or caspase-3, and cleavage of poly(ADP-ribose) polymerase. Finally, we show that DENV-2 replication is affected in PERK−/− and IRE1−/− mouse embryo fibroblasts when compared with wild-type mouse embryo fibroblasts. These results demonstrate that time-dependent activation of the unfolded protein response by DENV-2 can override inhibition of translation, prevent apoptosis, and prolong the viral life cycle. PMID:21385877

1 CFR 11.4 - The United States Government Manual.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 1 General Provisions 1 2011-01-01 2011-01-01 false The United States Government Manual. 11.4 Section 11.4 General Provisions ADMINISTRATIVE COMMITTEE OF THE FEDERAL REGISTER AVAILABILITY OF OFFICE OF THE FEDERAL REGISTER PUBLICATIONS SUBSCRIPTIONS § 11.4 The United States Government Manual. Copies of...

1 CFR 11.4 - The United States Government Manual.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 1 General Provisions 1 2010-01-01 2010-01-01 false The United States Government Manual. 11.4 Section 11.4 General Provisions ADMINISTRATIVE COMMITTEE OF THE FEDERAL REGISTER AVAILABILITY OF OFFICE OF THE FEDERAL REGISTER PUBLICATIONS SUBSCRIPTIONS § 11.4 The United States Government Manual. Copies of...

1 CFR 11.4 - The United States Government Manual.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 1 General Provisions 1 2014-01-01 2012-01-01 true The United States Government Manual. 11.4 Section 11.4 General Provisions ADMINISTRATIVE COMMITTEE OF THE FEDERAL REGISTER AVAILABILITY OF OFFICE OF THE FEDERAL REGISTER PUBLICATIONS SUBSCRIPTIONS § 11.4 The United States Government Manual. (a) The...

1 CFR 11.4 - The United States Government Manual.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 1 General Provisions 1 2013-01-01 2012-01-01 true The United States Government Manual. 11.4 Section 11.4 General Provisions ADMINISTRATIVE COMMITTEE OF THE FEDERAL REGISTER AVAILABILITY OF OFFICE OF THE FEDERAL REGISTER PUBLICATIONS SUBSCRIPTIONS § 11.4 The United States Government Manual. (a) The...

Coordinated activation of the secretory pathway during notochord formation in the Xenopus embryo.

PubMed

Tanegashima, Kosuke; Zhao, Hui; Rebbert, Martha L; Dawid, Igor B

2009-11-01

We compared the transcriptome in the developing notochord of Xenopus laevis embryos with that of other embryonic regions. A coordinated and intense activation of a large set of secretory pathway genes was observed in the notochord, but not in notochord precursors in the axial mesoderm at early gastrula stage. The genes encoding Xbp1 and Creb3l2 were also activated in the notochord. These two transcription factors are implicated in the activation of secretory pathway genes during the unfolded protein response, where cells react to the stress of a build-up of unfolded proteins in their endoplasmic reticulum. Xbp1 and Creb3l2 are differentially expressed but not differentially activated in the notochord. Reduction of expression of Xbp1 or Creb3l2 by injection of antisense morpholinos led to strong deficits in notochord but not somitic muscle development. In addition, the expression of some, but not all, genes encoding secretory proteins was inhibited by injection of xbp1 morpholinos. Furthermore, expression of activated forms of Xbp1 or Creb3l2 in animal explants could activate a similar subset of secretory pathway genes. We conclude that coordinated activation of a battery of secretory pathway genes mediated by Xbp1 and Creb/ATF factors is a characteristic and necessary feature of notochord formation.

New Model of Information Technology Governance in the Government of Gorontalo City using Framework COBIT 4.1

NASA Astrophysics Data System (ADS)

Bouty, A. A.; Koniyo, M. H.; Novian, D.

2018-02-01

This study aims to determine the level of maturity of information technology governance in Gorontalo city government by applying the COBIT framework 4.1. The research method is the case study method, by conducting surveys and data collection at 25 institution in Gorontalo City. The results of this study is the analysis of information technology needs based on the measurement of maturity level. The results of the measurement of the maturity level of information technology governance shows that there are still many business processes running at lower level, from 9 existing business processes there are 4 processes at level 2 (repetitive but intuitive) and 3 processes at level 1 (Initial/Ad hoc). With these results, is expected that the government of Gorontalo city immediately make improvements to the governance of information technology so that it can run more effectively and efficiently.

4 CFR 11.1 - Right to representation before the Government Accountability Office.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 4 Accounts 1 2010-01-01 2010-01-01 false Right to representation before the Government Accountability Office. 11.1 Section 11.1 Accounts GOVERNMENT ACCOUNTABILITY OFFICE PERSONNEL SYSTEM RECOGNITION OF ATTORNEYS AND OTHER REPRESENTATIVES § 11.1 Right to representation before the Government...

30 CFR 870.21 - Late payments.

Code of Federal Regulations, 2010 CFR

2010-07-01

... Government. The Treasury current value of funds rate is published annually in the Federal Register and on... fees and interest. (c) When a reclamation fee debt is more than 91 days overdue, a 6 percent annual... fee was owed are subject to interest. Late reclamation fee payments are subject to interest at the...

Shared governance in a clinic system.

PubMed

Meyers, Michelle M; Costanzo, Cindy

2015-01-01

Shared governance in health care empowers nurses to share in the decision-making process, which results in decentralized management and collective accountability. Share governance practices have been present in hospitals since the late 1970s. However, shared governance in ambulatory care clinics has not been well established. The subjects of this quality project included staff and administrative nurses in a clinic system. The stakeholder committee chose what model of shared governance to implement and educated clinic staff. The Index of Professional Nursing Governance measured a shared governance score pre- and postimplementation of the Clinic Nursing Council. The Clinic Nursing Council met bimonthly for 3 months during this project to discuss issues and make decisions related to nursing staff. The Index of Professional Nursing Governance scores indicated traditional governance pre- and postimplementation of the Clinic Nursing Council, which is to be expected. The stakeholder committee was beneficial to the initial implementation process and facilitated staff nurse involvement. Shared governance is an evolutionary process that develops empowered nurses and nurse leaders.

25 CFR 301.1 - Eligibility for use of Government stamp.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 25 Indians 2 2010-04-01 2010-04-01 false Eligibility for use of Government stamp. 301.1 Section 301.1 Indians INDIAN ARTS AND CRAFTS BOARD, DEPARTMENT OF THE INTERIOR NAVAJO, PUEBLO, AND HOPI SILVER AND TURQUOISE PRODUCTS; STANDARDS § 301.1 Eligibility for use of Government stamp. Subject to the...

26 CFR 305.7701-1 - Definition of Indian tribal government.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 26 Internal Revenue 18 2014-04-01 2014-04-01 false Definition of Indian tribal government. 305... INDIAN TRIBAL GOVERNMENTAL TAX STATUS ACT OF 1982 § 305.7701-1 Definition of Indian tribal government. (a... Indians, or Alaska Natives, qualifies as an Indian tribal government upon determination by the Internal...

26 CFR 305.7701-1 - Definition of Indian tribal government.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 26 Internal Revenue 18 2012-04-01 2012-04-01 false Definition of Indian tribal government. 305... INDIAN TRIBAL GOVERNMENTAL TAX STATUS ACT OF 1982 § 305.7701-1 Definition of Indian tribal government. (a... Indians, or Alaska Natives, qualifies as an Indian tribal government upon determination by the Internal...

26 CFR 305.7701-1 - Definition of Indian tribal government.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 26 Internal Revenue 18 2013-04-01 2013-04-01 false Definition of Indian tribal government. 305... INDIAN TRIBAL GOVERNMENTAL TAX STATUS ACT OF 1982 § 305.7701-1 Definition of Indian tribal government. (a... Indians, or Alaska Natives, qualifies as an Indian tribal government upon determination by the Internal...

Prenatal retinoic acid treatment upregulates late gestation lung protein 1 in the nitrofen-induced hypoplastic lung in late gestation.

PubMed

Ruttenstock, Elke Maria; Doi, Takashi; Dingemann, Jens; Puri, Prem

2011-02-01

Pulmonary hypoplasia (PH), the leading cause of mortality in congenital diaphragmatic hernia (CDH), is associated with arrested alveolarization. Late gestation lung protein 1 (LGL1) plays a crucial role in the regulation of alveolarization. Inhibition of LGL1 impairs alveolar maturation in fetal rat lungs. LGL1 heterozygotus knockout mice display delayed lung maturation. It is well known that prenatal administration of retinoic acid (RA) stimulates alveologenesis in nitrofen-induced PH. In vitro studies have reported that RA is a key modulator of LGL1 during alveologenesis. We hypothesized, that pulmonary gene expression of LGL1 is downregulated in the late stage of lung development, and that prenatal administration of RA upregulates pulmonary LGL1 expression in the nitrofen CDH model. Pregnant rats were exposed to nitrofen on day 9 (D9) of gestation. RA was given intraperitoneally on D18, D19 and D20. Fetal lungs were dissected on D21 and divided into control, control + RA, CDH and CDH + RA group. Expression levels of LGL1 were determined using RT-PCR and immunohistochemistry. On D21, LGL1 relative mRNA expression levels were significantly downregulated in CDH group compared to controls. After RA treatment, gene expression levels of LGL1 were significantly upregulated in CDH + RA and control + RA compared to CDH group. Immunohistochemical studies confirmed these results. Downregulation of pulmonary LGL1 gene expression in the late stage of lung development may interfere with normal alveologenesis. Upregulation of LGL1 pulmonary gene expression after RA treatment may promote lung growth by stimulating alveologenesis in the nitrofen CDH model.

7 CFR 792.10 - Late payment interest, penalty and administrative charges.

Code of Federal Regulations, 2010 CFR

2010-01-01

... State and local governments. Interest on debts owed by such entities shall be charged to the extent... debts. The late payment interest rate shall be equal to the higher of the Treasury Department's current... Prompt Payment Act was chosen as an alternative rate to ensure that the Government would recoup interest...

41 CFR 101-28.203-1 - Government storage activity.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 41 Public Contracts and Property Management 2 2014-07-01 2012-07-01 true Government storage... Management Regulations System FEDERAL PROPERTY MANAGEMENT REGULATIONS SUPPLY AND PROCUREMENT 28-STORAGE AND DISTRIBUTION 28.2-Interagency Cross-Servicing in Storage Activities § 101-28.203-1 Government storage activity...

Seattle Schools' Governance under Fire

ERIC Educational Resources Information Center

Archer, Jeff

2007-01-01

This article reports on how Seattle has joined the growing list of urban districts where policymakers are eyeing changes in school governance. A bill pending in the Washington state legislature, introduced late January 2007 by three lawmakers from the city, would permit citizens to petition to hold a local referendum on switching from the elected…

Incidental late diagnosis of cystic fibrosis following AH1N1 influenza virus pneumonia: a case report.

PubMed

Iadevaia, Carlo; Iacotucci, Paola; Carnovale, Vincenzo; Calabrese, Cecilia; Rea, Gaetano; Ferrara, Nicola; Perrotta, Fabio; Mazzarella, Gennaro; Bianco, Andrea

2017-10-01

Cystic fibrosis is an autosomal recessive disorder characterized by chronic progressive multisystem involvement. AH1N1 virus infections caused classic influenza symptoms in the majority of cystic fibrosis patients while others experienced severe outcomes. We report a case of late incidental cystic fibrosis diagnosis in a young Caucasian man suffering from respiratory failure following infection due to AH1N1 influenza virus. The patient was admitted to our department with fever, cough, and dyspnea at rest unresponsive to antibiotics CONCLUSIONS: Late diagnosis of cystic fibrosis in uncommon. This report highlights the importance of early cystic fibrosis diagnosis to minimize risk of occurrence of potential life-threatening complications.

1. Zinc Plant, looking north, down Government Gulch. 610 ft. ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

1. Zinc Plant, looking north, down Government Gulch. 610 ft. tall stack replaced original 200 ft. radial brick stack formerly at rear of Cottrell treater. - Sullivan Electrolytic Zinc Plant, Government Gulch, Kellogg, Shoshone County, ID

38 CFR 1.935 - Consideration of tax consequences to the Government.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 38 Pensions, Bonuses, and Veterans' Relief 1 2010-07-01 2010-07-01 false Consideration of tax consequences to the Government. 1.935 Section 1.935 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF... consequences to the Government. In negotiating a compromise, VA will consider the tax consequences to the...

An Exploration of the Emission Properties of X-Ray Bright Points Seen with SDO

NASA Technical Reports Server (NTRS)

Saar, S. H.; Elsden, T.; Muglach, K.

2012-01-01

We present preliminary results of a study of X-ray Bright Point (XBP) EUV emission and its dependence on other properties. The XBPs were located using a new, automated XBP finder for AlA developed as part of the Feature Finding Team for SDO Computer Vision. We analyze XBPs near disk center, comparing AlA EUV fluxes, HMI LOS magnetic fields, and photospheric flow fields (derived from HMI data) to look for relationships between XBP emission, magnetic flux, velocity fields, and XBP local environment. We find some evidence for differences in the mean XBP temperature with environment. Unsigned magnetic flux is correlated with XBP emission, though other parameters play a role. The majority of XBP footpoints are approaching each other, though at a slight angle from head-on on average. We discuss the results in the context of XBP heating.

Late-Glacial to Late-holocene Shifts in Global Precipitation Delta(sup 18)O

NASA Technical Reports Server (NTRS)

Jasechko, S.; Lechler, A.; Pausata, F.S.R.; Fawcett, P.J.; Gleeson, T.; Cendon, D.I.; Galewsky, J.; LeGrande, A. N.; Risi, C.; Sharp, Z. D.;

48 CFR 52.245-1 - Government Property.

Code of Federal Regulations, 2010 CFR

2010-10-01

... performing a contract, and to which the Government has title. Contractor inventory means— (1) Any property acquired by and in the possession of a Contractor or subcontractor under a contract for which title is... unusable for, and not restorable to, the purpose for which it was designed or is customarily used...

Inositol-requiring enzyme 1α is required for gut development in Xenopus lavies embryos

PubMed Central

Guo, Jing; Li, Xin-Xin; Feng, Jiao-Jiao; Yin, Chen-Yang; Wang, Xue-Jun; Wang, Ning; Yuan, Li

2013-01-01

AIM: To investigate the role of inositol-requiring enzyme 1α (IRE1α) in gut development of Xenopus lavies embryos. METHODS: Xenopus embryos were obtained with in vitro fertilization and cultured in 0.1 × MBSH. One and half nanogram of IRE1α, 1 ng of IRE1α-GR mRNA, 1 ng of IRE1αΔC-GR mRNA, and 50 ng of IRE1α morpholino oligonucleotide (MO) or XBP1(C)MO were injected into four blastomeres at 4-cell stage for scoring the phenotype and marker gene analysis. To rescue the effect of IRE1α MO, 1 ng of IRE1α-GR mRNA was co-injected with 50 ng of MO. For the activation of the GR-fusion proteins, dexamethasone was prepared as 5 mmol/L stock solutions in 100% ethanol and applied to the mRNA injected embryos at desired stages in a concentration of 10 μmol/L in 0.1 × MBSH. Embryos were kept in dexamethasone up to stage 41. Whole-mount in situ hybridization was used to determine specific gene expression, such as IRE1α, IRE1β, Xbra and Xsox17α. IRE1α protein expression during Xenopus embryogenesis was detected by Western blotting. RESULTS: In the whole-mount in situ hybridization analysis, xenopus IRE1α and IRE1β showed quite different expression pattern during tadpole stage. The relatively higher expression of IRE1α was observed in the pancreas, and significant transcription of IRE1β was found in the liver. IRE1α protein could be detected at all developmental stages analyzed, from stage 1 to stage 42. Gain-of-function assay showed that IRE1α mRNA injected embryos at tailbud stage were nearly normal and the expression of the pan-mesodermal marker gene Xbra and the endodermal gene Xsox17α at stage 10.5 was not significantly changed in embryos injected with IRE1α mRNA as compared to uninjected control embryos. And at tadpole stage, the embryos injected with IRE1α-GR mRNA did not display overt phenotype, such as gut-coiling defect. Loss-of-function assay demonstrated that the IRE1α MO injected embryos were morphologically normal before the tailbud stages

Inositol-requiring enzyme 1α is required for gut development in Xenopus lavies embryos.

PubMed

Guo, Jing; Li, Xin-Xin; Feng, Jiao-Jiao; Yin, Chen-Yang; Wang, Xue-Jun; Wang, Ning; Yuan, Li

2013-01-14

To investigate the role of inositol-requiring enzyme 1α (IRE1α) in gut development of Xenopus lavies embryos. Xenopus embryos were obtained with in vitro fertilization and cultured in 0.1 × MBSH. One and half nanogram of IRE1α, 1 ng of IRE1α-GR mRNA, 1 ng of IRE1αΔC-GR mRNA, and 50 ng of IRE1α morpholino oligonucleotide (MO) or XBP1(C)MO were injected into four blastomeres at 4-cell stage for scoring the phenotype and marker gene analysis. To rescue the effect of IRE1α MO, 1 ng of IRE1α-GR mRNA was co-injected with 50 ng of MO. For the activation of the GR-fusion proteins, dexamethasone was prepared as 5 mmol/L stock solutions in 100% ethanol and applied to the mRNA injected embryos at desired stages in a concentration of 10 μmol/L in 0.1 × MBSH. Embryos were kept in dexamethasone up to stage 41. Whole-mount in situ hybridization was used to determine specific gene expression, such as IRE1α, IRE1β, Xbra and Xsox17α. IRE1α protein expression during Xenopus embryogenesis was detected by Western blotting. In the whole-mount in situ hybridization analysis, xenopus IRE1α and IRE1β showed quite different expression pattern during tadpole stage. The relatively higher expression of IRE1α was observed in the pancreas, and significant transcription of IRE1β was found in the liver. IRE1α protein could be detected at all developmental stages analyzed, from stage 1 to stage 42. Gain-of-function assay showed that IRE1α mRNA injected embryos at tailbud stage were nearly normal and the expression of the pan-mesodermal marker gene Xbra and the endodermal gene Xsox17α at stage 10.5 was not significantly changed in embryos injected with IRE1α mRNA as compared to uninjected control embryos. And at tadpole stage, the embryos injected with IRE1α-GR mRNA did not display overt phenotype, such as gut-coiling defect. Loss-of-function assay demonstrated that the IRE1α MO injected embryos were morphologically normal before the tailbud stages. We did not observe a

49 CFR 1245.1 - Rules governing classification of employees, service, and compensation.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 49 Transportation 9 2010-10-01 2010-10-01 false Rules governing classification of employees..., RECORDS AND REPORTS CLASSIFICATION OF RAILROAD EMPLOYEES; REPORTS OF SERVICE AND COMPENSATION § 1245.1 Rules governing classification of employees, service, and compensation. The rules governing the...

49 CFR 1245.1 - Rules governing classification of employees, service, and compensation.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 49 Transportation 9 2011-10-01 2011-10-01 false Rules governing classification of employees..., RECORDS AND REPORTS CLASSIFICATION OF RAILROAD EMPLOYEES; REPORTS OF SERVICE AND COMPENSATION § 1245.1 Rules governing classification of employees, service, and compensation. The rules governing the...

43 CFR 8341.1 - Regulations governing use.

Code of Federal Regulations, 2014 CFR

2014-10-01

... MANAGEMENT, DEPARTMENT OF THE INTERIOR RECREATION PROGRAMS OFF-ROAD VEHICLES Conditions of Use § 8341.1 Regulations governing use. (a) The operation of off-road vehicles is permitted on those areas and trails designated as open to off-road vehicle use. (b) Any person operating an off-road vehicle on those areas and...

26 CFR 1.892-3T - Income of foreign governments (temporary regulations).

Code of Federal Regulations, 2013 CFR

2013-04-01

... functional currency) or in precious metals when held by a foreign government or central bank of issue (as... 26 Internal Revenue 9 2013-04-01 2013-04-01 false Income of foreign governments (temporary... foreign governments (temporary regulations). (a) Types of income exempt—(1) In general. Subject to the...

26 CFR 1.892-3T - Income of foreign governments (temporary regulations).

Code of Federal Regulations, 2014 CFR

2014-04-01

... functional currency) or in precious metals when held by a foreign government or central bank of issue (as... 26 Internal Revenue 9 2014-04-01 2014-04-01 false Income of foreign governments (temporary... foreign governments (temporary regulations). (a) Types of income exempt—(1) In general. Subject to the...

26 CFR 1.892-3T - Income of foreign governments (temporary regulations).

Code of Federal Regulations, 2012 CFR

2012-04-01

... functional currency) or in precious metals when held by a foreign government or central bank of issue (as... 26 Internal Revenue 9 2012-04-01 2012-04-01 false Income of foreign governments (temporary... foreign governments (temporary regulations). (a) Types of income exempt—(1) In general. Subject to the...

Curcumin alleviates ischemia reperfusion-induced late kidney fibrosis through the APPL1/Akt signaling pathway.

PubMed

Hongtao, Chen; Youling, Fan; Fang, Huang; Huihua, Peng; Jiying, Zhong; Jun, Zhou

2018-05-09

As a major cause of renal failure, transient renal ischemia and reperfusion induce both acute kidney injury and late fibrosis, which are the common pathological manifestations of end-stage renal disease. Curcumin is a biologically active polyphenolic compound found in turmeric. Increasing evidence has demonstrated that curcumin has a protective action against renal fibrosis, whereas mechanisms underlying the anti-fibrosis role of curcumin remain poorly defined. Here, we found that APPL1, an important intracellular binding partner for AdipoR, was involved in the pathogenesis of acute injury or fibrosis and was significantly upregulated by curcumin in a mouse model of ischemia reperfusion-induced late kidney fibrosis. Moreover, Akt signaling was the specific signaling pathway identified downstream of APPL1 in the pathogenesis of fibrosis. Our in vitro experiment demonstrated that curcumin alleviates ischemia reperfusion-induced late kidney fibrosis via the APPL1/Akt pathway. These data are helpful for understanding the anti-fibrosis mechanism of curcumin in the pathogenesis of AKI-induced late fibrosis. © 2018 Wiley Periodicals, Inc.

Inhibition of host cell translation elongation by Legionella pneumophila blocks the host cell unfolded protein response.

PubMed

Hempstead, Andrew D; Isberg, Ralph R

2015-12-08

Cells of the innate immune system recognize bacterial pathogens by detecting common microbial patterns as well as pathogen-specific activities. One system that responds to these stimuli is the IRE1 branch of the unfolded protein response (UPR), a sensor of endoplasmic reticulum (ER) stress. Activation of IRE1, in the context of Toll-like receptor (TLR) signaling, induces strong proinflammatory cytokine induction. We show here that Legionella pneumophila, an intravacuolar pathogen that replicates in an ER-associated compartment, blocks activation of the IRE1 pathway despite presenting pathogen products that stimulate this response. L. pneumophila TLR ligands induced the splicing of mRNA encoding XBP1s, the main target of IRE1 activity. L. pneumophila was able to inhibit both chemical and bacterial induction of XBP1 splicing via bacterial translocated proteins that interfere with host protein translation. A strain lacking five translocated translation elongation inhibitors was unable to block XBP1 splicing, but this could be rescued by expression of a single such inhibitor, consistent with limitation of the response by translation elongation inhibitors. Chemical inhibition of translation elongation blocked pattern recognition receptor-mediated XBP1 splicing, mimicking the effects of the bacterial translation inhibitors. In contrast, host cell-promoted inhibition of translation initiation in response to the pathogen was ineffective in blocking XBP1 splicing, demonstrating the need for the elongation inhibitors for protection from the UPR. The inhibition of host translation elongation may be a common strategy used by pathogens to limit the innate immune response by interfering with signaling via the UPR.

Hygromycin B hypersensitive (hhy) mutants implicate an intact trans-Golgi and late endosome interface in efficient Tor1 vacuolar localization and TORC1 function.

PubMed

Ejzykowicz, Daniele E; Locken, Kristopher M; Ruiz, Fiona J; Manandhar, Surya P; Olson, Daniel K; Gharakhanian, Editte

2017-06-01

Saccharomyces cerevisiae vacuoles are functionally analogous to mammalian lysosomes. Both also serve as physical platforms for Tor Complex 1 (TORC1) signal transduction, the master regulator of cellular growth and proliferation. Hygromycin B is a eukaryotic translation inhibitor. We recently reported on hygromycin B hypersensitive (hhy) mutants that fail to grow at subtranslation inhibitory concentrations of the drug and exhibit vacuolar defects (Banuelos et al. in Curr Genet 56:121-137, 2010). Here, we show that hhy phenotype is not due to increased sensitivity to translation inhibition and establish a super HHY (s-HHY) subgroup of genes comprised of ARF1, CHC1, DRS2, SAC1, VPS1, VPS34, VPS45, VPS52, and VPS54 that function exclusively or inclusively at trans-Golgi and late endosome interface. Live cell imaging of s-hhy mutants revealed that hygromycin B treatment disrupts vacuolar morphology and the localization of late endosome marker Pep12, but not that of late endosome-independent vacuolar SNARE Vam3. This, along with normal post-late endosome trafficking of the vital dye FM4-64, establishes that severe hypersensitivity to hygromycin B correlates specifically with compromised trans-Golgi and late endosome interface. We also show that Tor1p vacuolar localization and TORC1 anabolic functions, including growth promotion and phosphorylation of its direct substrate Sch9, are compromised in s-hhy mutants. Thus, an intact trans-Golgi and late endosome interface is a requisite for efficient Tor1 vacuolar localization and TORC1 function.

Essays on Public Documents and Government Policies (1).

ERIC Educational Resources Information Center

Morehead, Joe

1986-01-01

Four essays on U.S. government documents address the didactic nature of many government publications; the reliability of government information and statistics on energy, crime, consumer prices, and unemployment; user needs and access to government information; and sources and services for science and technology libraries. (EM)

The role of SCUBE1 in the development of late stent thrombosis presenting with ST-elevation myocardial infarction.

PubMed

Bolayır, Hasan Ata; Kıvrak, Tarık; Güneş, Hakan; Akaslan, Dursun; Şahin, Ömer; Bolayır, Aslı

2018-05-01

There is an important link between platelets and inflammation, thrombosis, and vascular and tissue repair mechanisms. SCUBE1 (signal peptide-CUB-EGF domain-containing protein 1) may function as a novel platelet-endothelial adhesion molecule and play pathological roles in cardiovascular biology. Stent thrombosis (ST) following percutaneous coronary intervention is an uncommon and potentially catastrophic event that can manifest as myocardial infarction and sudden death. High platelet reactivity is a risk factor for thrombotic events, including late ST. For this reason, in the current study, we researched the role of SCUBE1 in the development of late coronary ST. We included 40 patients admitted to our hospital with a diagnosis of ST-elevation myocardial infarction (STEMI) and signs of late ST on a coronary angiogram. For the control group, we recruited 50 healthy gender- and age-matched individuals who were seen for health check-ups. We also randomly included 100 patients with a diagnosis of STEMI without ST. There were no significant differences between the groups in terms of baseline and demographic characteristics. The mean SCUBE1 level in patients with STEMI with late ST at admission and the STEMI without ST group was significantly higher than in the control group (p<0.01). The mean SCUBE1 level in the STEMI with late ST group was significantly higher than in the STEMI without ST group (p=0.03). In multivariate regression analysis, serum SCUBE1 (odds ratio [OR]: 1.022; 95% confidence interval [CI]: 1.011-1.033, p<0.001) remained an independent predictor for the presence of late ST. In addition, receiver operating characteristic curve analysis was used to determine the optimal SCUBE1 cut-off value for predicting late ST. The area under the curve was 0.972 (95% CI 0.95-0.98). The SCUBE1 cut-off value was 59.2 ng/ml, with a sensitivity of 95.4% and specificity of 82.9%. The present work is the first clinical study to demonstrate that serum SCUBE1 levels are

Observation of spatial and temporal variations in X-ray bright point emergence patterns. [at solar surface

NASA Technical Reports Server (NTRS)

Golub, L.; Krieger, A. S.; Vaiana, G. S.

1976-01-01

Observations of X-ray bright points (XBP) over a six-month interval in 1973 show significant variations in both the number density of XBP as a function of heliographic longitude and in the full-sun average number of XBP from one rotation to the next. The observed increases in XBP emergence are estimated to be equivalent to several large active regions emerging per day for several months. The number of XBP emerging at high latitudes varies in phase with the low-latitude variation and reaches a maximum approximately simultaneous with a major outbreak of active regions. The quantity of magnetic flux emerging in the form of XBP at high latitudes alone is estimated to be as large as the contribution from all active regions.

Structural And Functional Studies of ALIX Interactions With YPXnL Late Domains of HIV-1 And EIAV

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

Zhai, Q.; Fisher, R.D.; Chung, H.-Y.

2009-05-28

Retrovirus budding requires short peptide motifs (late domains) located within the viral Gag protein that function by recruiting cellular factors. The YPX{sub n}L late domains of HIV and other lentiviruses recruit the protein ALIX (also known as AIP1), which also functions in vesicle formation at the multivesicular body and in the abscission stage of cytokinesis. Here, we report the crystal structures of ALIX in complex with the YPX{sub n}L late domains from HIV-1 and EIAV. The two distinct late domains bind at the same site on the ALIX V domain but adopt different conformations that allow them to make equivalentmore » contacts. Binding studies and functional assays verified the importance of key interface residues and revealed that binding affinities are tuned by context-dependent effects. These results reveal how YPX{sub n}L late domains recruit ALIX to facilitate virus budding and how ALIX can bind YPX{sub n}L sequences with both n = 1 and n = 3.« less

1. COPY OF A LATE 19TH CENTURY BUSINESS CARD FOR ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

1. COPY OF A LATE 19TH CENTURY BUSINESS CARD FOR A. ALEXANDER & SON FLOURING MILLS. CARD OWNED BY THOMAS R. WILSON. Photographer: Berni Rich, Score Photographers, September 1986. - Alexander's Grist Mill, Lock 37 on Ohio & Erie Canal, South of Cleveland, Valley View, Cuyahoga County, OH

31 CFR 270.1 - Rules governing availability of information.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 31 Money and Finance: Treasury 2 2010-07-01 2010-07-01 false Rules governing availability of information. 270.1 Section 270.1 Money and Finance: Treasury Regulations Relating to Money and Finance (Continued) FISCAL SERVICE, DEPARTMENT OF THE TREASURY FINANCIAL MANAGEMENT SERVICE AVAILABILITY OF RECORDS...

31 CFR 270.1 - Rules governing availability of information.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 31 Money and Finance:Treasury 2 2012-07-01 2012-07-01 false Rules governing availability of information. 270.1 Section 270.1 Money and Finance: Treasury Regulations Relating to Money and Finance (Continued) FISCAL SERVICE, DEPARTMENT OF THE TREASURY FINANCIAL MANAGEMENT SERVICE AVAILABILITY OF RECORDS...

48 CFR 970.4905-1 - Termination for convenience of the government and default.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 48 Federal Acquisition Regulations System 5 2010-10-01 2010-10-01 false Termination for convenience of the government and default. 970.4905-1 Section 970.4905-1 Federal Acquisition Regulations... Termination of Contracts 970.4905-1 Termination for convenience of the government and default. (a) The...

Activation of the unfolded protein response promotes axonal regeneration after peripheral nerve injury.

PubMed

Oñate, Maritza; Catenaccio, Alejandra; Martínez, Gabriela; Armentano, Donna; Parsons, Geoffrey; Kerr, Bredford; Hetz, Claudio; Court, Felipe A

2016-02-24

Although protein-folding stress at the endoplasmic reticulum (ER) is emerging as a driver of neuronal dysfunction in models of spinal cord injury and neurodegeneration, the contribution of this pathway to peripheral nerve damage remains poorly explored. Here we targeted the unfolded protein response (UPR), an adaptive reaction against ER stress, in mouse models of sciatic nerve injury and found that ablation of the transcription factor XBP1, but not ATF4, significantly delay locomotor recovery. XBP1 deficiency led to decreased macrophage recruitment, a reduction in myelin removal and axonal regeneration. Conversely, overexpression of XBP1s in the nervous system in transgenic mice enhanced locomotor recovery after sciatic nerve crush, associated to an improvement in key pro-regenerative events. To assess the therapeutic potential of UPR manipulation to axonal regeneration, we locally delivered XBP1s or an shRNA targeting this transcription factor to sensory neurons of the dorsal root ganglia using a gene therapy approach and found an enhancement or reduction of axonal regeneration in vivo, respectively. Our results demonstrate a functional role of specific components of the ER proteostasis network in the cellular changes associated to regeneration and functional recovery after peripheral nerve injury.

Magnetic properties of X-ray bright points. [in sun

NASA Technical Reports Server (NTRS)

Golub, L.; Krieger, A. S.; Harvey, J. W.; Vaiana, G. S.

1977-01-01

Using high-resolution Kitt Peak National Observatory magnetograms and sequences of simultaneous S-054 soft X-ray solar images, the properties of X-ray bright points (XBP) and ephemeral active regions (ER) are compared. All XBP appear on the magnetograms as bipolar features, except for very recently emerged or old and decayed XBP. The separation of the magnetic bipoles is found to increase with the age of the XBP, with an average emergence growth rate of 2.2 plus or minus 0.4 km per sec. The total magnetic flux in a typical XBP living about 8 hr is found to be about two times ten to the nineteenth power Mx. A proportionality is found between XBP lifetime and total magnetic flux, equivalent to about ten to the twentieth power Mx per day of lifetime.

