Genome-wide investigation and expression analyses of WD40 protein family in the model plant foxtail millet (Setaria italica L.).

PubMed

Mishra, Awdhesh Kumar; Muthamilarasan, Mehanathan; Khan, Yusuf; Parida, Swarup Kumar; Prasad, Manoj

2014-01-01

WD40 proteins play a crucial role in diverse protein-protein interactions by acting as scaffolding molecules and thus assisting in the proper activity of proteins. Hence, systematic characterization and expression profiling of these WD40 genes in foxtail millet would enable us to understand the networks of WD40 proteins and their biological processes and gene functions. In the present study, a genome-wide survey was conducted and 225 potential WD40 genes were identified. Phylogenetic analysis categorized the WD40 proteins into 5 distinct sub-families (I-V). Gene Ontology annotation revealed the biological roles of the WD40 proteins along with its cellular components and molecular functions. In silico comparative mapping with sorghum, maize and rice demonstrated the orthologous relationships and chromosomal rearrangements including duplication, inversion and deletion of WD40 genes. Estimation of synonymous and non-synonymous substitution rates revealed its evolutionary significance in terms of gene-duplication and divergence. Expression profiling against abiotic stresses provided novel insights into specific and/or overlapping expression patterns of SiWD40 genes. Homology modeling enabled three-dimensional structure prediction was performed to understand the molecular functions of WD40 proteins. Although, recent findings had shown the importance of WD40 domains in acting as hubs for cellular networks during many biological processes, it has invited a lesser research attention unlike other common domains. Being a most promiscuous interactors, WD40 domains are versatile in mediating critical cellular functions and hence this genome-wide study especially in the model crop foxtail millet would serve as a blue-print for functional characterization of WD40s in millets and bioenergy grass species. In addition, the present analyses would also assist the research community in choosing the candidate WD40s for comprehensive studies towards crop improvement of millets and biofuel grasses.

Genome-Wide Investigation and Expression Analyses of WD40 Protein Family in the Model Plant Foxtail Millet (Setaria italica L.)

PubMed Central

Mishra, Awdhesh Kumar; Muthamilarasan, Mehanathan; Khan, Yusuf; Parida, Swarup Kumar; Prasad, Manoj

2014-01-01

WD40 proteins play a crucial role in diverse protein-protein interactions by acting as scaffolding molecules and thus assisting in the proper activity of proteins. Hence, systematic characterization and expression profiling of these WD40 genes in foxtail millet would enable us to understand the networks of WD40 proteins and their biological processes and gene functions. In the present study, a genome-wide survey was conducted and 225 potential WD40 genes were identified. Phylogenetic analysis categorized the WD40 proteins into 5 distinct sub-families (I–V). Gene Ontology annotation revealed the biological roles of the WD40 proteins along with its cellular components and molecular functions. In silico comparative mapping with sorghum, maize and rice demonstrated the orthologous relationships and chromosomal rearrangements including duplication, inversion and deletion of WD40 genes. Estimation of synonymous and non-synonymous substitution rates revealed its evolutionary significance in terms of gene-duplication and divergence. Expression profiling against abiotic stresses provided novel insights into specific and/or overlapping expression patterns of SiWD40 genes. Homology modeling enabled three-dimensional structure prediction was performed to understand the molecular functions of WD40 proteins. Although, recent findings had shown the importance of WD40 domains in acting as hubs for cellular networks during many biological processes, it has invited a lesser research attention unlike other common domains. Being a most promiscuous interactors, WD40 domains are versatile in mediating critical cellular functions and hence this genome-wide study especially in the model crop foxtail millet would serve as a blue-print for functional characterization of WD40s in millets and bioenergy grass species. In addition, the present analyses would also assist the research community in choosing the candidate WD40s for comprehensive studies towards crop improvement of millets and biofuel grasses. PMID:24466268

The Work Disability Functional Assessment Battery (WD-FAB): Feasibility and Psychometric Properties

PubMed Central

Meterko, Mark; Marfeo, Elizabeth E.; McDonough, Christine M.; Jette, Alan M.; Ni, Pengsheng; Bogusz, Kara; Rasch, Elizabeth K; Brandt, Diane E.; Chan, Leighton

2015-01-01

Objectives To assess the feasibility and psychometric properties of eight scales covering two domains of the newly developed Work Disability Functional Assessment Battery (WD-FAB): physical function (PF) and behavioral health (BH) function. Design Cross-sectional. Setting Community. Participants Adults unable to work due to a physical (n=497) or mental (n=476) disability. Interventions None. Main Outcome Measures Each disability group responded to a survey consisting of the relevant WD-FAB scales and existing measures of established validity. The WD-FAB scales were evaluated with regard to data quality (score distribution; percent “I don’t know” responses), efficiency of administration (number of items required to achieve reliability criterion; time required to complete the scale) by computerized adaptive testing (CAT), and measurement accuracy as tested by person fit. Construct validity was assessed by examining both convergent and discriminant correlations between the WD-FAB scales and scores on same-domain and cross-domain established measures. Results Data quality was good and CAT efficiency was high across both WD-FAB domains. Measurement accuracy was very good for the PF scales; BH scales demonstrated more variability. Construct validity correlations, both convergent and divergent, between all WD-FAB scales and established measures were in the expected direction and range of magnitude. Conclusions The data quality, CAT efficacy, person fit and construct validity of the WD-FAB scales were well supported and suggest that the WD-FAB could be used to assess physical and behavioral health function related to work disability. Variation in scale performance suggests the need for future work on item replenishment and refinement, particularly regarding the Self-Efficacy scale. PMID:25528263

Bioinformatic analyses implicate the collaborating meiotic crossover/chiasma proteins Zip2, Zip3, and Spo22/Zip4 in ubiquitin labeling

PubMed Central

Perry, Jason; Kleckner, Nancy; Börner, G. Valentin

2005-01-01

Zip2 and Zip3 are meiosis-specific proteins that, in collaboration with several partners, act at the sites of crossover-designated, axis-associated recombinational interactions to mediate crossover/chiasma formation. Here, Spo22 (also called Zip4) is identified as a probable functional collaborator of Zip2/3. The molecular roles of Zip2, Zip3, and Spo22/Zip4 are unknown. All three proteins are part of a small evolutionary cohort comprising similar homologs in four related yeasts. Zip3 is shown to contain a RING finger whose structural features most closely match those of known ubiquitin E3s. Further, Zip3 exhibits major domainal homologies to Rad18, a known DNA-binding ubiquitin E3. Also described is an approach to the identification and mapping of repeated protein sequence motifs, Alignment Based Repeat Annotation (ABRA), that we have developed. When ABRA is applied to Zip2 and Spo22/Zip4, they emerge as a 14-blade WD40-like repeat protein and a 22-unit tetratricopeptide repeat protein, respectively. WD40 repeats of Cdc20, Cdh1, and Cdc16 and tetratricopeptide repeats of Cdc16, Cdc23, and Cdc27, all components of the anaphase-promoting complex, are also analyzed. These and other findings suggest that Zip2, Zip3, and Zip4 act together to mediate a process that involves Zip3-mediated ubiquitin labeling, potentially as a unique type of ubiquitin-conjugating complex. PMID:16314568

A Neutron Star-White Dwarf Binary Model for Repeating Fast Radio Burst 121102

NASA Astrophysics Data System (ADS)

Gu, Wei-Min; Dong, Yi-Ze; Liu, Tong; Ma, Renyi; Wang, Junfeng

2016-06-01

We propose a compact binary model for the fast radio burst (FRB) repeaters, where the system consists of a magnetic white dwarf (WD) and a neutron star (NS) with strong bipolar magnetic fields. When the WD fills its Roche lobe, mass transfer will occur from the WD to the NS through the inner Lagrange point. The accreted magnetized materials may trigger magnetic reconnection when they approach the NS surface, and therefore the electrons can be accelerated to an ultra-relativistic speed. In this scenario, the curvature radiation of the electrons moving along the NS magnetic field lines can account for the characteristic frequency and the timescale of an FRB. Owing to the conservation of angular momentum, the WD may be kicked away after a burst, and the next burst may appear when the system becomes semi-detached again through the gravitational radiation. By comparing our analyses with the observations, we show that such an intermittent Roche-lobe overflow mechanism can be responsible for the observed repeating behavior of FRB 121102.

The C-terminal region of Ge-1 presents conserved structural features required for P-body localization.

PubMed

Jinek, Martin; Eulalio, Ana; Lingel, Andreas; Helms, Sigrun; Conti, Elena; Izaurralde, Elisa

2008-10-01

The removal of the 5' cap structure by the DCP1-DCP2 decapping complex irreversibly commits eukaryotic mRNAs to degradation. In human cells, the interaction between DCP1 and DCP2 is bridged by the Ge-1 protein. Ge-1 contains an N-terminal WD40-repeat domain connected by a low-complexity region to a conserved C-terminal domain. It was reported that the C-terminal domain interacts with DCP2 and mediates Ge-1 oligomerization and P-body localization. To understand the molecular basis for these functions, we determined the three-dimensional crystal structure of the most conserved region of the Drosophila melanogaster Ge-1 C-terminal domain. The region adopts an all alpha-helical fold related to ARM- and HEAT-repeat proteins. Using structure-based mutants we identified an invariant surface residue affecting P-body localization. The conservation of critical surface and structural residues suggests that the C-terminal region adopts a similar fold with conserved functions in all members of the Ge-1 protein family.

Pwp2 mediates UTP-B assembly via two structurally independent domains.

PubMed

Boissier, Fanny; Schmidt, Christina Maria; Linnemann, Jan; Fribourg, Sébastien; Perez-Fernandez, Jorge

2017-06-09

The SSU processome constitutes a large ribonucleoprotein complex involved in the early steps of ribosome biogenesis. UTP-B is one of the first multi-subunit protein complexes that associates with the pre-ribosomal RNA to form the SSU processome. To understand the molecular basis of the hierarchical assembly of the SSU-processome, we have undergone a structural and functional analysis of the UTP-B subunit Pwp2p. We show that Pwp2p is required for the proper assembly of UTP-B and for a productive association of UTP-B with pre-rRNA. These two functions are mediated by two distinct structural domains. The N-terminal domain of Pwp2p folds into a tandem WD-repeat (tWD) that associates with Utp21p, Utp18p, and Utp6p to form a core complex. The CTDs of Pwp2p and Utp21p mediate the assembly of the heterodimer Utp12p:Utp13p that is required for the stable incorporation of the UTP-B complex in the SSU processome. Finally, we provide evidence suggesting a role of UTP-B as a platform for the binding of assembly factors during the maturation of 20S rRNA precursors.

Ama1p-activated anaphase-promoting complex regulates the destruction of Cdc20p during meiosis II

PubMed Central

Tan, Grace S.; Magurno, Jennifer; Cooper, Katrina F.

2011-01-01

The execution of meiotic divisions in Saccharomyces cerevisiae is regulated by anaphase-promoting complex/cyclosome (APC/C)–mediated protein degradation. During meiosis, the APC/C is activated by association with Cdc20p or the meiosis-specific activator Ama1p. We present evidence that, as cells exit from meiosis II, APC/CAma1 mediates Cdc20p destruction. APC/CAma1 recognizes two degrons on Cdc20p, the destruction box and destruction degron, with either domain being sufficient to mediate Cdc20p destruction. Cdc20p does not need to associate with the APC/C to bind Ama1p or be destroyed. Coimmunoprecipitation analyses showed that the diverged amino-terminal region of Ama1p recognizes both Cdc20p and Clb1p, a previously identified substrate of APC/CAma1. Domain swap experiments revealed that the C-terminal WD region of Cdh1p, when fused to the N-terminal region of Ama1p, could direct most of Ama1p functions, although at a reduced level. In addition, this fusion protein cannot complement the spore wall defect in ama1Δ strains, indicating that substrate specificity is also derived from the WD repeat domain. These findings provide a mechanism to temporally down-regulate APC/CCdc20 activity as the cells complete meiosis II and form spores. PMID:21118994

Crystal structure of EML1 reveals the basis for Hsp90 dependence of oncogenic EML4-ALK by disruption of an atypical β-propeller domain

PubMed Central

Richards, Mark W.; Law, Edward W. P.; Rennalls, La’Verne P.; Busacca, Sara; O’Regan, Laura; Fry, Andrew M.; Fennell, Dean A.; Bayliss, Richard

2014-01-01

Proteins of the echinoderm microtubule-associated protein (EMAP)-like (EML) family contribute to formation of the mitotic spindle and interphase microtubule network. They contain a unique hydrophobic EML protein (HELP) motif and a variable number of WD40 repeats. Recurrent gene rearrangements in nonsmall cell lung cancer fuse EML4 to anaplastic lymphoma kinase (ALK), causing expression of several fusion oncoprotein variants. We have determined a 2.6-Å crystal structure of the representative ∼70-kDa core of EML1, revealing an intimately associated pair of β-propellers, which we term a TAPE (tandem atypical propeller in EMLs) domain. One propeller is highly atypical, having a discontinuous subdomain unrelated to a WD40 motif in place of one of its blades. This unexpected feature shows how a propeller structure can be assembled from subdomains with distinct folds. The HELP motif is not an independent domain but forms part of the hydrophobic core that joins the two β-propellers. The TAPE domain binds α/β-tubulin via its conserved, concave surface, including part of the atypical blade. Mapping the characteristic breakpoints of each EML4-ALK variant onto our structure indicates that the EML4 TAPE domain is truncated in many variants in a manner likely to make the fusion protein structurally unstable. We found that the heat shock protein 90 (Hsp90) inhibitor ganetespib induced degradation of these variants whereas others lacking a partial TAPE domain were resistant in both overexpression models and patient-derived cell lines. The Hsp90-sensitive EML4-ALK variants are exceptions to the rule that oncogenic fusion proteins involve breakpoints in disordered regions of both partners. PMID:24706829

Crystal structure of EML1 reveals the basis for Hsp90 dependence of oncogenic EML4-ALK by disruption of an atypical β-propeller domain.

PubMed

Richards, Mark W; Law, Edward W P; Rennalls, La'Verne P; Busacca, Sara; O'Regan, Laura; Fry, Andrew M; Fennell, Dean A; Bayliss, Richard

2014-04-08

Proteins of the echinoderm microtubule-associated protein (EMAP)-like (EML) family contribute to formation of the mitotic spindle and interphase microtubule network. They contain a unique hydrophobic EML protein (HELP) motif and a variable number of WD40 repeats. Recurrent gene rearrangements in nonsmall cell lung cancer fuse EML4 to anaplastic lymphoma kinase (ALK), causing expression of several fusion oncoprotein variants. We have determined a 2.6-Å crystal structure of the representative ∼70-kDa core of EML1, revealing an intimately associated pair of β-propellers, which we term a TAPE (tandem atypical propeller in EMLs) domain. One propeller is highly atypical, having a discontinuous subdomain unrelated to a WD40 motif in place of one of its blades. This unexpected feature shows how a propeller structure can be assembled from subdomains with distinct folds. The HELP motif is not an independent domain but forms part of the hydrophobic core that joins the two β-propellers. The TAPE domain binds α/β-tubulin via its conserved, concave surface, including part of the atypical blade. Mapping the characteristic breakpoints of each EML4-ALK variant onto our structure indicates that the EML4 TAPE domain is truncated in many variants in a manner likely to make the fusion protein structurally unstable. We found that the heat shock protein 90 (Hsp90) inhibitor ganetespib induced degradation of these variants whereas others lacking a partial TAPE domain were resistant in both overexpression models and patient-derived cell lines. The Hsp90-sensitive EML4-ALK variants are exceptions to the rule that oncogenic fusion proteins involve breakpoints in disordered regions of both partners.

NIDO, AMOP and vWD domains of MUC4 play synergic role in MUC4 mediated signaling

PubMed Central

Liu, Xian; Xie, Kun-Ling; Tang, Jie; Jiang, Kui-Rong; Gao, Wen-Tao; Tian, Lei; Zhang, Kai; Xu, Ze-Kuan; Miao, Yi

2017-01-01

MUC4 mucin is well known as an important potential target to overcome pancreatic cancer. Three unique domains (NIDO, AMOP, and vWD) with unclear roles only present in MUC4 but are not found in other membrane-bound mucins. Our previous studies first reported that its splice variant, MUC4/Y can be a model of MUC4 (MUC4 gene fragment is more than 30KB, too huge to clone and eukaryotic express) in pancreatic cancer. More importantly, based on MUC4/Y with the appropriate length of gene sequence, it is easy to construct the unique domain-lacking models of MUC4/Y (MUC4) for research. The present study focuses on investigation of the respective role of the unique NIDO, AMOP, and vWD domain or their synergistic effect on MUC4(MUC4/Y)-mediated functions and mechanisms by series of in vitro assays, sequence-based transcriptome analysis, validation of qRT-PCR & Western blot, and systematic comparative analysis. Our results demonstrate: 1) NIDO, AMOP, and vWD domain or their synergy play significant roles on MUC4/Y-mediated malignant function of pancreatic cancer, downstream of molecule mechanisms, particularly MUC4/Y-triggered malignancy-related positive feedback loops, respectively. 2) The synergistic roles of three unique domains on MUC4/Y-mediated functions and mechanisms are more prominent than the respective domain because the synergy of three domain plays the more remarkable effects on MUC4/Y-mediated signaling hub. Thus, to improve reversed effects of domain-lacking and break the synergism of domains will contribute to block MUC4/Y(MUC4) triggering various oncogenic signaling pathways. PMID:28060749

NIDO, AMOP and vWD domains of MUC4 play synergic role in MUC4 mediated signaling.

PubMed

Zhu, Yi; Zhang, Jing-Jing; Peng, Yun-Peng; Liu, Xian; Xie, Kun-Ling; Tang, Jie; Jiang, Kui-Rong; Gao, Wen-Tao; Tian, Lei; Zhang, Kai; Xu, Ze-Kuan; Miao, Yi

2017-02-07

MUC4 mucin is well known as an important potential target to overcome pancreatic cancer. Three unique domains (NIDO, AMOP, and vWD) with unclear roles only present in MUC4 but are not found in other membrane-bound mucins. Our previous studies first reported that its splice variant, MUC4/Y can be a model of MUC4 (MUC4 gene fragment is more than 30KB, too huge to clone and eukaryotic express) in pancreatic cancer. More importantly, based on MUC4/Y with the appropriate length of gene sequence, it is easy to construct the unique domain-lacking models of MUC4/Y (MUC4) for research. The present study focuses on investigation of the respective role of the unique NIDO, AMOP, and vWD domain or their synergistic effect on MUC4(MUC4/Y)-mediated functions and mechanisms by series of in vitro assays, sequence-based transcriptome analysis, validation of qRT-PCR & Western blot, and systematic comparative analysis. Our results demonstrate: 1) NIDO, AMOP, and vWD domain or their synergy play significant roles on MUC4/Y-mediated malignant function of pancreatic cancer, downstream of molecule mechanisms, particularly MUC4/Y-triggered malignancy-related positive feedback loops, respectively. 2) The synergistic roles of three unique domains on MUC4/Y-mediated functions and mechanisms are more prominent than the respective domain because the synergy of three domain plays the more remarkable effects on MUC4/Y-mediated signaling hub. Thus, to improve reversed effects of domain-lacking and break the synergism of domains will contribute to block MUC4/Y(MUC4) triggering various oncogenic signaling pathways.

Clinical efficacy and safety of chelation treatment with typical penicillamine in cross combination with DMPS repeatedly for Wilson's disease.

PubMed

Xu, San-Qing; Li, Xu-Fang; Zhu, Hui-Yun; Liu, Yan; Fang, Feng; Chen, Ling

2013-10-01

The aim of this study was to assess the clinical efficacy and safety of chelation treatment with penicillamine (PCA) in cross combination with sodium 2, 3-dimercapto-1-propane sulfonate (DMPS) repeatedly in patients with Wilson's disease (WD). Thirty-five patients with WD were enrolled. They were administrated intravenous DMPS in cross combination with oral PCA alternately which was practiced repeatedly, all with Zinc in the meantime. During the treatment, clinical observations and 24-h urine copper excretion as well as adverse effects of medicines were recorded and analyzed. Although the incidence of adverse effects was not significantly different after either intravenous DMPS or oral PCA treatment, levels of 24-h urine copper tended to be higher after short-term intravenous DMPS than that of oral PCA. Adverse effects in the course of intravenous DMPS were mainly neutropenia, thrombocytopenia, allergic reaction and bleeding tendency. As compared with oral PCA alone or intravenous DMPS alone, such repeated cross combination treatment could as much as possible avoid continued drug adverse effects or poor curative effect and had less chance to stop treatment in WD patients. Improved or recovered liver function in 71% of the patients, alleviated neurologic symptoms in 50% of the patients, and disappeared hematuria in 70% of the patients could be observed during the follow-up period of 6 months to 5 years after such combined chelation regimen. Chelation treatment repeatedly with oral penicillamine in cross combination with intravenous DMPS alternately could be more beneficial for WD patients to relieve symptoms, avoid continued drug adverse effects and maintain lifelong therapy.

A pomegranate (Punica granatum L.) WD40-repeat gene is a functional homologue of Arabidopsis TTG1 and is involved in the regulation of anthocyanin biosynthesis during pomegranate fruit development.

PubMed

Ben-Simhon, Zohar; Judeinstein, Sylvie; Nadler-Hassar, Talia; Trainin, Taly; Bar-Ya'akov, Irit; Borochov-Neori, Hamutal; Holland, Doron

2011-11-01

Anthocyanins are the major pigments responsible for the pomegranate (Punica granatum L.) fruit skin color. The high variability in fruit external color in pomegranate cultivars reflects variations in anthocyanin composition. To identify genes involved in the regulation of anthocyanin biosynthesis pathway in the pomegranate fruit skin we have isolated, expressed and characterized the pomegranate homologue of the Arabidopsis thaliana TRANSPARENT TESTA GLABRA1 (TTG1), encoding a WD40-repeat protein. The TTG1 protein is a regulator of anthocyanins and proanthocyanidins (PAs) biosynthesis in Arabidopsis, and acts by the formation of a transcriptional regulatory complex with two other regulatory proteins: bHLH and MYB. Our results reveal that the pomegranate gene, designated PgWD40, recovered the anthocyanin, PAs, trichome and seed coat mucilage phenotype in Arabidopsis ttg1 mutant. PgWD40 expression and anthocyanin composition in the skin were analyzed during pomegranate fruit development, in two accessions that differ in skin color intensity and timing of appearance. The results indicate high positive correlation between the total cyanidin derivatives quantity (red pigments) and the expression level of PgWD40. Furthermore, strong correlation was found between the steady state levels of PgWD40 transcripts and the transcripts of pomegranate homologues of the structural genes PgDFR and PgLDOX. PgWD40, PgDFR and PgLDOX expression also correlated with the expression of pomegranate homologues of the regulatory genes PgAn1 (bHLH) and PgAn2 (MYB). On the basis of our results we propose that PgWD40 is involved in the regulation of anthocyanin biosynthesis during pomegranate fruit development and that expression of PgWD40, PgAn1 and PgAn2 in the pomegranate fruit skin is required to regulate the expression of downstream structural genes involved in the anthocyanin biosynthesis.