Late-Onset Inner Retinal Dysfunction in Mice Lacking Sigma Receptor 1 (σR1)

PubMed Central

Ha, Yonju; Saul, Alan; Tawfik, Amany; Williams, Cory; Bollinger, Kathryn; Smith, Robert; Tachikawa, Masanori; Zorrilla, Eric; Ganapathy, Vadivel

2011-01-01

Purpose. Sigma receptor 1 (σR1) is expressed abundantly in the eye, and several reports suggest that this putative molecular chaperone plays a role in lens cell survival, control of intraocular pressure (IOP), and retinal neuroprotection. The present study examined the consequence of the absence of σR1 on ocular development, structure, and function. Methods. Wild-type (σR1+/+), heterozygous (σR1+/−), and homozygous (σR1−/−, knockout) mice aged 5 to 59 weeks were subjected to comprehensive electrophysiological testing and IOP measurement. The eyes were examined by light and electron microscopy and subjected to morphometric examination and detection of apoptosis. Results. Cornea and lens of σR1−/− mice were similar to wild-type mice in morphologic appearance at all ages examined, and IOP was within normal limits. Comprehensive ERG and morphometric analyses initially yielded normal findings in the σR1−/− mice compared with those in the wild-type. By 12 months, however, significantly decreased ERG b-wave amplitudes and diminished negative scotopic threshold responses, consistent with inner retinal dysfunction, were detected in σR1−/− mice. Concomitant with these late-onset changes were increased TUNEL- and active caspase 3-positive cells in the inner retina and significant loss of cells in the ganglion cell layer, particularly in the central retina. Before these functional and structural abnormalities, there was ultrastructural evidence of axonal disruption in the optic nerve head of σR1−/− mice as early as 6 months of age, although there were no alterations observed in retinal vascularization in σR1−/− mice. Conclusions. These data suggest that lack of σR1 leads to development of late-onset retinal dysfunction with similarities to optic neuropathy. PMID:21862648

Late-onset inner retinal dysfunction in mice lacking sigma receptor 1 (σR1).

PubMed

Ha, Yonju; Saul, Alan; Tawfik, Amany; Williams, Cory; Bollinger, Kathryn; Smith, Robert; Tachikawa, Masanori; Zorrilla, Eric; Ganapathy, Vadivel; Smith, Sylvia B

2011-09-29

Sigma receptor 1 (σR1) is expressed abundantly in the eye, and several reports suggest that this putative molecular chaperone plays a role in lens cell survival, control of intraocular pressure (IOP), and retinal neuroprotection. The present study examined the consequence of the absence of σR1 on ocular development, structure, and function. Wild-type (σR1⁺/⁺), heterozygous (σR1⁺/⁻), and homozygous (σR1⁻/⁻, knockout) mice aged 5 to 59 weeks were subjected to comprehensive electrophysiological testing and IOP measurement. The eyes were examined by light and electron microscopy and subjected to morphometric examination and detection of apoptosis. Cornea and lens of σR1⁻/⁻ mice were similar to wild-type mice in morphologic appearance at all ages examined, and IOP was within normal limits. Comprehensive ERG and morphometric analyses initially yielded normal findings in the σR1⁻/⁻ mice compared with those in the wild-type. By 12 months, however, significantly decreased ERG b-wave amplitudes and diminished negative scotopic threshold responses, consistent with inner retinal dysfunction, were detected in σR1⁻/⁻ mice. Concomitant with these late-onset changes were increased TUNEL- and active caspase 3-positive cells in the inner retina and significant loss of cells in the ganglion cell layer, particularly in the central retina. Before these functional and structural abnormalities, there was ultrastructural evidence of axonal disruption in the optic nerve head of σR1⁻/⁻ mice as early as 6 months of age, although there were no alterations observed in retinal vascularization in σR1⁻/⁻ mice. These data suggest that lack of σR1 leads to development of late-onset retinal dysfunction with similarities to optic neuropathy.

Unfolded protein response regulation in keloid cells.

PubMed

Butler, Paris D; Wang, Zhen; Ly, Daphne P; Longaker, Michael T; Koong, Albert C; Yang, George P

2011-05-01

Keloids are a common form of pathologic wound healing characterized by excessive production of extracellular matrix. The unfolded protein response (UPR) is a cellular response to hypoxia, a component of the wound microenvironment, capable of protecting cells from the effects of over-accumulation of misfolded proteins. Since keloids have hypersecretion of extracellular matrix, we hypothesized that keloid fibroblasts (KFs) may have enhanced activation of the UPR compared with normal fibroblasts (NFs). KFs and NFs were placed in a hypoxia chamber for 0, 24, and 48h. We also used tunicamycin to specifically up-regulate the UPR. UPR activation was assayed by PCR for xbp-1 splicing and by immunoblotting with specific antibodies for the three UPR transducers. Nuclear localization of XBP-1 protein in KFs was confirmed by immunofluorescence. There is increased activation of XBP-1 protein in KFs compared with NFs following exposure to hypoxia. Pancreatic ER kinase (PERK) and ATF-6, two other pathways activated by the UPR, show comparable activation between KFs and NFs. We confirmed that there is enhanced activation of XBP-1 by demonstrating increased nuclear localization of XBP-1 using immunofluorescence. In contrast to our initial hypothesis that keloids would have broad activation of the UPR, we demonstrate here that there is a specific up-regulation of one facet of the UPR response. This may represent a specific molecular defect in KFs compared with NFs, and also suggests modulation of the UPR can be used in wound healing therapy. Published by Elsevier Inc.

Comprehensive Analysis of the Unfolded Protein Response in Breast Cancer Subtypes.

PubMed

Jiang, Dadi; Turner, Brandon; Song, Jie; Li, Ruijiang; Diehn, Maximilian; Le, Quynh-Thu; Khatri, Purvesh; Koong, Albert C

2017-01-01

Triple-negative breast cancers (TNBCs) are associated with a worse prognosis and patients with TNBC have fewer therapeutic options than patients with non-TNBC. Recently, the IRE1α-XBP1 branch of the unfolded protein response (UPR) was implicated in TNBC prognosis on the basis of a relatively small patient population, suggesting the diagnostic and therapeutic value of this pathway in TNBCs. In addition, the IRE1α-XBP1 and hypoxia-induced factor 1 α (HIF1α) pathways have been identified as interacting partners in TNBC, suggesting a novel mechanism of regulation. To comprehensively evaluate and validate these findings, we investigated the relative activities and relevance to patient survival of the UPR and HIF1α pathways in different breast cancer subtypes in large populations of patients. We performed a comprehensive analysis of gene expression and survival data from large cohorts of patients with breast cancer. The patients were stratified based on the average expression of the UPR or HIF1α gene signatures. We identified a strong positive association between the XBP1 gene signature and estrogen receptor-positive status or the HIF1α gene signature, as well as the predictive value of the XBP1 gene signature for survival of patients who are estrogen receptor negative, or have TNBC or HER2 + . In contrast, another important UPR branch, the ATF4/CHOP pathway, lacks prognostic value in breast cancer in general. Activity of the HIF1α pathway is correlated with patient survival in all the subtypes evaluated. These findings clarify the relevance of the UPR pathways in different breast cancer subtypes and underscore the potential therapeutic importance of the IRE1α-XBP1 branch in breast cancer treatment.

26 CFR 31.3306(c)(11)-1 - Services in employ of foreign government.

Code of Federal Regulations, 2010 CFR

2010-04-01

... immaterial. It is also immaterial whether the foreign government grants an equivalent exemption with respect... 26 Internal Revenue 15 2010-04-01 2010-04-01 false Services in employ of foreign government. 31...) § 31.3306(c)(11)-1 Services in employ of foreign government. (a) Services performed by an employee in...

Posterior N1 asymmetry to English and Welsh words in Early and Late English-Welsh bilinguals.

PubMed

Grossi, Giordana; Savill, Nicola; Thomas, Enlli; Thierry, Guillaume

2010-09-01

We investigated the lateralization of the posterior event-related potential (ERP) component N1 (120-170 ms) to written words in two groups of bilinguals. Fourteen Early English-Welsh bilinguals and 14 late learners of Welsh performed a semantic categorization task on separate blocks of English and Welsh words. In both groups, the N1 was strongly lateralized over the left posterior sites for both languages. A robust correlation was found between N1 asymmetry for English and N1 asymmetry for Welsh words in both groups. Furthermore, in Late Bilinguals, the N1 asymmetry for Welsh words increased with years of experience in Welsh. These data suggest that, in Late Bilinguals, the lateralization of neural circuits involved in written word recognition for the second language is associated to the organization for the first language, and that increased experience with the second language is associated to a larger functional cerebral asymmetry in favor of the left hemisphere. Copyright (c) 2010 Elsevier B.V. All rights reserved.

7 CFR 920.112 - Late payments.

Code of Federal Regulations, 2010 CFR

2010-01-01

... Miscellaneous Provisions § 920.112 Late payments. Pursuant to § 920.41(a), interest will be charged at a 1.5 percent monthly simple interest rate. Assessments for kiwifruit shall be deemed late if not received... late charge will be assessed when payment becomes 30 days late. Interest and late payment charges shall...

Progesterone inhibits contraction and increases TREK-1 potassium channel expression in late pregnant rat uterus

PubMed Central

Yin, Zongzhi; Li, Yun; He, Wenzhu; Li, Dan; Li, Hongyan; Yang, Yuanyuan; Shen, Bing; Wang, Xi; Cao, Yunxia; Khalil, Raouf A.

2018-01-01

Objective The aim of this study was to investigate the effect and mechanism by which progesterone regulates uterine contraction in late pregnant rats Results Progesterone caused concentration-dependent relaxation of uterine strips that was enhanced compared with control nontreated uterine strips. Uterine strips incubated with progesterone showed a significant increase in TREK-1 mRNA expression and protein level. TREK-1 inhibitor L-methionine partly reversed uterine relaxation caused by the progesterone, while TREK-1 activator arachidonic acid did not cause significant change in progesterone-induced relaxation. Conclusions Progesterone inhibits uterine contraction and induces uterine relaxation in late pregnancy. The progesterone-induced inhibition of uterine contraction appears to partly involve increased potassium channel TREK-1 expression/activity. Materials and Methods Uterus from late-pregnant rats (gestational day 19) was isolated, and uterine strips were prepared for isometric contraction measurement. Oxytocin-induced contraction was compared in uterine strips pretreated with different concentration of progesterone. TREK-1 potassium channel inhibitor L-methionine and TREK-1 agonist arachidonic acid were used to determine whether the changes caused by progesterone involve changes in TREK-1 activity. The mRNA and protein expression of TREK-1 in uterine tissues were measured using qPCR and Western blot. PMID:29416642

Vitiligo-inducing phenols activate the unfolded protein response in melanocytes resulting in upregulation of IL6 and IL8.

PubMed

Toosi, Siavash; Orlow, Seth J; Manga, Prashiela

2012-11-01

Vitiligo is characterized by depigmented skin patches caused by loss of epidermal melanocytes. Oxidative stress may have a role in vitiligo onset, while autoimmunity contributes to disease progression. In this study, we sought to identify mechanisms that link disease triggers and spreading of lesions. A hallmark of melanocytes at the periphery of vitiligo lesions is dilation of the endoplasmic reticulum (ER). We hypothesized that oxidative stress results in redox disruptions that extend to the ER, causing accumulation of misfolded peptides, which activates the unfolded protein response (UPR). We used 4-tertiary butyl phenol and monobenzyl ether of hydroquinone, known triggers of vitiligo. We show that expression of key UPR components, including the transcription factor X-box-binding protein 1 (XBP1), is increased following exposure of melanocytes to phenols. XBP1 activation increases production of immune mediators IL6 and IL8. Co-treatment with XBP1 inhibitors reduced IL6 and IL8 production induced by phenols, while overexpression of XBP1 alone increased their expression. Thus, melanocytes themselves produce cytokines associated with activation of an immune response following exposure to chemical triggers of vitiligo. These results expand our understanding of the mechanisms underlying melanocyte loss in vitiligo and pathways linking environmental stressors and autoimmunity.

Vitiligo inducing phenols activate the unfolded protein response in melanocytes resulting in upregulation of IL6 and IL8

PubMed Central

Toosi, Siavash; Orlow, Seth J.; Manga, Prashiela

2012-01-01

Vitiligo is characterized by depigmented skin patches due to loss of epidermal melanocytes. Oxidative stress may play a role in vitiligo onset, while autoimmunity contributes to disease progression. In this study we sought to identify mechanisms that link disease triggers and spreading of lesions. A hallmark of melanocytes at the periphery of vitiligo lesions is dilation of the endoplasmic reticulum (ER). We hypothesized that oxidative stress results in redox disruptions that extend to the ER, causing accumulation of misfolded peptides, which activates the unfolded protein response (UPR). We used 4-tertiary butyl phenol (4-TBP) and monobenzyl ether of hydroquinone (MBEH), known triggers of vitiligo. We show that expression of key UPR components, including the transcription factor X-box binding protein 1 (XBP1), are increased following exposure of melanocytes to phenols. XBP1 activation increases production of immune mediators interleukin-6 (IL6) and IL8. Co-treatment with XBP1 inhibitors reduced IL6 and IL8 production induced by phenols, while over-expression of XBP1 alone increased their expression. Thus, melanocytes themselves produce cytokines associated with activation of an immune response following exposure to chemical triggers of vitiligo. These results expand our understanding of the mechanisms underlying melanocyte loss in vitiligo and pathways linking environmental stressors and autoimmunity. PMID:22696056

The RtcB RNA ligase is an essential component of the metazoan unfolded protein response.

PubMed

Kosmaczewski, Sara Guckian; Edwards, Tyson James; Han, Sung Min; Eckwahl, Matthew J; Meyer, Benjamin Isaiah; Peach, Sally; Hesselberth, Jay R; Wolin, Sandra L; Hammarlund, Marc

2014-12-01

RNA ligation can regulate RNA function by altering RNA sequence, structure and coding potential. For example, the function of XBP1 in mediating the unfolded protein response requires RNA ligation, as does the maturation of some tRNAs. Here, we describe a novel in vivo model in Caenorhabditis elegans for the conserved RNA ligase RtcB and show that RtcB ligates the xbp-1 mRNA during the IRE-1 branch of the unfolded protein response. Without RtcB, protein stress results in the accumulation of unligated xbp-1 mRNA fragments, defects in the unfolded protein response, and decreased lifespan. RtcB also ligates endogenous pre-tRNA halves, and RtcB mutants have defects in growth and lifespan that can be bypassed by expression of pre-spliced tRNAs. In addition, animals that lack RtcB have defects that are independent of tRNA maturation and the unfolded protein response. Thus, RNA ligation by RtcB is required for the function of multiple endogenous target RNAs including both xbp-1 and tRNAs. RtcB is uniquely capable of performing these ligation functions, and RNA ligation by RtcB mediates multiple essential processes in vivo. © 2014 The Authors.

The RtcB RNA ligase is an essential component of the metazoan unfolded protein response

PubMed Central

Kosmaczewski, Sara Guckian; Edwards, Tyson James; Han, Sung Min; Eckwahl, Matthew J; Meyer, Benjamin Isaiah; Peach, Sally; Hesselberth, Jay R; Wolin, Sandra L; Hammarlund, Marc

2014-01-01

RNA ligation can regulate RNA function by altering RNA sequence, structure and coding potential. For example, the function of XBP1 in mediating the unfolded protein response requires RNA ligation, as does the maturation of some tRNAs. Here, we describe a novel in vivo model in Caenorhabditis elegans for the conserved RNA ligase RtcB and show that RtcB ligates the xbp-1 mRNA during the IRE-1 branch of the unfolded protein response. Without RtcB, protein stress results in the accumulation of unligated xbp-1 mRNA fragments, defects in the unfolded protein response, and decreased lifespan. RtcB also ligates endogenous pre-tRNA halves, and RtcB mutants have defects in growth and lifespan that can be bypassed by expression of pre-spliced tRNAs. In addition, animals that lack RtcB have defects that are independent of tRNA maturation and the unfolded protein response. Thus, RNA ligation by RtcB is required for the function of multiple endogenous target RNAs including both xbp-1 and tRNAs. RtcB is uniquely capable of performing these ligation functions, and RNA ligation by RtcB mediates multiple essential processes in vivo. Subject Categories Protein Biosynthesis & Quality Control; RNA Biology PMID:25366321

Nothing but Net: American Workers and the Information Economy. Work Trends: Americans' Attitudes about Work, Employers and Government.

ERIC Educational Resources Information Center

Rutgers, The State Univ., New Brunswick, NJ. John J. Heldrich Center for Workforce Development.

A study explored the implications of the information economy of the late 1990s for American workers, focusing on workers' experience with computers in the workplace, workers' perceptions about their future in the information economy, and the role of government in the information age. Research data were gathered through a survey of 1,005 adults…

XRCC1 Polymorphism Associated With Late Toxicity After Radiation Therapy in Breast Cancer Patients

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

Seibold, Petra; Behrens, Sabine; Schmezer, Peter

Purpose: To identify single-nucleotide polymorphisms (SNPs) in oxidative stress–related genes associated with risk of late toxicities in breast cancer patients receiving radiation therapy. Methods and Materials: Using a 2-stage design, 305 SNPs in 59 candidate genes were investigated in the discovery phase in 753 breast cancer patients from 2 prospective cohorts from Germany. The 10 most promising SNPs in 4 genes were evaluated in the replication phase in up to 1883 breast cancer patients from 6 cohorts identified through the Radiogenomics Consortium. Outcomes of interest were late skin toxicity and fibrosis of the breast, as well as an overall toxicity score (Standardized Totalmore » Average Toxicity). Multivariable logistic and linear regression models were used to assess associations between SNPs and late toxicity. A meta-analysis approach was used to summarize evidence. Results: The association of a genetic variant in the base excision repair gene XRCC1, rs2682585, with normal tissue late radiation toxicity was replicated in all tested studies. In the combined analysis of discovery and replication cohorts, carrying the rare allele was associated with a significantly lower risk of skin toxicities (multivariate odds ratio 0.77, 95% confidence interval 0.61-0.96, P=.02) and a decrease in Standardized Total Average Toxicity scores (−0.08, 95% confidence interval −0.15 to −0.02, P=.016). Conclusions: Using a stage design with replication, we identified a variant allele in the base excision repair gene XRCC1 that could be used in combination with additional variants for developing a test to predict late toxicities after radiation therapy in breast cancer patients.« less

Endoplasmic reticulum stress and IRE-1 signaling cause apoptosis in colon cancer cells in response to andrographolide treatment.

PubMed

Banerjee, Aditi; Ahmed, Hafiz; Yang, Peixin; Czinn, Steven J; Blanchard, Thomas G

2016-07-05

The plant metabolite andrographolide induces cell cycle arrest and apoptosis in cancer cells. The mechanism(s) by which andrographolide induces apoptosis however, have not been elucidated. The present study was performed to determine the molecular events that promote apoptosis in andrographolide treated cells using T84, HCT116 and COLO 205 colon cancer cell lines. Andrographolide was determined to limit colony formation and Ki67 expression, alter nuclear morphology, increase cytoplasmic histone-associated-DNA-fragments, and increase cleaved caspase-3 levels. Andrographolide also induced significantly higher expression of endoplasmic reticulum (ER) stress proteins GRP-78 and IRE-1 by 48 h but not PERK or ATF6. Apoptosis signaling molecules BAX, spliced XBP-1 and CHOP were also significantly increased. Moreover, chemical inhibition of ER stress or IRE-1 depletion with siRNA in andrographolide treated cells significantly limited expression of IRE-1 and CHOP as determined by immunofluorescence staining, real time PCR, or immunobloting. This was accompanied by a decreased BAX/Bcl-2 ratio. Andrographolide significantly promotes cancer cell death compared to normal cells. These data demonstrate that andrographolide associated ER stress contributes to apoptosis through the activation of a pro-apoptotic GRP-78/IRE-1/XBP-1/CHOP signaling pathway.

7 CFR 999.1 - Regulation governing the importation of dates.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 7 Agriculture 8 2014-01-01 2014-01-01 false Regulation governing the importation of dates. 999.1 Section 999.1 Agriculture Regulations of the Department of Agriculture (Continued) AGRICULTURAL MARKETING SERVICE (MARKETING AGREEMENTS AND ORDERS; FRUITS, VEGETABLES, NUTS), DEPARTMENT OF AGRICULTURE SPECIALTY...

Atg1 kinase regulates early and late steps during autophagy

PubMed Central

Kijanska, Monika; Peter, Matthias

2013-01-01

The notion that phosphorylation constitutes a major mechanism to induce autophagy was established 15 years ago when a conserved Atg1/ULK kinase family was identified as an essential component of the autophagy machinery. The key observation was that starved atg1Δ cells lack autophagosomes in the cytosol and fail to accumulate autophagic bodies in the vacuole. Although many studies have revealed important details of Atg1 activation and function, a cohesive model for how Atg1 regulates the autophagic machinery is lacking. Our recent findings identified conserved steps of temporal and spatial regulation of Atg1/ULK1 kinase at both the PAS and autophagosomal membranes, suggesting that Atg1 not only promotes autophagy induction, but may also facilitate late stages of autophagosome biogenesis. PMID:23108207

Neonatal Outcomes of Low-Risk, Late-Preterm Twins Compared With Late-Preterm Singletons.

PubMed

Salem, Shimrit Yaniv; Kibel, Mia; Asztalos, Elizabeth; Zaltz, Arthur; Barrett, Jon; Melamed, Nir

2017-09-01

To test the hypothesis that the risk of neonatal morbidity among late-preterm twins is similar to that of late-preterm singletons. We conducted a retrospective cohort study of all women with twin or singleton pregnancy who gave birth during the late-preterm period in a single tertiary center between 2008 and 2015. Neonatal outcomes of low-risk, late-preterm twins were compared with those of low-risk, late-preterm singletons. The primary outcome was the same primary composite respiratory morbidity variable that was used in the randomized controlled trial of Gyamfi-Bannerman et al on the administration of antenatal corticosteroids during the late-preterm period. A total of 922 singleton and 721 twin late-preterm neonates met the inclusion criteria. The rates of composite respiratory morbidity and severe composite respiratory morbidity were similar for twins and singletons (8.3% compared with 7.4%, P=.5 and 6.8% compared with 6.0%, P=.5, respectively), but were lower than the rates of the same composite respiratory morbidity variable in the randomized controlled study described previously. The odds for respiratory morbidity were similar for twins and singletons for both composite respiratory morbidity (adjusted odds ratio [OR] 0.73, 95% CI 0.48-1.12) and severe composite respiratory morbidity (adjusted OR 0.79, 95% CI 0.50-1.24). The risk of respiratory morbidity among late-preterm twins is similar to that of late-preterm singletons. Still, the low absolute rates of the composite respiratory morbidity in our population suggest that administration of antenatal corticosteroids may be mostly justified among neonates born closer to 34 weeks of gestation.

XBP1, Unfolded Protein Response, and Endocrine Responsiveness

DTIC Science & Technology

2012-05-01

cancer resistance problems. While perhaps not all of the criteria apply, getting the scientific community to engineer an agreed solution could well...a more intimate relationship between apoptosis and autophagy, implying sig- nificant communication between these 2 activities. Such com- munication...localization. Cellular signaling occurs in the context of interactive networks (58, 97), and a considerable degree of integration and communication

Exocrine pancreas ER stress is differentially induced by different fatty acids.

PubMed

Danino, Hila; Ben-Dror, Karin; Birk, Ruth

2015-12-10

Exocrine pancreas acinar cells have a highly developed endoplasmic reticulum (ER), accommodating their high protein production rate. Overload of dietary fat (typical to obesity) is a recognized risk factor in pancreatitis and pancreatic cancer. Dietary fat, especially saturated fat, has been suggested by others and us to induce an acinar lipotoxic effect. The effect of different dietary fatty acids on the ER stress response is unknown. We studied the effect of acute (24h) challenge with different fatty acids (saturated, mono and poly-unsaturated) at different concentrations (between 200 and 500µM, typical to normal and obese states, respectively), testing fat accumulation, ER stress indicators, X-box binding protein 1 (Xbp1) splicing and nuclear translocation, as well as unfolded protein response (UPR) transcripts and protein levels using exocrine pancreas acinar AR42J and primary cells. Acute exposure of AR42J cells to different fatty acids caused increased accumulation of triglycerides, dependent on the type of fat. Different FAs had different effects on ER stress: most notably, saturated palmitic acid significantly affected the UPR response, as demonstrated by altered Xbp1 splicing, elevation in transcript levels of UPR (Xbp, CHOP, Bip) and immune factors (Tnfα, Tgfβ), and enhanced Xbp1 protein levels and Xbp1 time-dependent nuclear translocation. Poly-unsaturated FAs caused milder elevation of ER stress markers, while mono-unsaturated oleic acid attenuated the ER stress response. Thus, various fatty acids differentially affect acinar cell fat accumulation and, apart from oleic acid, induce ER stress. The differential effect of the various fatty acids could have potential nutritional and therapeutic implications. Copyright © 2015 Elsevier Inc. All rights reserved.

Activation of the unfolded protein response promotes axonal regeneration after peripheral nerve injury

PubMed Central

Oñate, Maritza; Catenaccio, Alejandra; Martínez, Gabriela; Armentano, Donna; Parsons, Geoffrey; Kerr, Bredford; Hetz, Claudio; Court, Felipe A.

2016-01-01

Although protein-folding stress at the endoplasmic reticulum (ER) is emerging as a driver of neuronal dysfunction in models of spinal cord injury and neurodegeneration, the contribution of this pathway to peripheral nerve damage remains poorly explored. Here we targeted the unfolded protein response (UPR), an adaptive reaction against ER stress, in mouse models of sciatic nerve injury and found that ablation of the transcription factor XBP1, but not ATF4, significantly delay locomotor recovery. XBP1 deficiency led to decreased macrophage recruitment, a reduction in myelin removal and axonal regeneration. Conversely, overexpression of XBP1s in the nervous system in transgenic mice enhanced locomotor recovery after sciatic nerve crush, associated to an improvement in key pro-regenerative events. To assess the therapeutic potential of UPR manipulation to axonal regeneration, we locally delivered XBP1s or an shRNA targeting this transcription factor to sensory neurons of the dorsal root ganglia using a gene therapy approach and found an enhancement or reduction of axonal regeneration in vivo, respectively. Our results demonstrate a functional role of specific components of the ER proteostasis network in the cellular changes associated to regeneration and functional recovery after peripheral nerve injury. PMID:26906090

Effects of 1,25-dihydroxycholecalciferol on recovery and resolution of late transient neonatal hypocalcemia

USDA-ARS?s Scientific Manuscript database

Late transient neonatal hypocalcemia with hyperphosphatemia is potentially life-threatening. The use of 1.25 dihydroxycholecalciferol in the management of neonatal hypocalcemia is unexplored. We hypothesized adding 1.25 dihydroxycholecalciferol to intravenous continuous calcium infusion (CaI) will a...

7 CFR 1403.9 - Late payment interest and administrative charges.

Code of Federal Regulations, 2010 CFR

2010-01-01

... apply: (i) To debts owed by Federal agencies and State and local governments. Interest on debts owed by... the rate of interest charged by the U.S. Treasury for funds borrowed by CCC on the day the debt became... shall be expressed as an annual rate of interest which CCC charges on delinquent debts. The late payment...

Students and the Governance of Higher Education: A UK Perspective

ERIC Educational Resources Information Center

Rodgers, Timothy; Freeman, Rebecca; Williams, James; Kane, David

2011-01-01

In the United Kingdom, the higher education landscape has undergone a transformation since the late 1980s as seen in the "massification" of higher education and the "quality revolution". These changes have resulted in an increased sense of accountability, to principle stakeholders: the government, the taxpayer and students…

E-Democracy and E-Government: How Will These Affect Libraries?

ERIC Educational Resources Information Center

Pare, Richard

In the late 1980s, when few Canadian citizens had Internet access, federal departments and agencies in Canada were already preparing for the future by putting information and documentation online. This paper outlines several government-sponsored programs--SchoolNet, the Canadian Investment Fund, Community Access Program, Canada Foundation for…

TGF{beta}1 polymorphisms and late clinical radiosensitivity in patients treated for gynecologic tumors

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

Ruyck, Kim de; Van Eijkeren, Marc; Claes, Kathleen

2006-07-15

Purpose: To investigate the association between six transforming growth factor {beta}1 gene (TGF{beta}1) polymorphisms (-1.552delAGG, -800G>A, -509C>T, Leu10Pro, Arg25Pro, Thr263Ile) and the occurrence of late normal tissue reactions after gynecologic radiotherapy (RT). Methods and Materials: Seventy-eight women with cervical or endometrial cancer and 140 control individuals were included in the study. According to the Common Terminology Criteria for Adverse Events version 3.0 (CTCAEv3.0) scale, 25 patients showed late adverse RT reactions (CTC2+), of whom 11 had severe complications (CTC3+). Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), single base extension and genotyping assays were performed to examine the polymorphic sites inmore » TGF{beta}1. Results: Homozygous variant -1.552delAGG, -509TT, and 10Pro genotypes were associated with the risk of developing late severe RT reactions. Triple (variant) homozygous patients had a 3.6 times increased risk to develop severe RT reactions (p = 0.26). Neither the -800A allele, nor the 25Pro allele or the 263Ile allele were associated with clinical radiosensitivity. There was perfect linkage disequilibrium (LD) between the -1.552delAGG and the -509C>T polymorphisms, and tight LD between the -1.552/-509 and the Leu10Pro polymorphisms. Haplotype analysis revealed two major haplotypes but could not distinguish radiosensitive from nonradiosensitive patients. Conclusions: The present study shows that homozygous variant TGF{beta}1 -1.552delAGG, -509TT, and 10Pro genotypes may be associated with severe clinical radiosensitivity after gynecologic RT.« less

PGRMC1 participates in late events of bovine granulosa cells mitosis and oocyte meiosis.

PubMed

Terzaghi, L; Tessaro, I; Raucci, F; Merico, V; Mazzini, G; Garagna, S; Zuccotti, M; Franciosi, F; Lodde, V

2016-08-02

Progesterone Receptor Membrane Component 1 (PGRMC1) is expressed in both oocyte and ovarian somatic cells, where it is found in multiple cellular sub-compartments including the mitotic spindle apparatus. PGRMC1 localization in the maturing bovine oocytes mirrors its localization in mitotic cells, suggesting a possible common action in mitosis and meiosis. To test the hypothesis that altering PGRMC1 activity leads to similar defects in mitosis and meiosis, PGRMC1 function was perturbed in cultured bovine granulosa cells (bGC) and maturing oocytes and the effect on mitotic and meiotic progression assessed. RNA interference-mediated PGRMC1 silencing in bGC significantly reduced cell proliferation, with a concomitant increase in the percentage of cells arrested at G2/M phase, which is consistent with an arrested or prolonged M-phase. This observation was confirmed by time-lapse imaging that revealed defects in late karyokinesis. In agreement with a role during late mitotic events, a direct interaction between PGRMC1 and Aurora Kinase B (AURKB) was observed in the central spindle at of dividing cells. Similarly, treatment with the PGRMC1 inhibitor AG205 or PGRMC1 silencing in the oocyte impaired completion of meiosis I. Specifically the ability of the oocyte to extrude the first polar body was significantly impaired while meiotic figures aberration and chromatin scattering within the ooplasm increased. Finally, analysis of PGRMC1 and AURKB localization in AG205-treated oocytes confirmed an altered localization of both proteins when meiotic errors occur. The present findings demonstrate that PGRMC1 participates in late events of both mammalian mitosis and oocyte meiosis, consistent with PGRMC1's localization at the mid-zone and mid-body of the mitotic and meiotic spindle.

47 CFR 1.1164 - Penalties for late or insufficient regulatory fee payments.

Code of Federal Regulations, 2013 CFR

2013-10-01

... the respondent regulatee. See 47 U.S.C. 402(b)(5). (4) Any regulatee failing to submit a regulatory... 47 Telecommunication 1 2013-10-01 2013-10-01 false Penalties for late or insufficient regulatory... penalty. (b) In cases were a fee payment fails due to error by the payor's bank, as evidenced by an...

47 CFR 1.1164 - Penalties for late or insufficient regulatory fee payments.

Code of Federal Regulations, 2012 CFR

2012-10-01

... the respondent regulatee. See 47 U.S.C. 402(b)(5). (4) Any regulatee failing to submit a regulatory... 47 Telecommunication 1 2012-10-01 2012-10-01 false Penalties for late or insufficient regulatory... penalty. (b) In cases were a fee payment fails due to error by the payor's bank, as evidenced by an...

47 CFR 1.1164 - Penalties for late or insufficient regulatory fee payments.

Code of Federal Regulations, 2011 CFR

2011-10-01

... the respondent regulatee. See 47 U.S.C. 402(b)(5). (4) Any regulatee failing to submit a regulatory... 47 Telecommunication 1 2011-10-01 2011-10-01 false Penalties for late or insufficient regulatory... regulatory fee by a date certain, in addition to assessing a 25 percent penalty. (b) In cases were a fee...

47 CFR 1.1164 - Penalties for late or insufficient regulatory fee payments.

Code of Federal Regulations, 2014 CFR

2014-10-01

... the respondent regulatee. See 47 U.S.C. 402(b)(5). (4) Any regulatee failing to submit a regulatory... 47 Telecommunication 1 2014-10-01 2014-10-01 false Penalties for late or insufficient regulatory... penalty. (b) In cases were a fee payment fails due to error by the payor's bank, as evidenced by an...