An allelic series reveals essential roles for FY in plant development in addition to flowering-time control.

PubMed

Henderson, Ian R; Liu, Fuquan; Drea, Sinead; Simpson, Gordon G; Dean, Caroline

2005-08-01

The autonomous pathway functions to promote flowering in Arabidopsis by limiting the accumulation of the floral repressor FLOWERING LOCUS C (FLC). Within this pathway FCA is a plant-specific, nuclear RNA-binding protein, which interacts with FY, a highly conserved eukaryotic polyadenylation factor. FCA and FY function to control polyadenylation site choice during processing of the FCA transcript. Null mutations in the yeast FY homologue Pfs2p are lethal. This raises the question as to whether these essential RNA processing functions are conserved in plants. Characterisation of an allelic series of fy mutations reveals that null alleles are embryo lethal. Furthermore, silencing of FY, but not FCA, is deleterious to growth in Nicotiana. The late-flowering fy alleles are hypomorphic and indicate a requirement for both intact FY WD repeats and the C-terminal domain in repression of FLC. The FY C-terminal domain binds FCA and in vitro assays demonstrate a requirement for both C-terminal FY-PPLPP repeats during this interaction. The expression domain of FY supports its roles in essential and flowering-time functions. Hence, FY may mediate both regulated and constitutive RNA 3'-end processing.

RACK1 interacts with filamin-A to regulate plasma membrane levels of the cystic fibrosis transmembrane conductance regulator

PubMed Central

Smith, Laura; Litman, Paul; Kohli, Ekta; Amick, Joseph; Page, Richard C.; Misra, Saurav

2013-01-01

Mutations in cystic fibrosis transmembrane regulator (CFTR), a chloride channel in the apical membranes of secretory epithelial cells, underlie the fatal genetic disorder cystic fibrosis. Certain CFTR mutations, including the common mutation ΔF508-CFTR, result in greatly decreased levels of active CFTR at the apical membrane. Direct interactions between CFTR and the cytoskeletal adaptors filamin-A (FlnA) and Na+/H+ exchanger regulatory factor 1 (NHERF1) stabilize the expression and localization of CFTR at the plasma membrane. The scaffold protein receptor for activated C kinase 1 (RACK1) also stabilizes CFTR surface expression; however, RACK1 does not interact directly with CFTR and its mechanism of action is unknown. In the present study, we report that RACK1 interacts directly with FlnA in vitro and in a Calu-3 airway epithelial cell line. We mapped the interaction between RACK1 and FlnA to the WD4 and WD6 repeats of RACK1 and to a segment of the large rod domain of FlnA, consisting of immunoglobulin-like repeats 8–15. Disruption of the RACK1-FlnA interaction causes a reduction in CFTR surface levels. Our results suggest that a novel RACK1-FlnA interaction is an important regulator of CFTR surface localization. PMID:23636454

Cognitive profile in Wilson's disease: a case series of 31 patients.

PubMed

Wenisch, E; De Tassigny, A; Trocello, J-M; Beretti, J; Girardot-Tinant, N; Woimant, F

2013-12-01

Wilson's disease (WD) is a rare autosomal recessive disorder of copper metabolism. If untreated, WD, which is initially a liver disease, can turn into a multi-systemic disease with neurological involvement. Very few studies have described cognitive impairment in WD. The aim of this study is to report the cognitive profile of 31 treated WD patients. Patients were classed into two groups using the Unified Wilson Disease Rating Scale (UWDRS): WD patients without neurological signs (WD-N(-)) (n=13), and WD patients with neurological signs (WD-N(+)) (n=18). The patients participated in a neuropsychological assessment evaluating memory, executive function and visuo-spatial abilities. Both groups performed well for verbal intelligence and episodic memory skills. However, the majority of these patients exhibited altered performance for at least one cognitive test, particularly in the executive domain. The WD-N(+) group performed less well than the WD-N(-) group on cognitive tests involving rapid motor function, abstract thinking, working memory and top-down inhibitory control. Cognitive impairment in treated WD patients essentially affects executive function involving fronto-striatal circuits. Verbal intelligence and episodic memory abilities seem to be remarkably preserved. Neuropsychological assessment is a valuable tool to evaluate the presence and the consequences of these cognitive impairments in WD patients with or without neurological signs in the course of this chronic disease. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

The LuWD40-1 gene encoding WD repeat protein regulates growth and pollen viability in flax (Linum Usitatissimum L.).

PubMed

Kumar, Santosh; Jordan, Mark C; Datla, Raju; Cloutier, Sylvie

2013-01-01

As a crop, flax holds significant commercial value for its omega-3 rich oilseeds and stem fibres. Canada is the largest producer of linseed but there exists scope for significant yield improvements. Implementation of mechanisms such as male sterility can permit the development of hybrids to assist in achieving this goal. Temperature sensitive male sterility has been reported in flax but the leakiness of this system in field conditions limits the production of quality hybrid seeds. Here, we characterized a 2,588 bp transcript differentially expressed in male sterile lines of flax. The twelve intron gene predicted to encode a 368 amino acid protein has five WD40 repeats which, in silico, form a propeller structure with putative nucleic acid and histone binding capabilities. The LuWD40-1 protein localized to the nucleus and its expression increased during the transition and continued through the vegetative stages (seed, etiolated seedling, stem) while the transcript levels declined during reproductive development (ovary, anthers) and embryonic morphogenesis of male fertile plants. Knockout lines for LuWD40-1 in flax failed to develop shoots while overexpression lines showed delayed growth phenotype and were male sterile. The non-viable flowers failed to open and the pollen grains from these flowers were empty. Three independent transgenic lines overexpressing the LuWD40-1 gene had ∼80% non-viable pollen, reduced branching, delayed flowering and maturity compared to male fertile genotypes. The present study provides new insights into a male sterility mechanism present in flax.

Kale BoRACK1 is involved in the plant response to salt stress and Peronospora brassicae Gaumann.

PubMed

Li, Da-Hong; Shen, Fu-Jia; Li, Hong-Yan; Li, Wei

2017-06-01

The receptor for activated C kinase 1 (RACK1) belongs to a protein subfamily containing a tryptophan-aspartic acid-domain (WD) repeat structure. Compelling evidence indicates that RACK1 can interact with many signal molecules and affect different signal transduction pathways. In this study, a kale (Brassica oleracea var. acephala f.tricolor) RACK1 gene (BoRACK1) was cloned by RT-PCR. The amino acid sequence of BoRACK1 had seven WD repeats in which there were typical GH (glycine-histidine) and WD dipeptides. Comparison with AtRACK1 from Arabidopsis revealed 87.1% identity at the amino acid level. Expression pattern analysis by RT-PCR showed that BoRACK1 was expressed in all analyzed tissues of kale and that its transcription in leaves was down-regulated by salt, abscisic acid, and H 2 O 2 at a high concentration. Overexpression of BoRACK1 in kale led to a reduction in symptoms caused by Peronospora brassicae Gaumann on kale leaves. The expression levels of the pathogenesis-related protein genes, PR-1 and PRB-1, increased 2.5-4-fold in transgenic kale, and reactive oxygen species production was more active than in the wild-type. They also exhibited increased tolerance to salt stress in seed germination. H 2 O 2 may also be involved in the regulation of BoRACK1 during seed germination under salt stress. Quantitative real-time PCR analyses showed that the transcript levels of BoRbohs genes were significantly higher in overexpression of BoRACK1 transgenic lines. Yeast two-hybrid assays showed that BoRACK1 could interact with WNK8, eIF6, RAR1, and SGT1. This study and previous work lead us to believe that BoRACK1 may form a complex with regulators of plant salt and disease resistance to coordinate kale reactions to pathogens. Copyright © 2017 Elsevier GmbH. All rights reserved.

Assessment of volume measurement of breast cancer-related lymphedema by three methods: circumference measurement, water displacement, and dual energy X-ray absorptiometry.

PubMed

Gjorup, Caroline; Zerahn, Bo; Hendel, Helle W

2010-06-01

Following treatment for breast cancer 12%-60% develop breast cancer-related lymphedema (BCRL). There are several ways of assessing BCRL. Circumference measurement (CM) and water displacement (WD) for volume measurements (VM) are frequently used methods in practice and research, respectively. The aim of this study was to evaluate CM and WD for VM of the BCRL arm and the contralateral arm, comparing the results with regional dual energy X-ray absorptiometry (DXA). Twenty-four women with unilateral BCRL were included in the study. Blinded duplicate VM were obtained from both arms using the three methods mentioned above. CM and DXA were performed by two observers. WD was performed by a group of observers. Mean differences (d) in duplicated volumes, limits of agreement (LOA), and 95% confidence intervals (CI) were calculated for each method. The repeatability expressed as d (95% CI) between the duplicated VM of the BCRL arm and the contralateral arm was for DXA 3 ml (-6-11) and 3 ml (1-7), respectively. For CM and WD, the d (95% CI) of the BCRL arm were 107 ml (86-127) and 26 ml (-26-79), respectively and in the contralateral arm 100 ml (78-122) and -6 ml (-29-17), respectively. DXA is superior in repeatability when compared to CM and WD for VM, especially for the BCRL arm but also the contralateral arm.

The Potential of the MAGIC TOM Parental Accessions to Explore the Genetic Variability in Tomato Acclimation to Repeated Cycles of Water Deficit and Recovery

PubMed Central

Ripoll, Julie; Urban, Laurent; Bertin, Nadia

2016-01-01

Episodes of water deficit (WD) during the crop cycle of tomato may negatively impact plant growth and fruit yield, but they may also improve fruit quality. Moreover, a moderate WD may induce a plant “memory effect” which is known to stimulate plant acclimation and defenses for upcoming stress episodes. The objective of this study was to analyze the positive and negative impacts of repeated episodes of WD at the plant and fruit levels. Three episodes of WD (–38, –45, and –55% of water supply) followed by three periods of recovery (“WD treatments”), were applied to the eight parents of the Multi-Parent Advanced Generation Inter-Cross population which offers the largest allelic variability observed in tomato. Predawn and midday water potentials, chlorophyll a fluorescence, growth and fruit quality traits [contents in sugars, acids, carotenoids, and ascorbic acid (AsA)] were measured throughout the experiment. Important genotypic variations were observed both at the plant and fruit levels and variations in fruit and leaf traits were found not to be correlated. Overall, the WD treatments were at the origin of important osmotic regulations, reduction of leaf growth, acclimation of photosynthetic functioning, notably through an increase in the chlorophyll content and in the quantum yield of the electron transport flux until PSI acceptors (J0RE1/JABS). The effects on fruit sugar, acid, carotenoid and AsA contents on a dry matter basis ranged from negative to positive to nil depending on genotypes and stress intensity. Three small fruit size accessions were richer in AsA on a fresh matter basis, due to concentration effects. So, fruit quality was improved under WD mainly through concentration effects. On the whole, two accessions, LA1420 and Criollo appeared as interesting genetic resources, cumulating adaptive traits both at the leaf and fruit levels. Our observations show that the complexity involved in plant responses, when considering a broad range of physiological traits and the variability of genotypic effects, represent a true challenge for upcoming studies aiming at taking advantage of, not just dealing with WD. PMID:26779213

Microtubule association of EML proteins and the EML4-ALK variant 3 oncoprotein require an N-terminal trimerization domain.

PubMed

Richards, Mark W; O'Regan, Laura; Roth, Daniel; Montgomery, Jessica M; Straube, Anne; Fry, Andrew M; Bayliss, Richard

2015-05-01

Proteins of the echinoderm microtubule (MT)-associated protein (EMAP)-like (EML) family contribute to formation of the mitotic spindle and interphase MT network. EML1-4 consist of Trp-Asp 40 (WD40) repeats and an N-terminal region containing a putative coiled-coil. Recurrent gene rearrangements in non-small cell lung cancer (NSCLC) fuse EML4 to anaplastic lymphoma kinase (ALK) causing expression of several oncogenic fusion variants. The fusions have constitutive ALK activity due to self-association through the EML4 coiled-coil. We have determined crystal structures of the coiled-coils from EML2 and EML4, which describe the structural basis of both EML self-association and oncogenic EML4-ALK activation. The structures reveal a trimeric oligomerization state directed by a conserved pattern of hydrophobic residues and salt bridges. We show that the trimerization domain (TD) of EML1 is necessary and sufficient for self-association. The TD is also essential for MT binding; however, this property requires an adjacent basic region. These observations prompted us to investigate MT association of EML4-ALK and EML1-ABL1 (Abelson 1) fusions in which variable portions of the EML component are present. Uniquely, EML4-ALK variant 3, which includes the TD and basic region of EML4 but none of the WD40 repeats, was localized to MTs, both when expressed recombinantly and when expressed in a patient-derived NSCLC cell line (H2228). This raises the question of whether the mislocalization of ALK activity to MTs might influence downstream signalling and malignant properties of cells. Furthermore, the structure of EML4 TD may enable the development of protein-protein interaction inhibitors targeting the trimerization interface, providing a possible avenue towards therapeutic intervention in EML4-ALK NSCLC.

Improving measures of work-related physical functioning.

PubMed

McDonough, Christine M; Ni, Pengsheng; Peterik, Kara; Marfeo, Elizabeth E; Marino, Molly E; Meterko, Mark; Rasch, Elizabeth K; Brandt, Diane E; Jette, Alan M; Chan, Leighton

2017-03-01

To expand content of the physical function domain of the Work Disability Functional Assessment Battery (WD-FAB), developed for the US Social Security Administration's (SSA) disability determination process. Newly developed questions were administered to 3532 recent SSA applicants for work disability benefits and 2025 US adults. Factor analyses and item response theory (IRT) methods were used to calibrate and link the new items to the existing WD-FAB, and computer-adaptive test simulations were conducted. Factor and IRT analyses supported integration of 44 new items into three existing WD-FAB scales and the addition of a new 11-item scale (Community Mobility). The final physical function domain consisting of: Basic Mobility (56 items), Upper Body Function (34 items), Fine Motor Function (45 items), and Community Mobility (11 items) demonstrated acceptable psychometric properties. The WD-FAB offers an important tool for enhancement of work disability determination. The FAB could provide relevant information about work-related functioning for initial assessment of claimants; identifying denied applicants who may benefit from interventions to improve work and health outcomes; enhancing periodic review of work disability beneficiaries; and assessing outcomes for policies, programs and services targeting people with work disability.

Improving Measures of Work-Related Physical Functioning

PubMed Central

McDonough, Christine M.; Ni, Pengsheng; Peterik, Kara; Marfeo, Elizabeth E.; Marino, Molly E.; Meterko, Mark; Rasch, Elizabeth K; Brandt, Diane E.; Jette, Alan M; Chan, Leighton

2016-01-01

Purpose To expand content of the physical function domain of the Work Disability Functional Assessment Battery (WD-FAB), developed for the US Social Security Administration’s (SSA) disability determination process. Methods Newly developed questions were administered to 3,532 recent SSA applicants for work disability benefits and 2,025 US adults. Factor analyses and item response theory (IRT) methods were used to calibrate and link the new items to existing WD-FAB, and computer-adaptive test simulations were conducted. Results Factor and IRT analyses supported integration of 44 new items into 3 existing WD-FAB scales and the addition of a new 11-item scale (Community Mobility). The final physical function domain consisting of: Basic Mobility (56 items), Upper Body Function (34 items), Fine Motor Function (45 items), and Community Mobility (11 items) demonstrated acceptable psychometric properties. Conclusions The WD-FAB offers an important tool for enhancement of work disability determination. The FAB could provide relevant information about work-related functioning for initial assessment of claimants, identifying denied applicants who may benefit from interventions to improve work and health outcomes; enhancing periodic review of work disability beneficiaries; and assessing outcomes for policies, programs and services targeting people with work disability. PMID:28005243

Structural model of the dimeric Parkinson’s protein LRRK2 reveals a compact architecture involving distant interdomain contacts

PubMed Central

Guaitoli, Giambattista; Raimondi, Francesco; Gilsbach, Bernd K.; Gómez-Llorente, Yacob; Deyaert, Egon; Renzi, Fabiana; Li, Xianting; Schaffner, Adam; Jagtap, Pravin Kumar Ankush; Boldt, Karsten; von Zweydorf, Felix; Gotthardt, Katja; Lorimer, Donald D.; Yue, Zhenyu; Burgin, Alex; Janjic, Nebojsa; Sattler, Michael; Versées, Wim; Ueffing, Marius; Ubarretxena-Belandia, Iban; Kortholt, Arjan; Gloeckner, Christian Johannes

2016-01-01

Leucine-rich repeat kinase 2 (LRRK2) is a large, multidomain protein containing two catalytic domains: a Ras of complex proteins (Roc) G-domain and a kinase domain. Mutations associated with familial and sporadic Parkinson’s disease (PD) have been identified in both catalytic domains, as well as in several of its multiple putative regulatory domains. Several of these mutations have been linked to increased kinase activity. Despite the role of LRRK2 in the pathogenesis of PD, little is known about its overall architecture and how PD-linked mutations alter its function and enzymatic activities. Here, we have modeled the 3D structure of dimeric, full-length LRRK2 by combining domain-based homology models with multiple experimental constraints provided by chemical cross-linking combined with mass spectrometry, negative-stain EM, and small-angle X-ray scattering. Our model reveals dimeric LRRK2 has a compact overall architecture with a tight, multidomain organization. Close contacts between the N-terminal ankyrin and C-terminal WD40 domains, and their proximity—together with the LRR domain—to the kinase domain suggest an intramolecular mechanism for LRRK2 kinase activity regulation. Overall, our studies provide, to our knowledge, the first structural framework for understanding the role of the different domains of full-length LRRK2 in the pathogenesis of PD. PMID:27357661

Chemical migration during soil water retention curve evaluation.

PubMed

Pires, Luiz F; Villanueva, Felipe C A; Dias, Nivea M P; Bacchi, Osny O Santos; Reichardt, Klaus

2011-09-01

Wetting and drying (W-D) cycles can induce important elemental migrations in soils. The main purpose of this work was to study the possible existence of soil chemical elemental migrations in samples submitted to repeated W-D cycles during evaluations of soil water retention curve (SWRC). The experimental measurements were carried out by Atomic Absorption Spectrometry (AAS) for Ca(2+), Mg(2+) and K(+) on samples of three different Brazilian tropical soils (Geric Ferralsol, Eutric Nitosol and Rhodic Ferralsol). Results demonstrate an increase in the electrical conductivity of the water extracted from the samples and significant losses of Ca(2+), Mg(2+) and K(+) during the applications of up to nine W-D cycles. It was also observed differences in SWRC for all soils when samples submitted to the application of several W-D cycles were compared with samples not submitted to it. These differences occurred at the region of both structural and textural pores. A possible explanation for these results could be the soil chemical migration during the sequences of W-D cycles, which can affect the soil structure development.

Work disability in Argentinian patients with systemic lupus erythematosus is prevalent and it is due to ethnic, socioeconomic and disease-related factors.

PubMed

Pisoni, Cecilia N; Muñoz, Sebastián A; Tamborenea, María N; García, Mercedes; Curti, Ana; Cappuccio, Ana; Rillo, Oscar; Imamura, Patricia M; Schneeberger, Emilce; Ballent, Marcela; Cousseau, Mario L; Velasco Zamora, Jorge; Saurit, Verónica; Toloza, Sergio; Danielsen, María C; Bellomio, Verónica I; Graf, Cesar; Paira, Sergio; Cavallasca, Javier; Pons Estel, Bernardo; Moreno, José L C; Díaz, Mónica; Alba, Paula; Verando, Marcela; Tate, Guillermo; Mysler, Eduardo; Sarano, Judith; Civit, Emma E; Risueño, Fabián; Álvarez Sepúlveda, Pablo; Larroude, María S; Méndez, Marcos F; Conforti, Andrea; Sohn, Débora

2018-04-02

To study the prevalence and the associated factors of work disability (WD) in systemic lupus erythematosus (SLE) patients. A sample of 419 SLE patients from an observational cross-sectional multicenter study was included. Sociodemographic features, disease characteristics, comorbidities, quality of life, unhealthy behaviors, and work-related factors were measured in a standardized interview. Work disability was defined by patient self-report of not being able to work because of SLE. To identify variables associated with work disability, two different multivariate regression models using a stepwise backward method were performed. Prevalence of WD due to SLE was 24.3%. Eighty-nine percent were female and 51% were Caucasians. Mean disease duration was 8.9 ± 7.2 years, and median System Lupus International Collaborating Clinics/American College of Rheumatology damage index SLICC-SDI was 1.5 (range 0-17). In stepwise multivariate logistic regression, living below the poverty line (odds ratio [OR] = 4.65), less than 12 years of education (OR = 2.84), Mestizo ethnicity (OR = 1.94) and SLICC-SDI (OR = 1.25) were predictors of WD. A second model was performed including patient-derived measures; in this model sedentary lifestyle (OR = 2.69) and lower emotional health domain score of the Lupus Quality of Life (LupusQoL) questionnaire (OR = 1.03) were found to be associated to WD and a higher score in LupusQoL physical health domain (OR = 0.93) was protective. The prevalence of WD in Argentinian SLE patients was 24.3%. WD was associated with ethnic (Mestizo), socioeconomic (poverty) and disease-related factors. Patient-related outcomes such us sedentary lifestyle and poor emotional quality of life were also associated with WD. © 2018 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.

Platelet glycoprotein Ibalpha forms catch bonds with human WT vWF but not with type 2B von Willebrand disease vWF.

PubMed

Yago, Tadayuki; Lou, Jizhong; Wu, Tao; Yang, Jun; Miner, Jonathan J; Coburn, Leslie; López, José A; Cruz, Miguel A; Dong, Jing-Fei; McIntire, Larry V; McEver, Rodger P; Zhu, Cheng

2008-09-01

Arterial blood flow enhances glycoprotein Ibalpha (GPIbalpha) binding to vWF, which initiates platelet adhesion to injured vessels. Mutations in the vWF A1 domain that cause type 2B von Willebrand disease (vWD) reduce the flow requirement for adhesion. Here we show that increasing force on GPIbalpha/vWF bonds first prolonged ("catch") and then shortened ("slip") bond lifetimes. Two type 2B vWD A1 domain mutants, R1306Q and R1450E, converted catch bonds to slip bonds by prolonging bond lifetimes at low forces. Steered molecular dynamics simulations of GPIbalpha dissociating from the A1 domain suggested mechanisms for catch bonds and their conversion by the A1 domain mutations. Catch bonds caused platelets and GPIbalpha-coated microspheres to roll more slowly on WT vWF and WT A1 domains as flow increased from suboptimal levels, explaining flow-enhanced rolling. Longer bond lifetimes at low forces eliminated the flow requirement for rolling on R1306Q and R1450E mutant A1 domains. Flowing platelets agglutinated with microspheres bearing R1306Q or R1450E mutant A1 domains, but not WT A1 domains. Therefore, catch bonds may prevent vWF multimers from agglutinating platelets. A disintegrin and metalloproteinase with a thrombospondin type 1 motif-13 (ADAMTS-13) reduced platelet agglutination with microspheres bearing a tridomain A1A2A3 vWF fragment with the R1450E mutation in a shear-dependent manner. We conclude that in type 2B vWD, prolonged lifetimes of vWF bonds with GPIbalpha on circulating platelets may allow ADAMTS-13 to deplete large vWF multimers, causing bleeding.