47 CFR 1.1164 - Penalties for late or insufficient regulatory fee payments.

Code of Federal Regulations, 2010 CFR

2010-10-01

... the respondent regulatee. See 47 U.S.C. 402(b)(5). (4) Any regulatee failing to submit a regulatory... 47 Telecommunication 1 2010-10-01 2010-10-01 false Penalties for late or insufficient regulatory... regulatory fee by a date certain, in addition to assessing a 25 percent penalty. (b) In cases were a fee...

Late-stage galaxy mergers in cosmos to z ∼ 1

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

Lackner, C. N.; Silverman, J. D.; Salvato, M.

2014-12-01

The role of major mergers in galaxy and black hole formation is not well-constrained. To help address this, we develop an automated method to identify late-stage galaxy mergers before coalescence of the galactic cores. The resulting sample of mergers is distinct from those obtained using pair-finding and morphological indicators. Our method relies on median-filtering of high-resolution images to distinguish two concentrated galaxy nuclei at small separations. This method does not rely on low surface brightness features to identify mergers, and is therefore reliable to high redshift. Using mock images, we derive statistical contamination and incompleteness corrections for the fraction ofmore » late-stage mergers. The mock images show that our method returns an uncontaminated (<10%) sample of mergers with projected separations between 2.2 and 8 kpc out to z∼1. We apply our new method to a magnitude-limited (m{sub FW} {sub 814}<23) sample of 44,164 galaxies from the COSMOS HST/ACS catalog. Using a mass-complete sample with logM{sub ∗}/M{sub ⊙}>10.6 and 0.25« less

Activity-induced histone modifications govern Neurexin-1 mRNA splicing and memory preservation.

PubMed

Ding, Xinlu; Liu, Sanxiong; Tian, Miaomiao; Zhang, Wenhao; Zhu, Tao; Li, Dongdong; Wu, Jiawei; Deng, HaiTeng; Jia, Yichang; Xie, Wei; Xie, Hong; Guan, Ji-Song

2017-05-01

Epigenetic mechanisms regulate the formation, consolidation and reconsolidation of memories. However, the signaling path from neuronal activation to epigenetic modifications within the memory-related brain circuit remains unknown. We report that learning induces long-lasting histone modifications in hippocampal memory-activated neurons to regulate memory stability. Neuronal activity triggers a late-onset shift in Nrxn1 splice isoform choice at splicing site 4 by accumulating a repressive histone marker, H3K9me3, to modulate the splicing process. Activity-dependent phosphorylation of p66α via AMP-activated protein kinase recruits HDAC2 and Suv39h1 to establish repressive histone markers and changes the connectivity of the activated neurons. Removal of Suv39h1 abolished the activity-dependent shift in Nrxn1 splice isoform choice and reduced the stability of established memories. We uncover a cell-autonomous process for memory preservation in which memory-related neurons initiate a late-onset reduction of their rewiring capacities through activity-induced histone modifications.

The development of mountain risk governance: challenges for application

NASA Astrophysics Data System (ADS)

Link, S.; Stötter, J.

2015-01-01

The complexity the management of mountain risks in the Alps has considerably increased since its institutionalisation in the late nineteenth century. In the history of approaches to dealing with mountain risks four successive paradigms can be distinguished on the basis of key indicators such as guiding principles, characteristic elements and typical instruments: "hazard protection", "hazard management", "risk management", and "risk governance". In this contribution, special attention is paid to the development of hazard zone planning and the growing importance of communication and participation over the course of this transformation. At present, the risk management paradigm has reached maturity. In the Alps, risk governance frameworks are not yet applied to risks from natural hazards. Based on a historical analysis, the suitability and applicability of general risk governance frameworks in the context of mountain risks are discussed. Necessary adaptations (e.g., in administration, educational, and legal structures) are proposed for the upcoming transformation towards mountain risk governance.

Student Government.

ERIC Educational Resources Information Center

Morrow, Joyce

Materials for running a student government program at the junior high school level are provided in three general sections. Section 1 is a description of student government operations. Topics covered include student government responsibilities and activities, student council meeting procedures, parliamentary rules, responsibilities of the…

48 CFR 52.249-1 - Termination for Convenience of the Government (Fixed-Price) (Short Form).

Code of Federal Regulations, 2010 CFR

2010-10-01

... Convenience of the Government (Fixed-Price) (Short Form). 52.249-1 Section 52.249-1 Federal Acquisition... (Fixed-Price) (Short Form). As prescribed in 49.502(a)(1), insert the following clause: Termination for Convenience of the Government (Fixed-Price) (Short Form) (APR 1984) The Contracting Officer, by written notice...

Characterization of a major late herpes simplex virus type 1 mRNA.

PubMed

Costa, R H; Devi, B G; Anderson, K P; Gaylord, B H; Wagner, E K

1981-05-01

A major, late 6-kilobase (6-kb) mRNa mapping in the large unique region of herpes simplex virus type 1 (HSV-1) was characterized by using two recombinant DNA clones, one containing EcoRI fragment G (0.190 to 0.30 map units) in lambda. WES.B (L. Enquist, M. Madden, P. Schiop-Stansly, and G. Vandl Woude, Science 203:541-544, 1979) and one containing HindIII fragment J (0.181 to 0.259 map units) in pBR322. This 6-kb mRNA had its 3' end to the left of 0.231 on the prototypical arrangement of the HSV-1 genome and was transcribed from right to left. It was bounded on both sides by regions containing a large number of distinct mRNA species, and its 3' end was partially colinear with a 1.5-kb mRNA which encoded a 35,000-dalton polypeptide. The 6-kb mRNA encoded a 155,000-dalton polypeptide which was shown to be the only one of this size detectable by hybrid-arrested translation encoded by late polyadenylated polyribosomal RNA. The S1 nuclease mapping experiments indicated that there were no introns in the coding sequence for this mRNA and that its 3' end mapped approximately 800 nucleotides to the left of the BglII site at 0.231, whereas its 5' end extended very close to the BamHI site at 0.266.

26 CFR 31.3121(b)(11)-1 - Services in the employ of a foreign government.

Code of Federal Regulations, 2010 CFR

2010-04-01

... residence of the employee is immaterial. It is also immaterial whether the foreign government grants an... 26 Internal Revenue 15 2010-04-01 2010-04-01 false Services in the employ of a foreign government... 1954) General Provisions § 31.3121(b)(11)-1 Services in the employ of a foreign government. (a...

Estrogen Receptor β Agonist Attenuates Endoplasmic Reticulum Stress-Induced Changes in Social Behavior and Brain Connectivity in Mice.

PubMed

Crider, Amanda; Nelson, Tyler; Davis, Talisha; Fagan, Kiley; Vaibhav, Kumar; Luo, Matthew; Kamalasanan, Sunay; Terry, Alvin V; Pillai, Anilkumar

2018-02-12

Impaired social interaction is a key feature of several major psychiatric disorders including depression, autism, and schizophrenia. While, anatomically, the prefrontal cortex (PFC) is known as a key regulator of social behavior, little is known about the cellular mechanisms that underlie impairments of social interaction. One etiological mechanism implicated in the pathophysiology of the aforementioned psychiatric disorders is cellular stress and consequent adaptive responses in the endoplasmic reticulum (ER) that can result from a variety of environmental and physical factors. The ER is an organelle that serves essential roles in protein modification, folding, and maturation of proteins; however, the specific role of ER stress in altered social behavior is unknown. In this study, treatment with tunicamycin, an ER stress inducer, enhanced the phosphorylation level of inositol-requiring ER-to-nucleus signal kinase 1 (IRE1) and increased X-box-binding protein 1 (XBP1) mRNA splicing activity in the mouse PFC, whereas inhibition of IRE1/XBP1 pathway in PFC by a viral particle approach attenuated social behavioral deficits caused by tunicamycin treatment. Reduced estrogen receptor beta (ERβ) protein levels were found in the PFC of male mice following tunicamycin treatment. Pretreatment with an ERβ specific agonist, ERB-041 significantly attenuated tunicamycin-induced deficits in social behavior, and activation of IRE1/XBP1 pathway in mouse PFC. Moreover, ERB-041 inhibited tunicamycin-induced increases in functional connectivity between PFC and hippocampus in male mice. Together, these results show that ERβ agonist attenuates ER stress-induced deficits in social behavior through the IRE-1/XBP1 pathway.

WELLTON GOVERNMENT CAMP, PERMANENT GARAGE TYPE 1G. PLAN, ELEVATIONS, AND ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

WELLTON GOVERNMENT CAMP, PERMANENT GARAGE TYPE 1-G. PLAN, ELEVATIONS, AND SECTIONS. Drawing 50-308-4552, dated October 25, 1949. U.S. Department of the Interior, Bureau of Reclamation, Yuma, Arizona - Wellton-Mohawk Irrigation System, Permanent Garage Type 1-G, 30601 Wellton-Mohawk Drive, Wellton, Yuma County, AZ

Modeling Late-Onset Sporadic Alzheimer's Disease through BMI1 Deficiency.

PubMed

Flamier, Anthony; El Hajjar, Jida; Adjaye, James; Fernandes, Karl J; Abdouh, Mohamed; Bernier, Gilbert

2018-05-29

Late-onset sporadic Alzheimer's disease (AD) is the most prevalent form of dementia, but its origin remains poorly understood. The Bmi1/Ring1 protein complex maintains transcriptional repression of developmental genes through histone H2A mono-ubiquitination, and Bmi1 deficiency in mice results in growth retardation, progeria, and neurodegeneration. Here, we demonstrate that BMI1 is silenced in AD brains, but not in those with early-onset familial AD, frontotemporal dementia, or Lewy body dementia. BMI1 expression was also reduced in cortical neurons from AD patient-derived induced pluripotent stem cells but not in neurons overexpressing mutant APP and PSEN1. BMI1 knockout in human post-mitotic neurons resulted in amyloid beta peptide secretion and deposition, p-Tau accumulation, and neurodegeneration. Mechanistically, BMI1 was required to repress microtubule associated protein tau (MAPT) transcription and prevent GSK3beta and p53 stabilization, which otherwise resulted in neurodegeneration. Restoration of BMI1 activity through genetic or pharmaceutical approaches could represent a therapeutic strategy against AD. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Late calcium EDTA rescues hippocampal CA1 neurons from global ischemia-induced death.

PubMed

Calderone, Agata; Jover, Teresa; Mashiko, Toshihiro; Noh, Kyung-min; Tanaka, Hidenobu; Bennett, Michael V L; Zukin, R Suzanne

2004-11-03

Transient global ischemia induces a delayed rise in intracellular Zn2+, which may be mediated via glutamate receptor 2 (GluR2)-lacking AMPA receptors (AMPARs), and selective, delayed death of hippocampal CA1 neurons. The molecular mechanisms underlying Zn2+ toxicity in vivo are not well delineated. Here we show the striking finding that intraventricular injection of the high-affinity Zn2+ chelator calcium EDTA (CaEDTA) at 30 min before ischemia (early CaEDTA) or at 48-60 hr (late CaEDTA), but not 3-6 hr, after ischemia, afforded robust protection of CA1 neurons in approximately 50% (late CaEDTA) to 75% (early CaEDTA) of animals. We also show that Zn2+ acts via temporally distinct mechanisms to promote neuronal death. Early CaEDTA attenuated ischemia-induced GluR2 mRNA and protein downregulation (and, by inference, formation of Zn2+-permeable AMPARs), the delayed rise in Zn2+, and neuronal death. These findings suggest that Zn2+ acts at step(s) upstream from GluR2 gene downregulation and implicate Zn2+ in transcriptional regulation and/or GluR2 mRNA stability. Early CaEDTA also blocked mitochondrial release of cytochrome c and Smac/DIABLO (second mitochondria-derived activator of caspases/direct inhibitor of apoptosis protein-binding protein with low pI), caspase-3 activity (but not procaspase-3 cleavage), p75NTR induction, and DNA fragmentation. These findings indicate that CaEDTA preserves the functional integrity of the mitochondrial outer membrane and arrests the caspase death cascade. Late injection of CaEDTA at a time when GluR2 is downregulated and caspase is activated inhibited the delayed rise in Zn2+, p75NTR induction, DNA fragmentation, and cell death. The finding of neuroprotection by late CaEDTA administration has striking implications for intervention in the delayed neuronal death associated with global ischemia.

Settlement Patterns and the Governing Structures of 19th Century School Systems.

ERIC Educational Resources Information Center

Richardson, John G.

Examination of state school governance structures in the late 19th century reveals three regional models, each springing from particular patterns of settlement and political administration. Historical explanations for school system origins have drawn mainly on the histories of northeastern cities and states. They have underemphasized regional…

Clinical, serologic, and immunogenetic characterization (HLA-DRB1) of late-onset lupus erythematosus in a Colombian population.

PubMed

Peñaranda-Parada, E; Quintana, G; Yunis, J J; Mantilla, R; Rojas, W; Panqueva, U; Caminos, J E; Garces, M F; Sanchez, E; Rondón-Herrera, F; de Jesús Iglesias-Gamarra, A

2015-10-01

Late-onset systemic lupus erythematosus (SLE) represents a specific subgroup that is defined as onset after 50 years of age. Late-onset lupus may have a different clinical course and serological findings, which may delay diagnosis and timely treatment. The objective of this paper is to determine the clinical, serologic, and immunogenetic differences among Colombian patients with late-onset SLE versus conventional SLE patients. This was a cross-sectional study in a Colombian population. Patients and their medical records were analyzed from the services of Rheumatology in Bogotá and met the criteria for SLE, according to the American College of Rheumatology (ACR) revised criteria for the classification of SLE.In a reference group of late-onset SLE patients (98 participants, with an onset after 50 years of age) and a group of conventional SLE patients (72 participants, with an onset of age of 49 years or less), multiple clinical variables (age, clinical criteria for lupus, alopecia, weight loss, fever, Raynaud's phenomenon) and multiple serological variables (blood count, blood chemistry profile, autoantibodies) were analyzed. Additionally, the HLA class II (DRB1) of all the patients was genotyped, including an additional group of patients without the autoimmune disease. Statistical analysis was performed using the STATA 10.0 package. In the group of late-onset lupus, there was a higher frequency of pleurisy (p = 0.002), pericarditis (p = 0.026), dry symptoms (p = 0.029), lymphopenia (p = 0.007), and higher titers of rheumatoid factor (p = 0.001) compared with the group of conventional SLE. Late-onset SLE patients had a lower seizure frequency (p = 0.019), weight loss (p = 0.009), alopecia (p < 0.001), and Raynaud's phenomenon (p = 0.013) compared to the conventional SLE group. In late-onset SLE, HLA DR17 (DR3) was found more frequently compared with individuals without autoimmune disease (OR 3.81, 95% CI 1.47 to 10.59) (p = 0

7 CFR 1.634 - What is the law governing ex parte communications?

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 1 2010-01-01 2010-01-01 false What is the law governing ex parte communications? 1.634 Section 1.634 Agriculture Office of the Secretary of Agriculture ADMINISTRATIVE REGULATIONS Conditions in FERC Hydropower Licenses General Provisions Related to Hearings § 1.634 What is the law...

LHD1, an allele of DTH8/Ghd8, controls late heading date in common wild rice (Oryza rufipogon).

PubMed

Dai, Xiaodong; Ding, Younian; Tan, Lubin; Fu, Yongcai; Liu, Fengxia; Zhu, Zuofeng; Sun, Xianyou; Sun, Xuewen; Gu, Ping; Cai, Hongwei; Sun, Chuanqing

2012-10-01

Flowering at suitable time is very important for plants to adapt to complicated environments and produce their seeds successfully for reproduction. In rice (Oryza rufipogon Griff.) photoperiod regulation is one of the important factors for controlling heading date. Common wild rice, the ancestor of cultivated rice, exhibits a late heading date and a more sensitive photoperiodic response than cultivated rice. Here, through map-based cloning, we identified a major quantitative trait loci (QTL) LHD1 (Late Heading Date 1), an allele of DTH8/Ghd8, which controls the late heading date of wild rice and encodes a putative HAP3/NF-YB/CBF-A subunit of the CCAAT-box-binding transcription factor. Sequence analysis revealed that several variants in the coding region of LHD1 were correlated with a late heading date, and a further complementary study successfully rescued the phenotype. These results suggest that a functional site for LHD1 could be among those variants present in the coding region. We also found that LHD1 could down-regulate the expression of several floral transition activators such as Ehd1, Hd3a and RFT1 under long-day conditions, but not under short-day conditions. This indicates that LHD1 may delay flowering by repressing the expression of Ehd1, Hd3a and RFT1 under long-day conditions. © 2012 Institute of Botany, Chinese Academy of Sciences.

17 CFR 1.69 - Voting by interested members of self-regulatory organization governing boards and various...

Code of Federal Regulations, 2012 CFR

2012-04-01

... of self-regulatory organization governing boards and various committees. 1.69 Section 1.69 Commodity... EXCHANGE ACT Miscellaneous § 1.69 Voting by interested members of self-regulatory organization governing... violation of the rules of the self-regulatory organization except those cases where the person or committee...

17 CFR 1.69 - Voting by interested members of self-regulatory organization governing boards and various...

Code of Federal Regulations, 2013 CFR

2013-04-01

... of self-regulatory organization governing boards and various committees. 1.69 Section 1.69 Commodity... EXCHANGE ACT Miscellaneous § 1.69 Voting by interested members of self-regulatory organization governing... violation of the rules of the self-regulatory organization except those cases where the person or committee...

17 CFR 1.69 - Voting by interested members of self-regulatory organization governing boards and various...

Code of Federal Regulations, 2014 CFR

2014-04-01

... of self-regulatory organization governing boards and various committees. 1.69 Section 1.69 Commodity... EXCHANGE ACT Miscellaneous § 1.69 Voting by interested members of self-regulatory organization governing... violation of the rules of the self-regulatory organization except those cases where the person or committee...

17 CFR 1.69 - Voting by interested members of self-regulatory organization governing boards and various...

Code of Federal Regulations, 2011 CFR

2011-04-01

... of self-regulatory organization governing boards and various committees. 1.69 Section 1.69 Commodity... EXCHANGE ACT Miscellaneous § 1.69 Voting by interested members of self-regulatory organization governing... violation of the rules of the self-regulatory organization except those cases where the person or committee...

The Importance of Mid-to-Late-Life Body Mass Index Trajectories on Late-Life Gait Speed.

PubMed

Windham, B Gwen; Griswold, Michael E; Wang, Wanmei; Kucharska-Newton, Anna; Demerath, Ellen W; Gabriel, Kelley Pettee; Pompeii, Lisa A; Butler, Kenneth; Wagenknecht, Lynne; Kritchevsky, Stephen; Mosley, Thomas H

2017-08-01

Prior studies suggest being overweight may be protective against poor functional outcomes in older adults. Body mass index (BMI, kg/m2) was measured over 25 years across five visits (1987-2011) among Atherosclerosis Risk in Communities Study participants (baseline Visit 1 n = 15,720, aged 45-64 years). Gait speed was measured at Visit 5 ("late-life", aged ≥65 years, n = 6,229). BMI trajectories were examined using clinical cutpoints and continuous mixed models to estimate effects of patterns of BMI change on gait speed, adjusting for demographics and comorbidities. Mid-life BMI (baseline visit; 55% women; 27% black) was associated with late-life gait speed 25 years later; gait speeds were 94.3, 89.6, and 82.1 cm/s for participants with baseline normal BMI (<25), overweight (25 ≤ BMI < 30), and obese (BMI ≥ 30) (p < .001). In longitudinal analyses, late-life gait speeds were 96.9, 88.8, and 81.3 cm/s for participants who maintained normal, overweight, and obese weight status, respectively, across 25 years (p < .01). Increasing BMI over 25 years was associated with poorer late-life gait speeds; a 1%/year BMI increase for a participant with a baseline BMI of 22.5 (final BMI 28.5) was associated with a 4.6-cm/s (95% confidence interval: -7.0, -1.8) slower late-life gait speed than a participant who maintained a baseline BMI of 22.5. Being overweight in older age was not protective of mobility function. Maintaining a normal BMI in mid- and late-life may help preserve late-life mobility. © The Author 2016. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Governance and health in the Arab world.

PubMed

Batniji, Rajaie; Khatib, Lina; Cammett, Melani; Sweet, Jeffrey; Basu, Sanjay; Jamal, Amaney; Wise, Paul; Giacaman, Rita

2014-01-25

Since late 2010, the Arab world has entered a tumultuous period of change, with populations demanding more inclusive and accountable government. The region is characterised by weak political institutions, which exclude large proportions of their populations from political representation and government services. Building on work in political science and economics, we assess the extent to which the quality of governance, or the extent of electoral democracy, relates to adult, infant, and maternal mortality, and to the perceived accessibility and improvement of health services. We compiled a dataset from the World Bank, WHO, Institute for Health Metrics and Evaluation, Arab Barometer Survey, and other sources to measure changes in demographics, health status, and governance in the Arab World from 1980 to 2010. We suggest an association between more effective government and average reductions in mortality in this period; however, there does not seem to be any relation between the extent of democracy and mortality reductions. The movements for changing governance in the region threaten access to services in the short term, forcing migration and increasing the vulnerability of some populations. In view of the patterns observed in the available data, and the published literature, we suggest that efforts to improve government effectiveness and to reduce corruption are more plausibly linked to population health improvements than are efforts to democratise. However, these patterns are based on restricted mortality data, leaving out subjective health metrics, quality of life, and disease-specific data. To better guide efforts to transform political and economic institutions, more data are needed for health-care access, health-care quality, health status, and access to services of marginalised groups. Copyright © 2014 Elsevier Ltd. All rights reserved.

Regulation of a transcription factor network by Cdk1 coordinates late cell cycle gene expression

PubMed Central

Landry, Benjamin D; Mapa, Claudine E; Arsenault, Heather E; Poti, Kristin E; Benanti, Jennifer A

2014-01-01

To maintain genome stability, regulators of chromosome segregation must be expressed in coordination with mitotic events. Expression of these late cell cycle genes is regulated by cyclin-dependent kinase (Cdk1), which phosphorylates a network of conserved transcription factors (TFs). However, the effects of Cdk1 phosphorylation on many key TFs are not known. We find that elimination of Cdk1-mediated phosphorylation of four S-phase TFs decreases expression of many late cell cycle genes, delays mitotic progression, and reduces fitness in budding yeast. Blocking phosphorylation impairs degradation of all four TFs. Consequently, phosphorylation-deficient mutants of the repressors Yox1 and Yhp1 exhibit increased promoter occupancy and decreased expression of their target genes. Interestingly, although phosphorylation of the transcriptional activator Hcm1 on its N-terminus promotes its degradation, phosphorylation on its C-terminus is required for its activity, indicating that Cdk1 both activates and inhibits a single TF. We conclude that Cdk1 promotes gene expression by both activating transcriptional activators and inactivating transcriptional repressors. Furthermore, our data suggest that coordinated regulation of the TF network by Cdk1 is necessary for faithful cell division. PMID:24714560

Regulation of a transcription factor network by Cdk1 coordinates late cell cycle gene expression.

PubMed

Landry, Benjamin D; Mapa, Claudine E; Arsenault, Heather E; Poti, Kristin E; Benanti, Jennifer A

2014-05-02

To maintain genome stability, regulators of chromosome segregation must be expressed in coordination with mitotic events. Expression of these late cell cycle genes is regulated by cyclin-dependent kinase (Cdk1), which phosphorylates a network of conserved transcription factors (TFs). However, the effects of Cdk1 phosphorylation on many key TFs are not known. We find that elimination of Cdk1-mediated phosphorylation of four S-phase TFs decreases expression of many late cell cycle genes, delays mitotic progression, and reduces fitness in budding yeast. Blocking phosphorylation impairs degradation of all four TFs. Consequently, phosphorylation-deficient mutants of the repressors Yox1 and Yhp1 exhibit increased promoter occupancy and decreased expression of their target genes. Interestingly, although phosphorylation of the transcriptional activator Hcm1 on its N-terminus promotes its degradation, phosphorylation on its C-terminus is required for its activity, indicating that Cdk1 both activates and inhibits a single TF. We conclude that Cdk1 promotes gene expression by both activating transcriptional activators and inactivating transcriptional repressors. Furthermore, our data suggest that coordinated regulation of the TF network by Cdk1 is necessary for faithful cell division.

IgG1-iS18 impedes the adhesive and invasive potential of early and late stage malignant melanoma cells.

PubMed

Munien, Carmelle; Rebelo, Thalia M; Ferreira, Eloise; Weiss, Stefan F T

2017-02-15

The 37kDa/67kDa laminin receptor (LRP/LR) is a non-integrin laminin receptor which is overexpressed in tumorigenic cells and supports progression of cancer via promoting metastasis, angiogenesis and telomerase activity and impediment of apoptosis. The present study investigates the role of LRP/LR on the metastatic potential of early (A375) and late (A375SM) stage malignant melanoma cells. Flow cytometry revealed that both early and late stage malignant melanoma cells display high levels of LRP/LR on their cell surface. Flow cytometry and western blot analysis showed that late stage malignant melanoma cells display significantly higher total and cell surface LRP/LR levels in comparison to early stage malignant melanoma cells and the poorly invasive breast cancer (MCF-7) control cell line. Targeting LRP/LR using the LRP/LR specific antibody IgG1-iS18 resulted in a significant reduction of the adhesive potential to laminin-1 and the invasive potential through the 'ECM-simulating' Matrigel™ of both early and late stage malignant melanoma cells. Furthermore, Pearson's correlation coefficient confirmed that increased LRP levels correlate with the increased invasive and adhesive potential in early and late stage melanoma cells. Thus, blocking LRP/LR using the IgG1-iS18 antibody may therefore be a promising therapeutic strategy for early and late stage malignant melanoma treatment. Copyright © 2017 Elsevier Inc. All rights reserved.

Analysis of glutathione S-transferase Pi isoform (GSTP1) single-nucleotide polymorphisms and macular telangiectasia type 2.

PubMed

Szental, Joshua A; Baird, Paul N; Richardson, Andrea J; Islam, F M Amirul; Scholl, Hendrik P N; Charbel Issa, Peter; Holz, Frank G; Gillies, Mark; Guymer, Robyn H

2010-12-01

Recent imaging studies have suggested that macular pigment is decreased centrally in macular telangiectasia type 2 (MT2). The uptake of xanthophyll pigment into the macula is thought to be facilitated by a xanthophyll-binding protein (XBP). The Pi isoform of glutathione S-transferase (GSTP1) represents one such XBP with high binding affinity. This case-control study aimed to determine whether two common single-nucleotide polymorphisms (SNPs) of GSTP1 were associated with MT2. DNA samples from 39 cases and 21 controls were collected. Two polymorphic sites of Ile105Val and Ala114Val in exons 5 and 6 respectively, of the GSTP1 gene were analysed. Comparison of alleles and genotypes between cases and controls indicated that there were no statistically significant differences for either the Ile105Val SNP (P=0.43) or the Ala114Val SNP (P=0.85), or for any combinations; however, the homozygous at-risk genotype (GG) of the Ile105Val SNP was present in 8% of cases but absent in controls. This study found no statistically significant association between two common GSTP1 SNPs and MT2; however, a trend towards a greater frequency of the GG genotype of the Ile105Val SNP in cases is of great interest. The biological plausibility of disturbed macular pigment uptake in MT2 makes GSTP1 an excellent candidate gene. Further investigation is warranted in future studies of MT2.

Are late-night eating habits and sleep duration associated with glycemic control in adult type 1 diabetes patients treated with insulin pumps?

PubMed

Matejko, Bartlomiej; Kiec-Wilk, Beata; Szopa, Magdalena; Trznadel Morawska, Iwona; Malecki, Maciej T; Klupa, Tomasz

2015-07-01

Little is known about the impact of sleep duration and late-night snacking on glycemic control in patients with type 1 diabetes using insulin pumps. The aim of the present study was to examine whether late-night eating habits and short sleep duration are associated with glycemic control in continuous subcutaneous insulin infusion-treated type 1 diabetic patients. We included 148 consecutive adult type 1 diabetic subjects using an insulin pump (100 women and 48 men). Participants completed a questionnaire regarding sleep duration (classified as short if ≤6 h) and late-night snacking. Other sources of information included medical records and data from blood glucose meters. Glycemic control was assessed by glycated hemoglobin (HbA1c) levels and mean self-monitoring of blood glucose (SMBG) readings. The mean age of patients was 26 years, mean type 1 diabetes duration was 13.4 years and mean HbA1c level was 7.2%. In a univariate regression analysis, sleep duration was a predictor of both HbA1c (β = 0.51, P = 0.01) and SMBG levels (β = 11.4, P = 0.02). Additionally, an association was found between frequent late-night snacking and higher SMBG readings (often snacking β = 18.1, P = 0.05), but not with increased HbA1c levels. In the multivariate linear regression, independent predictors for HbA1c and SMBG were sleep duration and patient age. In a univariate logistic regression, sleep duration and frequency of late-night snacking were not predictors of whether HbA1c target levels were achieved. Short sleep duration, but not late-night snacking, seems to be associated with poorer glycemic control in type 1 diabetic patients treated with continuous subcutaneous insulin infusion.

Genetic vaccines to potentiate the effective CD103+ dendritic cell-mediated cross-priming of antitumor immunity.

PubMed

Zhang, Yi; Chen, Guo; Liu, Zuqiang; Tian, Shenghe; Zhang, Jiying; Carey, Cara D; Murphy, Kenneth M; Storkus, Walter J; Falo, Louis D; You, Zhaoyang

2015-06-15

The development of effective cancer vaccines remains an urgent, but as yet unmet, clinical need. This deficiency is in part due to an incomplete understanding of how to best invoke dendritic cells (DC) that are crucial for the induction of tumor-specific CD8(+) T cells capable of mediating durable protective immunity. In this regard, elevated expression of the transcription factor X box-binding protein 1 (XBP1) in DC appears to play a decisive role in promoting the ability of DC to cross-present Ags to CD8(+) T cells in the therapeutic setting. Delivery of DNA vaccines encoding XBP1 and tumor Ag to skin DC resulted in increased IFN-α production by plasmacytoid DC (pDC) from skin/tumor draining lymph nodes and the cross-priming of Ag-specific CD8(+) T cell responses associated with therapeutic benefit. Antitumor protection was dependent on cross-presenting Batf3(+) DC, pDC, and CD8(+) T cells. CD103(+) DC from the skin/tumor draining lymph nodes of the immunized mice appeared responsible for activation of Ag-specific naive CD8(+) T cells, but were dependent on pDC for optimal effectiveness. Similarly, human XBP1 improved the capacity of human blood- and skin-derived DC to activate human T cells. These data support an important intrinsic role for XBP1 in DC for effective cross-priming and orchestration of Batf3(+) DC-pDC interactions, thereby enabling effective vaccine induction of protective antitumor immunity. Copyright © 2015 by The American Association of Immunologists, Inc.

The Arabidopsis USL1 controls multiple aspects of development by affecting late endosome morphology.

PubMed

Yuan, Rongrong; Lan, Jingqiu; Fang, Yuxing; Yu, Hao; Zhang, Jinzhe; Huang, Jiaying; Qin, Genji

2018-06-13

The polar transport of auxin controls many aspects of plant development. However, the molecular mechanisms underlying auxin tranport regulation remain to be further elucidated. We identified a mutant named as usl1 (unflattened and small leaves) in a genetic screen in Arabidopsis thaliana. The usl1 displayed multiple aspects of developmental defects in leaves, embryogenesis, cotyledons, silique phyllotaxy and lateral roots in addition to abnormal leaves. USL1 encodes a protein orthologous to the yeast vacuolar protein sorting (Vps) 38p and human UV RADIATION RESISTANCE-ASSOCIATED GENE (UVRAG). Cell biology, Co-IP/MS and yeast two-hybrid were used to identify the function of USL1. USL1 colocalizes at the subcellular level with VPS29, a key factor of the retromer complex that controls auxin transport. The morphology of the VPS29-associated late endosomes (LE) is altered from small dots in the wild-type to aberrant enlarged circles in the usl1 mutants. The usl1 mutant synergistically interacts with vps29. We also found that USL1 forms a complex with AtVPS30 and AtVPS34. We propose that USL1 controls multiple aspects of plant development by affecting late endosome morphology and by regulating the PIN1 polarity. Our findings provide a new layer of the understanding on the mechanisms of plant development regulation. © 2018 The Authors. New Phytologist © 2018 New Phytologist Trust.

30 CFR 1218.40 - Assessments for incorrect or late reports and failure to report.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 30 Mineral Resources 3 2013-07-01 2013-07-01 false Assessments for incorrect or late reports and failure to report. 1218.40 Section 1218.40 Mineral Resources OFFICE OF NATURAL RESOURCES REVENUE, DEPARTMENT OF THE INTERIOR NATURAL RESOURCES REVENUE COLLECTION OF ROYALTIES, RENTALS, BONUSES, AND OTHER MONIES DUE THE FEDERAL GOVERNMENT General...

30 CFR 1218.40 - Assessments for incorrect or late reports and failure to report.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 30 Mineral Resources 3 2012-07-01 2012-07-01 false Assessments for incorrect or late reports and failure to report. 1218.40 Section 1218.40 Mineral Resources OFFICE OF NATURAL RESOURCES REVENUE, DEPARTMENT OF THE INTERIOR NATURAL RESOURCES REVENUE COLLECTION OF ROYALTIES, RENTALS, BONUSES, AND OTHER MONIES DUE THE FEDERAL GOVERNMENT General...

30 CFR 1218.40 - Assessments for incorrect or late reports and failure to report.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 30 Mineral Resources 3 2014-07-01 2014-07-01 false Assessments for incorrect or late reports and failure to report. 1218.40 Section 1218.40 Mineral Resources OFFICE OF NATURAL RESOURCES REVENUE, DEPARTMENT OF THE INTERIOR NATURAL RESOURCES REVENUE COLLECTION OF ROYALTIES, RENTALS, BONUSES, AND OTHER MONIES DUE THE FEDERAL GOVERNMENT General...

Pancreatic and Duodenal Homeobox Protein 1 (Pdx-1) Maintains Endoplasmic Reticulum Calcium Levels through Transcriptional Regulation of Sarco-endoplasmic Reticulum Calcium ATPase 2b (SERCA2b) in the Islet β Cell*

PubMed Central

Johnson, Justin S.; Kono, Tatsuyoshi; Tong, Xin; Yamamoto, Wataru R.; Zarain-Herzberg, Angel; Merrins, Matthew J.; Satin, Leslie S.; Gilon, Patrick; Evans-Molina, Carmella

2014-01-01

Although the pancreatic duodenal homeobox 1 (Pdx-1) transcription factor is known to play an indispensable role in β cell development and secretory function, recent data also implicate Pdx-1 in the maintenance of endoplasmic reticulum (ER) health. The sarco-endoplasmic reticulum Ca2+ ATPase 2b (SERCA2b) pump maintains a steep Ca2+ gradient between the cytosol and ER lumen. In models of diabetes, our data demonstrated loss of β cell Pdx-1 that occurs in parallel with altered SERCA2b expression, whereas in silico analysis of the SERCA2b promoter revealed multiple putative Pdx-1 binding sites. We hypothesized that Pdx-1 loss under inflammatory and diabetic conditions leads to decreased SERCA2b levels and activity with concomitant alterations in ER health. To test this, siRNA-mediated knockdown of Pdx-1 was performed in INS-1 cells. The results revealed reduced SERCA2b expression and decreased ER Ca2+, which was measured using fluorescence lifetime imaging microscopy. Cotransfection of human Pdx-1 with a reporter fused to the human SERCA2 promoter increased luciferase activity 3- to 4-fold relative to an empty vector control, and direct binding of Pdx-1 to the proximal SERCA2 promoter was confirmed by chromatin immunoprecipitation. To determine whether restoration of SERCA2b could rescue ER stress induced by Pdx-1 loss, Pdx1+/− mice were fed a high-fat diet. Isolated islets demonstrated an increased spliced-to-total Xbp1 ratio, whereas SERCA2b overexpression reduced the Xbp1 ratio to that of wild-type controls. Together, these results identify SERCA2b as a novel transcriptional target of Pdx-1 and define a role for altered ER Ca2+ regulation in Pdx-1-deficient states. PMID:25271154

EDEM1 targets misfolded HLA-B27 dimers for endoplasmic reticulum associated degradation

PubMed Central

Guiliano, David B.; Fussell, Helen; Lenart, Izabela; Tsao, Edward; Nesbeth, Darren; Fletcher, Adam J.; Campbell, Elaine C.; Yousaf, Nasim; Williams, Sarah; Santos, Susana; Cameron, Amy; Towers, Greg J.; Kellam, Paul; Hebert, Daniel N.; Gould, Keith; Powis, Simon J.; Antoniou, Antony N.

2015-01-01

Objective HLA-B27 forms misfolded heavy chain dimers, which may predispose individuals to inflammatory arthritis by inducing endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). We wanted to define the role of the UPR induced ER associated degradation (ERAD) pathway in the disposal of HLA-B27 dimeric conformers. Methods HeLa cell lines expressing only two copies of a carboxy terminally Sv5 tagged HLA-B27 were generated. The ER stress induced EDEM1 protein was over expressed by transfection and dimer levels monitored by immunoblotting. EDEM1, the UPR associated transcription factor XBP-1, the E3 ubiquitin ligase HRD1, the degradation associated derlin 1 and 2 proteins were inhibited by either short hairpin RNA or dominant negative mutants. The UPR associated ERAD of HLA-B27 was confirmed using ER stress inducing pharamacological agents in kinetic and pulse chase assays. Results We demonstrate that UPR induced machinery can target HLA-B27 dimers, and that dimer formation can be controlled by alterations to expression levels of components of the UPR induced ERAD pathway. HLA-B27 dimers and misfolded MHC class I monomeric molecules were detected bound to EDEM1, with overexpression of EDEM1 inhibiting HLA-B27 dimer formation. EDEM1 inhibition resulted in upregulation of HLA-B27 dimers, whilst UPR induced ERAD of dimers was prevented in the absence of EDEM1. HLA-B27 dimer formation was also enhanced in the absence of XBP-1, HRD1 and derlin1/2. Conclusion The UPR ERAD pathway as described here can dispose of HLA-B27 dimers and presents a potential novel therapeutic target for the modulation of HLA-B27 associated inflammatory disease. PMID:25132672

Two-stage arterial switch operation: is late ever too late?

PubMed

Al Qethamy, Howaida O; Aizaz, Khawar; Aboelnazar, Saber A R; Hijab, Samina; Al Faraidi, Yahya

2002-09-01

Results of the two-stage arterial switch operation in 49 patients with transposition of the great arteries, performed between January 1995 and September 2000, were reviewed retrospectively. Twenty-one patients had a ventricular septal defect. Anatomical correction was carried out 21.89 +/- 9.86 months after pulmonary artery banding, with or without a modified Blalock-Taussig shunt. Hospital mortality was 8% (4 patients). During follow-up of 30.12 +/- 14.38 months, there was 1 late death and 1 patient required reoperation for pseudoaneurysm of the ascending aorta. Actuarial survival and freedom from reoperation at 5 years were 90% and 97%, respectively. Late anatomic correction (> 6 months) after the preliminary procedure can be performed with an acceptable mortality and morbidity, but undue delay may lead to left ventricular dysfunction, arrhythmias, and new aortic valve regurgitation or subaortic stenosis.

Silencing of six susceptibility genes results in potato late blight resistance.

PubMed

Sun, Kaile; Wolters, Anne-Marie A; Vossen, Jack H; Rouwet, Maarten E; Loonen, Annelies E H M; Jacobsen, Evert; Visser, Richard G F; Bai, Yuling

2016-10-01

Phytophthora infestans, the causal agent of late blight, is a major threat to commercial potato production worldwide. Significant costs are required for crop protection to secure yield. Many dominant genes for resistance (R-genes) to potato late blight have been identified, and some of these R-genes have been applied in potato breeding. However, the P. infestans population rapidly accumulates new virulent strains that render R-genes ineffective. Here we introduce a new class of resistance which is based on the loss-of-function of a susceptibility gene (S-gene) encoding a product exploited by pathogens during infection and colonization. Impaired S-genes primarily result in recessive resistance traits in contrast to recognition-based resistance that is governed by dominant R-genes. In Arabidopsis thaliana, many S-genes have been detected in screens of mutant populations. In the present study, we selected 11 A. thaliana S-genes and silenced orthologous genes in the potato cultivar Desiree, which is highly susceptible to late blight. The silencing of five genes resulted in complete resistance to the P. infestans isolate Pic99189, and the silencing of a sixth S-gene resulted in reduced susceptibility. The application of S-genes to potato breeding for resistance to late blight is further discussed.

[Development of modern medical doctors in Japan from late Edo to early Meiji].

PubMed

Kim, OckJoo; Takuya, Miyagawa

2011-12-31

Western medicine began to be introduced to Japan since late 16th century. Japanese encounter with Western medicine centered on Dejima in Nagasaki in the seventeenth and eighteenth century and the initial process of introduction was gradual and slow. In the mid-nineteenth century, facing threats from Western countries, Tokugawa bakufu asked Dutch naval surgeon, J. L. C. Pompe van Meerdervoort to teach western medicine at the Kaigun Denshujo naval academy in Nagasaki. The government also supported the western medical school in Edo. This paper deals with how modern western medical doctors were developed in Japan from late Edo to early Meiji. The publication of the New Text on Anatomy in 1774 translated by Sugita Genpaku and his colleagues stimulated Japanese doctors and scholars to study western medicine, called Rangaku. During the Edo period, western medicine spread into major cities and countryside in Japan through Rangaku doctors. In 1838, for example, Dr. Ogata Koan established the Rangaku school named Tekijuku and educated many people with western medicine. When smallpox vaccination was introduced in Japan in 1849, Rangaku doctors played an important role in practiving the vaccination in cities and in countryside. After the Edo bakufu and the feudal lords of han(han) actively pursued to introduce western medicine to their hans by sending their Samurai to Edo or Nagasaki or abroad and by establishing medical schools and hospitals until their abolition in 1871. In late Edo and early Meiii military doctors were the main focus of training to meet the urgent need of military doctors in the battle fields of civil wars. The new Meiji government initiated a series of top-down reformations concerning army recruitment, national school system, public health and medical system. In 1874, the government introduced a law on medicine to adopt western medicine only and to launch a national licence system for medical doctors. Issuing supplementary regulations in the following

IVUS Findings in Late and Very Late Stent Thrombosis. A Comparison Between Bare-metal and Drug-eluting Stents.

PubMed

Fuentes, Lara; Gómez-Lara, Josep; Salvatella, Neus; Gonzalo, Nieves; Hernández-Hernández, Felipe; Fernández-Nofrerias, Eduard; Sánchez-Recalde, Ángel; Alfonso, Fernando; Romaguera, Rafael; Ferreiro, José Luis; Roura, Gerard; Teruel, Luis; Gracida, Montserrat; Marcano, Ana Lucrecia; Gómez-Hospital, Joan-Antoni; Cequier, Ángel

2018-05-01

Stent thrombosis (ST) is a life-threatening complication after stent implantation. Intravascular ultrasound is able to discern most causes of ST. The aim of this study was to compare intravascular ultrasound findings between bare-metal stents (BMS) and drug-eluting stents (DES) in patients with late (31 days to 1 year) or very late ST (> 1 year). Of 250 consecutive patients with late or very late ST in 7 Spanish institutions, 114 patients (45.5% BMS and 54.5% DES) were imaged with intravascular ultrasound. Off-line intravascular ultrasound analysis was performed to assess malapposition, underexpansion, and neoatherosclerosis. The median time from stent implantation to ST was 4.0 years with BMS and 3.4 years with DES (P = .04). Isolated malapposition was similarly observed in both groups (36.5% vs 46.8%; P = .18) but was numerically lower with BMS (26.6% vs 48.0%; P = .07) in patients with very late ST. Isolated underexpansion was similarly observed in both groups (13.5% vs 11.3%; P = .47). Isolated neoatherosclerosis occurred only in patients with very late ST and was more prevalent with BMS (22.9%) than with DES (6.0%); P = .02. At 2.9 years' follow-up, there were 0% and 6.9% cardiac deaths, respectively (P = .06) and recurrent ST occurred in 4.0% and 5.2% of patients, respectively (P = .60). Malapposition was the most common finding in patients with late and very late ST and is more prevalent with DES in very late ST. In contrast, neoatherosclerosis was exclusively observed in patients with very late ST and mainly with BMS. Copyright © 2017 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.

Responses to highly active antiretroviral therapy and clinical events in patients with a low CD4 cell count: late presenters vs. late starters.

PubMed

Waters, L; Fisher, M; Anderson, J; Wood, C; Delpech, V; Hill, T; Walsh, J; Orkin, C; Bansi, L; Gompels, M; Phillips, A; Johnson, M; Gilson, R; Easterbrook, P; Leen, C; Porter, K; Gazzard, B; Sabin, C

2011-05-01

We investigated whether adverse responses to highly active antiretroviral therapy (HAART) associated with late HIV presentation are secondary to low CD4 cell count per se or other confounding factors. A longitudinal analysis of the UK Collaborative HIV Cohort (CHIC) Study of individuals starting HAART in 1998-2007 was carried out, comparing late presenters (presenting/starting HAART at a CD4 count <200 cells/μL) with late starters (presenting at a CD4 count>350 cells/μL; starting HAART at a CD4 count<200 cells/μL), using 'ideal starters' (presenting at a CD4 count>350 cells/μL; starting HAART at a CD4 count of 200-350 cells/μL) as a comparator. Virological, immunological and clinical (new AIDS event/death) outcomes at 48 and 96 weeks were analysed, with the analysis being limited to those remaining on HAART for>3 months. A total of 4978 of 9095 individuals starting first-line HAART with HIV RNA>500 HIV-1 RNA copies/mL were included in the analysis: 2741 late presenters, 947 late starters and 1290 ideal starters. Late presenters were more commonly female, heterosexual and Black African. Most started nonnucleoside reverse transcriptase inhibitors (NNRTIs); 48-week virological suppression was similar in late presenters and starters (and marginally lower than in ideal starters); by week 96 differences were reduced and nonsignificant. The median CD4 cell count increase in late presenters was significantly lower than that in late starters (weeks 48 and 96). During year 1, new clinical events were more frequent for late presenters [odds ratio (OR) 2.04; 95% confidence interval (CI) 1.19-3.51; P=0.01]; by year 2, event rates were similar in all groups. Amongst patients who initiate, and remain on, HAART, late presentation is associated with lower rates of virological suppression, blunted CD4 cell count increases and more clinical events compared with late starters in year 1, but similar clinical and immunological outcomes by year 2 to those of both late and ideal

Mapping of Ppd-B1, a Major Candidate Gene for Late Heading on Wild Emmer Chromosome Arm 2BS and Assessment of Its Interactions with Early Heading QTLs on 3AL.

PubMed

Zhou, Wei; Wu, Shasha; Ding, Mingquan; Li, Jingjuan; Shi, Zhaobin; Wei, Wei; Guo, Jialian; Zhang, Hua; Jiang, Yurong; Rong, Junkang

2016-01-01

Wheat heading date is an important agronomic trait determining maturation time and yield. A set of common wheat (Triticum aestivum var. Chinese Spring; CS)-wild emmer (T. turgidum L. subsp. dicoccoides (TDIC)) chromosome arm substitution lines (CASLs) was used to identify and allocate QTLs conferring late or early spike emergence by examining heading date. Genetic loci accelerating heading were found on TDIC chromosome arms 3AL and 7BS, while loci delaying heading were located on 4AL and 2BS. To map QTLs conferring late heading on 2BS, F2 populations derived from two cross combinations of CASL2BS × CS and CASL3AL × CASL2BS were developed and each planted at two times, constituting four F2 mapping populations. Heading date varied continuously among individuals of these four populations, suggesting quantitative characteristics. A genetic map of 2BS, consisting of 23 SSR and one single-stranded conformation polymorphism (SSCP) marker(s), was constructed using these F2 populations. This map spanned a genetic length of 53.2 cM with average marker density of 2.3 cM. The photoperiod-sensitivity gene Ppd-B1 was mapped to chromosome arm 2BS as a SSCP molecular marker, and was validated as tightly linked to a major QTL governing late heading of CASL2BS in all mapping populations. A significant dominance by additive effect of Ppd-B1 with the LUX gene located on 3AL was also detected. CS had more copies of Ppd-B1 than CASL2BS, implying that increased copy number could elevate the expression of Ppd-1 in CS, also increasing expression of LUX and FT genes and causing CS to have an earlier heading date than CASL2BS in long days.

Mapping of Ppd-B1, a Major Candidate Gene for Late Heading on Wild Emmer Chromosome Arm 2BS and Assessment of Its Interactions with Early Heading QTLs on 3AL

PubMed Central

Ding, Mingquan; Li, Jingjuan; Shi, Zhaobin; Wei, Wei; Guo, Jialian; Zhang, Hua; Jiang, Yurong; Rong, Junkang

2016-01-01

Wheat heading date is an important agronomic trait determining maturation time and yield. A set of common wheat (Triticum aestivum var. Chinese Spring; CS)-wild emmer (T. turgidum L. subsp. dicoccoides (TDIC)) chromosome arm substitution lines (CASLs) was used to identify and allocate QTLs conferring late or early spike emergence by examining heading date. Genetic loci accelerating heading were found on TDIC chromosome arms 3AL and 7BS, while loci delaying heading were located on 4AL and 2BS. To map QTLs conferring late heading on 2BS, F2 populations derived from two cross combinations of CASL2BS × CS and CASL3AL × CASL2BS were developed and each planted at two times, constituting four F2 mapping populations. Heading date varied continuously among individuals of these four populations, suggesting quantitative characteristics. A genetic map of 2BS, consisting of 23 SSR and one single-stranded conformation polymorphism (SSCP) marker(s), was constructed using these F2 populations. This map spanned a genetic length of 53.2 cM with average marker density of 2.3 cM. The photoperiod-sensitivity gene Ppd-B1 was mapped to chromosome arm 2BS as a SSCP molecular marker, and was validated as tightly linked to a major QTL governing late heading of CASL2BS in all mapping populations. A significant dominance by additive effect of Ppd-B1 with the LUX gene located on 3AL was also detected. CS had more copies of Ppd-B1 than CASL2BS, implying that increased copy number could elevate the expression of Ppd-1 in CS, also increasing expression of LUX and FT genes and causing CS to have an earlier heading date than CASL2BS in long days. PMID:26848576

SORL1 variants and risk of late-onset Alzheimer's disease.

PubMed

Li, Yonghong; Rowland, Charles; Catanese, Joseph; Morris, John; Lovestone, Simon; O'Donovan, Michael C; Goate, Alison; Owen, Michael; Williams, Julie; Grupe, Andrew

2008-02-01

A recent study reported significant association of late-onset Alzheimer's disease (LOAD) with multiple single nucleotide polymorphisms (SNPs) and haplotypes in SORL1, a neuronal sortilin-related receptor protein known to be involved in the trafficking and processing of amyloid precursor protein. Here we attempted to validate this finding in three large, well characterized case-control series. Approximately 2000 samples from the three series were individually genotyped for 12 SNPs, including the 10 reported significant SNPs and 2 that constitute the reported significant haplotypes. A total of 25 allelic and haplotypic association tests were performed. One SNP rs2070045 was marginally replicated in the three sample sets combined (nominal P=0.035); however, this result does not remain significant when accounting for multiple comparisons. Further validation in other sample sets will be required to assess the true effects of SORL1 variants in LOAD.

Renewing governance.

PubMed

Loos, Gregory P

2003-01-01

Globalization's profound influence on social and political institutions need not be negative. Critics of globalization have often referred to the "Impossible Trinity" because decision-making must 1. respect national sovereignty, 2. develop and implement firm regulation, and 3. allow capital markets to be as free as possible. To many, such goals are mutually exclusive because history conditions us to view policy-making and governance in traditional molds. Thus, transnational governance merely appears impossible because current forms of governance were not designed to provide it. The world needs new tools for governing, and its citizens must seize the opportunity to help develop them. The rise of a global society requires a greater level of generality and inclusion than is found in most policy bodies today. Politicians need to re-examine key assumptions about government. States must develop ways to discharge their regulatory responsibilities across borders and collaborate with neighboring jurisdictions, multilateral bodies, and business. Concepts such as multilateralism and tripartism show great promise. Governments must engage civil society in the spirit of shared responsibility and democratic decision-making. Such changes will result in a renewal of the state's purpose and better use of international resources and expertise in governance.

37 CFR 385.4 - Late payments.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 385.4 Patents, Trademarks, and Copyrights COPYRIGHT ROYALTY BOARD, LIBRARY OF CONGRESS RATES AND TERMS... AND DISTRIBUTING OF PHYSICAL AND DIGITAL PHONORECORDS Physical Phonorecord Deliveries, Permanent Digital Downloads and Ringtones § 385.4 Late payments. A Licensee shall pay a late fee of 1.5% per month...

37 CFR 385.4 - Late payments.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 385.4 Patents, Trademarks, and Copyrights COPYRIGHT ROYALTY BOARD, LIBRARY OF CONGRESS RATES AND TERMS... AND DISTRIBUTING OF PHYSICAL AND DIGITAL PHONORECORDS Physical Phonorecord Deliveries, Permanent Digital Downloads and Ringtones § 385.4 Late payments. A Licensee shall pay a late fee of 1.5% per month...

37 CFR 385.4 - Late payments.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 385.4 Patents, Trademarks, and Copyrights COPYRIGHT ROYALTY BOARD, LIBRARY OF CONGRESS RATES AND TERMS... AND DISTRIBUTING OF PHYSICAL AND DIGITAL PHONORECORDS Physical Phonorecord Deliveries, Permanent Digital Downloads and Ringtones § 385.4 Late payments. A Licensee shall pay a late fee of 1.5% per month...

37 CFR 385.4 - Late payments.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 385.4 Patents, Trademarks, and Copyrights COPYRIGHT ROYALTY BOARD, LIBRARY OF CONGRESS RATES AND TERMS... AND DISTRIBUTING OF PHYSICAL AND DIGITAL PHONORECORDS Physical Phonorecord Deliveries, Permanent Digital Downloads and Ringtones § 385.4 Late payments. A Licensee shall pay a late fee of 1.5% per month...

37 CFR 385.4 - Late payments.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 385.4 Patents, Trademarks, and Copyrights COPYRIGHT ROYALTY BOARD, LIBRARY OF CONGRESS RATES AND TERMS... AND DISTRIBUTING OF PHYSICAL AND DIGITAL PHONORECORDS Physical Phonorecord Deliveries, Permanent Digital Downloads and Ringtones § 385.4 Late payments. A Licensee shall pay a late fee of 1.5% per month...

Early school attainment in late-preterm infants.

PubMed

Peacock, Philip J; Henderson, John; Odd, David; Emond, Alan

2012-02-01

To investigate whether infants born late-preterm have poorer school attainment compared to those born at term. This study used data from the Avon Longitudinal Study of Parents and Children. Key stage one (KS1) school assessment results were obtained from local education authorities. Logistic regression models were used to investigate the effect of gestation, that is, late-preterm (32-36 weeks) versus term (37-41 weeks), on success in KS1 teacher assessments. Regression models were adjusted for potential confounders, including maternal education and markers of socioeconomic status. There were 12 089 term infants and 734 late-preterm infants. 71% of late-preterm children were successful in KS1 assessments compared to 79% of those born at term (OR 0.64 (95% CI 0.53 to 0.78); p<0.001). This difference persisted on adjusting for potential confounders (OR 0.74 (95% CI 0.59 to 0.92); p=0.007). Children born late-preterm are less likely to be successful in early school assessments than those born at term. This group of vulnerable children warrants closer surveillance for early identification of potential educational failure.

Hinode observations and 3D magnetic structure of an X-ray bright point

NASA Astrophysics Data System (ADS)

Alexander, C. E.; Del Zanna, G.; Maclean, R. C.

2011-02-01

Aims: We present complete Hinode Solar Optical Telescope (SOT), X-Ray Telescope (XRT)and EUV Imaging Spectrometer (EIS) observations of an X-ray bright point (XBP) observed on the 10, 11 of October 2007 over its entire lifetime (~12 h). We aim to show how the measured plasma parameters of the XBP change over time and also what kind of similarities the X-ray emission has to a potential magnetic field model. Methods: Information from all three instruments on-board Hinode was used to study its entire evolution. XRT data was used to investigate the structure of the bright point and to measure the X-ray emission. The EIS instrument was used to measure various plasma parameters over the entire lifetime of the XBP. Lastly, the SOT was used to measure the magnetic field strength and provide a basis for potential field extrapolations of the photospheric fields to be made. These were performed and then compared to the observed coronal features. Results: The XBP measured ~15´´ in size and was found to be formed directly above an area of merging and cancelling magnetic flux on the photosphere. A good correlation between the rate of X-ray emission and decrease in total magnetic flux was found. The magnetic fragments of the XBP were found to vary on very short timescales (minutes), however the global quasi-bipolar structure remained throughout the lifetime of the XBP. The potential field extrapolations were a good visual fit to the observed coronal loops in most cases, meaning that the magnetic field was not too far from a potential state. Electron density measurements were obtained using a line ratio of Fe XII and the average density was found to be 4.95 × 109 cm-3 with the volumetric plasma filling factor calculated to have an average value of 0.04. Emission measure loci plots were then used to infer a steady temperature of log Te [ K] ~ 6.1. The calculated Fe XII Doppler shifts show velocity changes in and around the bright point of ±15 km s-1 which are observed to change

Very late stent thrombosis and late target lesion revascularization after sirolimus-eluting stent implantation: five-year outcome of the j-Cypher Registry.

PubMed

Kimura, Takeshi; Morimoto, Takeshi; Nakagawa, Yoshihisa; Kawai, Kazuya; Miyazaki, Shunichi; Muramatsu, Toshiya; Shiode, Nobuo; Namura, Masanobu; Sone, Takahito; Oshima, Shigeru; Nishikawa, Hideo; Hiasa, Yoshikazu; Hayashi, Yasuhiko; Nobuyoshi, Masakiyo; Mitudo, Kazuaki

2012-01-31

There is a scarcity of long-term data from large-scale drug-eluting stent registries with a large enough sample to evaluate low-frequency events such as stent thrombosis (ST). Five-year outcomes were evaluated in 12 812 consecutive patients undergoing sirolimus-eluting stent (SES) implantation in the j-Cypher registry. Cumulative incidence of definite ST was low (30 day, 0.3%; 1 year, 0.6%; and 5 years, 1.6%). However, late and very late ST continued to occur without attenuation up to 5 years after sirolimus-eluting stent implantation (0.26%/y). Cumulative incidence of target lesion revascularization within the first year was low (7.3%). However, late target lesion revascularization beyond 1 year also continued to occur without attenuation up to 5 years (2.2%/y). Independent risk factors of ST were completely different according to the timing of ST onset, suggesting the presence of different pathophysiological mechanisms of ST according to the timing of ST onset: acute coronary syndrome and target of proximal left anterior descending coronary artery for early ST; side-branch stenting, diabetes mellitus, and end-stage renal disease with or without hemodialysis for late ST; and current smoking and total stent length >28 mm for very late ST. Independent risk factors of late target lesion revascularization beyond 1 year were generally similar to those risk factors identified for early target lesion revascularization. Late adverse events such as very late ST and late target lesion revascularization are continuous hazards, lasting at least up to 5 years after implantation of the first-generation drug-eluting stents (sirolimus-eluting stents), which should be the targets for developing improved coronary stents.

STIM1 and TRPV4 regulate fluid flow-induced calcium oscillation at early and late stages of osteoclast differentiation.

PubMed

Li, Ping; Bian, Xueyan; Liu, Chenglin; Wang, Shurong; Guo, Mengmeng; Tao, Yingjie; Huo, Bo

2018-05-01

Bone resorption is mainly mediated by osteoclasts (OCs), whose formation and function are regulated by intracellular Ca 2+ oscillation. Our previous studies demonstrated that fluid shear stress (FSS) lead to Ca 2+ oscillation through mechanosensitive cation-selective channels. However, the specific channels responsible for this FSS-induced Ca 2+ oscillation remain unknown. In the present study, we examined the expression of several Ca 2+ channels in OCs, including STIM1, ORAI1, TRPV1, TRPV4, TRPV5, and TRPV6, by western blotting and reverse transcription-polymerase chain reaction. The results showed that STIM1 was highly expressed in early stage OCs, while TRPV4 was highly expressed in late stage OCs. We observed intracellular Ca 2+ responses in OCs that were mechanically stimulated by FSS. When we blocked STIM1-dependent store-operated Ca 2+ entry or inhibited TRPV4 using siRNA or drug inhibition, FSS-induced Ca 2+ oscillations were almost undetectable in early and late stage OCs, respectively. These results indicate that STIM1 and TRPV4 act as mechanical transduction channels for OCs during the early and late differentiation stages, respectively, suggesting that these calcium channel could serve as markers of osteoclastogenesis or bone resorption. Copyright © 2017 Elsevier Ltd. All rights reserved.

iNKT-CELL ACTIVATION INDUCES LATE PRETERM BIRTH THAT IS ATTENUATED BY ROSIGLITAZONE1

PubMed Central

St Louis, Derek; Romero, Roberto; Plazyo, Olesya; Arenas-Hernandez, Marcia; Panaitescu, Bogdan; Xu, Yi; Milovic, Tatjana; Xu, Zhonghui; Bhatti, Gaurav; Qing-Sheng, Mi; Drewlo, Sascha; Tarca, Adi L.; Hassan, Sonia S.; Gomez-Lopez, Nardhy

2015-01-01

Preterm birth (PTB) is a leading cause of neonatal morbidity and mortality; however, its non-infection-related mechanisms are poorly understood. Herein, we show that the expansion of activated CD1d-restricted invariant NKT (iNKT) cells in the third trimester by administration of α-galactosylceramide (α-GalCer) induces late PTB and neonatal mortality. In vivo imaging revealed that fetuses from mice that underwent α-GalCer-induced late PTB had bradycardia and died shortly after delivery. Yet, administration of α-GalCer in the second trimester did not cause pregnancy loss. PPARγ activation, through rosiglitazone treatment, reduced the rate of α-GalCer-induced late PTB and improved neonatal survival. Administration of α-GalCer in the third trimester suppressed PPARγ activation as shown by the down-regulation of Fabp4 and Fatp4 in myometrial and decidual tissues, respectively; this suppression was rescued by rosiglitazone treatment. Administration of α-GalCer in the third trimester induced an increase in the activation of conventional CD4+ T cells in myometrial tissues and the infiltration of activated macrophages, neutrophils and mature DCs to myometrial and/or decidual tissues. All of these effects were blunted after rosiglitazone treatment. Administration of α-GalCer also up-regulated the expression of inflammatory genes at the maternal-fetal interface and systemically, and rosiglitazone treatment partially attenuated these responses. Finally, an increased infiltration of activated iNKT-like cells in human decidual tissues is associated with non-infection-related preterm labor/birth. Collectively, these results demonstrate that iNKT-cell activation in vivo leads to late PTB by initiating innate and adaptive immune responses and suggest that the PPARγ pathway has potential as a target for prevention of this syndrome. PMID:26740111

Architecture Governance: The Importance of Architecture Governance for Achieving Operationally Responsive Ground Systems

NASA Technical Reports Server (NTRS)

Kolar, Mike; Estefan, Jeff; Giovannoni, Brian; Barkley, Erik

2011-01-01

Topics covered (1) Why Governance and Why Now? (2) Characteristics of Architecture Governance (3) Strategic Elements (3a) Architectural Principles (3b) Architecture Board (3c) Architecture Compliance (4) Architecture Governance Infusion Process. Governance is concerned with decision making (i.e., setting directions, establishing standards and principles, and prioritizing investments). Architecture governance is the practice and orientation by which enterprise architectures and other architectures are managed and controlled at an enterprise-wide level

Toyocamycin attenuates free fatty acid-induced hepatic steatosis and apoptosis in cultured hepatocytes and ameliorates nonalcoholic fatty liver disease in mice.

PubMed

Takahara, Ikuko; Akazawa, Yuko; Tabuchi, Maiko; Matsuda, Katsuya; Miyaaki, Hisamitsu; Kido, Youko; Kanda, Yasuko; Taura, Naota; Ohnita, Ken; Takeshima, Fuminao; Sakai, Yusuke; Eguchi, Susumu; Nakashima, Masahiro; Nakao, Kazuhiko

2017-01-01

A high serum level of saturated free fatty acids (FFAs) is associated with the development of nonalcoholic fatty liver disease (NAFLD). X-box binding protein-1 (XBP-1) is activated by FFA treatment upon splicing. XBP-1 is a transcription factor induced by the endoplasmic reticulum (ER) stress sensor endoribonuclease inositol-requiring enzyme 1 alpha (IRE1α). However, the role of XBP-1 in NAFLD remains relatively unexplored. Toyocamycin was recently reported to attenuate the activation of XBP-1, possibly by inducing a conformational change in IRE1α. In this study, we examined the effect of toyocamycin on hepatocyte lipoapoptosis and steatosis. We also explored the effects of toyocamycin in a mouse model of NAFLD. Huh-7 cells and isolated rat primary hepatocytes were treated with palmitic acid (PA), which is a saturated FFA, in the presence or absence of toyocamycin. In addition, male C57BL/6J mice were fed a diet rich in saturated fat, fructose, and cholesterol (FFC) for 4 months, after which the effect of toyocamycin was assessed. Toyocamycin attenuated FFA-induced steatosis. It also significantly reduced PA-induced hepatocyte lipoapoptosis. In addition, toyocamycin reduced the expression of cytosine-cytosine-adenosine-adenosine-thymidine enhancer-binding protein homologous protein (CHOP), which is a key player in ER stress-mediated apoptosis, as well as its downstream cell death modulator, death receptor 5. In the in vivo study, toyocamycin ameliorated the liver injury caused by FFC-induced NAFLD. It also reduced hepatic steatosis and the expression of lipogenic genes. The data we obtained suggest that toyocamycin attenuates hepatocyte lipogenesis and ameliorates NAFLD in vivo and may therefore be beneficial in the treatment of NAFLD in humans.

Enemies or allies? The organ transplant medical community, the federal government, and the public in the United States, 1967-2000.