An allosteric conduit facilitates dynamic multisite substrate recognition by the SCFCdc4 ubiquitin ligase

NASA Astrophysics Data System (ADS)

Csizmok, Veronika; Orlicky, Stephen; Cheng, Jing; Song, Jianhui; Bah, Alaji; Delgoshaie, Neda; Lin, Hong; Mittag, Tanja; Sicheri, Frank; Chan, Hue Sun; Tyers, Mike; Forman-Kay, Julie D.

2017-01-01

The ubiquitin ligase SCFCdc4 mediates phosphorylation-dependent elimination of numerous substrates by binding one or more Cdc4 phosphodegrons (CPDs). Methyl-based NMR analysis of the Cdc4 WD40 domain demonstrates that Cyclin E, Sic1 and Ash1 degrons have variable effects on the primary Cdc4WD40 binding pocket. Unexpectedly, a Sic1-derived multi-CPD substrate (pSic1) perturbs methyls around a previously documented allosteric binding site for the chemical inhibitor SCF-I2. NMR cross-saturation experiments confirm direct contact between pSic1 and the allosteric pocket. Phosphopeptide affinity measurements reveal negative allosteric communication between the primary CPD and allosteric pockets. Mathematical modelling indicates that the allosteric pocket may enhance ultrasensitivity by tethering pSic1 to Cdc4. These results suggest negative allosteric interaction between two distinct binding pockets on the Cdc4WD40 domain may facilitate dynamic exchange of multiple CPD sites to confer ultrasensitive dependence on substrate phosphorylation.

The LRRK2 G2385R variant is a partial loss-of-function mutation that affects synaptic vesicle trafficking through altered protein interactions.

PubMed

Carrion, Maria Dolores Perez; Marsicano, Silvia; Daniele, Federica; Marte, Antonella; Pischedda, Francesca; Di Cairano, Eliana; Piovesana, Ester; von Zweydorf, Felix; Kremmer, Elisabeth; Gloeckner, Christian Johannes; Onofri, Franco; Perego, Carla; Piccoli, Giovanni

2017-07-14

Mutations in the Leucine-rich repeat kinase 2 gene (LRRK2) are associated with familial Parkinson's disease (PD). LRRK2 protein contains several functional domains, including protein-protein interaction domains at its N- and C-termini. In this study, we analyzed the functional features attributed to LRRK2 by its N- and C-terminal domains. We combined TIRF microscopy and synaptopHluorin assay to visualize synaptic vesicle trafficking. We found that N- and C-terminal domains have opposite impact on synaptic vesicle dynamics. Biochemical analysis demonstrated that different proteins are bound at the two extremities, namely β3-Cav2.1 at N-terminus part and β-Actin and Synapsin I at C-terminus domain. A sequence variant (G2385R) harboured within the C-terminal WD40 domain increases the risk for PD. Complementary biochemical and imaging approaches revealed that the G2385R variant alters strength and quality of LRRK2 interactions and increases fusion of synaptic vesicles. Our data suggest that the G2385R variant behaves like a loss-of-function mutation that mimics activity-driven events. Impaired scaffolding capabilities of mutant LRRK2 resulting in perturbed vesicular trafficking may arise as a common pathophysiological denominator through which different LRRK2 pathological mutations cause disease.

Lack of WDR36 leads to preimplantation embryonic lethality in mice and delays the formation of small subunit ribosomal RNA in human cells in vitro.

PubMed

Gallenberger, Martin; Meinel, Dominik M; Kroeber, Markus; Wegner, Michael; Milkereit, Philipp; Bösl, Michael R; Tamm, Ernst R

2011-02-01

Mutations in WD repeat domain 36 gene (WDR36) play a causative role in some forms of primary open-angle glaucoma, a leading cause of blindness worldwide. WDR36 is characterized by the presence of multiple WD40 repeats and shows homology to Utp21, an essential protein component of the yeast small subunit (SSU) processome required for maturation of 18S rRNA. To clarify the functional role of WDR36 in the mammalian organism, we generated and investigated mutant mice with a targeted deletion of Wdr36. In parallel experiments, we used RNA interference to deplete WDR36 mRNA in mouse embryos and cultured human trabecular meshwork (HTM-N) cells. Deletion of Wdr36 in the mouse caused preimplantation embryonic lethality, and essentially similar effects were observed when WDR36 mRNA was depleted in mouse embryos by RNA interference. Depletion of WDR36 mRNA in HTM-N cells caused apoptotic cell death and upregulation of mRNA for BAX, TP53 and CDKN1A. By immunocytochemistry, staining for WDR36 was observed in the nucleolus of cells, which co-localized with that of nucleolar proteins such as nucleophosmin and PWP2. In addition, recombinant and epitope-tagged WDR36 localized to the nucleolus of HTM-N cells. By northern blot analysis, a substantial decrease in 21S rRNA, the precursor of 18S rRNA, was observed following knockdown of WDR36. In addition, metabolic-labeling experiments consistently showed a delay of 18S rRNA maturation in WDR36-depleted cells. Our results provide evidence that WDR36 is an essential protein in mammalian cells which is involved in the nucleolar processing of SSU 18S rRNA.

WD40-repeat 47, a microtubule-associated protein, is essential for brain development and autophagy

PubMed Central

Kannan, Meghna; Bayam, Efil; Wagner, Christel; Rinaldi, Bruno; Kretz, Perrine F.; Tilly, Peggy; Roos, Marna; McGillewie, Lara; Bär, Séverine; Minocha, Shilpi; Chevalier, Claire; Po, Chrystelle; Chelly, Jamel; Mandel, Jean-Louis; Borgatti, Renato; Piton, Amélie; Loos, Ben; Adams, David J.; Hérault, Yann; Collins, Stephan C.; Godin, Juliette D.; Yalcin, Binnaz

2017-01-01

The family of WD40-repeat (WDR) proteins is one of the largest in eukaryotes, but little is known about their function in brain development. Among 26 WDR genes assessed, we found 7 displaying a major impact in neuronal morphology when inactivated in mice. Remarkably, all seven genes showed corpus callosum defects, including thicker (Atg16l1, Coro1c, Dmxl2, and Herc1), thinner (Kif21b and Wdr89), or absent corpus callosum (Wdr47), revealing a common role for WDR genes in brain connectivity. We focused on the poorly studied WDR47 protein sharing structural homology with LIS1, which causes lissencephaly. In a dosage-dependent manner, mice lacking Wdr47 showed lethality, extensive fiber defects, microcephaly, thinner cortices, and sensory motor gating abnormalities. We showed that WDR47 shares functional characteristics with LIS1 and participates in key microtubule-mediated processes, including neural stem cell proliferation, radial migration, and growth cone dynamics. In absence of WDR47, the exhaustion of late cortical progenitors and the consequent decrease of neurogenesis together with the impaired survival of late-born neurons are likely yielding to the worsening of the microcephaly phenotype postnatally. Interestingly, the WDR47-specific C-terminal to LisH (CTLH) domain was associated with functions in autophagy described in mammals. Silencing WDR47 in hypothalamic GT1-7 neuronal cells and yeast models independently recapitulated these findings, showing conserved mechanisms. Finally, our data identified superior cervical ganglion-10 (SCG10) as an interacting partner of WDR47. Taken together, these results provide a starting point for studying the implications of WDR proteins in neuronal regulation of microtubules and autophagy. PMID:29078390

WD40-repeat 47, a microtubule-associated protein, is essential for brain development and autophagy.

PubMed

Kannan, Meghna; Bayam, Efil; Wagner, Christel; Rinaldi, Bruno; Kretz, Perrine F; Tilly, Peggy; Roos, Marna; McGillewie, Lara; Bär, Séverine; Minocha, Shilpi; Chevalier, Claire; Po, Chrystelle; Chelly, Jamel; Mandel, Jean-Louis; Borgatti, Renato; Piton, Amélie; Kinnear, Craig; Loos, Ben; Adams, David J; Hérault, Yann; Collins, Stephan C; Friant, Sylvie; Godin, Juliette D; Yalcin, Binnaz

2017-10-31

The family of WD40-repeat (WDR) proteins is one of the largest in eukaryotes, but little is known about their function in brain development. Among 26 WDR genes assessed, we found 7 displaying a major impact in neuronal morphology when inactivated in mice. Remarkably, all seven genes showed corpus callosum defects, including thicker ( Atg16l1 , Coro1c , Dmxl2 , and Herc1 ), thinner ( Kif21b and Wdr89 ), or absent corpus callosum ( Wdr47 ), revealing a common role for WDR genes in brain connectivity. We focused on the poorly studied WDR47 protein sharing structural homology with LIS1, which causes lissencephaly. In a dosage-dependent manner, mice lacking Wdr47 showed lethality, extensive fiber defects, microcephaly, thinner cortices, and sensory motor gating abnormalities. We showed that WDR47 shares functional characteristics with LIS1 and participates in key microtubule-mediated processes, including neural stem cell proliferation, radial migration, and growth cone dynamics. In absence of WDR47, the exhaustion of late cortical progenitors and the consequent decrease of neurogenesis together with the impaired survival of late-born neurons are likely yielding to the worsening of the microcephaly phenotype postnatally. Interestingly, the WDR47-specific C-terminal to LisH (CTLH) domain was associated with functions in autophagy described in mammals. Silencing WDR47 in hypothalamic GT1-7 neuronal cells and yeast models independently recapitulated these findings, showing conserved mechanisms. Finally, our data identified superior cervical ganglion-10 (SCG10) as an interacting partner of WDR47. Taken together, these results provide a starting point for studying the implications of WDR proteins in neuronal regulation of microtubules and autophagy. Published under the PNAS license.

Source-Receptor Relationship Analysis of the Atmospheric Deposition of PAHs Subject to Long-Range Transport in Northeast Asia.

PubMed

Inomata, Yayoi; Kajino, Mizuo; Sato, Keiichi; Kurokawa, Junichi; Tang, Ning; Ohara, Toshimasa; Hayakawa, Kazuichi; Ueda, Hiromasa

2017-07-18

The source-receptor relationship analysis of PAH deposition in Northeast Asia was investigated using an Eulerian regional-scale aerosol chemical transport model. Dry deposition (DD) of PAH was controlled by wind flow patterns, whereas wet deposition (WD) depended on precipitation in addition to wind flow patterns. The contribution of WD was approximately 50-90% of the total deposition, except during winter in Northern China (NCHN) and Eastern Russia (ERUS) because of the low amount of precipitation. The amount of PAH deposition showed clear seasonal variation and was high in winter and low in summer in downwind (South Korea, Japan) and oceanic-receptor regions. In the downwind region, the contributions from NCHN (WD 28-52%; DD 54-55%) and Central China (CCHN) (WD 43-65%; DD 33-38%) were large in winter, whereas self-contributions (WD 20-51%; DD 79-81%) were relatively high in summer. In the oceanic-receptor region, the deposition amount decreased with distance from the Asian continent. The amount of DD was strongly influenced by emissions from neighboring domains. The contributions of WD from NCHN (16-20%) and CCHN (28-35%) were large. The large contributions from China in summer to the downwind region were linked to vertical transport of PAHs over the Asian continent associated with convection.

Stress-Related Gene Expression Reflects Morphophysiological Responses to Water Deficit1[OPEN

PubMed Central

Vile, Denis; Bediee, Alexis; Dauzat, Myriam; Luchaire, Nathalie; Kamrowska, Dominika; Granier, Christine

2017-01-01

Acclimation to water deficit (WD) enables plants to maintain growth under unfavorable environmental conditions, although the mechanisms are not completely understood. In this study, the natural variation of long-term acclimation to moderate and severe soil WD was investigated in 18 Arabidopsis (Arabidopsis thaliana) accessions using PHENOPSIS, an automated phenotyping platform. Soil water content was adjusted at an early stage of plant development and maintained at a constant level until reproductive age was achieved. The accessions were selected based on the expression levels of ANNEXIN1, a drought-related marker. Severe WD conditions had a greater effect on most of the measured morphophysiological traits than moderate WD conditions. Multivariate analyses indicated that trait responses associated with plant size and water management drove most of the variation. Accessions with similar responses at these two levels were grouped in clusters that displayed different response strategies to WD. The expression levels of selected stress-response genes revealed large natural variation under WD conditions. Responses of morphophysiological traits, such as projected rosette area, transpiration rate, and rosette water content, were correlated with changes in the expression of stress-related genes, such as NINE-CIS-EPOXYCAROTENOID DIOXYGENASE3 and N-MYC DOWNREGULATED-LIKE1 (NDL1), in response to WD. Interestingly, the morphophysiological acclimation response to WD also was reflected in the gene expression levels (most notably those of NDL1, CHALCONE SYNTHASE, and MYB DOMAIN PROTEIN44) in plants cultivated under well-watered conditions. Our results may lead to the development of biomarkers and predictors of plant morphophysiological responses based on gene expression patterns. PMID:28522456

Association studies of WD repeat domain 3 and chitobiosyldiphosphodolichol beta-mannosyltransferase genes with schizophrenia in a Japanese population

PubMed Central

Iwayama, Yoshimi; Yamamoto, Naoki; Toyota, Tomoko; Suzuki, Katsuaki; Kikuchi, Mitsuru; Hashimoto, Tasuku; Kanahara, Nobuhisa; Kurumaji, Akeo; Yoshikawa, Takeo

2018-01-01

Schizophrenia and schizophrenia-like symptoms induced by the dopamine agonists and N-methyl-D aspartate type glutamate receptor antagonists occur only after the adolescent period. Similarly, animal models of schizophrenia by these drugs are also induced after the critical period around postnatal week three. Based upon the development-dependent onsets of these psychotomimetic effects, by using a DNA microarray technique, we identified the WD repeat domain 3 (WDR3) and chitobiosyldiphosphodolichol beta-mannosyltransferase (ALG1) genes as novel candidates for schizophrenia-related molecules, whose mRNAs were up-regulated in the adult (postnatal week seven), but not in the infant (postnatal week one) rats by an indirect dopamine agonist, and phencyclidine, an antagonist of the NMDA receptor. WDR3 and other related proteins are the nuclear proteins presumably involved in various cellular activities, such as cell cycle progression, signal transduction, apoptosis, and gene regulation. ALG1 is presumed to be involved in the regulation of the protein N-glycosylation. To further elucidate the molecular pathophysiology of schizophrenia, we have evaluated the genetic association of WDR3 and ALG1 in schizophrenia. We examined 21 single nucleotide polymorphisms [SNPs; W1 (rs1812607)-W16 (rs6656360), A1 (rs8053916)-A10 (rs9673733)] from these genes using the Japanese case-control sample (1,808 schizophrenics and 2,170 matched controls). No significant genetic associations of these SNPs were identified. However, we detected a significant association of W4 (rs319471) in the female schizophrenics (allelic P = 0.003, genotypic P = 0.008). Based on a haplotype analysis, the observed haplotypes consisting of W4 (rs319471)–W5 (rs379058) also displayed a significant association in the female schizophrenics (P = 0.016). Even after correction for multiple testing, these associations remained significant. Our findings suggest that the WDR3 gene may likely be a sensitive factor in female patients with schizophrenia, and that modification of the WDR3 signaling pathway warrants further investigation as to the pathophysiology of schizophrenia. PMID:29309433

Artificial Recruitment of UAF1-USP Complexes by a PHLPP1-E1 Chimeric Helicase Enhances Human Papillomavirus DNA Replication

PubMed Central

Gagnon, David; Lehoux, Michaël

2015-01-01

ABSTRACT The E1 helicase from anogenital human papillomavirus (HPV) types interacts with the cellular WD repeat-containing protein UAF1 in complex with the deubiquitinating enzyme USP1, USP12, or USP46. This interaction stimulates viral DNA replication and is required for maintenance of the viral episome in keratinocytes. E1 associates with UAF1 through a short UAF1-binding site (UBS) located within the N-terminal 40 residues of the protein. Here, we investigated if the E1 UBS could be replaced by the analogous domain from an unrelated protein, the pleckstrin homology domain and leucine-rich repeat protein phosphatase 1 (PHLPP1). We found that PHLPP1 and E1 interact with UAF1 in a mutually exclusive manner and mapped the minimal PHLPP1 UBS (PUBS) to a 100-amino-acid region sufficient for assembly into UAF1-USP complexes. Similarly to the E1 UBS, overexpression of PUBS in trans inhibited HPV DNA replication, albeit less efficiently. Characterization of a PHLPP1-E1 chimeric helicase revealed that PUBS could partially substitute for the E1 UBS in enhancing viral DNA replication and that the stimulatory effect of PUBS likely involves recruitment of UAF1-USP complexes, as it was abolished by mutations that weaken UAF1-binding and by overexpression of catalytically inactive USPs. Although functionally similar to the E1 UBS, PUBS is larger in size and requires both the WD repeat region and C-terminal ubiquitin-like domain of UAF1 for interaction, in contrast to E1, which does not contact the latter. Overall, this comparison of two heterologous UBSs indicates that these domains function as transferable protein interaction modules and provide further evidence that the association of E1 with UAF1-containing deubiquitinating complexes stimulates HPV DNA replication. IMPORTANCE The E1 protein from anogenital HPV types interacts with the UAF1-associated deubiquitinating enzymes USP1, USP12, and USP46 to stimulate replication of the viral genome. Little is known about the molecular nature of the E1-UAF1 interaction and, more generally, how UAF1-USP complexes recognize their substrate proteins. To address this question, we characterized the UAF1-binding site (UBS) of PHLPP1, a protein unrelated to E1. Using a PHLPP1-E1 chimeric helicase, we show that the PHLPP1 UBS (PUBS) can partially substitute for the E1 UBS in stimulating HPV DNA replication. This stimulation required conserved sequences in PUBS that meditate its interaction with UAF1, including a motif common to the E1 UBS. These results indicate that UAF1-binding sequences function as transferable protein interaction modules and provide further evidence that UAF1-USP complexes stimulate HPV DNA replication. PMID:25833051

Artificial Recruitment of UAF1-USP Complexes by a PHLPP1-E1 Chimeric Helicase Enhances Human Papillomavirus DNA Replication.

PubMed

Gagnon, David; Lehoux, Michaël; Archambault, Jacques

2015-06-01

The E1 helicase from anogenital human papillomavirus (HPV) types interacts with the cellular WD repeat-containing protein UAF1 in complex with the deubiquitinating enzyme USP1, USP12, or USP46. This interaction stimulates viral DNA replication and is required for maintenance of the viral episome in keratinocytes. E1 associates with UAF1 through a short UAF1-binding site (UBS) located within the N-terminal 40 residues of the protein. Here, we investigated if the E1 UBS could be replaced by the analogous domain from an unrelated protein, the pleckstrin homology domain and leucine-rich repeat protein phosphatase 1 (PHLPP1). We found that PHLPP1 and E1 interact with UAF1 in a mutually exclusive manner and mapped the minimal PHLPP1 UBS (PUBS) to a 100-amino-acid region sufficient for assembly into UAF1-USP complexes. Similarly to the E1 UBS, overexpression of PUBS in trans inhibited HPV DNA replication, albeit less efficiently. Characterization of a PHLPP1-E1 chimeric helicase revealed that PUBS could partially substitute for the E1 UBS in enhancing viral DNA replication and that the stimulatory effect of PUBS likely involves recruitment of UAF1-USP complexes, as it was abolished by mutations that weaken UAF1-binding and by overexpression of catalytically inactive USPs. Although functionally similar to the E1 UBS, PUBS is larger in size and requires both the WD repeat region and C-terminal ubiquitin-like domain of UAF1 for interaction, in contrast to E1, which does not contact the latter. Overall, this comparison of two heterologous UBSs indicates that these domains function as transferable protein interaction modules and provide further evidence that the association of E1 with UAF1-containing deubiquitinating complexes stimulates HPV DNA replication. The E1 protein from anogenital HPV types interacts with the UAF1-associated deubiquitinating enzymes USP1, USP12, and USP46 to stimulate replication of the viral genome. Little is known about the molecular nature of the E1-UAF1 interaction and, more generally, how UAF1-USP complexes recognize their substrate proteins. To address this question, we characterized the UAF1-binding site (UBS) of PHLPP1, a protein unrelated to E1. Using a PHLPP1-E1 chimeric helicase, we show that the PHLPP1 UBS (PUBS) can partially substitute for the E1 UBS in stimulating HPV DNA replication. This stimulation required conserved sequences in PUBS that meditate its interaction with UAF1, including a motif common to the E1 UBS. These results indicate that UAF1-binding sequences function as transferable protein interaction modules and provide further evidence that UAF1-USP complexes stimulate HPV DNA replication. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Platelet glycoprotein Ibα forms catch bonds with human WT vWF but not with type 2B von Willebrand disease vWF

PubMed Central

Yago, Tadayuki; Lou, Jizhong; Wu, Tao; Yang, Jun; Miner, Jonathan J.; Coburn, Leslie; López, José A.; Cruz, Miguel A.; Dong, Jing-Fei; McIntire, Larry V.; McEver, Rodger P.; Zhu, Cheng

2008-01-01

Arterial blood flow enhances glycoprotein Ibα (GPIbα) binding to vWF, which initiates platelet adhesion to injured vessels. Mutations in the vWF A1 domain that cause type 2B von Willebrand disease (vWD) reduce the flow requirement for adhesion. Here we show that increasing force on GPIbα/vWF bonds first prolonged (“catch”) and then shortened (“slip”) bond lifetimes. Two type 2B vWD A1 domain mutants, R1306Q and R1450E, converted catch bonds to slip bonds by prolonging bond lifetimes at low forces. Steered molecular dynamics simulations of GPIbα dissociating from the A1 domain suggested mechanisms for catch bonds and their conversion by the A1 domain mutations. Catch bonds caused platelets and GPIbα-coated microspheres to roll more slowly on WT vWF and WT A1 domains as flow increased from suboptimal levels, explaining flow-enhanced rolling. Longer bond lifetimes at low forces eliminated the flow requirement for rolling on R1306Q and R1450E mutant A1 domains. Flowing platelets agglutinated with microspheres bearing R1306Q or R1450E mutant A1 domains, but not WT A1 domains. Therefore, catch bonds may prevent vWF multimers from agglutinating platelets. A disintegrin and metalloproteinase with a thrombospondin type 1 motif–13 (ADAMTS-13) reduced platelet agglutination with microspheres bearing a tridomain A1A2A3 vWF fragment with the R1450E mutation in a shear-dependent manner. We conclude that in type 2B vWD, prolonged lifetimes of vWF bonds with GPIbα on circulating platelets may allow ADAMTS-13 to deplete large vWF multimers, causing bleeding. PMID:18725999

Repeated Transient Jets from a Warped Disk in the Symbiotic Prototype Z And: A Link to the Long-lasting Active Phase

NASA Astrophysics Data System (ADS)

Skopal, Augustin; Tarasova, Taya. N.; Wolf, Marek; Dubovský, Pavol A.; Kudzej, Igor

2018-05-01

Active phases of some symbiotic binaries survive for a long time, from years to decades. The accretion process onto a white dwarf (WD) sustaining long-lasting activity, and sometimes leading to collimated ejection, is not well understood. We present the repeated emergence of highly collimated outflows (jets) from the symbiotic prototype Z And during its 2008 and 2009–10 outbursts and suggest their link to the current long-lasting (from 2000) active phase. We monitored Z And with high-resolution spectroscopy, multicolor UBVR C—and high time resolution—photometry. The well-pronounced bipolar jets were ejected again during the 2009–10 outburst together with the simultaneous emergence of the rapid photometric variability (Δm ≈ 0.06 mag) on the timescale of hours, showing similar properties as those during the 2006 outburst. These phenomena and the measured disk–jets connection could be caused by the radiation-induced warping of the inner disk due to a significant increase of the burning WD luminosity. Ejection of transient jets by Z And around outburst maxima signals a transient accretion at rates above the upper limit of the stable hydrogen burning on the WD surface, and thus proves the nature of Z And-type outbursts. The enhanced accretion through the disk warping, supplemented by the accretion from the giant’s wind, can keep a high luminosity of the WD for a long time, until depletion of the disk. In this way, the jets provide a link to long-lasting active phases of Z And.