PubMed

Festle, Mary Jo

2010-01-01

The transplant medical community in the United States has frequently been divided over the appropriate role of the federal government and of the public in matters related to organ transplantation. Using public statements in government hearings, newspapers, and press releases, this article traces the thinking of the transplant medical community in particular during three especially politicized periods: the heart transplant and brain death controversies in the late 1960s, consideration of the National Organ Transplant Act and other legislation during the mid-1980s, and the controversy over organ allocation regulations issued by the Department of Health and Human Services in the late 1990s. Even while sometimes denouncing "politicization," over time surgeons, physicians, representatives of the United Network for Organ Sharing, and other leaders in the field became increasingly politically active and more accustomed to the notion that because of the unique nature of organ transplantation, both the public and the federal government have a legitimate and potentially beneficial oversight role.

Aflatoxin M1 contamination of milk and ice cream in Abeokuta and Odeda local governments of Ogun State, Nigeria.

PubMed

Atanda, Olusegun; Oguntubo, Adenike; Adejumo, Oloyede; Ikeorah, John; Akpan, Iyang

2007-07-01

A survey was undertaken to determine the aflatoxin M(1) contamination of milk and some locally produced dairy products in Abeokuta and Odeda local governments of Ogun State, Nigeria. Samples of human and cow milk, yoghurt, "wara", ice cream and "nono" were collected randomly within the local governments and analysed for aflatoxin M(1) using the two-dimensional TLC. Aflatoxin M(1) contamination in the range of 2.04-4.00 microg l(-1) was noticed only in milk and ice cream. In particular, samples of human milk, cow milk and ice cream recorded high scores of 4.0 microg l(-1), 2.04 microg l(-1) and 2.23 microg l(-1), respectively in Abeokuta local governments and a score of 4.0 microg l(-1) for cow milk in Odeda local government. This indicates a high level contamination in the local governments since the weighted mean concentration of aflatoxin M1 in milk for African diet is 0.002 microg l(-1). Therefore the concentration of AFB1 in feeds which is transformed to AFM1 in milk should be reduced by good manufacturing and good storage practices. Furthermore, there is need for stringent quality control during processing and distribution of these products.

Specific interaction between hnRNP H and HPV16 L1 proteins: Implications for late gene auto-regulation enabling rapid viral capsid protein production

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

Zheng, Zi-Zheng; Sun, Yuan-Yuan; Zhao, Min

2013-01-18

Highlights: ► The RNA-binding hnRNP H regulates late viral gene expression. ► hnRNP H activity was inhibited by a late viral protein. ► Specific interaction between HPV L1 and hnRNP H was demonstrated. ► Co-localization of HPV L1 and hnRNP H inside cells was observed. ► Viral capsid protein production, enabling rapid capsid assembly, was implicated. -- Abstract: Heterogeneous nuclear ribonucleoproteins (hnRNPs), including hnRNP H, are RNA-binding proteins that function as splicing factors and are involved in downstream gene regulation. hnRNP H, which binds to G triplet regions in RNA, has been shown to play an important role in regulatingmore » the staged expression of late proteins in viral systems. Here, we report that the specific association between hnRNP H and a late viral capsid protein, human papillomavirus (HPV) L1 protein, leads to the suppressed function of hnRNP H in the presence of the L1 protein. The direct interaction between the L1 protein and hnRNP H was demonstrated by complex formation in solution and intracellularly using a variety of biochemical and immunochemical methods, including peptide mapping, specific co-immunoprecipitation and confocal fluorescence microscopy. These results support a working hypothesis that a late viral protein HPV16 L1, which is down regulated by hnRNP H early in the viral life cycle may provide an auto-regulatory positive feedback loop that allows the rapid production of HPV capsid proteins through suppression of the function of hnRNP H at the late stage of the viral life cycle. In this positive feedback loop, the late viral gene products that were down regulated earlier themselves disable their suppressors, and this feedback mechanism could facilitate the rapid production of capsid proteins, allowing staged and efficient viral capsid assembly.« less

Secrecy From Parents and Type 1 Diabetes Management in Late Adolescence

PubMed Central

Wiebe, Deborah J.; Van Bogart, Karina; Turner, Sara L.; Tucker, Christy; Butner, Jonathan E.; Berg, Cynthia A.

2015-01-01

Objectives This study examined (a) associations of parent–adolescent relationship characteristics and adolescent problem behavior with late adolescents’ secrecy from parents about type 1 diabetes management, and (b) whether secrecy was associated with diabetes and psychological outcomes independently of these factors. Methods Adolescents (N = 247, Mage = 17.76 years) completed survey measures of diabetes-related secrecy from parents, disclosure, parental acceptance, parental knowledge, and conduct problems. Mothers and adolescents reported on adolescent adherence to diabetes regimens and adolescents reported their depressive symptoms. Glycemic control was obtained from HbA1c test kits. Results Adolescent-reported disclosure to parents was uniquely negatively associated with secrecy from parents. Controlling for relationship variables, conduct problems, and sociodemographic and illness-related variables, secrecy from mothers was uniquely associated with poorer glycemic control and secrecy from both parents was associated with lower adherence. Conclusions Secrecy about type 1 diabetes management is uniquely associated with diabetes outcomes independent of other relationship characteristics and problem behaviors. PMID:26136405

Exploring Communication, Trust in Government, and Vaccination Intention Later in the 2009 H1N1 Pandemic: Results of a National Survey

PubMed Central

Parmer, John; Freimuth, Vicki S.; Hilyard, Karen M.; Musa, Donald; Kim, Kevin H.

2013-01-01

With the growing recognition of the critical role that risk communication plays in a public health emergency, a number of articles have provided prescriptive best practices to enhance such communication. However, little empirical research has examined perceptions of the quality of communication, the impact of uncertainty on changing communication, use of information sources, and trust in specific government spokespersons. Similarly, although there is significant conceptual focus on trust and communication as important in vaccination intent and acceptance, little research has explored these relationships empirically. We conducted an online survey in late January 2010 with a nationally representative sample (N=2,079) that included Hispanic and African American oversamples. The completion rate was 56%. We found that public health officials were the most trusted spokespersons, with President Obama being the most highly trusted elected official. Demographic variables, including race, accounted for 21% of the variance in trust of the president. Perceptions of the quality of communication were high, including significant understanding of uncertainty and appreciation for officials' openness about evolving information. Other factors that contributed to vaccination acceptance were quality of communication, closely following the news, and confidence in the vaccine because of a role model effect of the Obama daughters' immunizations; these factors significantly increased trust in government actions. Because the challenges of communication often vary over the course of a pandemic, there is a consistent need to pay close attention to both communication content and delivery and prepare public health officials at all levels to be effective communicators. PMID:23617721

3 CFR - Government Contracting

Code of Federal Regulations, 2010 CFR

2010-01-01

... 3 The President 1 2010-01-01 2010-01-01 false Government Contracting Presidential Documents Other Presidential Documents Memorandum of March 4, 2009 Government Contracting Memorandum for the Heads of Executive Departments and Agencies The Federal Government has an overriding obligation to American taxpayers. It should...

[Factional disputes on the retention or abolition of traditional Chinese medicine within the National Government].

PubMed

Hao, Xian-zhong; Zhu, De-pei

2008-07-01

The disputes between Western and traditional Chinese medicine (TCM) started at the turn of late Qing Dynasty to early Republican China, intensified in the period of construction of National Government at Nanking, lasting for several years. The scope of dispute also extended from the initial medical area to the mass media, and even to the government interior factions. The form of the combat also changed from the debates of original scientific theory to the confrontation of political ideology. It was the government interior factional disputes which caused "the case of abolition of the traditional Chinese medicine" to abort objectively, with the difficult advent of the regulations which saved TCM, to certain degree, from vanishing.

Divergent forms of endoplasmic reticulum stress trigger a robust unfolded protein response in honey bees.

PubMed

Johnston, Brittany A; Hooks, Katarzyna B; McKinstry, Mia; Snow, Jonathan W

2016-03-01

Honey bee colonies in the United States have suffered from an increased rate of die-off in recent years, stemming from a complex set of interacting stresses that remain poorly described. While we have some understanding of the physiological stress responses in the honey bee, our molecular understanding of honey bee cellular stress responses is incomplete. Thus, we sought to identify and began functional characterization of the components of the UPR in honey bees. The IRE1-dependent splicing of the mRNA for the transcription factor Xbp1, leading to translation of an isoform with more transactivation potential, represents the most conserved of the UPR pathways. Honey bees and other Apoidea possess unique features in the Xbp1 mRNA splice site, which we reasoned could have functional consequences for the IRE1 pathway. However, we find robust induction of target genes upon UPR stimulation. In addition, the IRE1 pathway activation, as assessed by splicing of Xbp1 mRNA upon UPR, is conserved. By providing foundational knowledge about the UPR in the honey bee and the relative sensitivity of this species to divergent stresses, this work stands to improve our understanding of the mechanistic underpinnings of honey bee health and disease. Copyright © 2015 Elsevier Ltd. All rights reserved.

Antidepressants differentially related to 1,25-(OH)₂ vitamin D₃ and 25-(OH) vitamin D₃ in late-life depression.

PubMed

Oude Voshaar, R C; Derks, W J; Comijs, H C; Schoevers, R A; de Borst, M H; Marijnissen, R M

2014-04-15

A low plasma 25-OH vitamin D3 level is a universal risk factor for a wide range of diseases and has also been implicated in late-life depression. It is currently unknown whether the biologically active form of vitamin D, that is, 1,25-(OH)2 vitamin D3, is also decreased in late-life depression, or whether vitamin D levels correlate with specific depression characteristics. We determined plasma 25-OH vitamin D3, 1,25-(OH)2 vitamin D3 and parathormone levels in 355 depressed older persons and 124 non-depressed comparison subjects (age 60 years). Psychopathology was established with the Composite International Diagnostic Interview 2.1, together with potential confounders and depression characteristics (severity, symptom profile, age of onset, recurrence, chronicity and antidepressant drug use). Adjusted for confounders, depressed patients had significantly lower levels of 25-OH vitamin D33 (Cohen's d =0.28 (95% confidence interval: 0.07-0.49), P=0.033) as well as 1,25-(OH)2 vitamin D3 (Cohen's d =0.48 (95% confidence interval: 0.27-0.70), P<0.001) than comparison subjects. Of all depression characteristics tested, only the use of tricyclic antidepressants (TCAs) was significantly correlated with lower 1,25-(OH)2 vitamin D3 levels (Cohen's d =0.86 (95% confidence interval: 0.53-1.19), P<0.001), but not its often measured precursor 25-OH vitamin D3. As vitamin D levels were significantly lower after adjustment for confounders, vitamin D might have an aetiological role in late-life depression. Differences between depressed and non-depressed subjects were largest for the biologically active form of vitamin D. The differential impact of TCAs on 25-OH vitamin D3 and 1,25-(OH)2 vitamin D3 levels suggests modulation of 1-α-hydroxylase and/or 24-hydroxylase, which may in turn have clinical implications for biological ageing mechanisms in late-life depression.

Late time cosmological phase transitions 1: Particle physics models and cosmic evolution

NASA Technical Reports Server (NTRS)

Frieman, Joshua A.; Hill, Christopher T.; Watkins, Richard

1991-01-01

We described a natural particle physics basis for late-time phase transitions in the universe. Such a transition can seed the formation of large-scale structure while leaving a minimal imprint upon the microwave background anisotropy. The key ingredient is an ultra-light pseudo-Nambu-Goldstone boson with an astronomically large (O(kpc-Mpc)) Compton wavelength. We analyze the cosmological signatures of and constraints upon a wide class of scenarios which do not involve domain walls. In addition to seeding structure, coherent ultra-light bosons may also provide unclustered dark matter in a spatially flat universe, omega sub phi approx. = 1.

Herpetology in the federal government: a personal view

USGS Publications Warehouse

Dodd, C. Kenneth

1999-01-01

In late 1976, I received a phone call from an ichthyological colleague who asked if I would be willing to take a temporary position in the U.S. Fish and Wildlife Service's (FWS) Office of Endangered Species (OES) in Washington. They had a backlog of proposed and final rules that needed to be finished, and they thought that a 30-day stint by a temporary herpetologist would clear the slate. Thus began a 23-year odyssey through the sometimes bizarre, sometimes rewarding, sometimes discouraging, but always different federal government. Fortunately, I have been able to stay involved with herpetology, both as a science and in terms of conservation policy. In my career, I have worked both in an administrative and in a research capacity. Many individuals with an interest in herpetology enter the federal government as field biologists and drift into administration as they become older and removed from the dynamically changing nature of their science. I moved in the other direction.

48 CFR 46.406 - Foreign governments.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 48 Federal Acquisition Regulations System 1 2010-10-01 2010-10-01 false Foreign governments. 46... MANAGEMENT QUALITY ASSURANCE Government Contract Quality Assurance 46.406 Foreign governments. Government contract quality assurance performed for foreign governments or international agencies shall be...

48 CFR 46.406 - Foreign governments.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 48 Federal Acquisition Regulations System 1 2013-10-01 2013-10-01 false Foreign governments. 46... MANAGEMENT QUALITY ASSURANCE Government Contract Quality Assurance 46.406 Foreign governments. Government contract quality assurance performed for foreign governments or international agencies shall be...

48 CFR 46.406 - Foreign governments.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 48 Federal Acquisition Regulations System 1 2014-10-01 2014-10-01 false Foreign governments. 46... MANAGEMENT QUALITY ASSURANCE Government Contract Quality Assurance 46.406 Foreign governments. Government contract quality assurance performed for foreign governments or international agencies shall be...

48 CFR 46.406 - Foreign governments.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 48 Federal Acquisition Regulations System 1 2012-10-01 2012-10-01 false Foreign governments. 46... MANAGEMENT QUALITY ASSURANCE Government Contract Quality Assurance 46.406 Foreign governments. Government contract quality assurance performed for foreign governments or international agencies shall be...

48 CFR 46.406 - Foreign governments.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 48 Federal Acquisition Regulations System 1 2011-10-01 2011-10-01 false Foreign governments. 46... MANAGEMENT QUALITY ASSURANCE Government Contract Quality Assurance 46.406 Foreign governments. Government contract quality assurance performed for foreign governments or international agencies shall be...

Food safety evaluation for R-proteins introduced by biotechnology: A case study of VNT1 in late blight protected potatoes.

PubMed

Habig, Jeffrey W; Rowland, Aaron; Pence, Matthew G; Zhong, Cathy X

2018-06-01

Resistance genes (R-genes) from wild potato species confer protection against disease and can be introduced into cultivated potato varieties using breeding or biotechnology. The R-gene, Rpi-vnt1, which encodes the VNT1 protein, protects against late blight, caused by Phytophthora infestans. Heterologous expression and purification of active VNT1 in quantities sufficient for regulatory biosafety studies was problematic, making it impractical to generate hazard characterization data. As a case study for R-proteins, a weight-of-evidence, tiered approach was used to evaluate the safety of VNT1. The hazard potential of VNT1 was identified from relevant safety information including history of safe use, bioinformatics, mode of action, expression levels, and dietary intake. From the assessment it was concluded that Tier II hazard characterization was not needed. R-proteins homologous to VNT1 and identified in edible crops, have a history of safe consumption. VNT1 does not share sequence identity with known allergens. Expression levels of R-proteins are generally low, and VNT1 was not detected in potato varieties expressing the Rpi-vnt1 gene. With minimal hazard and negligible exposure, the risks associated with consumption of R-proteins in late blight protected potatoes are exceedingly low. R-proteins introduced into potatoes to confer late blight protection are safe for consumption. Copyright © 2018 Elsevier Inc. All rights reserved.

The return of the city-state: urban governance and the New York City H1N1 pandemic.

PubMed

Hoffman, Lily M

2013-02-01

This article examines New York City's response to the 2009 H1N1 pandemic in the context of the post-9/11 US security regime. While the federal level 'all-hazards' approach made for greater depth of support, it also generated unrealistic assumptions at odds with an effective local response. The combination of structurally induced opportunity and actor specific strengths (size, expertise) made for effective local governance by the New York City Department of Health and Mental Hygiene. By underlining the importance of locality as a first line of defence and linking defence function to policy initiative in regard to health governance, this study illustrates the continuing relevance of Weber's insight into the institutional structure of the city. © 2012 The Author. Sociology of Health & Illness © 2012 Foundation for the Sociology of Health & Illness/Blackwell Publishing Ltd.

7 CFR 25.501 - Governments.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 7 Agriculture 1 2013-01-01 2013-01-01 false Governments. 25.501 Section 25.501 Agriculture Office....501 Governments. If more than one State or local government seeks to nominate an area under this part, any reference to or requirement of this part shall apply to all such governments. ...

7 CFR 25.501 - Governments.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 7 Agriculture 1 2012-01-01 2012-01-01 false Governments. 25.501 Section 25.501 Agriculture Office....501 Governments. If more than one State or local government seeks to nominate an area under this part, any reference to or requirement of this part shall apply to all such governments. ...

7 CFR 25.501 - Governments.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 1 2010-01-01 2010-01-01 false Governments. 25.501 Section 25.501 Agriculture Office....501 Governments. If more than one State or local government seeks to nominate an area under this part, any reference to or requirement of this part shall apply to all such governments. ...

7 CFR 25.501 - Governments.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 7 Agriculture 1 2014-01-01 2014-01-01 false Governments. 25.501 Section 25.501 Agriculture Office....501 Governments. If more than one State or local government seeks to nominate an area under this part, any reference to or requirement of this part shall apply to all such governments. ...

7 CFR 25.501 - Governments.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 7 Agriculture 1 2011-01-01 2011-01-01 false Governments. 25.501 Section 25.501 Agriculture Office....501 Governments. If more than one State or local government seeks to nominate an area under this part, any reference to or requirement of this part shall apply to all such governments. ...

PLK1 Activation in Late G2 Sets Up Commitment to Mitosis.

PubMed

Gheghiani, Lilia; Loew, Damarys; Lombard, Bérangère; Mansfeld, Jörg; Gavet, Olivier

2017-06-06

Commitment to mitosis must be tightly coordinated with DNA replication to preserve genome integrity. While we have previously established that the timely activation of CyclinB1-Cdk1 in late G2 triggers mitotic entry, the upstream regulatory mechanisms remain unclear. Here, we report that Polo-like kinase 1 (Plk1) is required for entry into mitosis during an unperturbed cell cycle and is rapidly activated shortly before CyclinB1-Cdk1. We determine that Plk1 associates with the Cdc25C1 phosphatase and induces its phosphorylation before mitotic entry. Plk1-dependent Cdc25C1 phosphosites are sufficient to promote mitotic entry, even when Plk1 activity is inhibited. Furthermore, we find that activation of Plk1 during G2 relies on CyclinA2-Cdk activity levels. Our findings thus elucidate a critical role for Plk1 in CyclinB1-Cdk1 activation and mitotic entry and outline how CyclinA2-Cdk, an S-promoting factor, poises cells for commitment to mitosis. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Discovery of Dihydrobenzoxazepinone (GS-6615) Late Sodium Current Inhibitor (Late INai), a Phase II Agent with Demonstrated Preclinical Anti-Ischemic and Antiarrhythmic Properties.

PubMed

Zablocki, Jeff A; Elzein, Elfatih; Li, Xiaofen; Koltun, Dmitry O; Parkhill, Eric Q; Kobayashi, Tetsuya; Martinez, Ruben; Corkey, Britton; Jiang, Haibo; Perry, Thao; Kalla, Rao; Notte, Gregory T; Saunders, Oliver; Graupe, Michael; Lu, Yafan; Venkataramani, Chandru; Guerrero, Juan; Perry, Jason; Osier, Mark; Strickley, Robert; Liu, Gongxin; Wang, Wei-Qun; Hu, Lufei; Li, Xiao-Jun; El-Bizri, Nesrine; Hirakawa, Ryoko; Kahlig, Kris; Xie, Cheng; Li, Cindy Hong; Dhalla, Arvinder K; Rajamani, Sridharan; Mollova, Nevena; Soohoo, Daniel; Lepist, Eve-Irene; Murray, Bernard; Rhodes, Gerry; Belardinelli, Luiz; Desai, Manoj C

2016-10-03

Late sodium current (late I Na ) is enhanced during ischemia by reactive oxygen species (ROS) modifying the Na v 1.5 channel, resulting in incomplete inactivation. Compound 4 (GS-6615, eleclazine) a novel, potent, and selective inhibitor of late I Na , is currently in clinical development for treatment of long QT-3 syndrome (LQT-3), hypertrophic cardiomyopathy (HCM), and ventricular tachycardia-ventricular fibrillation (VT-VF). We will describe structure-activity relationship (SAR) leading to the discovery of 4 that is vastly improved from the first generation late I Na inhibitor 1 (ranolazine). Compound 4 was 42 times more potent than 1 in reducing ischemic burden in vivo (S-T segment elevation, 15 min left anteriorior descending, LAD, occlusion in rabbits) with EC 50 values of 190 and 8000 nM, respectively. Compound 4 represents a new class of potent late I Na inhibitors that will be useful in delineating the role of inhibitors of this current in the treatment of patients.

HSP70.1 AND -70.3 ARE REQUIRED FOR LATE-PHASE PROTECTION INDUCED BY ISCHEMIC PRECONDITIONING OF MOUSE HEARTS

EPA Science Inventory

Heat-Shock Proteins 70.1 and 70.3 Are Required for Late-phase Protection
Induced by Ischemic Preconditioning of the Mouse Heart
Craig R. Hampton 1 , Akira Shimamoto 1 , Christine L. Rothnie 1 , Jeaneatte Griscavage-Ennis 1 ,
Albert Chong 1 , David J. Dix 2 , Edward D. Ve...

Exceptionally well preserved late Quaternary plant and vertebrate fossils from a blue hole on Abaco, The Bahamas.

PubMed

Steadman, David W; Franz, Richard; Morgan, Gary S; Albury, Nancy A; Kakuk, Brian; Broad, Kenneth; Franz, Shelley E; Tinker, Keith; Pateman, Michael P; Lott, Terry A; Jarzen, David M; Dilcher, David L

2007-12-11

We report Quaternary vertebrate and plant fossils from Sawmill Sink, a "blue hole" (a water-filled sinkhole) on Great Abaco Island, The Bahamas. The fossils are well preserved because of deposition in anoxic salt water. Vertebrate fossils from peat on the talus cone are radiocarbon-dated from approximately 4,200 to 1,000 cal BP (Late Holocene). The peat produced skeletons of two extinct species (tortoise Chelonoidis undescribed sp. and Caracara Caracara creightoni) and two extant species no longer in The Bahamas (Cuban crocodile, Crocodylus rhombifer; and Cooper's or Gundlach's Hawk, Accipiter cooperii or Accipiter gundlachii). A different, inorganic bone deposit on a limestone ledge in Sawmill Sink is a Late Pleistocene owl roost that features lizards (one species), snakes (three species), birds (25 species), and bats (four species). The owl roost fauna includes Rallus undescribed sp. (extinct; the first Bahamian flightless rail) and four other locally extinct species of birds (Cooper's/Gundlach's Hawk, A. cooperii/gundlachii; flicker Colaptes sp.; Cave Swallow, Petrochelidon fulva; and Eastern Meadowlark, Sturnella magna) and mammals (Bahamian hutia, Geocapromys ingrahami; and a bat, Myotis sp.). The exquisitely preserved fossils from Sawmill Sink suggest a grassy pineland as the dominant plant community on Abaco in the Late Pleistocene, with a heavier component of coppice (tropical dry evergreen forest) in the Late Holocene. Important in its own right, this information also will help biologists and government planners to develop conservation programs in The Bahamas that consider long-term ecological and cultural processes.

IRE1α pathway of endoplasmic reticulum stress induces neuronal apoptosis in the locus coeruleus of rats under single prolonged stress.

PubMed

Zhao, Wei; Han, Fang; Shi, Yuxiu

2016-08-01

Our previous studies have shown evidence of endoplasmic reticulum (ER) stress-induced apoptosis in the hippocampus and mPFC in an animal model of post- traumatic stress disorder (PTSD). Inositol-requiring enzyme 1α (IRE1α) and its downstream molecule X-box binding protein 1 (XBP1) play key roles in the ER-related apoptosis pathway. Dysregulation of the locus coeruleus (LC) has been reported to contribute to cognitive and/or arousal impairments associated with PTSD. The aim of the present study was to explore the role of IRE1α pathway in neuronal apoptosis in the LC of rat models of PTSD. We used an acute exposure to prolonged stress (single prolonged stress, SPS) to model PTSD in rats and examined the effects related to the IRE1α pathway. Neuronal apoptosis in LC was detected by transmission electron microscopy and TUNEL staining. The results showed that the level of LC neuronal apoptosis was markedly increased after SPS. SPS exposure triggered IRE1α pathway, as evidenced by the increased activity of IRE1α, specific splicing of XBP1, and up-regulated expression of binding immunoglobulin protein/78kDa glucose-regulated protein (BiP/GRP78), and C/EBP-homologous protein (CHOP). Treatment with STF-083010, an IRE1α RNase-specific inhibitor, successfully attenuated the above changes. These results indicate that excessive activation of the ER stress-associated IRE1α pathway is involved in LC neuronal apoptosis induced by SPS exposure; this may be a crucial mechanism of the pathogenesis of PTSD. Copyright © 2016 Elsevier Inc. All rights reserved.

Role of Unfolded Protein Response Dysregulation in Oxidative Injury of Retinal Pigment Epithelial Cells

PubMed Central

Chen, Chen; Cano, Marisol; Wang, Joshua J.; Li, Jingming; Huang, Chuangxin; Yu, Qiang; Herbert, Terence P.; Handa, James T.

2014-01-01

Abstract Aims: Age-related macular degeneration (AMD), a major cause of legal blindness in the elderly, is associated with genetic and environmental risk factors, such as cigarette smoking. Recent evidence shows that cigarette smoke (CS) that contains high levels of potent oxidants preferably targets retinal pigment epithelium (RPE) leading to oxidative damage and apoptosis; however, the mechanisms are poorly understood. The present study aimed to investigate the role of endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) in CS-related RPE apoptosis. Results: ER stress and proapoptotic gene C/EBP homologous protein (CHOP) were induced in the RPE/choroid complex from mice exposed to CS for 2 weeks and in human RPE cells treated with hydroquinone, a potent oxidant found at high concentrations in CS. Suppressing ER stress or inhibiting CHOP activation by pharmacological chaperones or genetic approaches attenuated hydroquinone-induced RPE cell apoptosis. In contrast to enhanced CHOP activation, protein level of active X-box binding protein 1 (XBP1), a major regulator of the adaptive UPR, was reduced in hydroquinone-treated cells. Conditional knockout of XBP1 gene in the RPE resulted in caspase-12 activation, increased CHOP expression, and decreased antiapoptotic gene Bcl-2. Furthermore, XBP1-deficient RPE cells are more sensitive to oxidative damage induced by hydroquinone or NaIO3, a CS-unrelated chemical oxidant. Conversely, overexpressing XBP1 protected RPE cells and attenuated oxidative stress-induced RPE apoptosis. Innovation and Conclusion: These findings provide strong evidence suggesting an important role of ER stress and the UPR in CS-related oxidative injury of RPE cells. Thus, the modulation of the UPR signaling may provide a promising target for the treatment of AMD. Antioxid. Redox Signal. 20, 2091–2106. PMID:24053669

Vitiligo - Part 1*

PubMed Central

Tarlé, Roberto Gomes; do Nascimento, Liliane Machado; Mira, Marcelo Távora; de Castro, Caio Cesar Silva

2014-01-01

Vitiligo is a chronic stigmatizing disease, already known for millennia, which mainly affects melanocytes from epidermis basal layer, leading to the development of hypochromic and achromic patches. Its estimated prevalence is 0.5% worldwide. The involvement of genetic factors controlling susceptibility to vitiligo has been studied over the last decades, and results of previous studies present vitiligo as a complex, multifactorial and polygenic disease. In this context, a few genes, including DDR1, XBP1 and NLRP1 have been consistently and functionally associated with the disease. Notwithstanding, environmental factors that precipitate or maintain the disease are yet to be described. The pathogenesis of vitiligo has not been totally clarified until now and many theories have been proposed. Of these, the autoimmune hypothesis is now the most cited and studied among experts. Dysfunction in metabolic pathways, which could lead to production of toxic metabolites causing damage to melanocytes, has also been investigated. Melanocytes adhesion deficit in patients with vitiligo is mainly speculated by the appearance of Köebner phenomenon, recently, new genes and proteins involved in this deficit have been found. PMID:24937821

Identification and Structural Characterization of the ALIX-Binding Late Domains of Simian Immunodeficiency Virus SIVmac239 and SIVagmTan-1

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

Zhai, Q.; Robinson, H.; Landesman, M. B.

2011-01-01

Retroviral Gag proteins contain short late-domain motifs that recruit cellular ESCRT pathway proteins to facilitate virus budding. ALIX-binding late domains often contain the core consensus sequence YPX{sub n}L (where X{sub n} can vary in sequence and length). However, some simian immunodeficiency virus (SIV) Gag proteins lack this consensus sequence, yet still bind ALIX. We mapped divergent, ALIX-binding late domains within the p6{sup Gag} proteins of SIV{sub mac239} ({sub 40}SREK{und P}YKE{und VT}ED{und L}LHLNSLF{sub 59}) and SIV{sub agmTan-1} ({sub 24}AAG{und A}YDP{und AR}KL{und L}EQYAKK{sub 41}). Crystal structures revealed that anchoring tyrosines (in lightface) and nearby hydrophobic residues (underlined) contact the ALIX V domain,more » revealing how lentiviruses employ a diverse family of late-domain sequences to bind ALIX and promote virus budding.« less

Evidence that a sequence similar to TAR is important for induction of the JC virus late promoter by human immunodeficiency virus type 1 Tat.

PubMed Central

Chowdhury, M; Taylor, J P; Chang, C F; Rappaport, J; Khalili, K

1992-01-01

A specific RNA sequence located in the leader of all human immunodeficiency virus type 1 (HIV-1) mRNAs termed the transactivation response element, or TAR, is a primary target for induction of HIV-1 long terminal repeat activity by the HIV-1-derived trans-regulatory protein, Tat. Human neurotropic virus, JC virus (JCV), a causative agent of the degenerative demyelinating disease progressive multifocal leukoencephalopathy, contains sequences in the 5' end of the late RNA species with an extensive homology to HIV-1 TAR. In this study, we examined the possible role of the JCV-derived TAR-homologous sequence in Tat-mediated activation of the JCV late promoter (Tada et al., Proc. Natl. Acad. Sci. USA 87:3479-3483, 1990). Results from site-directed mutagenesis revealed that critical G residues required for the function of HIV-1 TAR that are conserved in the JCV TAR homolog play an important role in Tat activation of the JCV promoter. In addition, in vivo competition studies suggest that shared regulatory components mediate Tat activation of the JCV late and HIV-1 long terminal repeat promoters. Furthermore, we showed that the JCV-derived TAR sequence behaves in the same way as HIV-1 TAR in response to two distinct Tat mutants, one of which that has no ability to bind to HIV-1 TAR and another that lacks transcriptional activity on a responsive promoter. These results suggest that the TAR homolog of the JCV late promoter is responsive to HIV-1 Tat induction and thus may participate in the overall activation of the JCV late promoter mediated by this transactivation. Images PMID:1331525

Center variation in the delivery of indicated late preterm births

PubMed Central

Aliaga, Sofia; Zhang, Jun; Long, D. Leann; Herring, Amy H.; Laughon, Matthew; Boggess, Kim; Reddy, Uma M.; Grantz, Katherine Laughon

2016-01-01

Objective Evidence for optimal timing of delivery for some pregnancy complications at late preterm gestation is limited. The purpose of this study was to identify center variation of indicated late preterm births. Study design Analysis of singleton late preterm and term births from a large U.S. retrospective obstetrical cohort. Births associated with spontaneous preterm labor, major congenital anomalies, chorioamnionitis, and emergency cesarean were excluded. We used modified Poisson fixed effects logistic regression with interaction terms to assess center variation of indicated late preterm births associated with four medical/obstetric comorbidities after adjusting for socio-demographics, co-morbidities, and hospital/provider characteristics. Results We identified 150,055 births from 16 hospitals; 9218 were indicated late preterm births. We found wide variation of indicated late preterm births across hospitals. The extent of center variation was greater for births associated with preterm premature rupture of membranes (RR across sites: 0.45 – 3.05), hypertensive disorders of pregnancy (RR across sites: 0.36 – 1.27), and placenta previa/abruption (RR across sites: 0.48 – 1.82). We found less center variation for births associated with diabetes (RR across sites: 0.65 – 1.39). Conclusion Practice variation in the management of indicated late preterm deliveries might be a source of preventable late preterm birth. PMID:27120474

Neural stem cells for disease modeling and evaluation of therapeutics for infantile (CLN1/PPT1) and late infantile (CLN2/TPP1) neuronal ceroid lipofuscinoses.

PubMed

Sima, Ni; Li, Rong; Huang, Wei; Xu, Miao; Beers, Jeanette; Zou, Jizhong; Titus, Steven; Ottinger, Elizabeth A; Marugan, Juan J; Xie, Xing; Zheng, Wei

2018-04-10

Infantile and late infantile neuronal ceroid lipofuscinoses (NCLs) are lysosomal storage diseases affecting the central nervous system (CNS). The infantile NCL (INCL) is caused by mutations in the PPT1 gene and late-infantile NCL (LINCL) is due to mutations in the TPP1 gene. Deficiency in PPT1 or TPP1 enzyme function results in lysosomal accumulation of pathological lipofuscin-like material in the patient cells. There is currently no small-molecular drug treatment for NCLs. We have generated induced pluripotent stem cells (iPSC) from three patient dermal fibroblast lines and further differentiated them into neural stem cells (NSCs). Using these new disease models, we evaluated the effect of δ-tocopherol (DT) and hydroxypropyl-β-cyclodextrin (HPBCD) with the enzyme replacement therapy as the control. Treatment with the relevant recombinant enzyme or DT significantly ameliorated the lipid accumulation and lysosomal enlargement in the disease cells. A combination therapy of δ-tocopherol and HPBCD further improved the effect compared to that of either drug used as a single therapy. The results demonstrate that these patient iPSC derived NCL NSCs are valid cell- based disease models with characteristic disease phenotypes that can be used for study of disease pathophysiology and drug development.

Loss of alleles from the distal short arm of chromosome 1 occurs late in melanoma tumor progression

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

Dracopoli, N.C.; Harnett, P.; Bale, S.J.

The gene for familial malignant melanoma and its precursor lesion, the dysplastic nevus, has been assigned to a region of the distal short arm of chromosome 1, which is frequently involved in karyotypic abnormalities in melanoma cells. The authors have examined loci on chromosome 1p for loss-of-constitutional heterozygosity in 35 melanomas and 21 melanoma cell lines to analyze the role of these abnormalities in melanocyte transformation. Loss-of-heterozygosity at loci on chromosome 1p was identified in 15/35 (43%) melanomas and 11/21 (52%) melanoma cell lines. Analysis of multiple metastases derived from the same patient and of melanoma and lymphoblastoid samples frommore » a family with hereditary melanoma showed that the loss-of-heterozygosity at loci on distal 1p is a late event in tumor progression, rather than the second mutation that would occur if melanoma were due to a cellular recessive mechanism. Comparisons with neuroblastoma and multiple endocrine neoplasia (MEN2) suggest that the frequent 1p loss-of-heterozygosity in these malignancies is a common late event of neuroectodermal tumor progression.« less

Differential roles of osteopontin/Eta-1 in early and late lpr disease

PubMed Central

Weber, G F; Cantor, H

2001-01-01

The cytokine osteopontin (Eta-1) leads to macrophage-dependent polyclonal B-cell activation and is induced early in autoimmune prone mice with the lpr mutation, suggesting a significant pathogenic role for this molecule. Indeed, C57BL/6-Faslpr/lpr mice crossed with osteopontin−/– mice display delayed onset of polyclonal B-cell activation, as judged by serum immunoglobulin levels. In contrast, they are subject to normal onset, but late exacerbation of lymphoproliferation and evidence of kidney disease. These observations define two stages of Faslpr/lpr disease with respect to osteopontin-dependent pathogenesis that should be taken into account in the design of therapeutic approaches to the clinical disease. PMID:11737079

mTORC1 activity repression by late endosomal phosphatidylinositol 3,4-bisphosphate.

PubMed

Marat, Andrea L; Wallroth, Alexander; Lo, Wen-Ting; Müller, Rainer; Norata, Giuseppe Danilo; Falasca, Marco; Schultz, Carsten; Haucke, Volker

2017-06-02

Nutrient sensing by mechanistic target of rapamycin complex 1 (mTORC1) on lysosomes and late endosomes (LyLEs) regulates cell growth. Many factors stimulate mTORC1 activity, including the production of phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P 3 ] by class I phosphatidylinositol 3-kinases (PI3Ks) at the plasma membrane. We investigated mechanisms that repress mTORC1 under conditions of growth factor deprivation. We identified phosphatidylinositol 3,4-bisphosphate [PI(3,4)P 2 ], synthesized by class II PI3K β (PI3KC2β) at LyLEs, as a negative regulator of mTORC1, whereas loss of PI3KC2β hyperactivated mTORC1. Growth factor deprivation induced the association of PI3KC2β with the Raptor subunit of mTORC1. Local PI(3,4)P 2 synthesis triggered repression of mTORC1 activity through association of Raptor with inhibitory 14-3-3 proteins. These results unravel an unexpected function for local PI(3,4)P 2 production in shutting off mTORC1. Copyright © 2017, American Association for the Advancement of Science.

How nations govern growth.

PubMed

1984-03-02

Officials in China admit that the killing or abondoning of baby girls stems from a government policy limiting couples to 1 child combined with an ancient preference for sons. At the same time leaders maintain that population growth is an national emergency and must be checked. And the 1-child policy remains. To enforce the policy, sterilization is compulsory for 1 parent in a 2-child family. Other reports claim that pregnant women face severe government and social pressure to have an abortion. Comunist governments are not alone in taking a forceful role in population control. In 1975 thousands of people in India were pressured to undergo "voluntary" sterilization. In many places, police and tax collectors, money in hand, "convinced" people to get sterilized. Critics recognize a horribla abuse of government powers in these population control efforts. Recognizing that the populations of the poorest nations will double in 20-30 years, 59 countries responded with some kind of population policy by 1980. These countries are spending an average of US$4.60 on population programs for each US$1 they received in UN aid. In many places, the effort is beginning to show results. A 1982 survey found that 35 countries -- with 88% of the 3rd world population -- had cut the growth of their birthrates by 5-34%. Generally, governments have chosen any of 3 ways to attack the problem: cash payments for sterilization or contraceptive use; penalties for big families; and "delayed incentives." At least 20 governments use money to convince people to have fewer babies. Some programs pay for sterilization,other for contraceptive use. All payments are low. Some governments personalize those who exceed a recommended family size. Other nations have adopted variations of the idea. Some governments, instead of paying up front cash, offer pension plans or bank accounts to limit family size. Almost all population experts believe that the mot successful programs are those which are not imposed from

Guns, Farms, and Foreign Languages: The Introduction of Western Learning and the First Government Schools in Late Nineteenth-Century Korea

ERIC Educational Resources Information Center

Yuh, Leighanne

2016-01-01

Despite the turbulent political circumstances of the 1880s, and notwithstanding opposition from key government officials, this decade witnessed the Korean government's initial attempts to establish educational institutions modelled after western schools--the Royal College (Yugyeong Gongweon), a military academy (Yeonmu Gongweon), and an…

Subduction Orogeny and the Late Cenozoic Evolution of the Mediterranean Arcs

NASA Astrophysics Data System (ADS)

Royden, Leigh; Faccenna, Claudio

2018-05-01

The Late Cenozoic tectonic evolution of the Mediterranean region, which is sandwiched between the converging African and European continents, is dominated by the process of subduction orogeny. Subduction orogeny occurs where localized subduction, driven by negative slab buoyancy, is more rapid than the convergence rate of the bounding plates; it is commonly developed in zones of early or incomplete continental collision. Subduction orogens can be distinguished from collisional orogens on the basis of driving mechanism, tectonic setting, and geologic expression. Three distinct Late Cenozoic subduction orogens can be identified in the Mediterranean region, making up the Western Mediterranean (Apennine, external Betic, Maghebride, Rif), Central Mediterranean (Carpathian), and Eastern Mediterranean (southern Dinaride, external Hellenide, external Tauride) Arcs. The Late Cenozoic evolution of these orogens, described in this article, is best understood in light of the processes that govern subduction orogeny and depends strongly on the buoyancy of the locally subducting lithosphere; it is thus strongly related to paleogeography. Because the slow (4–10 mm/yr) convergence rate between Africa and Eurasia has preserved the early collisional environment, and associated tectonism, for tens of millions of years, the Mediterranean region provides an excellent opportunity to elucidate the dynamic and kinematic processes of subduction orogeny and to better understand how these processes operate in other orogenic systems.

Cross-Sectional Analysis of Late HAART Initiation in Latin America and the Caribbean: Late Testers and Late Presenters

PubMed Central

Crabtree-Ramírez, Brenda; Caro-Vega, Yanink; Shepherd, Bryan E.; Wehbe, Firas; Cesar, Carina; Cortés, Claudia; Padgett, Denis; Koenig, Serena; Gotuzzo, Eduardo; Cahn, Pedro; McGowan, Catherine; Masys, Daniel; Sierra-Madero, Juan

2011-01-01

Background Starting HAART in a very advanced stage of disease is assumed to be the most prevalent form of initiation in HIV-infected subjects in developing countries. Data from Latin America and the Caribbean is still lacking. Our main objective was to determine the frequency, risk factors and trends in time for being late HAART initiator (LHI) in this region. Methodology Cross-sectional analysis from 9817 HIV-infected treatment-naïve patients initiating HAART at 6 sites (Argentina, Chile, Haiti, Honduras, Peru and Mexico) from October 1999 to July 2010. LHI had CD4+ count ≤200cells/mm3 prior to HAART. Late testers (LT) were those LHI who initiated HAART within 6 months of HIV diagnosis. Late presenters (LP) initiated after 6 months of diagnosis. Prevalence, risk factors and trends over time were analyzed. Principal Findings Among subjects starting HAART (n = 9817) who had baseline CD4+ available (n = 8515), 76% were LHI: Argentina (56%[95%CI:52–59]), Chile (80%[95%CI:77–82]), Haiti (76%[95%CI:74–77]), Honduras (91%[95%CI:87–94]), Mexico (79%[95%CI:75–83]), Peru (86%[95%CI:84–88]). The proportion of LHI statistically changed over time (except in Honduras) (p≤0.02; Honduras p = 0.7), with a tendency towards lower rates in recent years. Males had increased risk of LHI in Chile, Haiti, Peru, and in the combined site analyses (CSA). Older patients were more likely LHI in Argentina and Peru (OR 1.21 per +10-year of age, 95%CI:1.02–1.45; OR 1.20, 95%CI:1.02–1.43; respectively), but not in CSA (OR 1.07, 95%CI:0.94–1.21). Higher education was associated with decreased risk for LHI in Chile (OR 0.92 per +1-year of education, 95%CI:0.87–0.98) (similar trends in Mexico, Peru, and CSA). LHI with date of HIV-diagnosis available, 55% were LT and 45% LP. Conclusion LHI was highly prevalent in CCASAnet sites, mostly due to LT; the main risk factors associated were being male and older age. Earlier HIV-diagnosis and earlier treatment initiation

Gratkorn - A new late Middle Miocene vertebrate fauna from Styria (Late Sarmatian, Austria)

NASA Astrophysics Data System (ADS)

Gross, M.; Böhme, M.; Prieto, J.

2009-04-01

Integrated stratigraphic approaches provide precise correlations of global standard stages with regional Paratethys stages. Nevertheless, higher resolution stratigraphic matching of terrestrial deposits remains challenging due to the lack of a practical continental biostratigraphy. The mostly used tool for biostratigraphic correlation of non-marine deposits in the Old World is still the concept of Neogene Mammal-zones (MN-zones). However, at higher biostratigraphic resolution (<1 million years) this concept looses its practicability and has to be replaced by a taxon-range-zonation. To solve this problem a higher number of independently dated small-mammal localities are needed. This is especially crucial for the late Middle to earliest Late Miocene, for which vertebrate faunas in the (Central-)Paratethyan area rare. Recently, a new vertebrate fauna was discovered at the locality Gratkorn (clay pit St. Stefan) just beyond the northwestern margin of the Styrian Basin (Gratkorn Basin; 10 km NW Graz; 15°20'55"E/47°08'15"N). The fauna originates from a c. 0.5 m thick hydromorphic paleosol, underlain by fluvial sands and gravels and topped by c. 15 m thick limnic pelites (Gross, 2008). Sedimentological data as well as the gastropod (Harzhauser et al., 2008) and vertebrate faunas point to a highly structured, more or less vegetated alluvial fan/braided river landscape. Active and abandoned fluvial channels, moist floodplain-soils and ephemeral ponds but also nearby dryer open areas and limestone screes of the up-lifting Palaeozoic basement offered a wide range of habitats. The occurrence of xero- and thermophile terrestrial gastropods and ectothermic vertebrates correspond well with the late Middle/early Late Miocene dry-spell in Central Europe (Böhme et al., 2008). Furthermore, an overall semiarid climate is supported by the development of a calcrete horizon c. 0.6 m below the fossiliferous horizon. The vertebrate remains are irregularly distributed throughout the

The Effect of Free Primary Education Policy on Late School Entry in Urban Primary Schools in Kenya

ERIC Educational Resources Information Center

Ngware, Moses W.; Oketch, Moses; Ezeh, Alex C.; Mutisya, Maurice

2013-01-01

Late school entry is driven by several factors, one of the key ones being the cost barrier to schooling. Policies such as free primary education (FPE) that advocate for universal coverage are therefore partly aimed at removing the cost barrier. The Kenyan Government, like many in sub-Saharan Africa (SSA), introduced FPE in 2003 with the aim of…

State Education Finance and Governance Profile: Delaware

ERIC Educational Resources Information Center

Canon, Katherine

2010-01-01

This article presents the state education finance and governance of Delaware. Funding for public education generally comes from three sources: the federal government (7.6%), the state government (64.3%), and local governments (28.1%). Educational expenditures for K-12 public schools in Delaware total $1.66 billion. Per-pupil expenditure in the…

The herpes simplex virus 1 virion host shutoff protein enhances translation of viral late mRNAs by preventing mRNA overload.

PubMed

Dauber, Bianca; Saffran, Holly A; Smiley, James R

2014-09-01

We recently demonstrated that the virion host shutoff (vhs) protein, an mRNA-specific endonuclease, is required for efficient herpes simplex virus 1 (HSV-1) replication and translation of viral true-late mRNAs, but not other viral and cellular mRNAs, in many cell types (B. Dauber, J. Pelletier, and J. R. Smiley, J. Virol. 85:5363-5373, 2011, http://dx.doi.org/10.1128/JVI.00115-11). Here, we evaluated whether the structure of true-late mRNAs or the timing of their transcription is responsible for the poor translation efficiency in the absence of vhs. To test whether the highly structured 5' untranslated region (5'UTR) of the true-late gC mRNA is the primary obstacle for translation initiation, we replaced it with the less structured 5'UTR of the γ-actin mRNA. However, this mutation did not restore translation in the context of a vhs-deficient virus. We then examined whether the timing of transcription affects translation efficiency at late times. To this end, we engineered a vhs-deficient virus mutant that transcribes the true-late gene US11 with immediate-early kinetics (IEUS11-ΔSma). Interestingly, IEUS11-ΔSma showed increased translational activity on the US11 transcript at late times postinfection, and US11 protein levels were restored to wild-type levels. These results suggest that mRNAs can maintain translational activity throughout the late stage of infection if they are present before translation factors and/or ribosomes become limiting. Taken together, these results provide evidence that in the absence of the mRNA-destabilizing function of vhs, accumulation of viral mRNAs overwhelms the capacity of the host translational machinery, leading to functional exclusion of the last mRNAs that are made during infection. The process of mRNA translation accounts for a significant portion of a cell's energy consumption. To ensure efficient use of cellular resources, transcription, translation, and mRNA decay are tightly linked and highly regulated. However, during

The WOPR Protein Ros1 Is a Master Regulator of Sporogenesis and Late Effector Gene Expression in the Maize Pathogen Ustilago maydis

PubMed Central

Tollot, Marie; Assmann, Daniela; Becker, Christian; Altmüller, Janine; Dutheil, Julien Y.; Wegner, Carl-Eric; Kahmann, Regine

2016-01-01

The biotrophic basidiomycete fungus Ustilago maydis causes smut disease in maize. Hallmarks of the disease are large tumors that develop on all aerial parts of the host in which dark pigmented teliospores are formed. We have identified a member of the WOPR family of transcription factors, Ros1, as major regulator of spore formation in U. maydis. ros1 expression is induced only late during infection and hence Ros1 is neither involved in plant colonization of dikaryotic fungal hyphae nor in plant tumor formation. However, during late stages of infection Ros1 is essential for fungal karyogamy, massive proliferation of diploid fungal cells and spore formation. Premature expression of ros1 revealed that Ros1 counteracts the b-dependent filamentation program and induces morphological alterations resembling the early steps of sporogenesis. Transcriptional profiling and ChIP-seq analyses uncovered that Ros1 remodels expression of about 30% of all U. maydis genes with 40% of these being direct targets. In total the expression of 80 transcription factor genes is controlled by Ros1. Four of the upregulated transcription factor genes were deleted and two of the mutants were affected in spore development. A large number of b-dependent genes were differentially regulated by Ros1, suggesting substantial changes in this regulatory cascade that controls filamentation and pathogenic development. Interestingly, 128 genes encoding secreted effectors involved in the establishment of biotrophic development were downregulated by Ros1 while a set of 70 “late effectors” was upregulated. These results indicate that Ros1 is a master regulator of late development in U. maydis and show that the biotrophic interaction during sporogenesis involves a drastic shift in expression of the fungal effectome including the downregulation of effectors that are essential during early stages of infection. PMID:27332891

2 CFR 25.340 - Local government.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 2 Grants and Agreements 1 2014-01-01 2014-01-01 false Local government. 25.340 Section 25.340... CENTRAL CONTRACTOR REGISTRATION Definitions § 25.340 Local government. Local government means a: (a... district; (j) School district; (k) Intrastate district; (l) Council of governments, whether or not...

2 CFR 25.340 - Local government.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 2 Grants and Agreements 1 2012-01-01 2012-01-01 false Local government. 25.340 Section 25.340... IDENTIFIER AND CENTRAL CONTRACTOR REGISTRATION Definitions § 25.340 Local government. Local government means...; (i) Special district; (j) School district; (k) Intrastate district; (l) Council of governments...

2 CFR 25.340 - Local government.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 2 Grants and Agreements 1 2013-01-01 2013-01-01 false Local government. 25.340 Section 25.340... IDENTIFIER AND CENTRAL CONTRACTOR REGISTRATION Definitions § 25.340 Local government. Local government means...; (i) Special district; (j) School district; (k) Intrastate district; (l) Council of governments...

2 CFR 25.340 - Local government.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 2 Grants and Agreements 1 2011-01-01 2011-01-01 false Local government. 25.340 Section 25.340... IDENTIFIER AND CENTRAL CONTRACTOR REGISTRATION Definitions § 25.340 Local government. Local government means...; (i) Special district; (j) School district; (k) Intrastate district; (l) Council of governments...

Solar-Geophysical Data Number 497, January 1986. Part 1: (Prompt reports). Date for December 1985, November 1985 and late data

NASA Technical Reports Server (NTRS)

Coffey, H. E.

1986-01-01

Solar-Geophysical Data Number 497, January 1986, Part 1 (prompt reports); Data for December 1985, November 1985 and Late Data contains the Data for December 1985-(IUWDS alert periods (advance and worldwide), solar activity indices, Solar flares, Vostok inferred interplanetary magnetic field polarity, Stanford mean solar magnetic field); data for November 1985-(solar active regions, sudden ionospheric disturbances, solar radio spectral observations, cosmic ray measurements by neutron monitor, geomagnetic indices, radio propagation indices); and late data-(geomagnetic indices, calcium plage data).

Late Frasnian-Famennian climates based on palynomorph analyses and the question of the Late Devonian glaciations

NASA Astrophysics Data System (ADS)

Streel, Maurice; Caputo, Mário V.; Loboziak, Stanislas; Melo, José Henrique G.

2000-11-01

Palynomorph distribution in Euramerica and western Gondwana, from the Latest Givetian to the Latest Famennian, may be explained, to some extent, by climatic changes. Detailed miospore stratigraphy dates accurately the successive steps of these changes. Interpretation is built on three postulates which are discussed: Euramerica at slightly lower latitudes than generally accepted by most paleomagnetic reconstructions; a conodont time-scale accepted as the most used available subdivision of time; and Late Devonian sea-level fluctuations mainly governed by glacio-eustasy. The Frasnian-Famennian timescale is also evaluated. The comparison, based on conodont correlations, between Givetian and most of the Frasnian miospore assemblages from, respectively, northern and southern Euramerica demonstrates a high taxonomic diversity in the equatorial belt and much difference between supposed equatorial and (sub) tropical vegetations. On the contrary, a similar vegetation pattern and therefore probably compatible climatic conditions were present from tropical to subpolar areas. A rather hot climate culminated during the Latest Frasnian when equatorial miospore assemblages reached their maximum width. The miospore diversity shows also a rather clear global Late Frasnian minimum which is also recorded during the Early and Middle Famennian but only in low latitude regions while, in high latitude, very cold climates without perennial snow may explain the scarcity of miospores and so, of vegetation. The Early and Middle Famennian conspicuous latitudinal gradient of the vegetation seems to attenuate towards the Late and Latest Famennian but this might be above all the result of the development, of cosmopolitan coastal lowland vegetations (downstream swamps) depending more on the moisture and equable local microclimates than on the probably adverse climates of distant hinterland areas. During that time, periods of cold climate without perennial snow cover and with rare vegetation may

22 CFR 41.22 - Officials of foreign governments.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 22 Foreign Relations 1 2011-04-01 2011-04-01 false Officials of foreign governments. 41.22 Section... IMMIGRATION AND NATIONALITY ACT, AS AMENDED Foreign Government Officials § 41.22 Officials of foreign governments. (a) Criteria for classification of foreign government officials. (1) An alien is classifiable A-1...

22 CFR 41.22 - Officials of foreign governments.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 22 Foreign Relations 1 2010-04-01 2010-04-01 false Officials of foreign governments. 41.22 Section... IMMIGRATION AND NATIONALITY ACT, AS AMENDED Foreign Government Officials § 41.22 Officials of foreign governments. (a) Criteria for classification of foreign government officials. (1) An alien is classifiable A-1...

22 CFR 41.22 - Officials of foreign governments.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 22 Foreign Relations 1 2012-04-01 2012-04-01 false Officials of foreign governments. 41.22 Section... IMMIGRATION AND NATIONALITY ACT, AS AMENDED Foreign Government Officials § 41.22 Officials of foreign governments. (a) Criteria for classification of foreign government officials. (1) An alien is classifiable A-1...

22 CFR 41.22 - Officials of foreign governments.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 22 Foreign Relations 1 2013-04-01 2013-04-01 false Officials of foreign governments. 41.22 Section... IMMIGRATION AND NATIONALITY ACT, AS AMENDED Foreign Government Officials § 41.22 Officials of foreign governments. (a) Criteria for classification of foreign government officials. (1) An alien is classifiable A-1...

Late smoking relapse among adolescent quitters.

PubMed

Peterson, Arthur V; Marek, Patrick M

2017-02-01

Whereas some data are available about late smoking relapse among adult quitters, there are none for teen quitters. This study is a 6-year follow-up of teen quitters (n=253) for whom we collected (retrospectively) data on the extent and timing of relapse. We found that even after a strictly defined quit (six-months prolonged abstinence) at one year, substantial relapse occurred both early and late: the majority (55%) of relapses occurred after the 0-1year interval after having quit. These findings have implication for the need for research into the relapse process for teen quitters, and for the need to develop interventions for teens (as for adults) to prevent (early and) late relapse. Copyright © 2016. Published by Elsevier Ltd.

Governing Tomorrow's Campus. Perspectives and Agendas.

ERIC Educational Resources Information Center

Schuster, Jack H.; And Others

A collection of original essays about who will and should share in governing colleges and universities is presented. Five parts contain 15 chapters as follows: (1) The Context of Contemporary Campus Governance: "Academic Governance: An Evolutionary Perspective," (W. Metzger); (2) New Perspectives on Campus Governance: "Leadership and Followership:…

EarthCube - Results of Test Governance in Geoscience Cyberinfrastructure

NASA Astrophysics Data System (ADS)

Davis, R.; Allison, M. L.; Keane, C. M.; Robinson, E.

2016-12-01

In September 2016, the EarthCube Test Enterprise Governance Project completed its three-year long process to engage the community and test a demonstration governing organization with the goal of facilitating a community-led process on designing and developing a geoscience cyberinfrastructure to transform geoscience research. The EarthCube initiative is making an important transition from creating a coherent community towards adoption and implemention of technologies that can serve scientists working in and across many domains. The emerging concept of a "system of systems" approach to cyberinfrastructure architecture is a critical concept in the EarthCube program, but has not been fully defined. Recommendations from an NSF-appointed Advisory Committee include: a. developing a succinct definition of EarthCube; b. changing the community-elected governance approach towards structured rather than consensus-driven decision-making; c. restructuring the process to articulate program solicitations; and d. producing an effective implementation roadmap. These are seen as prerequisites to adoption of best practices, system concepts, and evolving to a production track. The EarthCube governing body is preparing responses to the Advisory Committee findings and recommendations with a target delivery date of late 2016 but broader involvement may be warranted. We conclude that there is ample justification to continue evolving to a governance framework that facilitates convergence on a system architecture that guides EarthCube activities and plays an influential role in making operational the EarthCube vision of cyberinfrastructure for the geosciences. There is widespread community expectation for support of a multiyear EarthCube governing effort to put into practice the science, technical, and organizational plans that are continuing to emerge. However, the active participants in EarthCube represent a small sub-set of the larger population of geoscientists.

Secrecy From Parents and Type 1 Diabetes Management in Late Adolescence.

PubMed

Main, Alexandra; Wiebe, Deborah J; Van Bogart, Karina; Turner, Sara L; Tucker, Christy; Butner, Jonathan E; Berg, Cynthia A

2015-01-01

This study examined (a) associations of parent-adolescent relationship characteristics and adolescent problem behavior with late adolescents' secrecy from parents about type 1 diabetes management, and (b) whether secrecy was associated with diabetes and psychological outcomes independently of these factors. Adolescents (N = 247, Mage = 17.76 years) completed survey measures of diabetes-related secrecy from parents, disclosure, parental acceptance, parental knowledge, and conduct problems. Mothers and adolescents reported on adolescent adherence to diabetes regimens and adolescents reported their depressive symptoms. Glycemic control was obtained from HbA1c test kits. Adolescent-reported disclosure to parents was uniquely negatively associated with secrecy from parents. Controlling for relationship variables, conduct problems, and sociodemographic and illness-related variables, secrecy from mothers was uniquely associated with poorer glycemic control and secrecy from both parents was associated with lower adherence. Secrecy about type 1 diabetes management is uniquely associated with diabetes outcomes independent of other relationship characteristics and problem behaviors. © The Author 2015. Published by Oxford University Press on behalf of the Society of Pediatric Psychology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

26 CFR 1.1441-8 - Exemption from withholding for payments to foreign governments, international organizations...

Code of Federal Regulations, 2010 CFR

2010-04-01

... foreign governments, international organizations, foreign central banks of issue, and the Bank for International Settlements. 1.1441-8 Section 1.1441-8 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES Withholding of Tax on Nonresident Aliens...

2 CFR 200.64 - Local government.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 2 Grants and Agreements 1 2014-01-01 2014-01-01 false Local government. 200.64 Section 200.64... REQUIREMENTS FOR FEDERAL AWARDS Acronyms and Definitions Acronyms § 200.64 Local government. Local government means any unit of government within a state, including a: (a) County; (b) Borough; (c) Municipality; (d...

What governs governance, and how does it evolve? The sociology of governance-in-action.

PubMed

Fox, Nick J; Ward, Katie J

2008-09-01

Governance addresses a wide range of issues including social, economic and political continuity, security and integrity, individual and collective safety and the liberty and rights to self-actualization of citizens. Questions to be answered include how governance can be achieved and sustained within a social context imbued with cultural values and in which power is distributed unevenly and dynamically, and how governance impacts on individuals and institutions. Drawing on Gramscian notions of hegemony and consent, and recent political science literatures on regulation and meta-regulation, this paper develops a sociological model of governance that emphasizes a dynamic and responsive governance in action. Empirical data from a study of pharmaceutical governance is used to show how multiple institutions and actors are involved in sustaining effective governance. The model addresses issues of how governance is sustained in the face of change, why governance of practices varies from setting to setting, and how governance is achieved without legislation.

Market or government: lessons from a comparative analysis of the experience of Pakistan and India.

PubMed

Papanek, G F

1991-01-01

A comparison of India and Pakistan (and Bangladesh) in the last 40 years is made in view of the consensus emerging in the 1980s about the supremacy of market-oriented strategy to overcome and alleviate poverty even in less developed countries (LDC). For 4 decades India consistently intervened in the economy, while Pakistan had periods of deregulation and more reliance on market forces. The period from 1947 to 1969-1970, the 1970's, and the 1980s were examined. Dirigiste strategy produced similar or lower production in Pakistan and Bangladesh as in India (1% growth), however, market strategy production in the former countries (3%). Foreign aid (over 10% of gross domestic product in Pakistan and less than one-half of that in India) also stimulated growth. In the late 1970s and late 1980s the import surplus of Pakistan and Bangladesh was 11% vs. 25% of that in India. In the 1950s Pakistan's exports grew rapidly, and in the 1960s the rate of growth in manufactured goods was double that of India due to the Export Bonus Voucher System. The reverse was true during 1969-70 and 1976-77 when India's total manufactured exports grew at twice the rate of Pakistan as the abolition of the voucher scheme occurred, inflation climbed and export duties were imposed. In the late 1970s to mid 1980s military governments in Pakistan and Bangladesh relied heavily on the market devaluing by 100%, deregulating imported inputs, and introducing incentives for exports. Dirigism produced a 50% higher grown in India vs. 200% in the other countries by market efforts. Government intervention tended to aggravate market distortions, although it produced positive results in nontraditional exports in Pakistan and in agricultural infrastructure building, primary school attendance and health services, electrification, and road building in India. Market-induced rapid growth used more unskilled labor and alleviated poverty.

Determinants and prevalence of late HIV testing in Tijuana, Mexico.

PubMed

Carrizosa, Claudia M; Blumberg, Elaine J; Hovell, Melbourne F; Martinez-Donate, Ana P; Garcia-Gonzalez, Gregorio; Lozada, Remedios; Kelley, Norma J; Hofstetter, C Richard; Sipan, Carol L

2010-05-01

Timely diagnosis of HIV is essential to improve survival rates and reduce transmission of the virus. Insufficient progress has been made in effecting earlier HIV diagnoses. The Mexican border city of Tijuana has one of the highest AIDS incidence and mortality rates in all of Mexico. This study examined the prevalence and potential correlates of late HIV testing in Tijuana, Mexico. Late testers were defined as participants who had at least one of: (1) an AIDS-defining illness within 1 year of first positive HIV test; (2) a date of AIDS diagnosis within 1 year of first positive HIV test; or (3) an initial CD4 cell count below 200 cells per microliter within 1 year of first positive HIV test. Medical charts of 670 HIV-positive patients from two HIV/AIDS public clinics in Tijuana were reviewed and abstracted; 362 of these patients were interviewed using a cross-sectional survey. Using multivariate logistic regression, we explored potential correlates of late HIV testing based on the Behavioral Ecological Model. From 342 participants for whom late testing could be determined, the prevalence of late testing was 43.2%. Multivariate logistic regression results (n = 275) revealed five significant correlates of late testing: "I preferred not to know I had HIV" (adjusted odds ratio [AOR] = 2.78, 1.46-5.31); clinic (AOR = 1.90, 1.06-3.41); exposure to peers engaging in high-risk sexual behavior (AOR = 1.14, 1.02-1.27); stigma regarding HIV-infected individuals (AOR = 0.65, 0.47-0.92); and stigma regarding HIV testing (AOR = 0.66, 0.45-0.97). These findings may inform the design of interventions to increase timely HIV testing and help reduce HIV transmission in the community at large.

22 CFR 221.43 - Governing law.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 22 Foreign Relations 1 2010-04-01 2010-04-01 false Governing law. 221.43 Section 221.43 Foreign... Administration § 221.43 Governing law. This Guarantee shall be governed by and construed in accordance with the laws of the United States of America governing contracts and commercial transactions of the United...

22 CFR 62.29 - Government visitors.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 22 Foreign Relations 1 2014-04-01 2014-04-01 false Government visitors. 62.29 Section 62.29... Program Provisions § 62.29 Government visitors. (a) Purpose. The government visitor category is for the exclusive use of the U.S. federal, state, or local government agencies. Programs under this section are for...

22 CFR 62.29 - Government visitors.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 22 Foreign Relations 1 2012-04-01 2012-04-01 false Government visitors. 62.29 Section 62.29... Program Provisions § 62.29 Government visitors. (a) Purpose. The government visitor category is for the exclusive use of the U.S. federal, state, or local government agencies. Programs under this section are for...

22 CFR 62.29 - Government visitors.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 22 Foreign Relations 1 2011-04-01 2011-04-01 false Government visitors. 62.29 Section 62.29... Program Provisions § 62.29 Government visitors. (a) Purpose. The government visitor category is for the exclusive use of the U.S. federal, state, or local government agencies. Programs under this section are for...

22 CFR 62.29 - Government visitors.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 22 Foreign Relations 1 2010-04-01 2010-04-01 false Government visitors. 62.29 Section 62.29... Program Provisions § 62.29 Government visitors. (a) Purpose. The government visitor category is for the exclusive use of the U.S. federal, state, or local government agencies. Programs under this section are for...

22 CFR 62.29 - Government visitors.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 22 Foreign Relations 1 2013-04-01 2013-04-01 false Government visitors. 62.29 Section 62.29... Program Provisions § 62.29 Government visitors. (a) Purpose. The government visitor category is for the exclusive use of the U.S. federal, state, or local government agencies. Programs under this section are for...

Harnessing biosynthesis and quantitative NMR for late stage functionalization of lead molecules: Application to the M1 positive allosteric modulator (PAM) program.