Transgenesis of the Wolffian duct visualizes dynamic behavior of cells undergoing tubulogenesis in vivo.

PubMed

Atsuta, Yuji; Tadokoro, Ryosuke; Saito, Daisuke; Takahashi, Yoshiko

2013-05-01

Deciphering how the tubulogenesis is regulated is an essential but unsolved issue in developmental biology. Here, using Wolffian duct (WD) formation in chicken embryos, we have developed a novel method that enables gene manipulation during tubulogenesis in vivo. Exploiting that WD arises from a defined site located anteriorly in the embryo (pronephric region), we targeted this region with the enhanced green fluorescent protein (EGFP) gene by the in ovo electroporation technique. EGFP-positive signals were detected in a wide area of elongating WD, where transgenic cells formed an epithelial component in a mosaic manner. Time-lapse live imaging analyses further revealed dynamic behavior of cells during WD elongation: some cells possessed numerous filopodia, and others exhibited cellular tails that repeated elongation and retraction. The retraction of the tail was precisely regulated by Rho activity via actin dynamics. When electroporated with the C3 gene, encoding Rho inhibitor, WD cells failed to contract their tails, resulting in an aberrantly elongated process. We further combined with the Tol2 transposon-mediated gene transfer technique, and could trace EGFP-positive cells at later stages in the ureteric bud sprouting from WD. This is the first demonstration that exogenous gene(s) can directly be introduced into elongating tubular structures in living amniote embryos. This method has opened a way to investigate how a complex tubulogenesis proceeds in higher vertebrates. © 2013 The Authors Development, Growth & Differentiation © 2013 Japanese Society of Developmental Biologists.

Stress-Related Gene Expression Reflects Morphophysiological Responses to Water Deficit.

PubMed

Rymaszewski, Wojciech; Vile, Denis; Bediee, Alexis; Dauzat, Myriam; Luchaire, Nathalie; Kamrowska, Dominika; Granier, Christine; Hennig, Jacek

2017-07-01

Acclimation to water deficit (WD) enables plants to maintain growth under unfavorable environmental conditions, although the mechanisms are not completely understood. In this study, the natural variation of long-term acclimation to moderate and severe soil WD was investigated in 18 Arabidopsis ( Arabidopsis thaliana ) accessions using PHENOPSIS, an automated phenotyping platform. Soil water content was adjusted at an early stage of plant development and maintained at a constant level until reproductive age was achieved. The accessions were selected based on the expression levels of ANNEXIN1 , a drought-related marker. Severe WD conditions had a greater effect on most of the measured morphophysiological traits than moderate WD conditions. Multivariate analyses indicated that trait responses associated with plant size and water management drove most of the variation. Accessions with similar responses at these two levels were grouped in clusters that displayed different response strategies to WD The expression levels of selected stress-response genes revealed large natural variation under WD conditions. Responses of morphophysiological traits, such as projected rosette area, transpiration rate, and rosette water content, were correlated with changes in the expression of stress-related genes, such as NINE-CIS-EPOXYCAROTENOID DIOXYGENASE3 and N-MYC DOWNREGULATED-LIKE1 ( NDL1 ), in response to WD Interestingly, the morphophysiological acclimation response to WD also was reflected in the gene expression levels (most notably those of NDL1 , CHALCONE SYNTHASE , and MYB DOMAIN PROTEIN44 ) in plants cultivated under well-watered conditions. Our results may lead to the development of biomarkers and predictors of plant morphophysiological responses based on gene expression patterns. © 2017 American Society of Plant Biologists. All Rights Reserved.

Functional analysis of the global repressor Tup1 for maltose metabolism in Saccharomyces cerevisiae: different roles of the functional domains.

PubMed

Lin, Xue; Yu, Ai-Qun; Zhang, Cui-Ying; Pi, Li; Bai, Xiao-Wen; Xiao, Dong-Guang

2017-11-09

Tup1 is a general transcriptional repressor of diverse gene families coordinately controlled by glucose repression, mating type, and other mechanisms in Saccharomyces cerevisiae. Several functional domains of Tup1 have been identified, each of which has differing effects on transcriptional repression. In this study, we aim to investigate the role of Tup1 and its domains in maltose metabolism of industrial baker's yeast. To this end, a battery of in-frame truncations in the TUP1 gene coding region were performed in the industrial baker's yeasts with different genetic background, and the maltose metabolism, leavening ability, MAL gene expression levels, and growth characteristics were investigated. The results suggest that the TUP1 gene is essential to maltose metabolism in industrial baker's yeast. Importantly, different domains of Tup1 play different roles in glucose repression and maltose metabolism of industrial baker's yeast cells. The Ssn6 interaction, N-terminal repression and C-terminal repression domains might play roles in the regulation of MAL transcription by Tup1 for maltose metabolism of baker's yeast. The WD region lacking the first repeat could influence the regulation of maltose metabolism directly, rather than indirectly through glucose repression. These findings lay a foundation for the optimization of industrial baker's yeast strains for accelerated maltose metabolism and facilitate future research on glucose repression in other sugar metabolism.

The WD40 Domain Protein MSI1 Functions in a Histone Deacetylase Complex to Fine-Tune Abscisic Acid Signaling.

PubMed

Mehdi, Saher; Derkacheva, Maria; Ramström, Margareta; Kralemann, Lejon; Bergquist, Jonas; Hennig, Lars

2016-01-01

MSI1 belongs to a family of histone binding WD40-repeat proteins. Arabidopsis thaliana contains five genes encoding MSI1-like proteins, but their functions in diverse chromatin-associated complexes are poorly understood. Here, we show that MSI1 is part of a histone deacetylase complex. We copurified HISTONE DEACETYLASE19 (HDA19) with MSI1 and transcriptional regulatory SIN3-like proteins and provide evidence that MSI1 and HDA19 associate into the same complex in vivo. These data suggest that MSI1, HDA19, and HISTONE DEACETYLATION COMPLEX1 protein form a core complex that can integrate various SIN3-like proteins. We found that reduction of MSI1 or HDA19 causes upregulation of abscisic acid (ABA) receptor genes and hypersensitivity of ABA-responsive genes. The MSI1-HDA19 complex fine-tunes ABA signaling by binding to the chromatin of ABA receptor genes and by maintaining low levels of acetylation of histone H3 at lysine 9, thereby affecting the expression levels of ABA receptor genes. Reduced MSI1 or HDA19 levels led to increased tolerance to salt stress corresponding to the increased ABA sensitivity of gene expression. Together, our results reveal the presence of an MSI1-HDA19 complex that fine-tunes ABA signaling in Arabidopsis. © 2016 American Society of Plant Biologists. All rights reserved.

Enhanced Expression of WD Repeat-Containing Protein 35 via Nuclear Factor-Kappa B Activation in Bupivacaine-Treated Neuro2a Cells

PubMed Central

Huang, Lei; Kondo, Fumio; Harato, Misako; Feng, Guo-Gang; Ishikawa, Naoshisa; Fujiwara, Yoshihiro; Okada, Shoshiro

2014-01-01

The family of WD repeat proteins comprises a large number of proteins and is involved in a wide variety of cellular processes such as signal transduction, cell growth, proliferation, and apoptosis. Bupivacaine is a sodium channel blocker administered for local infiltration, nerve block, epidural, and intrathecal anesthesia. Recently, we reported that bupivacaine induces reactive oxygen species (ROS) generation and p38 mitogen-activated protein kinase (MAPK) activation, resulting in an increase in the expression of WD repeat-containing protein 35 (WDR35) in mouse neuroblastoma Neuro2a cells. It has been shown that ROS activate MAPK through phosphorylation, followed by activation of nuclear factor-kappa B (NF-κB) and activator protein 1 (AP-1). The present study was undertaken to test whether NF-κB and c-Jun/AP-1 are involved in bupivacaine-induced WDR35 expression in Neuro2a cells. Bupivacaine activated both NF-κB and c-Jun in Neuro2a cells. APDC, an NF-κB inhibitor, attenuated the increase in NF-κB activity and WDR35 protein expression in bupivacaine-treated Neuro2a cells. GW9662, a selective peroxisome proliferator-activated receptor-γ antagonist, enhanced the increase in NF-κB activity and WDR35 protein expression in bupivacaine-treated Neuro2a cells. In contrast, c-Jun siRNA did not inhibit the bupivacaine-induced increase in WDR35 mRNA expression. These results indicate that bupivacaine induces the activation of transcription factors NF-κB and c-Jun/AP-1 in Neuro2a cells, while activation of NF-κB is involved in bupivacaine-induced increases in WDR35 expression. PMID:24466034

WDR1 expression in the normal and noise-damaged chick vestibule.

PubMed

Suh, Myung Whan; Shin, Dong Hoon; Lee, Ho Sun; Park, Ji Yeong; Kim, Chong Sun; Oh, Seung Ha

2007-01-01

Unlike mammals, avian cochlear hair cells can regenerate after acoustic overstimulation. The WDR1 gene is one of the genes suspected to play an important role in this difference. In an earlier study, we found that the WDR1 gene is over-expressed in the chick cochlea after acoustic overstimulation. The aim of this study was to compare the expression of WDR1 before and after acoustic overstimulation in the chick vestibule. Seven-day-old chicks were divided into three groups: normal group, damage group, and regeneration group. The damage and regeneration group was exposed to 120 dB SPL white noise for 5-6 hours. The damage group was euthanized shortly after the impulse, but the regeneration group was allowed to recover for 2 days. The utricle, saccule, and the three ampullae of each semicircular canal were dissected and immunohistochemically stained with anti-WD40 repeat protein 1 antibody. For quantitative analysis, immunoreactive densities were measured and quantitative real-time RT PCR was performed. WD40 repeat protein 1 expression was elevated in all the semicircular canals and utricle, two days after an acoustic overstimulation (P=0.001). WDR1 mRNA expression was 1.34 times higher in the regeneration group compared to the normal group, but it was not statistically significant. Exceptionally, WD40 repeat protein 1 expression did not increase in the saccule of the regeneration group. Elevated WDR1 expression in the avian vestibule may have a role in the hair cell regenerating ability as in the avian cochlea. A similar mechanism of hair cell regeneration may exist in the avian cochlea and vestibule.

Multiple TPR motifs characterize the Fanconi anemia FANCG protein.

PubMed

Blom, Eric; van de Vrugt, Henri J; de Vries, Yne; de Winter, Johan P; Arwert, Fré; Joenje, Hans

2004-01-05

The genome protection pathway that is defective in patients with Fanconi anemia (FA) is controlled by at least eight genes, including BRCA2. A key step in the pathway involves the monoubiquitylation of FANCD2, which critically depends on a multi-subunit nuclear 'core complex' of at least six FANC proteins (FANCA, -C, -E, -F, -G, and -L). Except for FANCL, which has WD40 repeats and a RING finger domain, no significant domain structure has so far been recognized in any of the core complex proteins. By using a homology search strategy comparing the human FANCG protein sequence with its ortholog sequences in Oryzias latipes (Japanese rice fish) and Danio rerio (zebrafish) we identified at least seven tetratricopeptide repeat motifs (TPRs) covering a major part of this protein. TPRs are degenerate 34-amino acid repeat motifs which function as scaffolds mediating protein-protein interactions, often found in multiprotein complexes. In four out of five TPR motifs tested (TPR1, -2, -5, and -6), targeted missense mutagenesis disrupting the motifs at the critical position 8 of each TPR caused complete or partial loss of FANCG function. Loss of function was evident from failure of the mutant proteins to complement the cellular FA phenotype in FA-G lymphoblasts, which was correlated with loss of binding to FANCA. Although the TPR4 mutant fully complemented the cells, it showed a reduced interaction with FANCA, suggesting that this TPR may also be of functional importance. The recognition of FANCG as a typical TPR protein predicts this protein to play a key role in the assembly and/or stabilization of the nuclear FA protein core complex.

[Clinical and genetic study of Wilson's disease in affected twins and siblings].

PubMed

Cheng, Nan; Wang, Xun; Yu, Xuen; Zhou, Zhihua; Gao, Mingwei; Rao, Rao; Hu, Jiyuan; Yang, Renmin; Han, Yongzhu

2013-06-01

To study the clinical and genetic characteristics of twins and siblings affected with Wilson's disease (WD). Clinical data and blood samples were collected from the subjects after informed consent was obtained. Genomic DNA was extracted and potential mutations in the exons in ATP7B gene were detected with PCR-DNA sequencing. Short tandem repeat (STR) genotyping was performed to determine the zygosity of the twins. The 5 pairs of twins have all met the diagnostic criteria for WD. STR genotyping has confirmed that 4 pairs were monozygotic twins. 3 pairs of twins had an onset with liver symptoms, the other 2 had an onset with brain symptoms. ATP7B gene mutations were detected in 4 pairs of twins, which have all located in exons 8 and 13. A heterozygous p.R778W mutation in exon 8 and homozygous p.P992L mutation in exon 13 were detected in all patients from one family, whose parents have carried a heterozygous p.R778W mutation and p.P992L heterozygous mutation, respectively, which suggested loss of heterozygosity (LOH). In one family, no mutation was detected in all exons of the ATP7B gene in the patients and their parents. For a triplet, one female was with definite WD and brain symptoms at the onset, one male had subclinical type with WD, whilst another female was completely normal. The triplets and their mother have all carried a p.P992L heterozygous mutation . Above results have confirmed an important role for genetic factors in the pathogenesis of WD. In addition to point mutations, LOH is also involved in the pathogenesis for WD.

Overview of platelet physiology and laboratory evaluation of platelet function.

PubMed

Rodgers, G M

1999-06-01

Appropriate laboratory testing for the platelet-type bleeding disorders hinges on an adequate assessment in the history and physical examination. Patients with histories and screening laboratory results consistent with coagulation disorders (hemophilia, disseminated intravascular coagulation) are not appropriate candidates for platelet function testing. In contrast, patients with a lifelong history of platelet-type bleeding symptoms and perhaps a positive family history of bleeding would be appropriate for testing. Figure 6 depicts one strategy to evaluate these patients. Platelet morphology can easily be evaluated to screen for two uncommon qualitative platelet disorders: Bernard-Soulier syndrome (associated with giant platelets) and gray platelet syndrome, a subtype of storage pool disorder in which platelet granulation is morphologically abnormal by light microscopy. If the bleeding disorder occurred later in life (no bleeding with surgery or trauma early in life), the focus should be on acquired disorders of platelet function. For those patients thought to have an inherited disorder, testing for vWD should be done initially because approximately 1% of the population has vWD. The complete vWD panel (factor VIII coagulant activity, vWf antigen, ristocetin cofactor activity) should be performed because many patients will have abnormalities of only one particular panel component. Patients diagnosed with vWD should be classified using multimeric analysis to identify the type 1 vWD patients likely to respond to DDAVP. If vWD studies are normal, platelet aggregation testing should be performed, ensuring that no antiplatelet medications have been ingested at least 1 week before testing. If platelet aggregation tests are normal and if suspicion for an inherited disorder remains high, vWD testing should be repeated. The evaluation of thrombocytopenia may require bone marrow examination to exclude primary hematologic disorders. If future studies with thrombopoietin assays confirm preliminary results, however, the bone marrow examination of certain patients may be replaced by a thrombopoietin level.

The effects of close binaries on the magnetic activity of M dwarfs as probed using close white dwarf companions

NASA Astrophysics Data System (ADS)

Morgan, D. P.

2017-01-01

I present a study of close white dwarf (WD) and M dwarf (dM) binary systems (WD+dM) to examine the effects that close companions have on magnetic field generation in dMs. Using the Sloan Digital Sky Survey (SDSS) Data Release 8 spectroscopic database, I constructed a sample of 1756 WD+dM high-quality pairs. I show that early-type dMs (M4), where stars become fully convective, the activity fraction and activity lifetimes of WD+dM binary systems become more comparable to those of the field dMs. The implications of having a close binary companion may include: increased stellar rotation through disk disruption, tidal effects, and/or angular momentum exchange. Thus, the similarity in activity between late-type field dMs and late-type dMs with close companions is likely due to the mechanism generating magnetic fields being less sensitive to the effects caused by a close companion; namely, increased stellar rotation. Using a subset of 181 close WD+dM pairs, matched to the time-domain SDSS Stripe 82 catalog, I show that enhanced magnetic activity extends to the flaring behavior of dMs in close binaries. Specifically, early spectral type dMs (M0-M4), in close WD+dM pairs, are two orders of magnitude more likely to flare than field dMs, whereas late-type dMs (M4-M6) in close WD+dM pairs flare as frequently or less than the late-type field dM sample. To test whether the presence of a close companion leads to star-star interactions, I searched for correlations between the WD occultations and flares from the dM member in KOI-256, an eclipsing WD+dM system. I find no correlations between the flaring activity of the dM and the WD occultations, indicating the there are no obvious signs of star-star interactions at work. In addition, the dM member of KOI-256 flares more than any other dM observed by Kepler and shows evidence for solar-like magnetic activity cycles, a feature not seen in many dMs to date.

Inhibition of Human Papillomavirus DNA Replication by an E1-Derived p80/UAF1-Binding Peptide

PubMed Central

Lehoux, Michaël; Fradet-Turcotte, Amélie; Lussier-Price, Mathieu; Omichinski, James G.

2012-01-01

The papillomavirus E1 helicase is recruited by E2 to the viral origin, where it assembles into a double hexamer that orchestrates replication of the viral genome. We previously identified the cellular WD40 repeat-containing protein p80/UAF1 as a novel interaction partner of E1 from anogenital human papillomavirus (HPV) types. p80 was found to interact with the first 40 residues of HPV type 31 (HPV31) E1, and amino acid substitutions within this domain abrogated the maintenance of the viral episome in keratinocytes. In this study, we report that these p80-binding substitutions reduce by 70% the ability of E1 to support transient viral DNA replication without affecting its interaction with E2 and assembly at the origin in vivo. Microscopy studies revealed that p80 is relocalized from the cytoplasm to discrete subnuclear foci by E1 and E2. Chromatin immunoprecipitation assays further revealed that p80 is recruited to the viral origin in an E1- and E2-dependent manner. Interestingly, overexpression of a 40-amino-acid-long p80-binding peptide, derived from HPV31 E1, was found to inhibit viral DNA replication by preventing the recruitment of endogenous p80 to the origin. Mutant peptides defective for p80 interaction were not inhibitory, demonstrating the specificity of this effect. Characterization of this E1 peptide by nuclear magnetic resonance (NMR) showed that it is intrinsically disordered in solution, while mapping studies indicated that the WD repeats of p80 are required for E1 interaction. These results provide additional evidence for the requirement for p80 in anogenital HPV DNA replication and highlight the potential of E1-p80 interaction as a novel antiviral target. PMID:22278251

Core Histones and HIRIP3, a Novel Histone-Binding Protein, Directly Interact with WD Repeat Protein HIRA

PubMed Central

Lorain, Stéphanie; Quivy, Jean-Pierre; Monier-Gavelle, Frédérique; Scamps, Christine; Lécluse, Yann; Almouzni, Geneviève; Lipinski, Marc

1998-01-01

The human HIRA gene has been named after Hir1p and Hir2p, two corepressors which together appear to act on chromatin structure to control gene transcription in Saccharomyces cerevisiae. HIRA homologs are expressed in a regulated fashion during mouse and chicken embryogenesis, and the human gene is a major candidate for the DiGeorge syndrome and related developmental disorders caused by a reduction to single dose of a fragment of chromosome 22q. Western blot analysis and double-immunofluorescence experiments using a specific antiserum revealed a primary nuclear localization of HIRA. Similar to Hir1p, HIRA contains seven amino-terminal WD repeats and probably functions as part of a multiprotein complex. HIRA and core histone H2B were found to physically interact in a yeast double-hybrid protein interaction trap, in GST pull-down assays, and in coimmunoprecipitation experiments performed from cellular extracts. In vitro, HIRA also interacted with core histone H4. H2B- and H4-binding domains were overlapping but distinguishable in the carboxy-terminal region of HIRA, and the region for HIRA interaction was mapped to the amino-terminal tail of H2B and the second α helix of H4. HIRIP3 (HIRA-interacting protein 3) is a novel gene product that was identified from its HIRA-binding properties in the yeast protein interaction trap. In vitro, HIRIP3 directly interacted with HIRA but also with core histones H2B and H3, suggesting that a HIRA-HIRIP3-containing complex could function in some aspects of chromatin and histone metabolism. Insufficient production of HIRA, which we report elsewhere interacts with homeodomain-containing DNA-binding factors during mammalian embryogenesis, could perturb the stoichiometric assembly of multimolecular complexes required for normal embryonic development. PMID:9710638

Signal analysis by means of time-frequency (Wigner-type) distributions -- Applications to sonar and radar echoes

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

Gaunaurd, G.; Strifors, H.C.

1996-09-01

Time series data have been traditionally analyzed in either the time or the frequency domains. For signals with a time-varying frequency content, the combined time-frequency (TF) representations, based on the Cohen class of (generalized) Wigner distributions (WD`s) offer a powerful analysis tool. Using them, it is possible to: (1) trace the time-evolution of the resonance features usually present in a standard sonar cross section (SCS), or in a radar cross section (RCS) and (2) extract target information that may be difficult to even notice in an ordinary SCS or RCS. After a brief review of the fundamental properties of themore » WD, the authors discuss ways to reduce or suppress the cross term interference that appears in the WD of multicomponent systems. These points are illustrated with a variety of three-dimensional (3-D) plots of Wigner and pseudo-Wigner distributions (PWD), in which the strength of the distribution is depicted as the height of a Wigner surface with height scales measured by various color shades or pseudocolors. The authors also review studies they have made of the echoes returned by conducting or dielectric targets in the atmosphere, when they are illuminated by broadband radar pings. A TF domain analysis of these impulse radar returns demonstrates their superior informative content. These plots allow the identification of targets in an easier and clearer fashion than by the conventional RCS of narrowband systems. The authors show computed and measured plots of WD and PWD of various types of aircraft to illustrate the classification advantages of the approach at any aspect angle. They also show analogous results for metallic objects buried underground, in dielectric media, at various depths.« less

Functional and Morphological Correlates in the Drosophila LRRK2 loss-of-function Model of Parkinson’s Disease: Drug Effects of Withania somnifera (Dunal) Administration

PubMed Central

Catelani, Tiziano; Setzu, Maria Dolores; Solla, Paolo; Marrosu, Francesco; Sanna, Enrico; Kasture, Sanjay; Acquas, Elio

2016-01-01

The common fruit fly Drosophila melanogaster (Dm) is a simple animal species that contributed significantly to the development of neurobiology whose leucine-rich repeat kinase 2 mutants (LRRK2) loss-of-function in the WD40 domain represent a very interesting tool to look into physiopathology of Parkinson’s disease (PD). Accordingly, LRRK2 Dm have also the potential to contribute to reveal innovative therapeutic approaches to its treatment. Withania somnifera Dunal, a plant that grows spontaneously also in Mediterranean regions, is known in folk medicine for its anti-inflammatory and protective properties against neurodegeneration. The aim of this study was to evaluate the neuroprotective effects of its standardized root methanolic extract (Wse) on the LRRK2 loss-of-function Dm model of PD. To this end mutant and wild type (WT) flies were administered Wse, through diet, at different concentrations as larvae and adults (L+/A+) or as adults (L-/A+) only. LRRK2 mutants have a significantly reduced lifespan and compromised motor function and mitochondrial morphology compared to WT flies 1% Wse-enriched diet, administered to Dm LRRK2 as L-/A+and improved a) locomotor activity b) muscle electrophysiological response to stimuli and also c) protected against mitochondria degeneration. In contrast, the administration of Wse to Dm LRRK2 as L+/A+, no matter at which concentration, worsened lifespan and determined the appearance of increased endosomal activity in the thoracic ganglia. These results, while confirming that the LRRK2 loss-of-function in the WD40 domain represents a valid model of PD, reveal that under appropriate concentrations Wse can be usefully employed to counteract some deficits associated with the disease. However, a careful assessment of the risks, likely related to the impaired endosomal activity, is required. PMID:26727265

GROWING WHITE DWARFS TO THE CHANDRASEKHAR LIMIT: THE PARAMETER SPACE OF THE SINGLE DEGENERATE SN Ia CHANNEL

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

Hillman, Y.; Prialnik, D.; Kovetz, A.

Can a white dwarf (WD), accreting hydrogen-rich matter from a non-degenerate companion star, ever exceed the Chandrasekhar mass and explode as a SN Ia? We explore the range of accretion rates that allow a WD to secularly grow in mass, and derive limits on the accretion rate and on the initial mass that will allow it to reach 1.4M{sub ⊙}—the Chandrasekhar mass. We follow the evolution through a long series of hydrogen flashes, during which a thick helium shell accumulates. This determines the effective helium mass accretion rate for long-term, self-consistent evolutionary runs with helium flashes. We find that netmore » mass accumulation always occurs despite helium flashes. Although the amount of mass lost during the first few helium shell flashes is a significant fraction of that accumulated prior to the flash, that fraction decreases with repeated helium shell flashes. Eventually no mass is ejected at all during subsequent flashes. This unexpected result occurs because of continual heating of the WD interior by the helium shell flashes near its surface. The effect of heating is to lower the electron degeneracy throughout the WD, especially in the outer layers. This key result yields helium burning that is quasi-steady state, instead of explosive. We thus find a remarkably large parameter space within which long-term, self-consistent simulations show that a WD can grow in mass and reach the Chandrasekhar limit, despite its helium flashes.« less

The Long Non-coding RNA HOTTIP Enhances Pancreatic Cancer Cell Proliferation, Survival and Migration

EPA Science Inventory

ABSTRACTHOTTIP is a long non-coding RNA (lncRNA) transcribed from the 5' tip of the HOXA locus and is associated with the polycomb repressor complex 2 (PRC2) and WD repeat containing protein 5 (WDR5)/mixed lineage leukemia 1 (MLL1) chromatin modifying complexes. HOTTIP is expres...

WRKY domain-encoding genes of a crop legume chickpea (Cicer arietinum): comparative analysis with Medicago truncatula WRKY family and characterization of group-III gene(s).

PubMed

Kumar, Kamal; Srivastava, Vikas; Purayannur, Savithri; Kaladhar, V Chandra; Cheruvu, Purnima Jaiswal; Verma, Praveen Kumar

2016-06-01

The WRKY genes have been identified as important transcriptional modulators predominantly during the environmental stresses, but they also play critical role at various stages of plant life cycle. We report the identification of WRKY domain (WD)-encoding genes from galegoid clade legumes chickpea (Cicer arietinum L.) and barrel medic (Medicago truncatula). In total, 78 and 98 WD-encoding genes were found in chickpea and barrel medic, respectively. Comparative analysis suggests the presence of both conserved and unique WRKYs, and expansion of WRKY family in M. truncatula primarily by tandem duplication. Exclusively found in galegoid legumes, CaWRKY16 and its orthologues encode for a novel protein having a transmembrane and partial Exo70 domains flanking a group-III WD. Genomic region of galegoids, having CaWRKY16, is more dynamic when compared with millettioids. In onion cells, fused CaWRKY16-EYFP showed punctate fluorescent signals in cytoplasm. The chickpea WRKY group-III genes were further characterized for their transcript level modulation during pathogenic stress and treatments of abscisic acid, jasmonic acid, and salicylic acid (SA) by real-time PCR. Differential regulation of genes was observed during Ascochyta rabiei infection and SA treatment. Characterization of A. rabiei and SA inducible gene CaWRKY50 showed that it localizes to plant nucleus, binds to W-box, and have a C-terminal transactivation domain. Overexpression of CaWRKY50 in tobacco plants resulted in early flowering and senescence. The in-depth comparative account presented here for two legume WRKY genes will be of great utility in hastening functional characterization of crop legume WRKYs and will also help in characterization of Exo70Js. © The Author 2016. Published by Oxford University Press on behalf of Kazusa DNA Research Institute.

Presence of tannins in sorghum grains is conditioned by different natural alleles of Tannin1

PubMed Central

Wu, Yuye; Li, Xianran; Xiang, Wenwen; Zhu, Chengsong; Lin, Zhongwei; Wu, Yun; Li, Jiarui; Pandravada, Satchidanand; Ridder, Dustan D.; Bai, Guihua; Wang, Ming L.; Trick, Harold N.; Bean, Scott R.; Tuinstra, Mitchell R.; Tesso, Tesfaye T.; Yu, Jianming

2012-01-01

Sorghum, an ancient old-world cereal grass, is the dietary staple of over 500 million people in more than 30 countries in the tropics and semitropics. Its C4 photosynthesis, drought resistance, wide adaptation, and high nutritional value hold the promise to alleviate hunger in Africa. Not present in other major cereals, such as rice, wheat, and maize, condensed tannins (proanthocyanidins) in the pigmented testa of some sorghum cultivars have been implicated in reducing protein digestibility but recently have been shown to promote human health because of their high antioxidant capacity and ability to fight obesity through reduced digestion. Combining quantitative trait locus mapping, meta-quantitative trait locus fine-mapping, and association mapping, we showed that the nucleotide polymorphisms in the Tan1 gene, coding a WD40 protein, control the tannin biosynthesis in sorghum. A 1-bp G deletion in the coding region, causing a frame shift and a premature stop codon, led to a nonfunctional allele, tan1-a. Likewise, a different 10-bp insertion resulted in a second nonfunctional allele, tan1-b. Transforming the sorghum Tan1 ORF into a nontannin Arabidopsis mutant restored the tannin phenotype. In addition, reduction in nucleotide diversity from wild sorghum accessions to landraces and cultivars was found at the region that codes the highly conserved WD40 repeat domains and the C-terminal region of the protein. Genetic research in crops, coupled with nutritional and medical research, could open the possibility of producing different levels and combinations of phenolic compounds to promote human health. PMID:22699509

Molecular characterization and analysis of the acrB gene of Aspergillus nidulans: a gene identified by genetic interaction as a component of the regulatory network that includes the CreB deubiquitination enzyme.

PubMed Central

Boase, Natasha A; Lockington, Robin A; Adams, Julian R J; Rodbourn, Louise; Kelly, Joan M

2003-01-01

Mutations in the acrB gene, which were originally selected through their resistance to acriflavine, also result in reduced growth on a range of sole carbon sources, including fructose, cellobiose, raffinose, and starch, and reduced utilization of omega-amino acids, including GABA and beta-alanine, as sole carbon and nitrogen sources. The acrB2 mutation suppresses the phenotypic effects of mutations in the creB gene that encodes a regulatory deubiquitinating enzyme, and in the creC gene that encodes a WD40-repeat-containing protein. Thus AcrB interacts with a regulatory network controlling carbon source utilization that involves ubiquitination and deubiquitination. The acrB gene was cloned and physically analyzed, and it encodes a novel protein that contains three putative transmembrane domains and a coiled-coil region. AcrB may play a role in the ubiquitination aspect of this regulatory network. PMID:12750323

Biophysical regulation of epigenetic state and cell reprogramming

NASA Astrophysics Data System (ADS)

Downing, Timothy L.; Soto, Jennifer; Morez, Constant; Houssin, Timothee; Fritz, Ashley; Yuan, Falei; Chu, Julia; Patel, Shyam; Schaffer, David V.; Li, Song

2013-12-01

Biochemical factors can help reprogram somatic cells into pluripotent stem cells, yet the role of biophysical factors during reprogramming is unknown. Here, we show that biophysical cues, in the form of parallel microgrooves on the surface of cell-adhesive substrates, can replace the effects of small-molecule epigenetic modifiers and significantly improve reprogramming efficiency. The mechanism relies on the mechanomodulation of the cells’ epigenetic state. Specifically, decreased histone deacetylase activity and upregulation of the expression of WD repeat domain 5 (WDR5)—a subunit of H3 methyltranferase—by microgrooved surfaces lead to increased histone H3 acetylation and methylation. We also show that microtopography promotes a mesenchymal-to-epithelial transition in adult fibroblasts. Nanofibrous scaffolds with aligned fibre orientation produce effects similar to those produced by microgrooves, suggesting that changes in cell morphology may be responsible for modulation of the epigenetic state. These findings have important implications in cell biology and in the optimization of biomaterials for cell-engineering applications.

The application of the Wigner Distribution to wave type identification in finite length beams

NASA Technical Reports Server (NTRS)

Wahl, T. J.; Bolton, J. Stuart

1994-01-01

The object of the research described in this paper was to develop a means of identifying the wave-types propagating between two points in a finite length beam. It is known that different structural wave-types possess different dispersion relations: i.e., that their group speeds and the frequency dependence of their group speeds differ. As a result of those distinct dispersion relationships, different wave-types may be associated with characteristic features when structural responses are examined in the time frequency domain. Previously, the time-frequency character of analytically generated structural responses of both single element and multi-element structures were examined by using the Wigner Distribution (WD) along with filtering techniques that were designed to detect the wave-types present in the responses. In the work to be described here, the measure time-frequency response of finite length beam is examined using the WD and filtering procedures. This paper is organized as follows. First the concept of time-frequency analysis of structural responses is explained. The WD is then introduced along with a description of the implementation of a discrete version. The time-frequency filtering techniques are then presented and explained. The results of applying the WD and the filtering techniques to the analysis of a transient response is then presented.

Identification of Genes Related to Fungicide Resistance in Fusarium fujikuroi

PubMed Central

Choi, Younghae; Jung, Boknam; Li, Taiying

2017-01-01

We identified two genes related to fungicide resistance in Fusarium fujikuroi through random mutagenesis. Targeted gene deletions showed that survival factor 1 deletion resulted in higher sensitivity to fungicides, while deletion of the gene encoding F-box/WD-repeat protein increased resistance, suggesting that the genes affect fungicide resistance in different ways. PMID:28781543

Signatures of progenitors of Type Ia supernovae

NASA Astrophysics Data System (ADS)

Hoeflich, P.; Chakraborty, S.; Comaskey, W.; Fisher, A.; Hristov, B.; Collins, D.; Diamond, T. R.; Dragulin, P.; Hsiao, E. Y.; Sadler, B.

Thermonuclear Supernovae (SNe Ia) are one of the building blocks of modern cosmology and laboratories for the explosion physics of White Dwarf star/s (WD) in close binary systems. The second star may be a WD (double degenerate systems, DD), or a non-degenerated star (SD) with a main sequence star, red giant or a helium star as companion \\citep{branch95,nomoto03,wang2012}. Light curves and spectra of the explosion look similar because a 'stellar amnesia' \\citep{h06}. Basic nuclear physics determines the progenitor structure and the explosion physics, breaking the link between progenitor evolution, and the explosion, resulting in three main classes of explosion scenarios: a) dynamical merging of two WD and a heating on time scales of seconds \\citep{webbink84,isern11}, b) surface helium detonations on top of a WD which ignite the central C/O by a detonation wave traveling inwards \\citep{n82,hk96,Kromer2010}; c) compressional heating in an accreting WD approaching the Chandrasekar mass on time of up to 108 years which may originated from SD and DD systems \\citep{WI73,Piersanti2004}. Simulations of the explosions depend on the inital conditions at the onset of the explosions, namely the mass and angular momentum of the WD(s). For all scenarios, diversity in SNe Ia must be expected because the WD originates from a range of Main Sequence masses (MMS < 8 M_⊙) and metallicities Z. Moreover, there is growing evidence that magnetic fields B may have to be added to the 'mix'. Only with recent advances in observations ranging from X-ray to radio, high precision spectroscopy, polarimetry and photometry and in the time-domain astronomy we obtain constraints for progenitor, on the explosion scenarios and links emerge between the progenitors and their environment with LCs and spectral signatures needed for high precision cosmology. It is too early to give final answers but we present our personal view. We will give some examples from the theory point of view and discuss future prospects with upcoming ground based, ELT, GMT and space based such as JWST, Euclide and WFIRST instruments.

Hepatic steatosis in Wilson disease--Role of copper and PNPLA3 mutations.

PubMed

Stättermayer, Albert Friedrich; Traussnigg, Stefan; Dienes, Hans-Peter; Aigner, Elmar; Stauber, Rudolf; Lackner, Karoline; Hofer, Harald; Stift, Judith; Wrba, Friedrich; Stadlmayr, Andreas; Datz, Christian; Strasser, Michael; Maieron, Andreas; Trauner, Michael; Ferenci, Peter

2015-07-01

The earliest characteristic alterations of the liver pathology in Wilson disease (WD) include steatosis, which is sometimes indistinguishable from non-alcoholic fatty liver disease (NAFLD). Steatosis in WD may reflect copper-induced mitochondrial dysfunction. A genetic polymorphism in rs738409, in the patatin-like phospholipase domain-containing 3 gene (PNPLA3), is strongly associated with appearance of in NAFLD. This study evaluated the role of PNPLA3 and hepatic copper content for development of steatosis in patients with WD. Liver biopsies obtained at diagnosis and the PNPLA3 genotype were analyzed in 98 Caucasian patients with WD (male: 52 [53.1%]; mean age: 27.6 years [CI 95%: 24.8-30.4, range: 5.8-61.5]). Steatosis was graded as percentage of lipid containing hepatocytes by an expert hepatopathologist unaware of the results of genetic testing. Moderate/severe steatosis (>33% of hepatocytes) was observed in 28 patients (pediatric: n=13/26 [50.0%], adult: n=15/72 [20.8%]; p=0.01). Forty-six patients (46.9%; pediatric: n=7, adult: n=39; p=0.022) had cirrhosis. Multivariate logistic regression identified PNPLA3 G allele (OR: 2.469, CI 95%: 1.203-5.068; p=0.014) and pediatric age (OR: 4.348; 1.577-11.905; p=0.004) as independent variables associated with moderate/severe steatosis. In contrast, hepatic copper content did not impact on moderate/severe steatosis (OR: 1.000, CI 95%: 1.000-1.001; p=0.297). Steatosis is common in WD and the PNPLA3 G allele contributes to its pathogenesis. The role of hepatic copper concentration and ATP7B mutations in steatosis development deserve further investigations. Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

The Molecular Chaperone TRiC/CCT Binds to the Trp-Asp 40 (WD40) Repeat Protein WDR68 and Promotes Its Folding, Protein Kinase DYRK1A Binding, and Nuclear Accumulation*

PubMed Central

Miyata, Yoshihiko; Shibata, Takeshi; Aoshima, Masato; Tsubata, Takuichi; Nishida, Eisuke

2014-01-01

Trp-Asp (WD) repeat protein 68 (WDR68) is an evolutionarily conserved WD40 repeat protein that binds to several proteins, including dual specificity tyrosine phosphorylation-regulated protein kinase (DYRK1A), MAPK/ERK kinase kinase 1 (MEKK1), and Cullin4-damage-specific DNA-binding protein 1 (CUL4-DDB1). WDR68 affects multiple and diverse physiological functions, such as controlling anthocyanin synthesis in plants, tissue growth in insects, and craniofacial development in vertebrates. However, the biochemical basis and the regulatory mechanism of WDR68 activity remain largely unknown. To better understand the cellular function of WDR68, here we have isolated and identified cellular WDR68 binding partners using a phosphoproteomic approach. More than 200 cellular proteins with wide varieties of biochemical functions were identified as WDR68-binding protein candidates. Eight T-complex protein 1 (TCP1) subunits comprising the molecular chaperone TCP1 ring complex/chaperonin-containing TCP1 (TRiC/CCT) were identified as major WDR68-binding proteins, and phosphorylation sites in both WDR68 and TRiC/CCT were identified. Co-immunoprecipitation experiments confirmed the binding between TRiC/CCT and WDR68. Computer-aided structural analysis suggested that WDR68 forms a seven-bladed β-propeller ring. Experiments with a series of deletion mutants in combination with the structural modeling showed that three of the seven β-propeller blades of WDR68 are essential and sufficient for TRiC/CCT binding. Knockdown of cellular TRiC/CCT by siRNA caused an abnormal WDR68 structure and led to reduction of its DYRK1A-binding activity. Concomitantly, nuclear accumulation of WDR68 was suppressed by the knockdown of TRiC/CCT, and WDR68 formed cellular aggregates when overexpressed in the TRiC/CCT-deficient cells. Altogether, our results demonstrate that the molecular chaperone TRiC/CCT is essential for correct protein folding, DYRK1A binding, and nuclear accumulation of WDR68. PMID:25342745

WIPI1 Coordinates Melanogenic Gene Transcription and Melanosome Formation via TORC1 Inhibition*

PubMed Central

Ho, Hsiang; Kapadia, Rubina; Al-Tahan, Sejad; Ahmad, Safoora; Ganesan, Anand K.

2011-01-01

Recent studies implicate a role for WD repeat domain, phosphoinositide-interacting 1 (WIPI1) in the biogenesis of melanosomes, cell type-specific lysosome-related organelles. In this study, we determined that WIPI1, an ATG18 homologue that is shown to localize to both autophagosomes and early endosomes, inhibited mammalian target of rapamycin (MTOR) signaling, leading to increased transcription of melanogenic enzymes and the formation of mature melanosomes. WIPI1 suppressed the target of rapamycin complex 1 (TORC1) activity, resulting in glycogen synthase kinase 3β inhibition, β-Catenin stabilization, and increased transcription of microphthalmia transcription factor and its target genes. WIPI1-depleted cells accumulated stage I melanosomes but lacked stage III-IV melanosomes. Inhibition of TORC1 by rapamycin treatment resulted in the accumulation of stage IV melanosomes but not autophagosomes, whereas starvation resulted in the formation of autophagosomes but not melanin accumulation. Taken together, our studies define a distinct role for WIPI1 and TORC1 signaling in controlling the transcription of melanogenic enzymes and melanosome maturation, a process that is distinct from starvation-induced autophagy. PMID:21317285

The structure of Erb1-Ytm1 complex reveals the functional importance of a high-affinity binding between two β-propellers during the assembly of large ribosomal subunits in eukaryotes

PubMed Central

Wegrecki, Marcin; Rodríguez-Galán, Olga; de la Cruz, Jesús; Bravo, Jeronimo

2015-01-01

Ribosome biogenesis is one of the most essential pathways in eukaryotes although it is still not fully characterized. Given the importance of this process in proliferating cells, it is obvious that understanding the macromolecular details of the interactions that take place between the assembly factors, ribosomal proteins and nascent pre-rRNAs is essentially required for the development of new non-genotoxic treatments for cancer. Herein, we have studied the association between the WD40-repeat domains of Erb1 and Ytm1 proteins. These are essential factors for the biogenesis of 60S ribosomal subunits in eukaryotes that form a heterotrimeric complex together with the also essential Nop7 protein. We provide the crystal structure of a dimer formed by the C-terminal part of Erb1 and Ytm1 from Chaetomium thermophilum at 2.1 Å resolution. Using a multidisciplinary approach we show that the β-propeller domains of these proteins interact in a novel manner that leads to a high-affinity binding. We prove that a point mutation within the interface of the complex impairs the interaction between the two proteins and negatively affects growth and ribosome production in yeast. Our study suggests insights into the association of the Erb1-Ytm1 dimer with pre-ribosomal particles. PMID:26476442

DEAD-box helicase DDX27 regulates 3′ end formation of ribosomal 47S RNA and stably associates with the PeBoW-complex

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

Kellner, Markus; Rohrmoser, Michaela; Forné, Ignasi

PeBoW, a trimeric complex consisting of pescadillo (Pes1), block of proliferation (Bop1), and the WD repeat protein 12 (WDR12), is essential for processing and maturation of mammalian 5.8S and 28S ribosomal RNAs. Applying a mass spectrometric analysis, we identified the DEAD-box helicase DDX27 as stably associated factor of the PeBoW-complex. DDX27 interacts with the PeBoW-complex via an evolutionary conserved F×F motif in the N-terminal domain and is recruited to the nucleolus via its basic C-terminal domain. This recruitment is RNA-dependent and occurs independently of the PeBoW-complex. Interestingly, knockdown of DDX27, but not of Pes1, induces the accumulation of an extendedmore » form of the primary 47S rRNA. We conclude that DDX27 can interact specifically with the Pes1 and Bop1 but fulfils critical function(s) for proper 3′ end formation of 47S rRNA independently of the PeBoW-complex. - Highlights: • DEAD-box helicase DDX27 is a new constituent of the PeBoW-complex. • The N-terminal F×F motif of DDX27 interacts with the PeBoW components Pes1 and Bop1. • Nucleolar anchoring of DDX27 via its basic C-terminal domain is RNA dependent. • Knockdown of DDX27 induces a specific defect in 3′ end formation of 47S rRNA.« less

Essential role of the NH2-terminal WD/EPF motif in the phosphorylation-activated protective function of mammalian Hsp27.