PubMed

Brodney, Michael A; Sharma, Raman; Lazzaro, John T; Walker, Gregory S; Scott Obach, R

2018-06-15

A facile method for late stage diversification of lead molecules for the M1 PAM program using biosynthesis is described. Liver microsomes from several species are screened to identify a high turnover system. Subsequent incubations using less than 1 mg of substrate generate nanomole quantities of drug metabolites that are purified, characterized by microcryoprobe NMR spectroscopy, and quantified to known concentrations to enable rapid biology testing. The late-stage diversification of lead compounds provides rapid SAR feedback to the medicinal chemistry design cycle. Copyright © 2018 Elsevier Ltd. All rights reserved.

Educational Directory, 1919-20. Bulletin, 1919, No. 71. Part 1: Government Educational Activities

ERIC Educational Resources Information Center

Bureau of Education, Department of the Interior, 1920

1920-01-01

The Educational Directory, 1919-20 is divided into seven distinct parts. Part I, Government Educational Activities, covers the following topic areas: (1) The United States Bureau of Education; (2) Department of State; (3) Department of War; (4) Department of the Navy; (5) Department of the Treasury; (6) Department of the Interior; (7) Department…

48 CFR 225.7303-3 - Government-to-government agreements.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 48 Federal Acquisition Regulations System 3 2012-10-01 2012-10-01 false Government-to-government... Military Sales 225.7303-3 Government-to-government agreements. If a government-to-government agreement between the United States and a foreign government for the sale, coproduction, or cooperative logistic...

48 CFR 225.7303-3 - Government-to-government agreements.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 48 Federal Acquisition Regulations System 3 2011-10-01 2011-10-01 false Government-to-government... Military Sales 225.7303-3 Government-to-government agreements. If a government-to-government agreement between the United States and a foreign government for the sale, coproduction, or cooperative logistic...

48 CFR 225.7303-3 - Government-to-government agreements.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 48 Federal Acquisition Regulations System 3 2013-10-01 2013-10-01 false Government-to-government... Military Sales 225.7303-3 Government-to-government agreements. If a government-to-government agreement between the United States and a foreign government for the sale, coproduction, or cooperative logistic...

48 CFR 225.7303-3 - Government-to-government agreements.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 48 Federal Acquisition Regulations System 3 2014-10-01 2014-10-01 false Government-to-government... Military Sales 225.7303-3 Government-to-government agreements. If a government-to-government agreement between the United States and a foreign government for the sale, coproduction, or cooperative logistic...

Antagonism between MCL-1 and PUMA governs stem/progenitor cell survival during hematopoietic recovery from stress

PubMed Central

Delbridge, Alex R. D.; Opferman, Joseph T.; Grabow, Stephanie

2015-01-01

Understanding the critical factors that govern recovery of the hematopoietic system from stress, such as during anticancer therapy and bone marrow transplantation, is of clinical significance. We investigated the importance of the prosurvival proteins myeloid cell leukemia-1 (MCL-1) and B-cell lymphoma–extra large (BCL-XL) in stem/progenitor cell survival and fitness during hematopoietic recovery from stress. Loss of a single Mcl-1 allele, which reduced MCL-1 protein levels, severely compromised hematopoietic recovery from myeloablative challenge and following bone marrow transplantation, whereas BCL-XL was dispensable in both contexts. We identified inhibition of proapoptotic p53 upregulated modulator of apoptosis (PUMA) as the key role of MCL-1 in both settings, with Mcl-1+/−;Puma−/− mice completely protected from the deleterious effects of loss of 1 Mcl-1 allele. These results reveal the molecular mechanisms that govern cell survival during hematopoietic recovery from stress. PMID:25847014

17 CFR 1.64 - Composition of various self-regulatory organization governing boards and major disciplinary...

Code of Federal Regulations, 2014 CFR

2014-04-01

... ACT Miscellaneous § 1.64 Composition of various self-regulatory organization governing boards and... organization means “self-regulatory organization” as defined in § 1.3(ee), not including a “clearing... authorized by a self-regulatory organization to conduct disciplinary hearings, to settle disciplinary charges...

17 CFR 1.64 - Composition of various self-regulatory organization governing boards and major disciplinary...

Code of Federal Regulations, 2010 CFR

2010-04-01

... ACT Miscellaneous § 1.64 Composition of various self-regulatory organization governing boards and... organization means “self-regulatory organization” as defined in § 1.3(ee), not including a “clearing... authorized by a self-regulatory organization to conduct disciplinary hearings, to settle disciplinary charges...

17 CFR 1.64 - Composition of various self-regulatory organization governing boards and major disciplinary...

Code of Federal Regulations, 2012 CFR

2012-04-01

... ACT Miscellaneous § 1.64 Composition of various self-regulatory organization governing boards and... organization means “self-regulatory organization” as defined in § 1.3(ee), not including a “clearing... authorized by a self-regulatory organization to conduct disciplinary hearings, to settle disciplinary charges...

17 CFR 1.64 - Composition of various self-regulatory organization governing boards and major disciplinary...

Code of Federal Regulations, 2013 CFR

2013-04-01

... ACT Miscellaneous § 1.64 Composition of various self-regulatory organization governing boards and... organization means “self-regulatory organization” as defined in § 1.3(ee), not including a “clearing... authorized by a self-regulatory organization to conduct disciplinary hearings, to settle disciplinary charges...

17 CFR 1.64 - Composition of various self-regulatory organization governing boards and major disciplinary...

Code of Federal Regulations, 2011 CFR

2011-04-01

... ACT Miscellaneous § 1.64 Composition of various self-regulatory organization governing boards and... organization means “self-regulatory organization” as defined in § 1.3(ee), not including a “clearing... authorized by a self-regulatory organization to conduct disciplinary hearings, to settle disciplinary charges...

17 CFR 1.59 - Activities of self-regulatory organization employees, governing board members, committee members...

Code of Federal Regulations, 2014 CFR

2014-04-01

... COMMODITY EXCHANGE ACT Miscellaneous § 1.59 Activities of self-regulatory organization employees, governing...) Self-regulatory organization means “self-regulatory organization,” as defined in § 1.3(ee), and... member, or functional equivalent thereof, of the board of governors of a self-regulatory organization. (3...

17 CFR 1.59 - Activities of self-regulatory organization employees, governing board members, committee members...

Code of Federal Regulations, 2013 CFR

2013-04-01

... COMMODITY EXCHANGE ACT Miscellaneous § 1.59 Activities of self-regulatory organization employees, governing...) Self-regulatory organization means “self-regulatory organization,” as defined in § 1.3(ee), and... member, or functional equivalent thereof, of the board of governors of a self-regulatory organization. (3...

Requirement of 8-mercaptoguanosine as a costimulus for IL-4-dependent mu to gamma1 class switch recombination in CD38-activated B cells.

PubMed

Tsukamoto, Yumiko; Uehara, Shoji; Mizoguchi, Chieko; Sato, Atsushi; Horikawa, Keisuke; Takatsu, Kiyoshi

2005-10-21

Mature B-2 cells expressing surface IgM and IgD proliferate upon stimulation by CD38, CD40 or lipopolysaccharide (LPS) and differentiate into IgG1-producing plasma cells in the presence of cytokines. The process of class switch recombination (CSR) from IgM to other isotypes is highly regulated by cytokines and activation-induced cytidine deaminase (AID). Blimp-1 and XBP-1 play an essential role in the terminal differentiation of switched B-2 cells to Ig-producing plasma cells. IL-5 induces AID and Blimp-1 expression in CD38- and CD40-activated B-2 cells, leading to mu to gamma1 CSR at DNA level and IgG1 production. IL-4, a well-known IgG1-inducing factor, does not induce mu to gamma1 CSR in CD38-activated B-2 cells or Blimp-1, while IL-4 induces mu to gamma1 CSR, XBP-1 expression, and IgG1 production expression in CD40-activated B-2 cells. Interestingly, the addition of 8-mercaptoguanosine (8-SGuo) with IL-4 to the culture of CD38-activated B cells can induce mu to gamma1 CSR, Blimp-1 expression, and IgG1 production. Intriguingly, 8-SGuo by itself induces AID expression in CD38-activated B cells. However, it does not induce mu to gamma1 CSR. These results imply that the mode of B-cell activation for extracellular stimulation affects the outcome of cytokine stimulation with respect to the efficiency and direction of CSR, and the requirements of the transcriptional regulator and the generation of antibody-secreting cells. Furthermore, our data suggest the requirement of additional molecules in addition to AID for CSR.

Pragmatic Functions in Late Talkers: A 1-Year Follow-Up Study

ERIC Educational Resources Information Center

MacRoy-Higgins, Michelle; Kliment, Sarah

2017-01-01

This study analyzed spontaneous language samples of three-year-olds with a history of expressive language delay (late talkers) and age-matched controls using Dore's Conversational Acts analysis (1978) and Mean Length of Utterance (MLU; Brown, 1973). Differences were observed between groups in utterances classified as organizational device and…

18β-Glycyrrhetinic acid preferentially blocks late Na current generated by ΔKPQ Nav1.5 channels

PubMed Central

Du, Yi-mei; Xia, Cheng-kun; Zhao, Ning; Dong, Qian; Lei, Ming; Xia, Jia-hong

2012-01-01

Aim: To compare the effects of two stereoisomeric forms of glycyrrhetinic acid on different components of Na+ current, HERG and Kv1.5 channel currents. Methods: Wild-type (WT) and long QT syndrome type 3 (LQT-3) mutant ΔKPQ Nav1.5 channels, as well as HERG and Kv1.5 channels were expressed in Xenopus oocytes. In addition, isolated human atrial myocytes were used. Two-microelectrode voltage-clamp technique was used to record the voltage-activated currents. Results: Superfusion of 18β-glycyrrhetinic acid (18β-GA, 1–100 μmol/L) blocked both the peak current (INa,P) and late current (INa,L) generated by WT and ΔKPQ Nav1.5 channels in a concentration-dependent manner, while 18α-glycyrrhetinic acid (18α-GA) at the same concentrations had no effects. 18β-GA preferentially blocked INa,L (IC50=37.2±14.4 μmol/L) to INa,P (IC50=100.4±11.2 μmol/L) generated by ΔKPQ Nav1.5 channels. In human atrial myocytes, 18β-GA (30 μmol/L) inhibited 47% of INa,P and 87% of INa,L induced by Anemonia sulcata toxin (ATX-II, 30 nmol/L). Superfusion of 18β-GA (100 μmol/L) had no effects on HERG and Kv1.5 channel currents. Conclusion: 18β-GA preferentially blocked the late Na current without affecting HERG and Kv1.5 channels. PMID:22609834

Two Late Pleistocene climate-driven incision/aggradation rhythms in the middle Dnieper River basin, west-central Russian Plain

NASA Astrophysics Data System (ADS)

Panin, Andrei; Adamiec, Grzegorz; Buylaert, Jan-Pieter; Matlakhova, Ekaterina; Moska, Piotr; Novenko, Elena

2017-06-01

In valleys of the River Seim and its tributaries in the middle Dnieper basin (west-central Russian Plain), two low terraces (T1, 10-16 m, and T0, 5-7 m above the river) and a floodplain (2-4 m) with characteristic large and small palaeochannels exist. A range of field and laboratory techniques was applied and ∼30 new numerical ages (OSL and 14C dates) were obtained to establish a chronology of incision and aggradation events that resulted in the current valley morphology. Two full incision/aggradation rhythms and one additional aggradation phase from the previous rhythm were recognized in the Late Pleistocene - Holocene climate cycle. The following events were detected. (1) Late MIS 5 - early MIS 4: aggradation of Terrace T1 following the deep incision at the end of MIS 6. (2) Late MIS 4 (40-30 ka): incision into Terrace T1 below the present-day river, formation of the main scarp in the bottom of the valley between Terrace T1 and Terrace T0/Floodplain levels. (3) MIS 2: aggradation of Terrace T0, lateral migrations of a shallow braided channel located few meters above the present-day river since ∼25 ka through the LGM. (4) 18-13 ka: incision into Terrace T0 below the modern river. Multiple-thread channels concentrated in a single flow that at some places formed large meanders. In the period 15-13 ka, high floods that rose above the present-day floods left large levees and overbank loams on Terrace T0. (5) Younger Dryas - Holocene transition: aggradation up to the modern channel level, transformation of large Late Glacial to small Holocene meanders. The established incision/aggradation rhythms are believed to be manifested over the Central Russian Plain outside the influence of ice sheets in the north and base level changes in the south. The two-phase deepening of the valley occurred in the last quarter of the last glacial epoch but can not be attributed directly to the glacial-interglacial transition. Both the detected incision events correspond to relatively

Ethnicity and the risk of late-pregnancy stillbirth.

PubMed

Drysdale, Henry; Ranasinha, Sanjeeva; Kendall, Amanda; Knight, Michelle; Wallace, Euan M

2012-09-03

To determine if maternal country of birth is associated with the risk of antepartum stillbirth in late pregnancy. Retrospective cross-sectional study of all singleton births at 37-42 weeks' gestation, excluding those with congenital abnormalities and intrapartum stillbirths, between 1 June 2001 and 31 May 2011 at Southern Health, a large metropolitan maternity service in Melbourne, Australia. Rate of late-pregnancy antepartum stillbirth, analysed by maternal country of birth. Among 44 326 births, there was a significant difference in the stillbirth rate by maternal country of birth (P < 0.001). The rate of stillbirth per 1000 births was 1.48 among Australian-born women, 3.55 among South Asian-born women and 1.06 among South-East-East Asian-born women. Women born in South Asia were 2.4 (95% CI, 1.4-4.0) times more likely to have a late-pregnancy stillbirth than women born in Australia (P < 0.001). There was no significant difference between women born in Australia and women born in South-East-East Asia (P = 0.34). Adjusting for potential confounding factors, South Asian maternal birth remained an independent risk factor for stillbirth (adjusted odds ratio, 2.5; 95% CI, 1.3-5.1; P = 0.009). Women born in South Asia have an increased risk of antepartum stillbirth in late pregnancy, compared with other women. This observation may have implications for the delivery of pregnancy care in Australia.

48 CFR 25.301-2 - Government support.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 48 Federal Acquisition Regulations System 1 2014-10-01 2014-10-01 false Government support. 25.301... SOCIOECONOMIC PROGRAMS FOREIGN ACQUISITION Contracts Performed Outside the United States 25.301-2 Government..., determines that— (1) Such Government support is available and is needed to ensure continuation of essential...

48 CFR 25.301-2 - Government support.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 48 Federal Acquisition Regulations System 1 2010-10-01 2010-10-01 false Government support. 25.301... SOCIOECONOMIC PROGRAMS FOREIGN ACQUISITION Contracts Performed Outside the United States 25.301-2 Government..., determines that— (1) Such Government support is available and is needed to ensure continuation of essential...

48 CFR 25.301-2 - Government support.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 48 Federal Acquisition Regulations System 1 2012-10-01 2012-10-01 false Government support. 25.301... SOCIOECONOMIC PROGRAMS FOREIGN ACQUISITION Contracts Performed Outside the United States 25.301-2 Government..., determines that— (1) Such Government support is available and is needed to ensure continuation of essential...

48 CFR 25.301-2 - Government support.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 48 Federal Acquisition Regulations System 1 2011-10-01 2011-10-01 false Government support. 25.301... SOCIOECONOMIC PROGRAMS FOREIGN ACQUISITION Contracts Performed Outside the United States 25.301-2 Government..., determines that— (1) Such Government support is available and is needed to ensure continuation of essential...

48 CFR 25.301-2 - Government support.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 48 Federal Acquisition Regulations System 1 2013-10-01 2013-10-01 false Government support. 25.301... SOCIOECONOMIC PROGRAMS FOREIGN ACQUISITION Contracts Performed Outside the United States 25.301-2 Government..., determines that— (1) Such Government support is available and is needed to ensure continuation of essential...

Game analysis among the central government, local governments, and firms in China’s environmental pollution governance

NASA Astrophysics Data System (ADS)

Li, Shuwen; Xu, Jin

2018-05-01

China’s environmental pollution governance has entered the game stage centered on interests, and there are three main bodies in environmental pollution governance: the central government, local governments and firms. The research firstly reveals the relationships among the central government, local governments, and firms in the process of environmental governance, and then analyzes the game among the central government, local governments and firms using game theory in Economics. Finally, the research makes a conclusion and proposes some corresponding policy proposals so as to solve the problem of environmental pollution.

Exploration of cloud computing late start LDRD #149630 : Raincoat. v. 2.1.

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

Echeverria, Victor T.; Metral, Michael David; Leger, Michelle A.

This report contains documentation from an interoperability study conducted under the Late Start LDRD 149630, Exploration of Cloud Computing. A small late-start LDRD from last year resulted in a study (Raincoat) on using Virtual Private Networks (VPNs) to enhance security in a hybrid cloud environment. Raincoat initially explored the use of OpenVPN on IPv4 and demonstrates that it is possible to secure the communication channel between two small 'test' clouds (a few nodes each) at New Mexico Tech and Sandia. We extended the Raincoat study to add IPSec support via Vyatta routers, to interface with a public cloud (Amazon Elasticmore » Compute Cloud (EC2)), and to be significantly more scalable than the previous iteration. The study contributed to our understanding of interoperability in a hybrid cloud.« less

Lateness to School Remediation Game

ERIC Educational Resources Information Center

Ugwuegbulam, Charles N.; Ibrahim, Haj. Naheed

2015-01-01

Primary and secondary school in Nigeria encourage punctuality to school yet a good number of the learners came late to school. This is especially true in the case of day students. Learners who come late to school are usually punished in one way or the other yet the lateness to school phenomenon still persist. Lateness to school behaviour affects…

Suppression of HPV-16 late L1 5′-splice site SD3632 by binding of hnRNP D proteins and hnRNP A2/B1 to upstream AUAGUA RNA motifs

PubMed Central

Li, Xiaoze; Johansson, Cecilia; Glahder, Jacob; Mossberg, Ann-Kristin; Schwartz, Stefan

2013-01-01

Human papillomavirus type 16 (HPV-16) 5′-splice site SD3632 is used exclusively to produce late L1 mRNAs. We identified a 34-nt splicing inhibitory element located immediately upstream of HPV-16 late 5′-splice site SD3632. Two AUAGUA motifs located in these 34 nt inhibited SD3632. Two nucleotide substitutions in each of the HPV-16 specific AUAGUA motifs alleviated splicing inhibition and induced late L1 mRNA production from episomal forms of the HPV-16 genome in primary human keratinocytes. The AUAGUA motifs bind specifically not only to the heterogeneous nuclear RNP (hnRNP) D family of RNA-binding proteins including hnRNP D/AUF, hnRNP DL and hnRNP AB but also to hnRNP A2/B1. Knock-down of these proteins induced HPV-16 late L1 mRNA expression, and overexpression of hnRNP A2/B1, hnRNP AB, hnRNP DL and the two hnRNP D isoforms hnRNP D37 and hnRNP D40 further suppressed L1 mRNA expression. This inhibition may allow HPV-16 to hide from the immune system and establish long-term persistent infections with enhanced risk at progressing to cancer. There is an inverse correlation between expression of hnRNP D proteins and hnRNP A2/B1 and HPV-16 L1 production in the cervical epithelium, as well as in cervical cancer, supporting the conclusion that hnRNP D proteins and A2/B1 inhibit HPV-16 L1 mRNA production. PMID:24013563

48 CFR 246.406 - Foreign governments.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 48 Federal Acquisition Regulations System 3 2011-10-01 2011-10-01 false Foreign governments. 246..., DEPARTMENT OF DEFENSE CONTRACT MANAGEMENT QUALITY ASSURANCE Government Contract Quality Assurance 246.406 Foreign governments. (1) Quality assurance among North Atlantic Treaty Organization (NATO) countries. (i...

48 CFR 246.406 - Foreign governments.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 48 Federal Acquisition Regulations System 3 2014-10-01 2014-10-01 false Foreign governments. 246..., DEPARTMENT OF DEFENSE CONTRACT MANAGEMENT QUALITY ASSURANCE Government Contract Quality Assurance 246.406 Foreign governments. (1) Quality assurance among North Atlantic Treaty Organization (NATO) countries. (i...

48 CFR 246.406 - Foreign governments.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 48 Federal Acquisition Regulations System 3 2012-10-01 2012-10-01 false Foreign governments. 246..., DEPARTMENT OF DEFENSE CONTRACT MANAGEMENT QUALITY ASSURANCE Government Contract Quality Assurance 246.406 Foreign governments. (1) Quality assurance among North Atlantic Treaty Organization (NATO) countries. (i...

48 CFR 246.406 - Foreign governments.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 48 Federal Acquisition Regulations System 3 2010-10-01 2010-10-01 false Foreign governments. 246..., DEPARTMENT OF DEFENSE CONTRACT MANAGEMENT QUALITY ASSURANCE Government Contract Quality Assurance 246.406 Foreign governments. (1) Quality assurance among North Atlantic Treaty Organization (NATO) countries. (i...

48 CFR 246.406 - Foreign governments.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 48 Federal Acquisition Regulations System 3 2013-10-01 2013-10-01 false Foreign governments. 246..., DEPARTMENT OF DEFENSE CONTRACT MANAGEMENT QUALITY ASSURANCE Government Contract Quality Assurance 246.406 Foreign governments. (1) Quality assurance among North Atlantic Treaty Organization (NATO) countries. (i...

Study of the costs and morbidities of late-preterm birth.

PubMed

Bérard, Anick; Le Tiec, Magali; De Vera, Mary A

2012-09-01

To compare late-preterm infants (33-36 weeks) with term infants (≥37 weeks) on incidence of morbidities in the first 3 years of life and healthcare costs during the first 2 years of life and third year of life. Administrative health records of live infants born between January 1, 1997, and December 31, 2000 with 3 years follow-up data (N=35733) were linked. First, diagnoses of morbidities were compared between late-preterm and term infants using Cox's proportional hazards models. Healthcare costs expressed as mean total costs and cost ratios, accrued following initial hospital discharge after birth, were also examined. The three most common reasons for hospitalisation in late-preterm and term infants were acute bronchitis, otitis media and pneumonia. The most frequent reasons for physician visits included acute upper respiratory infections, otitis media and bronchiolitis. The highest HR were detected for chronic bronchitis 1.64 (1.13-2.39), hearing loss 1.56 (1.14-2.15) and bacterial diseases 1.28 (1.09-1.49). The mean total cost for late-preterm infants during the first 2 years of life was $2568 CAD compared with $1285 CAD for term infants, cost ratio =1.99 (95% CI 1.90 to 2.09). In the third year of life, the cost ratio reduced to 1.46 (95% CI 1.39 to 1.54). Late-preterm infants are at higher risk of specific morbidities compared with term infants. Their mean total costs fall from almost double that of term infants during the first 2 years of life, to just 46% greater in the third year of life.

Government-to-Government E-Government: A Case Study of a Federal Financial Program

ERIC Educational Resources Information Center

Faokunla, Olumide Adegboyega

2012-01-01

The problem with the study of the concept of electronic government (e-Gov) is that scholars in the field have not adequately explored various dimensions of the concept. Literature on e-Gov is replete with works on the form of government to consumer e-Gov. Much less work had been done on the government to government (G2G) e-Gov. This qualitative…

Identification and Structural Characterization of the ALIX-Binding Late Domains of Simian Immunodeficiency Virus SIV mac239 and SIV agmTan-1

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

Q Zhai; M Landesman; H Robinson

2011-12-31

Retroviral Gag proteins contain short late-domain motifs that recruit cellular ESCRT pathway proteins to facilitate virus budding. ALIX-binding late domains often contain the core consensus sequence YPX{sub n}L (where X{sub n} can vary in sequence and length). However, some simian immunodeficiency virus (SIV) Gag proteins lack this consensus sequence, yet still bind ALIX. We mapped divergent, ALIX-binding late domains within the p6{sup Gag} proteins of SIV{sub MAC239} ({sub 40}SREK{und P}YKE{und VT}ED{und L}LHLNSLF{sub 59}) and SIV{sub agmTan-1} ({sub 24}AAG{und A}YDP{und AR}KL{und L}EQYAKK{sub 41}). Crystal structures revealed that anchoring tyrosines (in lightface) and nearby hydrophobic residues (underlined) contact the ALIX V domain,more » revealing how lentiviruses employ a diverse family of late-domain sequences to bind ALIX and promote virus budding.« less

48 CFR 47.207-8 - Government responsibilities.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 48 Federal Acquisition Regulations System 1 2010-10-01 2010-10-01 false Government....207-8 Government responsibilities. (a) The contracting officer shall state clearly the Government's... Government's responsibility to notify the contractor in advance when hazardous materials are included in a...

48 CFR 47.207-8 - Government responsibilities.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 48 Federal Acquisition Regulations System 1 2012-10-01 2012-10-01 false Government....207-8 Government responsibilities. (a) The contracting officer shall state clearly the Government's... Government's responsibility to notify the contractor in advance when hazardous materials are included in a...

48 CFR 47.207-8 - Government responsibilities.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 48 Federal Acquisition Regulations System 1 2011-10-01 2011-10-01 false Government....207-8 Government responsibilities. (a) The contracting officer shall state clearly the Government's... Government's responsibility to notify the contractor in advance when hazardous materials are included in a...

48 CFR 47.207-8 - Government responsibilities.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 48 Federal Acquisition Regulations System 1 2014-10-01 2014-10-01 false Government....207-8 Government responsibilities. (a) The contracting officer shall state clearly the Government's... Government's responsibility to notify the contractor in advance when hazardous materials are included in a...

48 CFR 47.207-8 - Government responsibilities.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 48 Federal Acquisition Regulations System 1 2013-10-01 2013-10-01 false Government....207-8 Government responsibilities. (a) The contracting officer shall state clearly the Government's... Government's responsibility to notify the contractor in advance when hazardous materials are included in a...

22 CFR 140.6 - Foreign government entities.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 22 Foreign Relations 1 2013-04-01 2013-04-01 false Foreign government entities. 140.6 Section 140... Enforcement § 140.6 Foreign government entities. (a) Determination Procedures. (1) The Country Narcotics... allegations that a key individual who is a senior government official of the host nation has been convicted of...

22 CFR 140.6 - Foreign government entities.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 22 Foreign Relations 1 2012-04-01 2012-04-01 false Foreign government entities. 140.6 Section 140... Enforcement § 140.6 Foreign government entities. (a) Determination Procedures. (1) The Country Narcotics... allegations that a key individual who is a senior government official of the host nation has been convicted of...

22 CFR 140.6 - Foreign government entities.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 22 Foreign Relations 1 2011-04-01 2011-04-01 false Foreign government entities. 140.6 Section 140... Enforcement § 140.6 Foreign government entities. (a) Determination Procedures. (1) The Country Narcotics... allegations that a key individual who is a senior government official of the host nation has been convicted of...

Governance.

ERIC Educational Resources Information Center

Moran, K. D.

Chapter 1 of a book on school law, this chapter summarizes 1979 cases related to school governance in several areas: authority of state boards of education and other governmental agencies, authority of state superintendents of education, powers and duties of school boards, open meeting laws, constitutional matters, conflicts of interest on the…

Governing through Parents: A Genealogical Enquiry of Education Policy and the Construction of Neoliberal Subjectivities in England

ERIC Educational Resources Information Center

Olmedo, Antonio; Wilkins, Andrew

2017-01-01

In this paper we explore the various spaces and sites through which the figure of the parent is summoned to inhabit and perform market norms and practices in the field of education in England. Since the late 1970s successive governments have called on parents to enact certain duties and obligations in relation to the state. These duties include…

Freedom of Speech as Protected by the States: A Review of Late Nineteenth and Early Twentieth Century State Court Decisions.

ERIC Educational Resources Information Center

Herbeck, Dale A.

While some analysts have asserted that the First Amendment was intended to prohibit laws against seditious libel (speech overtly critical of the government), the judicial record reveals a willingness to tolerate some onerous infringements on free expression. In the late 19th and early 20th centuries, 25 states passed "sedition" or…

42 CFR 137.211 - How does a Self-Governance Tribe learn whether self-governance activities have resulted in...

Code of Federal Regulations, 2010 CFR

2010-10-01

... 42 Public Health 1 2010-10-01 2010-10-01 false How does a Self-Governance Tribe learn whether self-governance activities have resulted in savings as described in § 137.210. 137.211 Section 137.211 Public... a Self-Governance Tribe learn whether self-governance activities have resulted in savings as...

42 CFR 137.211 - How does a Self-Governance Tribe learn whether self-governance activities have resulted in...

Code of Federal Regulations, 2011 CFR

2011-10-01

... 42 Public Health 1 2011-10-01 2011-10-01 false How does a Self-Governance Tribe learn whether self-governance activities have resulted in savings as described in § 137.210. 137.211 Section 137.211 Public... a Self-Governance Tribe learn whether self-governance activities have resulted in savings as...

Governing at a distance: social marketing and the (bio) politics of responsibility.

PubMed

Crawshaw, Paul

2012-07-01

In the recently published lectures from the College de France series, The Birth of Bio-Politics, Foucault (2009) offers his most explicit analysis of neo-liberal governmentality and its impact upon states and societies in the late twentieth century. Framed in terms of the bio-political as a mode of governance of populations and its relationship to neo-liberalism, these lectures offer a rich seam of theoretical resources with which to interrogate contemporary forms of governmentality. This paper seeks to apply these and some recent critical analysis by Foucauldian scholars, to the study of health governance, with particular reference to the use of social marketing as a strategy to improve the health of populations 'at a distance'. Reflecting a broader decollectivisation of welfare, such strategies are identified as exemplars of neo-liberal methods of governance through inculcating self management and individualisation of responsibility for health and wellbeing. Drawing on original empirical data collected with a sample of fifty long term unemployed men in 2009, this paper critically examines social marketing as a newer feature of health governance and reflects upon participants' responses to it as a strategy in the context of their wider understandings of health, choice and responsibility. Copyright © 2012 Elsevier Ltd. All rights reserved.

Applying TOGAF for e-government implementation based on service oriented architecture methodology towards good government governance

NASA Astrophysics Data System (ADS)

Hodijah, A.; Sundari, S.; Nugraha, A. C.

2018-05-01

As a Local Government Agencies who perform public services, General Government Office already has utilized Reporting Information System of Local Government Implementation (E-LPPD). However, E-LPPD has upgrade limitation for the integration processes that cannot accommodate General Government Offices’ needs in order to achieve Good Government Governance (GGG), while success stories of the ultimate goal of e-government implementation requires good governance practices. Currently, citizen demand public services as private sector do, which needs service innovation by utilizing the legacy system as a service based e-government implementation, while Service Oriented Architecture (SOA) to redefine a business processes as a set of IT enabled services and Enterprise Architecture from the Open Group Architecture Framework (TOGAF) as a comprehensive approach in redefining business processes as service innovation towards GGG. This paper takes a case study on Performance Evaluation of Local Government Implementation (EKPPD) system on General Government Office. The results show that TOGAF will guide the development of integrated business processes of EKPPD system that fits good governance practices to attain GGG with SOA methodology as technical approach.

Governance.

ERIC Educational Resources Information Center

Moran, K. D.

This chapter summarized and analyzes all state supreme court and federal court decisions as well as other significant court decisions affecting the realm of school governance. The cases discussed are generally limited to those decided during 1974 and reported in the General Digest on or before March 1, 1975. Because of its unusual significance,…

Solar-geophysical data number 499, March 1986. Part 1: (Prompt reports). Data for February 1986, January 1986 and late data

NASA Technical Reports Server (NTRS)

Coffey, H. E. (Editor)

1986-01-01

Solar-Geophysical Data Number 499, March 1986, Part 1 (Prompt Reports); Data for February 1986, January 1986 and Late Data, contains the following: Detailed index for 1985 to 1986; Data for February 1986--(IUWDS alert periods (Advance and worldwide), Solar activity indices, Solar flares, Solar radio emission, Vostok inferred interplanetary magnetic field polarity, Stanford mean solar magnetic field); data for January 1986--(Solar active regions, Sudden ionospheric disturbances, Solar radio spectral observations, Cosmic ray measurements by neutron monitor, Geomagnetic indices, Radio propagation indices); Late data-(Solar active regions, Solar radio spectral observations Culgoora, Cosmic ray measurements by neutron monitor, Calcium plage data).

27 CFR 19.282 - Breaking Government locks.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 27 Alcohol, Tobacco Products and Firearms 1 2010-04-01 2010-04-01 false Breaking Government locks... Breaking Government locks. Where affixed, Government locks shall not be removed without the authorization... obtain authorization from an appropriate TTB officer, Government locks may be removed, by the proprietor...

20 CFR 349.4 - Late completion of timely investigation.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 20 Employees' Benefits 1 2014-04-01 2012-04-01 true Late completion of timely investigation. 349.4 Section 349.4 Employees' Benefits RAILROAD RETIREMENT BOARD REGULATIONS UNDER THE RAILROAD UNEMPLOYMENT INSURANCE ACT FINALITY OF DECISIONS REGARDING UNEMPLOYMENT AND SICKNESS INSURANCE BENEFITS § 349.4 Late...

20 CFR 349.4 - Late completion of timely investigation.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 20 Employees' Benefits 1 2013-04-01 2012-04-01 true Late completion of timely investigation. 349.4 Section 349.4 Employees' Benefits RAILROAD RETIREMENT BOARD REGULATIONS UNDER THE RAILROAD UNEMPLOYMENT INSURANCE ACT FINALITY OF DECISIONS REGARDING UNEMPLOYMENT AND SICKNESS INSURANCE BENEFITS § 349.4 Late...

Late-intervention study with ebselen in an experimental model of type 1 diabetic nephropathy.