PubMed

Thériault, Jimmy R; Lambert, Herman; Chávez-Zobel, Aura T; Charest, Gabriel; Lavigne, Pierre; Landry, Jacques

2004-05-28

Hsp27 is expressed at high levels after mild heat shock and contributes to making cells extremely resistant to subsequent treatments. The activity of the protein is regulated at the transcriptional level, but also by phosphorylation, which occurs rapidly during stress and is responsible for causing the dissociation of large 700-kDa Hsp27 oligomers into dimers. We investigated the mechanism by which phosphorylation and oligomerization modulate the protective activity of Chinese hamster Hsp27. In contrast to oligomer dissociation, which only required Ser90 phosphorylation, activation of Hsp27 thermoprotective activity required the phosphorylation of both Ser90 and Ser15. Replacement of Ser90 by Ala90, which prevented the dissociation of the oligomer upon stress, did cause a severe defect in the protective activity. Dissociation was, however, not a sufficient condition to activate the protein because replacement of Ser15 by Ala15, which caused little effect in the oligomeric organization of the protein, also yielded an inactive protein. Analyzes of mutants with short deletions in the NH2 terminus identified the Hsp27 WD/EPF or PF-rich domain as essential for protection, maintenance of the oligomeric structure, and in vitro chaperone activity of the protein. In light of a three-dimensional model of Hsp27 based on the crystallographic structure of wheat Hsp16.9, we propose that the conserved WD/EPF motif of mammalian Hsp27 mediates important intramolecular interactions with hydrophic surfaces of the alpha-crystallin domain of the protein. These interactions are destabilized by Ser90 phosphorylation, making the motif free to interact with heterologous molecular targets upon the additional phosphorylation of the nearby Ser15.

Feature extraction and identification in distributed optical-fiber vibration sensing system for oil pipeline safety monitoring

NASA Astrophysics Data System (ADS)

Wu, Huijuan; Qian, Ya; Zhang, Wei; Tang, Chenghao

2017-12-01

High sensitivity of a distributed optical-fiber vibration sensing (DOVS) system based on the phase-sensitivity optical time domain reflectometry (Φ-OTDR) technology also brings in high nuisance alarm rates (NARs) in real applications. In this paper, feature extraction methods of wavelet decomposition (WD) and wavelet packet decomposition (WPD) are comparatively studied for three typical field testing signals, and an artificial neural network (ANN) is built for the event identification. The comparison results prove that the WPD performs a little better than the WD for the DOVS signal analysis and identification in oil pipeline safety monitoring. The identification rate can be improved up to 94.4%, and the nuisance alarm rate can be effectively controlled as low as 5.6% for the identification network with the wavelet packet energy distribution features.

Functional characterization of a basic helix-loop-helix (bHLH) transcription factor GhDEL65 from cotton (Gossypium hirsutum).

PubMed

Shangguan, Xiao-Xia; Yang, Chang-Qing; Zhang, Xiu-Fang; Wang, Ling-Jian

2016-10-01

Cotton fiber is proposed to share some similarity with the Arabidopsis thaliana leaf trichome, which is regulated by the MYB-bHLH-WD40 transcription complex. Although several MYB transcription factors and WD40 family proteins in cotton have been characterized, little is known about the role of bHLH family proteins in cotton. Here, we report that GhDEL65, a bHLH protein from cotton (Gossypium hirsutum), is a functional homologue of Arabidopsis GLABRA3 (GL3) and ENHANCER OF GLABRA3 (EGL3) in regulating trichome development. Transcripts of GhDEL65 were detected in 0 ∼ 1 days post-anthesis (DPA) ovules and abundant in 3-DPA fibers, implying that GhDEL65 may act in early fiber development. Ectopic expression of GhDEL65 in Arabidopsis gl3 egl3 double mutant partly rescued the trichome development, and constitutive expression of GhDEL65 in wild-type plants led to increased trichome density on rosette leaves and stems, mainly by activating the transcription of two key positive regulators of trichome development, GLABRA1 (GL1) and GLABRA2 (GL2), and suppressed the expression of a R3 single-repeat MYB factor TRIPTYCHON (TRY). GhDEL65 could interact with cotton R2R3 MYB transcription factors GhMYB2 and GhMYB3, as well as the WD40 protein GhTTG3, suggesting that the MYB-bHLH-WD40 protein complex also exists in cotton fiber cell, though its function in cotton fiber development awaits further investigation. © 2016 Scandinavian Plant Physiology Society.

Merging of a CO WD and a He-rich WD to produce a type Ia supernovae

NASA Astrophysics Data System (ADS)

Liu, D.; Wang, B.; Wu, C.; Han, Z.

2017-10-01

Context. Although type Ia supernovae (SNe Ia) play a key role in astrophysics, the companions of the exploding carbon-oxygen white dwarfs (CO WDs) are still not completely identified. It has been suggested recently that a He-rich WD (a He WD or a hybrid HeCO WD) that merges with a CO WD may produce an SN Ia. This theory was based on the double-detonation model, in which the shock compression in the CO core caused by the surface explosion of the He-rich shell might lead to the explosion of the whole CO WD. However, so far, very few binary population synthesis (BPS) studies have been made on the merger scenario of a CO WD and a He-rich WD in the context of SNe Ia. Aims: We aim to systematically study the Galactic birthrates and delay-time distributions of SNe Ia based on the merger scenario of a CO WD and a He-rich WD. Methods: We performed a series of Monte Carlo BPS simulations to investigate the properties of SNe Ia from the merging of a CO WD and a He-rich WD based on the Hurley rapid binary evolution code. We also considered the influence of different metallicities on the final results. Results: From our simulations, we found that no more than 15% of all SNe Ia stem from the merger scenario of a CO WD and a He-rich WD, and their delay times range from 110 Myr to the Hubble time. This scenario mainly contributes to SN Ia explosions with intermediate and long delay times. The present work indicates that the merger scenario of a CO WD and a He-rich WD can roughly reproduce the birthrates of SN 1991bg-like events, and cover the range of their delay times. We also found that SN Ia birthrates from this scenario would be higher for the cases with low metallicities.

A novel approach to oral apoA-I mimetic therapy[S

PubMed Central

Chattopadhyay, Arnab; Navab, Mohamad; Hough, Greg; Gao, Feng; Meriwether, David; Grijalva, Victor; Springstead, James R.; Palgnachari, Mayakonda N.; Namiri-Kalantari, Ryan; Su, Feng; Van Lenten, Brian J.; Wagner, Alan C.; Anantharamaiah, G. M.; Farias-Eisner, Robin; Reddy, Srinivasa T.; Fogelman, Alan M.

2013-01-01

Transgenic tomato plants were constructed with an empty vector (EV) or a vector expressing an apoA-I mimetic peptide, 6F. EV or 6F tomatoes were harvested, lyophilized, ground into powder, added to Western diet (WD) at 2.2% by weight, and fed to LDL receptor-null (LDLR−/−) mice at 45 mg/kg/day 6F. After 13 weeks, the percent of the aorta with lesions was 4.1 ± 4%, 3.3 ± 2.4%, and 1.9 ± 1.4% for WD, WD + EV, and WD + 6F, respectively (WD + 6F vs. WD, P = 0.0134; WD + 6F vs. WD + EV, P = 0.0386; WD + EV vs. WD, not significant). While body weight did not differ, plasma serum amyloid A (SAA), total cholesterol, triglycerides, and lysophosphatidic acid (LPA) levels were less in WD + 6F mice; P < 0.0295. HDL cholesterol and paroxonase-1 activity (PON) were higher in WD + 6F mice (P = 0.0055 and P = 0.0254, respectively), but not in WD + EV mice. Plasma SAA, total cholesterol, triglycerides, LPA, and 15-hydroxyeicosatetraenoic acid (HETE) levels positively correlated with lesions (P < 0.0001); HDL cholesterol and PON were inversely correlated (P < 0.0001). After feeding WD + 6F: i) intact 6F was detected in small intestine (but not in plasma); ii) small intestine LPA was decreased compared with WD + EV (P < 0.0469); and iii) small intestine LPA 18:2 positively correlated with the percent of the aorta with lesions (P < 0.0179). These data suggest that 6F acts in the small intestine and provides a novel approach to oral apoA-I mimetic therapy. PMID:23378594

Functional analysis of sporophytic transcripts repressed by the female gametophyte in the ovule of Arabidopsis thaliana.

PubMed

Armenta-Medina, Alma; Huanca-Mamani, Wilson; Sanchez-León, Nidia; Rodríguez-Arévalo, Isaac; Vielle-Calzada, Jean-Philippe

2013-01-01

To investigate the genetic and molecular regulation that the female gametophyte could exert over neighboring sporophytic regions of the ovule, we performed a quantitative comparison of global expression in wild-type and nozzle/sporocyteless (spl) ovules of Arabidopsis thaliana (Arabidopsis), using Massively Parallel Signature Sequencing (MPSS). This comparison resulted in 1517 genes showing at least 3-fold increased expression in ovules lacking a female gametophyte, including those encoding 89 transcription factors, 50 kinases, 25 proteins containing a RNA-recognition motif (RRM), and 20 WD40 repeat proteins. We confirmed that eleven of these genes are either preferentially expressed or exclusive of spl ovules lacking a female gametophyte as compared to wild-type, and showed that six are also upregulated in determinant infertile1 (dif1), a meiotic mutant affected in a REC8-like cohesin that is also devoided of female gametophytes. The sporophytic misexpression of IOREMPTE, a WD40/transducin repeat gene that is preferentially expressed in the L1 layer of spl ovules, caused the arrest of female gametogenesis after differentiation of a functional megaspore. Our results show that in Arabidopsis, the sporophytic-gametophytic cross talk includes a negative regulation of the female gametophyte over specific genes that are detrimental for its growth and development, demonstrating its potential to exert a repressive control over neighboring regions in the ovule.

Single Degenerate Models for Type Ia Supernovae: Progenitor's Evolution and Nucleosynthesis Yields

NASA Astrophysics Data System (ADS)

Nomoto, Ken'ichi; Leung, Shing-Chi

2018-06-01

We review how the single degenerate models for Type Ia supernovae (SNe Ia) works. In the binary star system of a white dwarf (WD) and its non-degenerate companion star, the WD accretes either hydrogen-rich matter or helium and undergoes hydrogen and helium shell-burning. We summarize how the stability and non-linear behavior of such shell-burning depend on the accretion rate and the WD mass and how the WD blows strong wind. We identify the following evolutionary routes for the accreting WD to trigger a thermonuclear explosion. Typically, the accretion rate is quite high in the early stage and gradually decreases as a result of mass transfer. With decreasing rate, the WD evolves as follows: (1) At a rapid accretion phase, the WD increase its mass by stable H burning and blows a strong wind to keep its moderate radius. The wind is strong enough to strip a part of the companion star's envelope to control the accretion rate and forms circumstellar matter (CSM). If the WD explodes within CSM, it is observed as an "SN Ia-CSM". (X-rays emitted by the WD are absorbed by CSM.) (2) If the WD continues to accrete at a lower rate, the wind stops and an SN Ia is triggered under steady-stable H shell-burning, which is observed as a super-soft X-ray source: "SN Ia-SSXS". (3) If the accretion continues at a still lower rate, H shell-burning becomes unstable and many flashes recur. The WD undergoes recurrent nova (RN) whose mass ejection is smaller than the accreted matter. Then the WD evolves to an "SN Ia-RN". (4) If the companion is a He star (or a He WD), the accretion of He can trigger He and C double detonations at the sub-Chandrasekhar mass or the WD grows to the Chandrasekhar mass while producing a He-wind: "SN Ia-He CSM". (5) If the accreting WD rotates quite rapidly, the WD mass can exceed the Chandrasekhar mass of the spherical WD, which delays the trigger of an SN Ia. After angular momentum is lost from the WD, the (super-Chandra) WD contracts to become a delayed SN Ia. The companion star has become a He WD and CSM has disappeared: "SN Ia-He WD". We update nucleosynthesis yields of the carbon deflagration model W7, delayed detonation model WDD2, and the sub-Chandrasekhar mass model to provide some constraints on the yields (such as Mn) from the comparison with the observations. We note the important metallicity effects on 58Ni and 55Mn.

Cyclin-dependent kinase (CDK) phosphorylation destabilizes somatic Wee1 via multiple pathways

PubMed Central

Watanabe, Nobumoto; Arai, Harumi; Iwasaki, Jun-ichi; Shiina, Masaaki; Ogata, Kazuhiro; Hunter, Tony; Osada, Hiroyuki

2005-01-01

At the onset of M phase, the activity of somatic Wee1 (Wee1A), the inhibitory kinase for cyclin-dependent kinase (CDK), is down-regulated primarily through proteasome-dependent degradation after ubiquitination by the E3 ubiquitin ligase SCFβ-TrCP. The F-box protein β-TrCP (β-transducin repeat-containing protein), the substrate recognition component of the ubiquitin ligase, binds to its substrates through a conserved binding motif (phosphodegron) containing two phosphoserines, DpSGXXpS. Although Wee1A lacks this motif, phosphorylation of serines 53 and 123 (S53 and S123) of Wee1A by polo-like kinase 1 (Plk1) and CDK, respectively, are required for binding to β-TrCP. The sequence surrounding phosphorylated S53 (DpSAFQE) is similar to the conserved β-TrCP-binding motif; however, the role of S123 phosphorylation (EEGFGSSpSPVK) in β-TrCP binding was not elucidated. In the present study, we show that phosphorylation of S123 (pS123) by CDK promoted the binding of Wee1A to β-TrCP through three independent mechanisms. The pS123 not only directly interacted with basic residues in the WD40 repeat domain of β-TrCP but also primed phosphorylation by two independent protein kinases, Plk1 and CK2 (formerly casein kinase 2), to create two phosphodegrons on Wee1A. In the case of Plk1, S123 phosphorylation created a polo box domain-binding motif (SpSP) on Wee1A to accelerate phosphorylation of S53 by Plk1. CK2 could phosphorylate S121, but only if S123 was phosphorylated first, thereby generating the second β-TrCP-binding site (EEGFGpS121). Using a specific inhibitor of CK2, we showed that the phosphorylation-dependent degradation of Wee1A is important for the proper onset of mitosis. PMID:16085715

Lenticular nucleus hyperechogenicity in Wilson's disease reflects local copper, but not iron accumulation.

PubMed

Walter, Uwe; Skowrońska, Marta; Litwin, Tomasz; Szpak, Grażyna Maria; Jabłonka-Salach, Katarzyna; Skoloudík, David; Bulska, Ewa; Członkowska, Anna

2014-10-01

In patients with Wilson's disease (WD) transcranial brain sonography typically reveals areas of increased echogenicity (hyperechogenicity) of the lenticular nucleus (LN). Correlation with T2-hypointensity on magnetic resonance images suggested that LN hyperechogenicity in WD is caused by trace metal accumulation. Accumulation of both, copper and iron, in the brain of WD patients has been reported. The present study was designed to elucidate whether LN hyperechogenicity in WD reflects accumulation of copper or iron. Post-mortem brains of 15 WD patients and one non-WD subject were studied with ultrasonography in an investigator-blinded fashion. LN hyperechogenicity was measured planimetrically by manual tracing as well as using digitized image analysis. The putaminal copper content was determined in samples of 11 WD brains and the non-WD brains using inductively coupled plasma mass spectrometry, and iron content was assessed using flame atomic absorption spectroscopy. LN was normal on ultrasonography only in the non-WD brain, but abnormal (hyperechogenic) in all WD brains. Digitized image analysis measures of LN hyperechogenicity and, by trend, manual measures correlated with putaminal copper content (Pearson test; digitized: r = 0.77, p = 0.04; manual: r = 0.57, p = 0.051) but not with iron content (each, p > 0.18). LN hyperechogenicity measures were unrelated to age at death of patients, age at onset of WD, WD duration, age of brain specimen, serum copper or serum ceruloplasmin (each, p > 0.1). We conclude that LN hyperechogenicity in WD reflects copper, but not iron accumulation. Further studies are warranted to elucidate the use of transcranial brain sonography for monitoring therapeutic effects of chelating agents in WD patients.

Hepatic F-Box Protein FBXW7 Maintains Glucose Homeostasis Through Degradation of Fetuin-A.

PubMed

Zhao, Jiejie; Xiong, Xuelian; Li, Yao; Liu, Xing; Wang, Tao; Zhang, Hong; Jiao, Yang; Jiang, Jingjing; Zhang, Huijie; Tang, Qiqun; Gao, Xin; Li, Xuejun; Lu, Yan; Liu, Bin; Hu, Cheng; Li, Xiaoying

2018-05-01

Type 2 diabetes mellitus (T2DM) has become one of the most serious and long-term threats to human health. However, the molecular mechanism that links obesity to insulin resistance remains largely unknown. Here, we show that F-box and WD repeat domain-containing 7 (FBXW7), an E3 ubiquitin protein ligase, is markedly downregulated in the liver of two obese mouse models and obese human subjects. We further identify a functional low-frequency human FBXW7 coding variant (p.Ala204Thr) in the Chinese population, which is associated with elevated blood glucose and T2DM risk. Notably, mice with liver-specific knockout of FBXW7 develop hyperglycemia, glucose intolerance, and insulin resistance even on a normal chow diet. Conversely, overexpression of FBXW7 in the liver not only prevents the development of high-fat diet-induced insulin resistance but also attenuates the disease signature of obese mice. Mechanistically, FBXW7 directly binds to hepatokine fetuin-A to induce its ubiquitination and subsequent proteasomal degradation, comprising an important mechanism maintaining glucose homeostasis. Thus, we provide evidence showing a beneficial role of FBXW7 in glucose homeostasis. © 2018 by the American Diabetes Association.

The BEACH-containing protein WDR81 coordinates p62 and LC3C to promote aggrephagy.

PubMed

Liu, Xuezhao; Li, Yang; Wang, Xin; Xing, Ruxiao; Liu, Kai; Gan, Qiwen; Tang, Changyong; Gao, Zhiyang; Jian, Youli; Luo, Shouqing; Guo, Weixiang; Yang, Chonglin

2017-05-01

Autophagy-dependent clearance of ubiquitinated and aggregated proteins is critical to protein quality control, but the underlying mechanisms are not well understood. Here, we report the essential role of the BEACH (beige and Chediak-Higashi) and WD40 repeat-containing protein WDR81 in eliminating ubiquitinated proteins through autophagy. WDR81 associates with ubiquitin (Ub)-positive protein foci, and its loss causes accumulation of Ub proteins and the autophagy cargo receptor p62. WDR81 interacts with p62, facilitating recognition of Ub proteins by p62. Furthermore, WDR81 interacts with LC3C through canonical LC3-interacting regions in the BEACH domain, promoting LC3C recruitment to ubiquitinated proteins. Inactivation of LC3C or defective autophagy results in accumulation of Ub protein aggregates enriched for WDR81. In mice, WDR81 inactivation causes accumulation of p62 bodies in cortical and striatal neurons in the brain. These data suggest that WDR81 coordinates p62 and LC3C to facilitate autophagic removal of Ub proteins, and provide important insights into CAMRQ2 syndrome, a WDR81-related developmental disorder. © 2017 Liu et al.

The BEACH-containing protein WDR81 coordinates p62 and LC3C to promote aggrephagy

PubMed Central

Xing, Ruxiao; Tang, Changyong; Gao, Zhiyang

2017-01-01

Autophagy-dependent clearance of ubiquitinated and aggregated proteins is critical to protein quality control, but the underlying mechanisms are not well understood. Here, we report the essential role of the BEACH (beige and Chediak–Higashi) and WD40 repeat-containing protein WDR81 in eliminating ubiquitinated proteins through autophagy. WDR81 associates with ubiquitin (Ub)-positive protein foci, and its loss causes accumulation of Ub proteins and the autophagy cargo receptor p62. WDR81 interacts with p62, facilitating recognition of Ub proteins by p62. Furthermore, WDR81 interacts with LC3C through canonical LC3-interacting regions in the BEACH domain, promoting LC3C recruitment to ubiquitinated proteins. Inactivation of LC3C or defective autophagy results in accumulation of Ub protein aggregates enriched for WDR81. In mice, WDR81 inactivation causes accumulation of p62 bodies in cortical and striatal neurons in the brain. These data suggest that WDR81 coordinates p62 and LC3C to facilitate autophagic removal of Ub proteins, and provide important insights into CAMRQ2 syndrome, a WDR81-related developmental disorder. PMID:28404643

Using XAS and SXRF to Study Copper in Wilson Disease at the Molecular and Tissue Level

NASA Astrophysics Data System (ADS)

Ralle, Martina; Blackburn, Ninian J.; Lutsenko, Svetlana

2007-02-01

Wilson disease (WD) is a genetic disorder of copper metabolism associated with severe hepatic, neurological, and psychiatric abnormalities. In WD, the billiary copper excretion is impaired and copper accumulates in tissues, particularly in the liver and the brain. The affected gene, ATP7B, encodes the copper transporting ATPase, Wilson disease protein (WNDP). WNDP has six copper binding sites in the N-terminal portion of the molecule. Each site includes the conserved amino acid sequence MXCXXC, and binds 1 Cu(I) through its 2 cysteine residues. We performed X-ray absorption studies at the Cu Kα-edge on the recombinant N-terminal domain of WNDP (N-WNDP). Copper was bound to N-WNDP either in vivo or in vitro in the presence of different reducing agents. We found that in N-WNDP copper is predominantly coordinated in a linear fashion by two cysteines, with the appearance of a Cu-Cu interaction when all metal binding sites are filled. Increasing amounts of reducing agents containing sulfide or phosphine groups led to binding of the exogenous ligands to copper thereby increasing the coordination number of copper from two to three. To better understand the role of copper in WD, we utilized livers of the 6-weeks-old Atp7b-/- mice (an animal model for WD) in which the copper concentration was 10-20-fold higher compared to that of the control mice. The distribution of copper in hepatocytes was evaluated by synchrotron based X-ray fluorescence microprobe (SXRF). We demonstrate that we can prepare liver slices that retain copper and can detect copper with subcellular resolution. On the same sections μ-XANES (spot size: 5 micron) was used to determine the oxidation state of copper.

Screening for Wilson disease in acute liver failure: a comparison of currently available diagnostic tests.

PubMed

Korman, Jessica D; Volenberg, Irene; Balko, Jody; Webster, Joe; Schiodt, Frank V; Squires, Robert H; Fontana, Robert J; Lee, William M; Schilsky, Michael L

2008-10-01

Acute liver failure (ALF) due to Wilson disease (WD) is invariably fatal without emergency liver transplantation. Therefore, rapid diagnosis of WD should aid prompt transplant listing. To identify the best method for diagnosis of ALF due to WD (ALF-WD), data and serum were collected from 140 ALF patients (16 with WD), 29 with other chronic liver diseases and 17 with treated chronic WD. Ceruloplasmin (Cp) was measured by both oxidase activity and nephelometry and serum copper levels by atomic absorption spectroscopy. In patients with ALF, a serum Cp <20 mg/dL by the oxidase method provided a diagnostic sensitivity of 21% and specificity of 84% while, by nephelometry, a sensitivity of 56% and specificity of 63%. Serum copper levels exceeded 200 microg/dL in all ALF-WD patients measured (13/16), but were also elevated in non-WD ALF. An alkaline phosphatase (AP) to total bilirubin (TB) ratio <4 yielded a sensitivity of 94%, specificity of 96%, and a likelihood ratio of 23 for diagnosing fulminant WD. In addition, an AST:ALT ratio >2.2 yielded a sensitivity of 94%, a specificity of 86%, and a likelihood ratio of 7 for diagnosing fulminant WD. Combining the tests provided a diagnostic sensitivity and specificity of 100%. Conventional WD testing utilizing serum ceruloplasmin and/or serum copper levels are less sensitive and specific in identifying patients with ALF-WD than other available tests. More readily available laboratory tests including alkaline phosphatase, bilirubin and serum aminotransferases by contrast provides the most rapid and accurate method for diagnosis of ALF due to WD.

Tidal dissipation and evolution of white dwarfs around massive black holes: an eccentric path to tidal disruption

NASA Astrophysics Data System (ADS)

Vick, Michelle; Lai, Dong; Fuller, Jim

2017-06-01

A white dwarf (WD) captured into a high-eccentricity orbit around a massive black hole (MBH) may undergo many pericentre passages before tidal disruption. During these passages, the tidal potential of the MBH excites internal oscillations or waves in the WD, and the dissipation of these oscillations can significantly influence the physical properties of the WD prior to its disruption. We calculate the amplitude of the tidally excited gravity (buoyancy) waves in the WD as a function of the pericentre distance and eccentricity for realistic WD models, under the assumption that these outgoing gravity waves are efficiently dissipated in the outer layers of the WD by non-linear effects or radiative damping. We obtain fitting formulae for the tidal energy and angular momentum transfer rates as well as the tidal heating rate. We find that these dynamical tides are much weaker than gravitational radiation in driving the orbital decay of the WD-MBH binary, and they are also inefficient in changing the WD spin during the orbital evolution. Incorporating our computed tidal dissipation rate into a mesa-based WD evolution code, we find that tidal heating can lead to appreciable brightening of the WD and may induce runaway fusion in the hydrogen envelope well before the WD undergoes tidal disruption.

Discovery of four new low-mass white-dwarf companions in the Kepler data

NASA Astrophysics Data System (ADS)

Faigler, Simchon; Kull, Ilya; Mazeh, Tsevi; Kiefer, Flavien; Latham, David W.; Bloemen, Steven

2015-12-01

We report the discovery of four new short-period eclipsing systems in the Kepler light curves, consisting of an A-star primary and a low-mass white-dwarf (WD) secondary (dA+WD) - KIC 4169521, KOI-3818, KIC 2851474 and KIC 9285587. These add to the 6 Kepler, and 19 non-Kepler, previously known short-period eclipsing dA+WD binaries.The discoveries were made through searching the light curves of bright Kepler stars for BEaming, Ellipsoidal and Reflection (BEER) modulations that are consistent with a compact companion, using the BEER search algorithm. This was followed by inspection of the search top hits, looking for eclipsing systems with a secondary eclipse deeper than the primary one, as expected for a WD that is hotter than the primary star. Follow-up spectroscopic radial-velocity (RV) observations confirmed the binarity of the systems. We derive the systems' parameters through analyses of the light curves' eclipses and phase modulations, combined with RV orbital solutions and stellar evolution models.The four systems' orbital periods of 1.17-3.82 days and WD masses of 0.19-0.22 Msun are similar to those reported for the previously known systems. These values are consistent with evolution models of such systems, that undergo a stable mass transfer from the WD progenitor to the current A star.For KIC 4169521 we derive a bloated WD radius of 0.09 Rsun that is well within the WD radius range of 0.04-0.43 Rsun of the known systems. For the remaining three systems we report WD radii of 0.026-0.035 Rsun, the smallest WD radii derived so far for short-period eclipsing dA+WD binaries.As suggested before, the previously known systems, together with KIC 4169521, all with hot and bloated WD secondaries, represent young systems probably at a proto-WD, or initial WD cooling track stage. The other three new systems - KOI-3818, KIC 2851474, and KIC 9285587, are probably positioned further along the WD cooling track, and extend the known population to older systems with cooler and smaller WD secondaries.

The progenitors of Type Ia supernovae with long delay times

NASA Astrophysics Data System (ADS)

Wang, Bo; Li, Xiang-Dong; Han, Zhan-Wen

2010-02-01

The nature of the progenitors of Type Ia supernovae (SNe Ia) is still unclear. In this paper, by considering the effect of the instability of accretion disc on the evolution of white dwarf (WD) binaries, we performed binary evolution calculations for about 2400 close WD binaries, in which a carbon-oxygen WD accretes material from a main-sequence (MS) star or a slightly evolved subgiant star (WD + MS channel), or a red-giant star (WD + RG channel) to increase its mass to the Chandrasekhar (Ch) mass limit. According to these calculations, we mapped out the initial parameters for SNe Ia in the orbital period-secondary mass (logPi - Mi2) plane for various WD masses for these two channels, respectively. We confirm that WDs in the WD + MS channel with a mass as low as 0.61Msolar can accrete efficiently and reach the Ch limit, while the lowest WD mass for the WD + RG channel is 1.0Msolar. We have implemented these results in a binary population synthesis study to obtain the SN Ia birthrates and the evolution of SN Ia birthrates with time for both a constant star formation rate and a single starburst. We find that the Galactic SN Ia birthrate from the WD + MS channel is ~1.8 × 10-3yr-1 according to our standard model, which is higher than the previous results. However, similar to the previous studies, the birthrate from the WD + RG channel is still low (~3 × 10-5yr-1). We also find that about one-third of SNe Ia from the WD + MS channel and all SNe Ia from the WD + RG channel can contribute to the old populations (>~1Gyr) of SN Ia progenitors.

Diet-induced obesity, energy metabolism and gut microbiota in C57BL/6J mice fed Western diets based on lean seafood or lean meat mixtures.

PubMed

Holm, Jacob Bak; Rønnevik, Alexander; Tastesen, Hanne Sørup; Fjære, Even; Fauske, Kristin Røen; Liisberg, Ulrike; Madsen, Lise; Kristiansen, Karsten; Liaset, Bjørn

2016-05-01

High protein diets may protect against diet-induced obesity, but little is known regarding the effects of different protein sources consumed at standard levels. We investigated how a mixture of lean seafood or lean meat in a Western background diet modulated diet-induced obesity, energy metabolism and gut microbiota. Male C57BL/6J mice fed a Western diet (WD) containing a mixture of lean seafood (seafood WD) for 12weeks accumulated less fat mass than mice fed a WD containing a mixture of lean meat (meat WD). Meat WD-fed mice exhibited increased fasting blood glucose, impaired glucose clearance, elevated fasting plasma insulin and increased plasma and liver lipid levels. We observed no first choice preference for either of the WDs, but over time, mice fed the seafood WD consumed less energy than mice fed the meat WD. Mice fed the seafood WD exhibited higher spontaneous locomotor activity and a lower respiratory exchange ratio (RER) than mice fed the meat WD. Thus, higher activity together with the decreased energy intake contributed to the different phenotypes observed in mice fed the seafood WD compared to mice fed the meat WD. Comparison of the gut microbiomes of mice fed the two WDs revealed significant differences in the relative abundance of operational taxonomic units (OTUs) belonging to the orders Bacteroidales and Clostridiales, with genes involved in metabolism of aromatic amino acids exhibiting higher relative abundance in the microbiomes of mice fed the seafood WD. Copyright © 2016 Elsevier Inc. All rights reserved.

Identification and Analysis of Novel Amino-Acid Sequence Repeats in Bacillus anthracis str. Ames Proteome Using Computational Tools

PubMed Central

Hemalatha, G. R.; Rao, D. Satyanarayana; Guruprasad, L.

2007-01-01

We have identified four repeats and ten domains that are novel in proteins encoded by the Bacillus anthracis str. Ames proteome using automated in silico methods. A “repeat” corresponds to a region comprising less than 55-amino-acid residues that occur more than once in the protein sequence and sometimes present in tandem. A “domain” corresponds to a conserved region with greater than 55-amino-acid residues and may be present as single or multiple copies in the protein sequence. These correspond to (1) 57-amino-acid-residue PxV domain, (2) 122-amino-acid-residue FxF domain, (3) 111-amino-acid-residue YEFF domain, (4) 109-amino-acid-residue IMxxH domain, (5) 103-amino-acid-residue VxxT domain, (6) 84-amino-acid-residue ExW domain, (7) 104-amino-acid-residue NTGFIG domain, (8) 36-amino-acid-residue NxGK repeat, (9) 95-amino-acid-residue VYV domain, (10) 75-amino-acid-residue KEWE domain, (11) 59-amino-acid-residue AFL domain, (12) 53-amino-acid-residue RIDVK repeat, (13) (a) 41-amino-acid-residue AGQF repeat and (b) 42-amino-acid-residue GSAL repeat. A repeat or domain type is characterized by specific conserved sequence motifs. We discuss the presence of these repeats and domains in proteins from other genomes and their probable secondary structure. PMID:17538688

The evolution of filamin – A protein domain repeat perspective

PubMed Central

Light, Sara; Sagit, Rauan; Ithychanda, Sujay S.; Qin, Jun; Elofsson, Arne

2013-01-01

Particularly in higher eukaryotes, some protein domains are found in tandem repeats, performing broad functions often related to cellular organization. For instance, the eukaryotic protein filamin interacts with many proteins and is crucial for the cytoskeleton. The functional properties of long repeat domains are governed by the specific properties of each individual domain as well as by the repeat copy number. To provide better understanding of the evolutionary and functional history of repeating domains, we investigated the mode of evolution of the filamin domain in some detail. Among the domains that are common in long repeat proteins, sushi and spectrin domains evolve primarily through cassette tandem duplications while scavenger and immunoglobulin repeats appear to evolve through clustered tandem duplications. Additionally, immunoglobulin and filamin repeats exhibit a unique pattern where every other domain shows high sequence similarity. This pattern may be the result of tandem duplications, serve to avert aggregation between adjacent domains or it is the result of functional constraints. In filamin, our studies confirm the presence of interspersed integrin binding domains in vertebrates, while invertebrates exhibit more varied patterns, including more clustered integrin binding domains. The most notable case is leech filamin, which contains a 20 repeat expansion and exhibits unique dimerization topology. Clearly, invertebrate filamins are varied and contain examples of similar adjacent integrin-binding domains. Given that invertebrate integrin shows more similarity to the weaker filamin binder, integrin β3, it is possible that the distance between integrin-binding domains is not as crucial for invertebrate filamins as for vertebrates. PMID:22414427

The evolution of filamin-a protein domain repeat perspective.

PubMed

Light, Sara; Sagit, Rauan; Ithychanda, Sujay S; Qin, Jun; Elofsson, Arne

2012-09-01

Particularly in higher eukaryotes, some protein domains are found in tandem repeats, performing broad functions often related to cellular organization. For instance, the eukaryotic protein filamin interacts with many proteins and is crucial for the cytoskeleton. The functional properties of long repeat domains are governed by the specific properties of each individual domain as well as by the repeat copy number. To provide better understanding of the evolutionary and functional history of repeating domains, we investigated the mode of evolution of the filamin domain in some detail. Among the domains that are common in long repeat proteins, sushi and spectrin domains evolve primarily through cassette tandem duplications while scavenger and immunoglobulin repeats appear to evolve through clustered tandem duplications. Additionally, immunoglobulin and filamin repeats exhibit a unique pattern where every other domain shows high sequence similarity. This pattern may be the result of tandem duplications, serve to avert aggregation between adjacent domains or it is the result of functional constraints. In filamin, our studies confirm the presence of interspersed integrin binding domains in vertebrates, while invertebrates exhibit more varied patterns, including more clustered integrin binding domains. The most notable case is leech filamin, which contains a 20 repeat expansion and exhibits unique dimerization topology. Clearly, invertebrate filamins are varied and contain examples of similar adjacent integrin-binding domains. Given that invertebrate integrin shows more similarity to the weaker filamin binder, integrin β3, it is possible that the distance between integrin-binding domains is not as crucial for invertebrate filamins as for vertebrates. Copyright © 2012 Elsevier Inc. All rights reserved.

Water deficit mechanisms in perennial shrubs Cerasus humilis leaves revealed by physiological and proteomic analyses.

PubMed

Yin, Zepeng; Ren, Jing; Zhou, Lijuan; Sun, Lina; Wang, Jiewan; Liu, Yulong; Song, Xingshun

2016-01-01

Drought (Water deficit, WD) poses a serious threat to extensively economic losses of trees throughout the world. Chinese dwarf cherry ( Cerasus humilis ) is a good perennial plant for studying the physiological and sophisticated molecular network under WD. The aim of this study is to identify the effect of WD on C. humilis through physiological and global proteomics analysis and improve understanding of the WD resistance of plants. Currently, physiological parameters were applied to investigate C. humilis response to WD. Moreover, we used two-dimensional gel electrophoresis (2DE) to identify differentially expressed proteins in C. humilis leaves subjected to WD (24 d). Furthermore, we also examined the correlation between protein and transcript levels. Several physiological parameters, including relative water content and Pn were reduced by WD. In addition, the malondialdehyde (MDA), relative electrolyte leakage (REL), total soluble sugar, and proline were increased in WD-treated C. humilis . Comparative proteomic analysis revealed 46 protein spots (representing 43 unique proteins) differentially expressed in C. humilis leaves under WD. These proteins were mainly involved in photosynthesis, ROS scavenging, carbohydrate metabolism, transcription, protein synthesis, protein processing, and nitrogen and amino acid metabolisms, respectively. WD promoted the CO 2 assimilation by increase light reaction and Calvin cycle, leading to the reprogramming of carbon metabolism. Moreover, the accumulation of osmolytes (i.e., proline and total soluble sugar) and enhancement of ascorbate-glutathione cycle and glutathione peroxidase/glutathione s-transferase pathway in leaves could minimize oxidative damage of membrane and other molecules under WD. Importantly, the regulation role of carbohydrate metabolisms (e. g. glycolysis, pentose phosphate pathways, and TCA) was enhanced. These findings provide key candidate proteins for genetic improvement of perennial plants metabolism under WD.

Duodeno-jejunal bypass restores β-cell hypersecretion and islet hypertrophy in western diet obese rats.

PubMed

Mendes, Mariana Carla; Bonfleur, Maria Lúcia; Ribeiro, Rosane Aparecida; Lubaczeuski, Camila; Fêo, Ana Flavia Justino; Vargas, Rodrigo; Carneiro, Everardo Magalhães; Boschero, Antonio Carlos; Araujo, Allan Cezar Faria; Balbo, Sandra Lucinei

2018-06-01

Duodeno-jejunal bypass (DJB) operation improves glucose homeostasis in morbid obesity, independently of weight loss or reductions in adiposity, through mechanisms not yet fully elucidated. Herein, we evaluated the effects of DJB upon glucose homeostasis, endocrine pancreatic morphology, and β-cell responsiveness to potentiating agents of cholinergic and cAMP pathways, in western diet (WD) obese rats, at 2 months after operation. From 8 to 18 weeks of age male Wistar rats fed on a WD. After this period, a sham (WD Sham group) or DJB (WD DJB) operations were performed. At 2 months after operation glucose homeostasis was verified. Body weight was similar between WD DJB and WD Sham rats, but WD DJB rats showed a decrease in Lee index, retroperitoneal and perigonadal fat pads. Also, WD DJB rats displayed reduced fasting glycemia and insulinemia, and increased insulin-induced Akt activation in the gastrocnemius. Islets from WD DJB rats secreted less amounts of insulin, in response to activators of the cholinergic (carbachol and phorbol 12-myristate 13-acetate) and cAMP (forskolin and 3-isobutyl-1-methyl-xantine) pathways. Islets of WD DJB rats had higher sintaxin-1 protein content than WD Sham, but without modification in muscarinic-3 receptor, protein kinase (PK)-Cα, and (PK)-Aα protein amounts. In addition, islets of WD DJB animals showed reduction in islets and β-cell masses. DJB surgery improves fasting glycemia and insulin action in skeletal muscle. Better endocrine pancreatic morphofunction was associated, at least in part, with the regulation of the cholinergic and cAMP pathways, and improvements in syntaxin-1 islet protein content induced by DJB.

A prefoldin-associated WD-repeat protein (WDR92) is required for the correct architectural assembly of motile cilia

PubMed Central

Patel-King, Ramila S.; King, Stephen M.

2016-01-01

WDR92 is a highly conserved WD-repeat protein that has been proposed to be involved in apoptosis and also to be part of a prefoldin-like cochaperone complex. We found that WDR92 has a phylogenetic signature that is generally compatible with it playing a role in the assembly or function of specifically motile cilia. To test this hypothesis, we performed an RNAi-based knockdown of WDR92 gene expression in the planarian Schmidtea mediterranea and were able to achieve a robust reduction in mRNA expression to levels undetectable under our standard RT-PCR conditions. We found that this treatment resulted in a dramatic reduction in the rate of organismal movement that was caused by a switch in the mode of locomotion from smooth, cilia-driven gliding to muscle-based, peristaltic contractions. Although the knockdown animals still assembled cilia of normal length and in similar numbers to controls, these structures had reduced beat frequency and did not maintain hydrodynamic coupling. By transmission electron microscopy we observed that many cilia had pleiomorphic defects in their architecture, including partial loss of dynein arms, incomplete closure of the B-tubule, and occlusion or replacement of the central pair complex by accumulated electron-dense material. These observations suggest that WDR92 is part of a previously unrecognized cytoplasmic chaperone system that is specifically required to fold key components necessary to build motile ciliary axonemes. PMID:26912790

Direct Interaction between the WD40 Repeat Protein WDR-23 and SKN-1/Nrf Inhibits Binding to Target DNA

PubMed Central

Leung, Chi K.; Hasegawa, Koichi; Wang, Ying; Deonarine, Andrew; Tang, Lanlan; Miwa, Johji

2014-01-01

SKN-1/Nrf transcription factors activate cytoprotective genes in response to reactive small molecules and strongly influence stress resistance, longevity, and development. The molecular mechanisms of SKN-1/Nrf regulation are poorly defined. We previously identified the WD40 repeat protein WDR-23 as a repressor of Caenorhabditis elegans SKN-1 that functions with a ubiquitin ligase to presumably target the factor for degradation. However, SKN-1 activity and nuclear accumulation are not always correlated, suggesting that there could be additional regulatory mechanisms. Here, we integrate forward genetics and biochemistry to gain insights into how WDR-23 interacts with and regulates SKN-1. We provide evidence that WDR-23 preferentially regulates one of three SKN-1 variants through a direct interaction that is required for normal stress resistance and development. Homology modeling predicts that WDR-23 folds into a β-propeller, and we identify the top of this structure and four motifs at the termini of SKN-1c as essential for the interaction. Two of these SKN-1 motifs are highly conserved in human Nrf1 and Nrf2 and two directly interact with target DNA. Lastly, we demonstrate that WDR-23 can block the ability of SKN-1c to interact with DNA sequences of target promoters identifying a new mechanism of regulation that is independent of the ubiquitin proteasome system, which can become occupied with damaged proteins during stress. PMID:24912676

Cooperative control between AtRGS1 and AtHXK1 in a WD40-repeat protein pathway in Arabidopsis thaliana

DOE PAGES

Huang, Jian -Ping; Tunc-Ozdemir, Meral; Chang, Ying; ...

2015-10-13

HEXOKINASE 1 (AtHXK1) and Regulator of G-protein Signaling 1 (AtRGS1) pathways, mediate D-glucose signaling in Arabidopsis. However, it is not known the degree, if any, that these pathways overlap and how. We show modest signaling crosstalk between these pathways, albeit complex with both epistatic interactions and additive effects that may be indirect. The action of HXK1 on AtRGS1 signaling lies downstream of the primary step in G protein-mediated sugar signaling in which the WD-repeat protein, AGB1, is the propelling signaling element. RHIP1, a previously unknown protein predicted here to have a 3-stranded helical structure, interacts with both AtRGS1 and AtHXK1more » in planta and is required for some glucose-regulated gene expression, providing a physical connection between these two proteins in sugar signaling. The rhip1 null mutant displays similar seedling growth phenotypes as rgs1-2 in response to glucose, further suggesting a role for RHIP1 in glucose signaling. Lastly, glucose signaling is a complex hierarchical relationship which is specific to the target gene and sugar phenotype and suggests that there are two glycolysis-independent glucose signaling sensors: AtRGS1 and AtHXK1 that weakly communicate with each other via feed-back and feed-forward loops to fine tune the response to glucose.« less

The WD-Repeat Protein CsTTG1 Regulates Fruit Wart Formation through Interaction with the Homeodomain-Leucine Zipper I Protein Mict1

PubMed Central

Yin, Shuai; Liu, Xingwang; Liu, Bin; Yang, Sen; Xue, Shudan; Cai, Yanling; Liu, Huiling; Dong, Mingming; Zhang, Yaqi; Zhao, Binyu

2016-01-01

The cucumber (Cucumis sativus) fruit is covered with bloom trichomes and warts (composed of spines and tubercules), which have an important impact on the commercial value of the crop. However, little is known about the regulatory mechanism underlying their formation. Here, we reported that the cucumber WD-repeat homolog CsTTG1, which is localized in the nucleus and cytomembrane, plays an important role in the formation of cucumber fruit bloom trichomes and warts. Functional characterization of CsTTG1 revealed that it is mainly expressed in the epidermis of cucumber ovary and that its overexpression in cucumber alters the density of fruit bloom trichomes and spines, thereby promoting the warty fruit trait. Conversely, silencing CsTTG1 expression inhibits the initiation of fruit spines. Molecular and genetic analyses showed that CsTTG1 acts in parallel to Mict/CsGL1, a key trichome formation factor, to regulate the initiation of fruit trichomes, including fruit bloom trichomes and spines, and that the further differentiation of fruit spines and formation of tubercules regulated by CsTTG1 is dependent on Mict. Using yeast two-hybrid assay and bimolecular fluorescence complementation assay, we determined that CsTTG1 directly interacts with Mict. Collectively, our results indicate that CsTTG1 is an important component of the molecular network that regulates fruit bloom trichome and wart formation in cucumber. PMID:27208299

Hypothesis: The Intratumoral Immune Response against a Cancer Progenitor Cell Impacts the Development of Well-Differentiated versus Dedifferentiated Disease in Liposarcoma

PubMed Central

Tseng, William W.; Chopra, Shefali; Engleman, Edgar G.; Pollock, Raphael E.

2016-01-01

Well-differentiated/dedifferentiated (WD/DD) liposarcoma is a rare malignancy of adipocyte origin (“fat cancer”). Tumors may be entirely WD, WD with a DD component, or rarely DD without a clear WD component. WD tumors are low grade and generally indolent, while tumors with a DD component are high grade and behave much more aggressively, with a modest potential for distant metastasis. The presence of cancer progenitor cells in WD/DD liposarcoma is suggested by clinical evidence and reported research findings. In addition, there are emerging data to support the existence of a naturally occurring, antigen-driven, and adaptive immune response within the tumor microenvironment. We hypothesize that the intratumoral immune response is directed against a cancer progenitor cell and that the outcome of this response impacts the development of WD versus DD disease. Further study will likely provide interesting insights into the disease biology of WD/DD liposarcoma that may be readily translated to other more common cancers. PMID:27376027

Report on von Willebrand Disease in Malaysia

PubMed Central

Periayah, Mercy Halleluyah; Halim, Ahmad Sukari; Saad, Arman Zaharil Mat; Yaacob, Nik Soriani; Karim, Faraizah Abdul

2016-01-01

BACKGROUND: Von Willebrand disease (vWD) is an inherited hemostatic disorder that affects the hemostasis pathway. The worldwide prevalence of vWD is estimated to be 1% of the general population but only 0.002% in Malaysia. AIM: Our present paper has been written to disclose the statistical counts on the number of vWD cases reported from 2011 to 2013. MATERIAL AND METHODS: This article is based on sociodemographic data, diagnoses and laboratory findings of vWD in Malaysia. A total of 92 patients were reported to have vWD in Malaysia from 2011 to 2013. RESULTS: Sociodemographic-analysis revealed that 60% were females, 63% were of the Malay ethnicity, 41.3% were in the 19-44 year old age group and 15.2% were from Sabah, with the East region having the highest registered number of vWD cases. In Malaysia, most patients are predominately affected by vWD type 1 (77.2%). Factor 8, von Willebrand factor: Antigen and vWF: Collagen-Binding was the strongest determinants in the laboratory profiles of vWD. CONCLUSION: This report has been done with great interest to provide an immense contribution from Malaysia, by revealing the statistical counts on vWD from 2011-2013. PMID:27275342

Antiviral drug acyclovir exhibits antitumor activity via targeting βTrCP1: Molecular docking and dynamics simulation study.