PubMed

Tan, S M; Sharma, A; Stefanovic, N; de Haan, J B

2015-03-01

Previous studies have shown that preventive treatment with the antioxidant, ebselen, in experimental models of type 1 diabetic nephropathy resulted in an attenuation of structural and functional damage in the kidney. However, evidence for the effectiveness of ebselen in late-intervention studies is lacking. Thus, we aimed to investigate the effects of ebselen in attenuating established renal injury in type 1 diabetic nephropathy using the Akita mouse model. Baseline blood glucose and albumin-to-creatinine ratio (ACR) were measured in wild-type (WT) and heterozygous Akita mice at 9 weeks of age. At 10 weeks of age, WT and Akita mice were randomized to receive either vehicle (5% carboxymethyl cellulose) or ebselen by oral gavage at 10mg/kg twice daily. Kidney and urine were collected after 16 weeks of treatment with ebselen for histological and functional analyses. At 9 weeks of age, Akita mice displayed well-established renal dysfunction with significant increases in ACR and urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels when compared with WT controls. After 16 weeks of treatment with ebselen, oxidative stress, as measured by nitrotyrosine immunostaining and urinary 8-OHdG levels, was significantly reduced in the Akita mice. Furthermore, gene expression of the major reactive oxygen species-producing nicotinamide adenine dinucleotide phosphate enzyme, Nox4, was also reduced by ebselen. However, ebselen had no effect on ACR and glomerulosclerosis. Chronic treatment with ebselen significantly reduced oxidative stress in the Akita mice. However, ebselen failed to attenuate functional or structural kidney damage in this late-intervention study using the Akita mouse model.

17 CFR 1.63 - Service on self-regulatory organization governing boards or committees by persons with...

Code of Federal Regulations, 2011 CFR

2011-04-01

... EXCHANGE ACT Miscellaneous § 1.63 Service on self-regulatory organization governing boards or committees by... organization means a “self-regulatory organization” as defined in Commission regulation 1.3(ee) (§ 1.3(ee... committee of persons, or any subcommittee thereof, that is authorized by a self-regulatory organization to...

17 CFR 1.63 - Service on self-regulatory organization governing boards or committees by persons with...

Code of Federal Regulations, 2012 CFR

2012-04-01

... EXCHANGE ACT Miscellaneous § 1.63 Service on self-regulatory organization governing boards or committees by... organization means a “self-regulatory organization” as defined in Commission regulation 1.3(ee) (§ 1.3(ee... committee of persons, or any subcommittee thereof, that is authorized by a self-regulatory organization to...

17 CFR 1.63 - Service on self-regulatory organization governing boards or committees by persons with...

Code of Federal Regulations, 2010 CFR

2010-04-01

... EXCHANGE ACT Miscellaneous § 1.63 Service on self-regulatory organization governing boards or committees by... organization means a “self-regulatory organization” as defined in Commission regulation 1.3(ee) (§ 1.3(ee... committee of persons, or any subcommittee thereof, that is authorized by a self-regulatory organization to...

Transcriptional deregulation of homeobox gene ZHX2 in Hodgkin lymphoma.

PubMed

Nagel, Stefan; Schneider, Björn; Meyer, Corinna; Kaufmann, Maren; Drexler, Hans G; Macleod, Roderick A F

2012-05-01

Recently, we identified a novel chromosomal rearrangement in Hodgkin lymphoma (HL), t(4;8)(q27;q24), which targets homeobox gene ZHX2 at the recurrent breakpoint 8q24. This aberration deletes the far upstream region of ZHX2 and results in silenced transcription pinpointing loss of activatory elements. Here, we have looked for potential binding sites within this deleted region to analyze the transcriptional deregulation of this tumor suppressor gene in B-cell malignancies. SiRNA-mediated knockdown and reporter gene analyses identified two transcription factors, homeodomain protein MSX1 and bZIP protein XBP1, directly regulating ZHX2 expression. Furthermore, MSX1-cofactor histone H1C mediated repression of ZHX2 and showed enhanced expression levels in cell line L-1236. As demonstrated by fluorescence in situ hybridization and genomic array analysis, the gene loci of MSX1 at 4p16 and H1C at 6p22 were rearranged in several HL cell lines, correlating with their altered expression activity. The expression of XBP1 was reduced in 6/7 HL cell lines as compared to primary hematopoietic cells. Taken together, our results demonstrate multiple mechanisms decreasing expression of tumor suppressor gene ZHX2 in HL cell lines: loss of enhancing binding sites, reduced expression of activators MSX1 and XBP1, and overexpression of MSX1-corepressor H1C. Moreover, chromosomal deregulations of genes involved in this regulative network highlight their role in development and malignancy of B-cells. Copyright © 2011 Elsevier Ltd. All rights reserved.

16 CFR 460.21 - Government claims.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 16 Commercial Practices 1 2012-01-01 2012-01-01 false Government claims. 460.21 Section 460.21 Commercial Practices FEDERAL TRADE COMMISSION TRADE REGULATION RULES LABELING AND ADVERTISING OF HOME INSULATION § 460.21 Government claims. Do not say or imply that a government agency uses, certifies...

16 CFR 460.21 - Government claims.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 16 Commercial Practices 1 2010-01-01 2010-01-01 false Government claims. 460.21 Section 460.21 Commercial Practices FEDERAL TRADE COMMISSION TRADE REGULATION RULES LABELING AND ADVERTISING OF HOME INSULATION § 460.21 Government claims. Do not say or imply that a government agency uses, certifies...

19 CFR 111.33 - Government records.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 19 Customs Duties 1 2012-04-01 2012-04-01 false Government records. 111.33 Section 111.33 Customs... CUSTOMS BROKERS Duties and Responsibilities of Customs Brokers § 111.33 Government records. A broker must not procure or attempt to procure, directly or indirectly, information from Government records or...

19 CFR 111.33 - Government records.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 19 Customs Duties 1 2013-04-01 2013-04-01 false Government records. 111.33 Section 111.33 Customs... CUSTOMS BROKERS Duties and Responsibilities of Customs Brokers § 111.33 Government records. A broker must not procure or attempt to procure, directly or indirectly, information from Government records or...

16 CFR 460.21 - Government claims.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 16 Commercial Practices 1 2011-01-01 2011-01-01 false Government claims. 460.21 Section 460.21 Commercial Practices FEDERAL TRADE COMMISSION TRADE REGULATION RULES LABELING AND ADVERTISING OF HOME INSULATION § 460.21 Government claims. Do not say or imply that a government agency uses, certifies...

16 CFR 460.21 - Government claims.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 16 Commercial Practices 1 2014-01-01 2014-01-01 false Government claims. 460.21 Section 460.21 Commercial Practices FEDERAL TRADE COMMISSION TRADE REGULATION RULES LABELING AND ADVERTISING OF HOME INSULATION § 460.21 Government claims. Do not say or imply that a government agency uses, certifies...

19 CFR 111.33 - Government records.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 19 Customs Duties 1 2011-04-01 2011-04-01 false Government records. 111.33 Section 111.33 Customs... CUSTOMS BROKERS Duties and Responsibilities of Customs Brokers § 111.33 Government records. A broker must not procure or attempt to procure, directly or indirectly, information from Government records or...

19 CFR 111.33 - Government records.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 19 Customs Duties 1 2010-04-01 2010-04-01 false Government records. 111.33 Section 111.33 Customs... CUSTOMS BROKERS Duties and Responsibilities of Customs Brokers § 111.33 Government records. A broker must not procure or attempt to procure, directly or indirectly, information from Government records or...

16 CFR 460.21 - Government claims.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 16 Commercial Practices 1 2013-01-01 2013-01-01 false Government claims. 460.21 Section 460.21 Commercial Practices FEDERAL TRADE COMMISSION TRADE REGULATION RULES LABELING AND ADVERTISING OF HOME INSULATION § 460.21 Government claims. Do not say or imply that a government agency uses, certifies...

19 CFR 111.33 - Government records.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 19 Customs Duties 1 2014-04-01 2014-04-01 false Government records. 111.33 Section 111.33 Customs... CUSTOMS BROKERS Duties and Responsibilities of Customs Brokers § 111.33 Government records. A broker must not procure or attempt to procure, directly or indirectly, information from Government records or...

22 CFR 221.43 - Governing law.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 22 Foreign Relations 1 2013-04-01 2013-04-01 false Governing law. 221.43 Section 221.43 Foreign Relations AGENCY FOR INTERNATIONAL DEVELOPMENT ISRAEL LOAN GUARANTEE STANDARD TERMS AND CONDITIONS Administration § 221.43 Governing law. This Guarantee shall be governed by and construed in accordance with the...

22 CFR 221.43 - Governing law.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 22 Foreign Relations 1 2014-04-01 2014-04-01 false Governing law. 221.43 Section 221.43 Foreign Relations AGENCY FOR INTERNATIONAL DEVELOPMENT ISRAEL LOAN GUARANTEE STANDARD TERMS AND CONDITIONS Administration § 221.43 Governing law. This Guarantee shall be governed by and construed in accordance with the...

22 CFR 221.43 - Governing law.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 22 Foreign Relations 1 2012-04-01 2012-04-01 false Governing law. 221.43 Section 221.43 Foreign Relations AGENCY FOR INTERNATIONAL DEVELOPMENT ISRAEL LOAN GUARANTEE STANDARD TERMS AND CONDITIONS Administration § 221.43 Governing law. This Guarantee shall be governed by and construed in accordance with the...

22 CFR 221.43 - Governing law.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 22 Foreign Relations 1 2011-04-01 2011-04-01 false Governing law. 221.43 Section 221.43 Foreign Relations AGENCY FOR INTERNATIONAL DEVELOPMENT ISRAEL LOAN GUARANTEE STANDARD TERMS AND CONDITIONS Administration § 221.43 Governing law. This Guarantee shall be governed by and construed in accordance with the...

48 CFR 225.7402-3 - Government support.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 48 Federal Acquisition Regulations System 3 2014-10-01 2014-10-01 false Government support. 225... States 225.7402-3 Government support. (a) Government support that may be authorized or required for... coordination with the combatant commander that— (1) Such Government support is available and is needed to...

48 CFR 225.7402-3 - Government support.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 48 Federal Acquisition Regulations System 3 2013-10-01 2013-10-01 false Government support. 225... States 225.7402-3 Government support. (a) Government support that may be authorized or required for... coordination with the combatant commander that— (1) Such Government support is available and is needed to...

48 CFR 225.7402-3 - Government support.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 48 Federal Acquisition Regulations System 3 2011-10-01 2011-10-01 false Government support. 225... States 225.7402-3 Government support. (a) Government support that may be authorized or required for... coordination with the combatant commander that— (1) Such Government support is available and is needed to...

48 CFR 225.7402-3 - Government support.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 48 Federal Acquisition Regulations System 3 2010-10-01 2010-10-01 false Government support. 225... States 225.7402-3 Government support. (a) Government support that may be authorized or required for... coordination with the combatant commander that— (1) Such Government support is available and is needed to...

48 CFR 225.7402-3 - Government support.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 48 Federal Acquisition Regulations System 3 2012-10-01 2012-10-01 false Government support. 225... States 225.7402-3 Government support. (a) Government support that may be authorized or required for... coordination with the combatant commander that— (1) Such Government support is available and is needed to...

22 CFR 204.43 - Governing law.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 22 Foreign Relations 1 2011-04-01 2011-04-01 false Governing law. 204.43 Section 204.43 Foreign Relations AGENCY FOR INTERNATIONAL DEVELOPMENT HOUSING GUARANTY STANDARD TERMS AND CONDITIONS Administration § 204.43 Governing law. This Guaranty shall be governed by and construed in accordance with the laws of...

22 CFR 204.43 - Governing law.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 22 Foreign Relations 1 2013-04-01 2013-04-01 false Governing law. 204.43 Section 204.43 Foreign Relations AGENCY FOR INTERNATIONAL DEVELOPMENT HOUSING GUARANTY STANDARD TERMS AND CONDITIONS Administration § 204.43 Governing law. This Guaranty shall be governed by and construed in accordance with the laws of...

22 CFR 204.43 - Governing law.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 22 Foreign Relations 1 2012-04-01 2012-04-01 false Governing law. 204.43 Section 204.43 Foreign Relations AGENCY FOR INTERNATIONAL DEVELOPMENT HOUSING GUARANTY STANDARD TERMS AND CONDITIONS Administration § 204.43 Governing law. This Guaranty shall be governed by and construed in accordance with the laws of...

22 CFR 204.43 - Governing law.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 22 Foreign Relations 1 2014-04-01 2014-04-01 false Governing law. 204.43 Section 204.43 Foreign Relations AGENCY FOR INTERNATIONAL DEVELOPMENT HOUSING GUARANTY STANDARD TERMS AND CONDITIONS Administration § 204.43 Governing law. This Guaranty shall be governed by and construed in accordance with the laws of...

22 CFR 204.43 - Governing law.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 22 Foreign Relations 1 2010-04-01 2010-04-01 false Governing law. 204.43 Section 204.43 Foreign Relations AGENCY FOR INTERNATIONAL DEVELOPMENT HOUSING GUARANTY STANDARD TERMS AND CONDITIONS Administration § 204.43 Governing law. This Guaranty shall be governed by and construed in accordance with the laws of...

32 CFR 310.12 - Government contractors.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 32 National Defense 2 2014-07-01 2014-07-01 false Government contractors. 310.12 Section 310.12... PROGRAM DOD PRIVACY PROGRAM Systems of Records § 310.12 Government contractors. (a) Applicability to government contractors. (1) When a DoD Component contract requires the operation or maintenance of a system...

32 CFR 310.12 - Government contractors.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 32 National Defense 2 2013-07-01 2013-07-01 false Government contractors. 310.12 Section 310.12... PROGRAM DOD PRIVACY PROGRAM Systems of Records § 310.12 Government contractors. (a) Applicability to government contractors. (1) When a DoD Component contract requires the operation or maintenance of a system...

32 CFR 310.12 - Government contractors.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 32 National Defense 2 2011-07-01 2011-07-01 false Government contractors. 310.12 Section 310.12... PROGRAM DOD PRIVACY PROGRAM Systems of Records § 310.12 Government contractors. (a) Applicability to government contractors. (1) When a DoD Component contract requires the operation or maintenance of a system...

32 CFR 310.12 - Government contractors.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 32 National Defense 2 2012-07-01 2012-07-01 false Government contractors. 310.12 Section 310.12... PROGRAM DOD PRIVACY PROGRAM Systems of Records § 310.12 Government contractors. (a) Applicability to government contractors. (1) When a DoD Component contract requires the operation or maintenance of a system...

32 CFR 310.12 - Government contractors.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 32 National Defense 2 2010-07-01 2010-07-01 false Government contractors. 310.12 Section 310.12... PROGRAM DOD PRIVACY PROGRAM Systems of Records § 310.12 Government contractors. (a) Applicability to government contractors. (1) When a DoD Component contract requires the operation or maintenance of a system...

Governance and performance: the performance of Dutch hospitals explained by governance characteristics.

PubMed

Blank, Jos L T; van Hulst, Bart Laurents

2011-10-01

This paper describes the efficiency of Dutch hospitals using the Data Envelopment Analysis (DEA) method with bootstrapping. In particular, the analysis focuses on accounting for cost inefficiency measures on the part of hospital corporate governance. We use bootstrap techniques, as introduced by Simar and Wilson (J. Econom. 136(1):31-64, 2007), in order to obtain more efficient estimates of the effects of governance on the efficiency. The results show that part of the cost efficiency can be explained with governance. In particular we find that a higher remuneration of the board as well as a higher remuneration of the supervisory board does not implicate better performance.

Born a bit too early: recent trends in late preterm births.

PubMed

Martin, Joyce A; Kirmeyer, Sharon; Osterman, Michelle; Shepherd, Ruth A

2009-11-01

The U.S. late preterm birth rate rose 20% from 1990 to 2006. If the late preterm rate had not risen from the 1990 level, more than 50,000 fewer infants would have been delivered late preterm in 2006. On average, more than 900 late preterm babies are born every day in the United States, or a total of one-third of 1 million infants (333,461). Increases in late preterm births are seen for mothers of all ages, and for non-Hispanic white and Hispanic mothers. The rate for black mothers declined during the 1990s, but has been on the rise since 2000. Late preterm birth rates rose for all U.S. states, but declined in the District of Columbia. The percentage of late preterm births for which labor was induced more than doubled from 1990 to 2006; the percentage of late preterm births delivered by cesarean also rose markedly.

Reforming the Governance of California Community Colleges.

ERIC Educational Resources Information Center

Nussbaum, Thomas J.

In this speech, Chancellor Thomas J. Nussbaum defends the existence of local governing boards for community colleges and offers suggestions for improving the current weak governance structure. He argues that doing away with local governing boards would: (1) create a greater inconsistency between the mission and the governance of the colleges; (2)…

Paradoxical physiological transitions from aging to late life in Drosophila.

PubMed

Shahrestani, Parvin; Quach, Julie; Mueller, Laurence D; Rose, Michael R

2012-02-01

In a variety of organisms, adulthood is divided into aging and late life, where aging is a period of exponentially increasing mortality rates and late life is a period of roughly plateaued mortality rates. In this study we used ∼57,600 Drosophila melanogaster from six replicate populations to examine the physiological transitions from aging to late life in four functional characters that decline during aging: desiccation resistance, starvation resistance, time spent in motion, and negative geotaxis. Time spent in motion and desiccation resistance declined less quickly in late life compared to their patterns of decline during aging. Negative geotaxis declined at a faster rate in late life compared to its rate of decline during aging. These results yield two key findings: (1) Late-life physiology is distinct from the physiology of aging, in that there is not simply a continuation of the physiological trends which characterize aging; and (2) late life physiology is complex, in that physiological characters vary with respect to their stabilization, deceleration, or acceleration in the transition from aging to late life. These findings imply that a correct understanding of adulthood requires identifying and appropriately characterizing physiology during properly delimited late-life periods as well as aging periods.

Paradoxical Physiological Transitions from Aging to Late Life in Drosophila

PubMed Central

Quach, Julie; Mueller, Laurence D.; Rose, Michael R.

2012-01-01

Abstract In a variety of organisms, adulthood is divided into aging and late life, where aging is a period of exponentially increasing mortality rates and late life is a period of roughly plateaued mortality rates. In this study we used ∼57,600 Drosophila melanogaster from six replicate populations to examine the physiological transitions from aging to late life in four functional characters that decline during aging: desiccation resistance, starvation resistance, time spent in motion, and negative geotaxis. Time spent in motion and desiccation resistance declined less quickly in late life compared to their patterns of decline during aging. Negative geotaxis declined at a faster rate in late life compared to its rate of decline during aging. These results yield two key findings: (1) Late-life physiology is distinct from the physiology of aging, in that there is not simply a continuation of the physiological trends which characterize aging; and (2) late life physiology is complex, in that physiological characters vary with respect to their stabilization, deceleration, or acceleration in the transition from aging to late life. These findings imply that a correct understanding of adulthood requires identifying and appropriately characterizing physiology during properly delimited late-life periods as well as aging periods. PMID:22233126

KECK NIRSPEC RADIAL VELOCITY OBSERVATIONS OF LATE-M DWARFS

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

Tanner, Angelle; White, Russel; Bailey, John

2012-11-15

We present the results of an infrared spectroscopic survey of 23 late-M dwarfs with the NIRSPEC echelle spectrometer on the Keck II telescope. Using telluric lines for wavelength calibration, we are able to achieve measurement precisions of down to 45 m s{sup -1} for our late-M dwarfs over a one- to four-year long baseline. Our sample contains two stars with radial velocity (RV) variations of >1000 m s{sup -1}. While we require more measurements to determine whether these RV variations are due to unseen planetary or stellar companions or are the result of starspots known to plague the surface ofmore » M dwarfs, we can place upper limits of <40 M{sub J} sin i on the masses of any companions around those two M dwarfs with RV variations of <160 m s{sup -1} at orbital periods of 10-100 days. We have also measured the rotational velocities for all the stars in our late-M dwarf sample and offer our multi-order, high-resolution spectra over 2.0-2.4 {mu}m to the atmospheric modeling community to better understand the atmospheres of late-M dwarfs.« less

22 CFR 231.16 - Governing law.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 22 Foreign Relations 1 2010-04-01 2010-04-01 false Governing law. 231.16 Section 231.16 Foreign... EMERGENCY WARTIME SUPPLEMENTAL APPROPRIATIONS ACT OF 2003, PUBLIC LAW 108-11-STANDARD TERMS AND CONDITIONS § 231.16 Governing law. This Guarantee shall be governed by and construed in accordance with the laws of...

4 CFR 83.19 - Government contractors.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 4 Accounts 1 2011-01-01 2011-01-01 false Government contractors. 83.19 Section 83.19 Accounts GOVERNMENT ACCOUNTABILITY OFFICE RECORDS PRIVACY PROCEDURES FOR PERSONNEL RECORDS § 83.19 Government contractors. When GAO provides by a contract for the operation by or on behalf of GAO of a system of personnel...

4 CFR 83.19 - Government contractors.

Code of Federal Regulations, 2013 CFR

2013-01-01

... 4 Accounts 1 2013-01-01 2013-01-01 false Government contractors. 83.19 Section 83.19 Accounts GOVERNMENT ACCOUNTABILITY OFFICE RECORDS PRIVACY PROCEDURES FOR PERSONNEL RECORDS § 83.19 Government contractors. When GAO provides by a contract for the operation by or on behalf of GAO of a system of personnel...

4 CFR 83.19 - Government contractors.

Code of Federal Regulations, 2012 CFR

2012-01-01

... 4 Accounts 1 2012-01-01 2012-01-01 false Government contractors. 83.19 Section 83.19 Accounts GOVERNMENT ACCOUNTABILITY OFFICE RECORDS PRIVACY PROCEDURES FOR PERSONNEL RECORDS § 83.19 Government contractors. When GAO provides by a contract for the operation by or on behalf of GAO of a system of personnel...

4 CFR 83.19 - Government contractors.

Code of Federal Regulations, 2014 CFR

2014-01-01

... 4 Accounts 1 2014-01-01 2013-01-01 true Government contractors. 83.19 Section 83.19 Accounts GOVERNMENT ACCOUNTABILITY OFFICE RECORDS PRIVACY PROCEDURES FOR PERSONNEL RECORDS § 83.19 Government contractors. When GAO provides by a contract for the operation by or on behalf of GAO of a system of personnel...

17 CFR 1.63 - Service on self-regulatory organization governing boards or committees by persons with...

Code of Federal Regulations, 2014 CFR

2014-04-01

... EXCHANGE ACT Miscellaneous § 1.63 Service on self-regulatory organization governing boards or committees by... organization means a “self-regulatory organization” as defined in § 1.3(ee), and includes a “clearing... self-regulatory organization to issue disciplinary charges, to conduct disciplinary proceedings, to...

17 CFR 1.63 - Service on self-regulatory organization governing boards or committees by persons with...

Code of Federal Regulations, 2013 CFR

2013-04-01

... EXCHANGE ACT Miscellaneous § 1.63 Service on self-regulatory organization governing boards or committees by... organization means a “self-regulatory organization” as defined in § 1.3(ee), and includes a “clearing... self-regulatory organization to issue disciplinary charges, to conduct disciplinary proceedings, to...

IUE observations of two late-type stars Bx Mon (M + pec) and TV Gem (M1 Iab)

NASA Technical Reports Server (NTRS)

Michalitsianos, A. G.; Hobbs, R. W.; Kafatos, M.

1981-01-01

The IUE observations of two late type stars BX Mon and TV Gem that reveal the emission properties in the ultraviolet of subluminous companions are discussed. Analysis of the continuum emission observed from BX Mon suggests the companion, is a middle A III star. High excitation emission lines observed between 1200 A and 2000 A that generally do not typify emission observed in either late M type variables or A type stars are also detected. It is suggested that these strong high excitation lines arise in a large volume of gas heated by nonradiation processes that could be the result of tidal interaction and mass exchange in the binary system. In contrast to stars such as BX Mon, the luminous M1 supergiant TV Gem shows unexpected intense UV continuum throughout the sensitivity range of IUE. The UV spectrum of TV Gem is characterized by intense continuum with broad absorption features detected in the short wavelength range. The analysis shows that the companion could be a B9 or A1 III-IV star. Alternate suggestions are presented for explaining the UV continuum in terms of an accretion disk in association with TV Gem.

A quasi-lentiviral green fluorescent protein reporter exhibits nuclear export features of late human immunodeficiency virus type 1 transcripts

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

Graf, Marcus; Ludwig, Christine; Kehlenbeck, Sylvia

2006-09-01

We have previously shown that Rev-dependent expression of HIV-1 Gag from CMV immediate early promoter critically depends on the AU-rich codon bias of the gag gene. Here, we demonstrate that adaptation of the green fluorescent protein (GFP) reporter gene to HIV codon bias is sufficient to turn this hivGFP RNA into a quasi-lentiviral message following the rules of late lentiviral gene expression. Accordingly, GFP expression was significantly decreased in transfected cells strictly correlating with reduced RNA levels. In the presence of the HIV 5' major splice donor, the hivGFP RNAs were stabilized in the nucleus and efficiently exported to themore » cytoplasm following fusion of the 3' Rev-responsive element (RRE) and coexpression of HIV-1 Rev. This Rev-dependent translocation was specifically inhibited by leptomycin B suggesting export via the CRM1-dependent pathway used by late lentiviral transcripts. In conclusion, this quasi-lentiviral reporter system may provide a new platform for developing sensitive Rev screening assays.« less

Endoplasmic reticulum degradation-enhancing α-mannosidase-like protein 1 targets misfolded HLA-B27 dimers for endoplasmic reticulum-associated degradation.

PubMed

Guiliano, David B; Fussell, Helen; Lenart, Izabela; Tsao, Edward; Nesbeth, Darren; Fletcher, Adam J; Campbell, Elaine C; Yousaf, Nasim; Williams, Sarah; Santos, Susana; Cameron, Amy; Towers, Greg J; Kellam, Paul; Hebert, Daniel N; Gould, Keith G; Powis, Simon J; Antoniou, Antony N

2014-11-01

HLA-B27 forms misfolded heavy chain dimers, which may predispose individuals to inflammatory arthritis by inducing endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). This study was undertaken to define the role of the UPR-induced ER-associated degradation (ERAD) pathway in the disposal of HLA-B27 dimeric conformers. HeLa cell lines expressing only 2 copies of a carboxy-terminally Sv5-tagged HLA-B27 were generated. The ER stress-induced protein ER degradation-enhancing α-mannosidase-like protein 1 (EDEM1) was overexpressed by transfection, and dimer levels were monitored by immunoblotting. EDEM1, the UPR-associated transcription factor X-box binding protein 1 (XBP-1), the E3 ubiquitin ligase hydroxymethylglutaryl-coenzyme A reductase degradation 1 (HRD1), and the degradation-associated proteins derlin 1 and derlin 2 were inhibited using either short hairpin RNA or dominant-negative mutants. The UPR-associated ERAD of HLA-B27 was confirmed using ER stress-inducing pharamacologic agents in kinetic and pulse chase assays. We demonstrated that UPR-induced machinery can target HLA-B27 dimers and that dimer formation can be controlled by alterations to expression levels of components of the UPR-induced ERAD pathway. HLA-B27 dimers and misfolded major histocompatibility complex class I monomeric molecules bound to EDEM1 were detected, and overexpression of EDEM1 led to inhibition of HLA-B27 dimer formation. EDEM1 inhibition resulted in up-regulation of HLA-B27 dimers, while UPR-induced ERAD of dimers was prevented in the absence of EDEM1. HLA-B27 dimer formation was also enhanced in the absence of XBP-1, HRD1, and derlins 1 and 2. The present findings indicate that the UPR ERAD pathway can dispose of HLA-B27 dimers, thus presenting a potential novel therapeutic target for modulation of HLA-B27-associated inflammatory disease. Copyright © 2014 by the American College of Rheumatology.

Late Paleozoic magmatism in South China: Oceanic subduction or intracontinental orogeny?

NASA Astrophysics Data System (ADS)

Liu, Q.; Yu, J.; Zhao, G.

2013-12-01

The significant late Paleozoic magmatism has been widely recognized in the East Asian Blocks, which sheds a light on the assembly and break-up of the Pangea supercontinent. As one of major components in East Asia, however, the South China Block (SCB) does not have much late Paleozoic magmatism recognized. Here we report a gneissic granite intrusion in northeastern Fujian Province, eastern SCB. It is a S-type granite characterized by high K2O and Al2O3, and low SiO2 and Na2O with a high A/CNK ratio of 1.22. Zircons with stubby morphology from this gneissic granite yield 206Pb/238U ages ranging from 326 Ma to 301 Ma with a weighted average age of 313×4 Ma, and negative epsilonHf(t) values from -8.35 to -1.74 with two-stage Hf model ages of 1.43 to 1.84 Ga. This S-type granite was probably originated from late Paleoproterozoic crust during an intracontinental orogeny, not under oceanic subduction. Integrated with previous results on the paleogeographic reconstruction of the SCB, the nature of Paleozoic basins, Early Permian volcanism and U-Pb-Hf isotope of detrital zircons from the late Paleozoic to early Mesozoic sedimentary rocks, our data support a late Paleozoic orogeny in the SCB, which may have included Late Carboniferous (340-310 Ma) compressive episode and Early Permian (287-270 Ma) post-orogenic or intraplate extensive episode. Our interpretation is consistent with the late Paleozoic orogenic events recognized in other Pangea microcontinents, and thus provides a window for the reconstruction of Pangea. Acknowledgements: NSFC (41190070, 41190075)

Medically significant late bleeding after treated crotaline envenomation: a systematic review.

PubMed

Lavonas, Eric J; Khatri, Vaishali; Daugherty, Claire; Bucher-Bartelson, Becki; King, Thomas; Dart, Richard C

2014-01-01

We estimate the proportion of patients with crotaline snake envenomation who are treated with Crotalidae polyvalent immune Fab (ovine) antivenom and who develop medically significant late bleeding. We performed a systematic review of all published cohort studies of North American crotaline snake envenomation patients treated with Fab antivenom. We searched PubMed, Ovid MEDLINE, and EMBASE from January 1, 1997, to April 30, 2012. Data were extracted by 2 trained researchers. Late bleeding was defined as bleeding that began or recurred after initial control of the envenomation syndrome. Medically significant late bleeding was defined a priori as late bleeding treated with RBC transfusion, vasoactive drug infusion, surgery, or rehospitalization or associated with a hemoglobin decrease of greater than or equal to 3 g/dL, hematocrit decrease of greater than or equal to 8%, disability, or death. Summary incidence and 95% confidence intervals (CIs) were calculated with a random-effects Poisson regression model. Nineteen unique cohort studies were identified. Four studies collected data prospectively, and in 9 studies, patients were followed actively after hospital discharge. A total of 1,017 subjects were enrolled in these cohort studies. Late bleeding was reported in 9 subjects (0.9%; 95% CI 0.4% to 2.2%), of whom 5 subjects (0.5%; 95% CI 0.1% to 1.7%) had medically significant late bleeding. Three patients received RBC transfusion; no deaths or permanent sequelae were reported. Estimates of risk may be affected by underreporting. Medically significant late bleeding appears to be uncommon in snakebite victims treated with Fab antivenom. Copyright © 2013 American College of Emergency Physicians. Published by Mosby, Inc. All rights reserved.

22 CFR 230.16 - Governing law.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 22 Foreign Relations 1 2010-04-01 2010-04-01 false Governing law. 230.16 Section 230.16 Foreign... SUPPLEMENTAL APPROPRIATIONS ACT OF 2003, PUB. L. 108-11-STANDARD TERMS AND CONDITIONS § 230.16 Governing law. This Guarantee shall be governed by and construed in accordance with the laws of the United States of...

48 CFR 552.246-71 - Source Inspection by Government.

Code of Federal Regulations, 2010 CFR

2010-10-01

... Government. 552.246-71 Section 552.246-71 Federal Acquisition Regulations System GENERAL SERVICES....246-71 Source Inspection by Government. As prescribed in 546.302-71, insert the following clause: Source Inspection by Government (JUNE 1, 2009) (a) Inspection by Government personnel. (1) Supplies to be...

A novel large deletion in the RYR1 gene in a Belgian family with late-onset and recessive core myopathy.

PubMed

Remiche, Gauthier; Kadhim, Hazim; Abramowicz, Marc; Mavroudakis, Nicolas; Monnier, Nicole; Lunardi, Joël

2015-05-01

We report a novel and particularly unusual type of mutation, namely, large deletion in the RYR1 gene, in a Belgian family with myopathy: Patients were found to be compound heterozygous and presented a clinico-pathological phenotype characterized by late-onset and recessive myopathy with cores. We depict the clinical, electrophysiological, pathological and molecular genetic characteristics of family members. To date, large deletions in the RYR1 gene have been reported in only two cases. Both involved different mutations and, in sharp contrast to our cases, presented with a very early-onset, neonatal, and a very severe or lethal phenotype. Overview of reported clinico-pathologic phenotypes, also highlights the rarity of combined late-onset/recessive co-occurrence in this group of myopathies with cores. Finally, this report underlines the broadening spectrum in this group of myopathologic disorders and highlights the concept of 'RYR1-associated/related core myopathies'. Copyright © 2015 Elsevier B.V. All rights reserved.

Solar-Geophysical Data Number 496, February 1986. Part 1: (Prompt reports). Data for January 1986,December 1985 and late data

NASA Technical Reports Server (NTRS)

Coffey, H. E.

1986-01-01