PubMed

Shafique, Shagufta; Rashid, Sajid

2017-03-01

The critical role of βTrCP1 in cancer development makes it a discerning target for the development of small drug like molecules. Currently, no inhibitor exists that is able to target its substrate binding site. Through molecular docking and dynamics simulation assays, we explored the comparative binding pattern of βTrCP1-WD40 domain with ACV and its phospho-derivatives (ACVMP, ACVDP and ACVTP). Consequently, through principal component analysis, βTrCP1-ACVTP was found to be more stable complex by obscuring a reduced conformational space than other systems. Thus based on the residual contribution and hydrogen bonding pattern, ACVTP was considered as a noteworthy inhibitor which demarcated binding in the cleft formed by βTrCP1-WD40 specific β-propeller. The outcomes of this study may provide a platform for rational design of specific and potent inhibitor against βTrCP1, with special emphasis on anticancer activity. Copyright © 2016 Elsevier Inc. All rights reserved.

Capturing complexity in work disability research: application of system dynamics modeling methodology.

PubMed

Jetha, Arif; Pransky, Glenn; Hettinger, Lawrence J

2016-01-01

Work disability (WD) is characterized by variable and occasionally undesirable outcomes. The underlying determinants of WD outcomes include patterns of dynamic relationships among health, personal, organizational and regulatory factors that have been challenging to characterize, and inadequately represented by contemporary WD models. System dynamics modeling (SDM) methodology applies a sociotechnical systems thinking lens to view WD systems as comprising a range of influential factors linked by feedback relationships. SDM can potentially overcome limitations in contemporary WD models by uncovering causal feedback relationships, and conceptualizing dynamic system behaviors. It employs a collaborative and stakeholder-based model building methodology to create a visual depiction of the system as a whole. SDM can also enable researchers to run dynamic simulations to provide evidence of anticipated or unanticipated outcomes that could result from policy and programmatic intervention. SDM may advance rehabilitation research by providing greater insights into the structure and dynamics of WD systems while helping to understand inherent complexity. Challenges related to data availability, determining validity, and the extensive time and technical skill requirements for model building may limit SDM's use in the field and should be considered. Contemporary work disability (WD) models provide limited insight into complexity associated with WD processes. System dynamics modeling (SDM) has the potential to capture complexity through a stakeholder-based approach that generates a simulation model consisting of multiple feedback loops. SDM may enable WD researchers and practitioners to understand the structure and behavior of the WD system as a whole, and inform development of improved strategies to manage straightforward and complex WD cases.

Genomic survey, expression profile and co-expression network analysis of OsWD40 family in rice

PubMed Central

2012-01-01

Background WD40 proteins represent a large family in eukaryotes, which have been involved in a broad spectrum of crucial functions. Systematic characterization and co-expression analysis of OsWD40 genes enable us to understand the networks of the WD40 proteins and their biological processes and gene functions in rice. Results In this study, we identify and analyze 200 potential OsWD40 genes in rice, describing their gene structures, genome localizations, and evolutionary relationship of each member. Expression profiles covering the whole life cycle in rice has revealed that transcripts of OsWD40 were accumulated differentially during vegetative and reproductive development and preferentially up or down-regulated in different tissues. Under phytohormone treatments, 25 OsWD40 genes were differentially expressed with treatments of one or more of the phytohormone NAA, KT, or GA3 in rice seedlings. We also used a combined analysis of expression correlation and Gene Ontology annotation to infer the biological role of the OsWD40 genes in rice. The results suggested that OsWD40 genes may perform their diverse functions by complex network, thus were predictive for understanding their biological pathways. The analysis also revealed that OsWD40 genes might interact with each other to take part in metabolic pathways, suggesting a more complex feedback network. Conclusions All of these analyses suggest that the functions of OsWD40 genes are diversified, which provide useful references for selecting candidate genes for further functional studies. PMID:22429805

Molecular modeling and molecular dynamics simulations based structural analysis of the SG2NA protein variants.

PubMed

Soni, Sangeeta; Tyagi, Chetna; Grover, Abhinav; Goswami, Shyamal K

2014-07-11

SG2NA is a member of the striatin sub-family of WD-40 repeat proteins. Striatin family members have been associated with diverse physiological functions. SG2NA has also been shown to have roles in cell cycle progression, signal transduction etc. They have been known to interact with a number of proteins including Caveolin and Calmodulin and also propagate the formation of a multimeric protein unit called striatin-interacting phosphatase and kinase. As a pre-requisite for such interaction ability, these proteins are known to be unstable and primarily disordered in their arrangement. Earlier we had identified that it has multiple isoforms (namely 35, 78, 87 kDa based on its molecular weight) which are generated by alternative splicing. However, detailed structural information of SG2NA is still eluding the researchers. This study was aimed towards three-dimensional molecular modeling and characterization of SG2NA protein and its isoforms. One structure out of five was selected for each variant having the least value for C score. Out of these, m35 kDa with a C score value of -3.21 was the most poorly determined structure in comparison to m78 kDa and m87 kDa variants with C scores of -1.16 and -1.97 respectively. Further evaluation resulted in about 61.6% residues of m35 kDa, 76.6% residues of m78 kDa and 72.1% residues of m87 kDa falling in the favorable regions of Ramchandran Plot. Molecular dynamics simulations were also carried out to obtain biologically relevant structural models and compared with previous atomic coordinates. N-terminal region of all variants was found to be highly disordered. This study provides first-hand detailed information to understand the structural conformation of SG2NA protein variants (m35 kDa, m78 kDa and m87 kDa). The WD-40 repeat domain was found to constitute antiparallel strands of β-sheets arranged circularly. This study elucidates the crucial structural features of SG2NA proteins which are involved in various protein-protein interactions and also reveals the extent of disorder present in the SG2NA structure crucial for excessive interaction and multimeric protein complexes. The study also potentiates the role of computational approaches for preliminary examination of unknown proteins in the absence of experimental information.

Tandem-repeat protein domains across the tree of life.

PubMed

Jernigan, Kristin K; Bordenstein, Seth R

2015-01-01

Tandem-repeat protein domains, composed of repeated units of conserved stretches of 20-40 amino acids, are required for a wide array of biological functions. Despite their diverse and fundamental functions, there has been no comprehensive assessment of their taxonomic distribution, incidence, and associations with organismal lifestyle and phylogeny. In this study, we assess for the first time the abundance of armadillo (ARM) and tetratricopeptide (TPR) repeat domains across all three domains in the tree of life and compare the results to our previous analysis on ankyrin (ANK) repeat domains in this journal. All eukaryotes and a majority of the bacterial and archaeal genomes analyzed have a minimum of one TPR and ARM repeat. In eukaryotes, the fraction of ARM-containing proteins is approximately double that of TPR and ANK-containing proteins, whereas bacteria and archaea are enriched in TPR-containing proteins relative to ARM- and ANK-containing proteins. We show in bacteria that phylogenetic history, rather than lifestyle or pathogenicity, is a predictor of TPR repeat domain abundance, while neither phylogenetic history nor lifestyle predicts ARM repeat domain abundance. Surprisingly, pathogenic bacteria were not enriched in TPR-containing proteins, which have been associated within virulence factors in certain species. Taken together, this comparative analysis provides a newly appreciated view of the prevalence and diversity of multiple types of tandem-repeat protein domains across the tree of life. A central finding of this analysis is that tandem repeat domain-containing proteins are prevalent not just in eukaryotes, but also in bacterial and archaeal species.

Dream Recall Frequencies and Dream Content in Wilson's Disease with and without REM Sleep Behaviour Disorder: A Neurooneirologic Study.

PubMed

Tribl, Gotthard G; Trindade, Mateus C; Schredl, Michael; Pires, Joana; Reinhard, Iris; Bittencourt, Thais; Lorenzi-Filho, Geraldo; Alves, Rosana Cardoso; de Andrade, Daniel Ciampi; Fonoff, Erich T; Bor-Seng-Shu, Edson; Machado, Alexandre A; Teixeira, Manoel J; Barbosa, Egberto R

2016-01-01

Objective. Violent dream content and its acting out during rapid eye movement sleep are considered distinctive for rapid eye movement sleep behaviour disorder (RBD). This study reports first quantitative data on dreaming in a cohort of patients with treated Wilson's disease (WD) and in patients with WD with RBD. Methods. Retrospective questionnaires on different dimensions of dreaming and a prospective two-week home dream diary with self-rating of emotions and blinded, categorical rating of content by an external judge. Results. WD patients showed a significantly lower dream word count and very few other differences in dream characteristics compared to age- and sex-matched healthy controls. Compared to WD patients without RBD, patients with WD and RBD reported significantly higher nightmare frequencies and more dreams with violent or aggressive content retrospectively; their prospectively collected dream reports contained significantly more negative emotions and aggression. Conclusions. The reduction in dream length might reflect specific cognitive deficits in WD. The lack of differences regarding dream content might be explained by the established successful WD treatment. RBD in WD had a strong impact on dreaming. In accordance with the current definition of RBD, violent, aggressive dream content seems to be a characteristic of RBD also in WD.

Dream Recall Frequencies and Dream Content in Wilson's Disease with and without REM Sleep Behaviour Disorder: A Neurooneirologic Study

PubMed Central

Trindade, Mateus C.; Schredl, Michael; Pires, Joana; Reinhard, Iris; Bittencourt, Thais; Lorenzi-Filho, Geraldo; Alves, Rosana Cardoso; de Andrade, Daniel Ciampi; Fonoff, Erich T.; Bor-Seng-Shu, Edson; Machado, Alexandre A.; Teixeira, Manoel J.; Barbosa, Egberto R.

2016-01-01

Objective. Violent dream content and its acting out during rapid eye movement sleep are considered distinctive for rapid eye movement sleep behaviour disorder (RBD). This study reports first quantitative data on dreaming in a cohort of patients with treated Wilson's disease (WD) and in patients with WD with RBD. Methods. Retrospective questionnaires on different dimensions of dreaming and a prospective two-week home dream diary with self-rating of emotions and blinded, categorical rating of content by an external judge. Results. WD patients showed a significantly lower dream word count and very few other differences in dream characteristics compared to age- and sex-matched healthy controls. Compared to WD patients without RBD, patients with WD and RBD reported significantly higher nightmare frequencies and more dreams with violent or aggressive content retrospectively; their prospectively collected dream reports contained significantly more negative emotions and aggression. Conclusions. The reduction in dream length might reflect specific cognitive deficits in WD. The lack of differences regarding dream content might be explained by the established successful WD treatment. RBD in WD had a strong impact on dreaming. In accordance with the current definition of RBD, violent, aggressive dream content seems to be a characteristic of RBD also in WD. PMID:27051076

[Effects of UO-126 on proliferation and fbw7 expression of HeLa cells].

PubMed

Sun, Di; Shen, Yi; Wang, Shao-hua; Xiang, Zi-wu; Xie, Ying-shan; Jiang, Xin

2010-02-01

To observe the effects of UO-126 on the expression of F-box and WD repeat domain-containing protein 7(FBW7)and on the proliferation of human cervical cancer cell lines (HeLa cells). HeLa cells were treated with different concentrations of UO-126, MTT assay was used to observe the proliferation of HeLa cells. Immunofluorescence showed the location and expression of FBW7 in HeLa cells. The mRNA and protein expression of FBW7 were detected by RT-PCR and Western blot before and after mitogen-activated protein kinases (MAPK)signal was blocked by UO-126 a MAPK inhibitor. MTT results showed that the concentration range of MAPK signaling pathway inhibitor UO-126 inhibited the proliferation of HeLa cells in a concentration-and time-dependent manner(P<0.05). Immunofluorescence showed that the expression of positive FBW7 had increased after HeLa cells were treated with UO-126. RT-PCR and Western blot exhibited that the FBW7 mRNA and protein expression had significantly increased before and after HeLa cells were treated with UO-126(P<0.05). UO-126 could inhibit HeLa cells proliferation, FBW7 lied downstream of MAPK signaling pathway.

Draft whole genome sequence of groundnut stem rot fungus Athelia rolfsii revealing genetic architect of its pathogenicity and virulence.

PubMed

Iquebal, M A; Tomar, Rukam S; Parakhia, M V; Singla, Deepak; Jaiswal, Sarika; Rathod, V M; Padhiyar, S M; Kumar, Neeraj; Rai, Anil; Kumar, Dinesh

2017-07-13

Groundnut (Arachis hypogaea L.) is an important oil seed crop having major biotic constraint in production due to stem rot disease caused by fungus, Athelia rolfsii causing 25-80% loss in productivity. As chemical and biological combating strategies of this fungus are not very effective, thus genome sequencing can reveal virulence and pathogenicity related genes for better understanding of the host-parasite interaction. We report draft assembly of Athelia rolfsii genome of ~73 Mb having 8919 contigs. Annotation analysis revealed 16830 genes which are involved in fungicide resistance, virulence and pathogenicity along with putative effector and lethal genes. Secretome analysis revealed CAZY genes representing 1085 enzymatic genes, glycoside hydrolases, carbohydrate esterases, carbohydrate-binding modules, auxillary activities, glycosyl transferases and polysaccharide lyases. Repeat analysis revealed 11171 SSRs, LTR, GYPSY and COPIA elements. Comparative analysis with other existing ascomycotina genome predicted conserved domain family of WD40, CYP450, Pkinase and ABC transporter revealing insight of evolution of pathogenicity and virulence. This study would help in understanding pathogenicity and virulence at molecular level and development of new combating strategies. Such approach is imperative in endeavour of genome based solution in stem rot disease management leading to better productivity of groundnut crop in tropical region of world.

Structure of the apoptosome: mechanistic insights into activation of an initiator caspase from Drosophila

PubMed Central

Pang, Yuxuan; Bai, Xiao-chen; Yan, Chuangye; Hao, Qi; Chen, Zheqin; Wang, Jia-Wei

2015-01-01

Apoptosis is executed by a cascade of caspase activation. The autocatalytic activation of an initiator caspase, exemplified by caspase-9 in mammals or its ortholog, Dronc, in fruit flies, is facilitated by a multimeric adaptor complex known as the apoptosome. The underlying mechanism by which caspase-9 or Dronc is activated by the apoptosome remains unknown. Here we report the electron cryomicroscopic (cryo-EM) structure of the intact apoptosome from Drosophila melanogaster at 4.0 Å resolution. Analysis of the Drosophila apoptosome, which comprises 16 molecules of the Dark protein (Apaf-1 ortholog), reveals molecular determinants that support the assembly of the 2.5-MDa complex. In the absence of dATP or ATP, Dronc zymogen potently induces formation of the Dark apoptosome, within which Dronc is efficiently activated. At 4.1 Å resolution, the cryo-EM structure of the Dark apoptosome bound to the caspase recruitment domain (CARD) of Dronc (Dronc-CARD) reveals two stacked rings of Dronc-CARD that are sandwiched between two octameric rings of the Dark protein. The specific interactions between Dronc-CARD and both the CARD and the WD40 repeats of a nearby Dark protomer are indispensable for Dronc activation. These findings reveal important mechanistic insights into the activation of initiator caspase by the apoptosome. PMID:25644603

Tandem-repeat protein domains across the tree of life

PubMed Central

Jernigan, Kristin K.

2015-01-01

Tandem-repeat protein domains, composed of repeated units of conserved stretches of 20–40 amino acids, are required for a wide array of biological functions. Despite their diverse and fundamental functions, there has been no comprehensive assessment of their taxonomic distribution, incidence, and associations with organismal lifestyle and phylogeny. In this study, we assess for the first time the abundance of armadillo (ARM) and tetratricopeptide (TPR) repeat domains across all three domains in the tree of life and compare the results to our previous analysis on ankyrin (ANK) repeat domains in this journal. All eukaryotes and a majority of the bacterial and archaeal genomes analyzed have a minimum of one TPR and ARM repeat. In eukaryotes, the fraction of ARM-containing proteins is approximately double that of TPR and ANK-containing proteins, whereas bacteria and archaea are enriched in TPR-containing proteins relative to ARM- and ANK-containing proteins. We show in bacteria that phylogenetic history, rather than lifestyle or pathogenicity, is a predictor of TPR repeat domain abundance, while neither phylogenetic history nor lifestyle predicts ARM repeat domain abundance. Surprisingly, pathogenic bacteria were not enriched in TPR-containing proteins, which have been associated within virulence factors in certain species. Taken together, this comparative analysis provides a newly appreciated view of the prevalence and diversity of multiple types of tandem-repeat protein domains across the tree of life. A central finding of this analysis is that tandem repeat domain-containing proteins are prevalent not just in eukaryotes, but also in bacterial and archaeal species. PMID:25653910

Neural stem cells for disease modeling of Wolman disease and evaluation of therapeutics.

PubMed

Aguisanda, Francis; Yeh, Charles D; Chen, Catherine Z; Li, Rong; Beers, Jeanette; Zou, Jizhong; Thorne, Natasha; Zheng, Wei

2017-06-28

Wolman disease (WD) is a rare lysosomal storage disorder that is caused by mutations in the LIPA gene encoding lysosomal acid lipase (LAL). Deficiency in LAL function causes accumulation of cholesteryl esters and triglycerides in lysosomes. Fatality usually occurs within the first year of life. While an enzyme replacement therapy has recently become available, there is currently no small-molecule drug treatment for WD. We have generated induced pluripotent stem cells (iPSCs) from two WD patient dermal fibroblast lines and subsequently differentiated them into neural stem cells (NSCs). The WD NSCs exhibited the hallmark disease phenotypes of neutral lipid accumulation, severely deficient LAL activity, and increased LysoTracker dye staining. Enzyme replacement treatment dramatically reduced the WD phenotype in these cells. In addition, δ-tocopherol (DT) and hydroxypropyl-beta-cyclodextrin (HPBCD) significantly reduced lysosomal size in WD NSCs, and an enhanced effect was observed in DT/HPBCD combination therapy. The results demonstrate that these WD NSCs are valid cell-based disease models with characteristic disease phenotypes that can be used to evaluate drug efficacy and screen compounds. DT and HPBCD both reduce LysoTracker dye staining in WD cells. The cells may be used to further dissect the pathology of WD, evaluate compound efficacy, and serve as a platform for high-throughput drug screening to identify new compounds for therapeutic development.

INTERPRETING PHYSICAL AND BEHAVIORAL HEALTH SCORES FROM NEW WORK DISABILITY INSTRUMENTS

PubMed Central

Marfeo, Elizabeth E.; Ni, Pengsheng; Chan, Leighton; Rasch, Elizabeth K.; McDonough, Christine M.; Brandt, Diane E.; Bogusz, Kara; Jette, Alan M.

2015-01-01

Objective To develop a system to guide interpretation of scores generated from 2 new instruments measuring work-related physical and behavioral health functioning (Work Disability – Physical Function (WD-PF) and WD – Behavioral Function (WD-BH)). Design Cross-sectional, secondary data from 3 independent samples to develop and validate the functional levels for physical and behavioral health functioning. Subjects Physical group: 999 general adult subjects, 1,017 disability applicants and 497 work-disabled subjects. Behavioral health group: 1,000 general adult subjects, 1,015 disability applicants and 476 work-disabled subjects. Methods Three-phase analytic approach including item mapping, a modified-Delphi technique, and known-groups validation analysis were used to develop and validate cut-points for functional levels within each of the WD-PF and WD-BH instrument’s scales. Results Four and 5 functional levels were developed for each of the scales in the WD-PF and WD-BH instruments. Distribution of the comparative samples was in the expected direction: the general adult samples consistently demonstrated scores at higher functional levels compared with the claimant and work-disabled samples. Conclusion Using an item-response theory-based methodology paired with a qualitative process appears to be a feasible and valid approach for translating the WD-BH and WD-PF scores into meaningful levels useful for interpreting a person’s work-related physical and behavioral health functioning. PMID:25729901

Sleep disorders of Whipple's disease of the brain.

PubMed

Panegyres, P K; Goh, J

2015-02-01

To understand the effects of Whipple's disease (WD) of the brain on sleep function. Clinical and polysomnographic studies of two patients with severe disruption of sleep due to WD: a 48-year-old female with primary WD of the brain and a 41-year-old male with secondary WD of the brain. The patient with primary WD had hypersomnolence with severe obstructive sleep apnoea, reduced sleep efficiency, frequent waking and sleep fragmentation. The patient with secondary WD was also hypersomnolent with oculomastictory myorhythmia. He was shown to have severe sleep initiation insomnia with poor sleep efficiency, severe obstructive sleep apnoea/hypopnoea and oculomasticatory myorhythmia at sleep-wake transitions. WD of the brain may affect sleep biology in its primary and secondary forms leading to hypersomnolence from obstructive sleep apnoea, sleep fragmentation, reduced sleep efficiency, sleep initiation insomnia and intrusive oculomasticatory myorhythmia. © The Author 2014. Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Stringent Control of NFE2L3 (Nuclear Factor, Erythroid 2-Like 3; NRF3) Protein Degradation by FBW7 (F-box/WD Repeat-containing Protein 7) and Glycogen Synthase Kinase 3 (GSK3)*

PubMed Central

Kannan, Meenakshi B.; Dodard-Friedman, Isadore; Blank, Volker

2015-01-01

The NFE2L3 transcription factor has been implicated in various cellular processes, including carcinogenesis, stress response, differentiation, and inflammation. Previously it has been shown that NFE2L3 has a rapid turnover and is stabilized by proteasomal inhibitors. The mechanisms regulating the degradation of this protein have not been investigated. Here we report ubiquitination of NFE2L3 and demonstrate that F-box/WD repeat-containing protein 7 (FBW7 or FBWX7), a component of Skp1, Cullin 1, F-box containing complex (SCF)-type E3 ligase, is the E3 ligase mediating the degradation of NFE2L3. We showed that FBW7 interacts with NFE2L3 and that dimerization of FBW7 is required for the degradation of the transcription factor. We also demonstrate that the kinase glycogen synthase kinase 3 (GSK3) mediates the FBW7-dependent ubiquitination of NFE2L3. We show phosphorylation of NFE2L3 by GSK3 and its significance in the regulation of NFE2L3 by the tumor suppressor FBW7. FBW7 abrogated NFE2L3-mediated repression of the NAD(P)H:quinone oxidoreductase 1 (NQO1) gene antioxidant response element (ARE). Our findings reveal FBW7 and GSK3 as novel regulators of the NFE2L3 transcription factor and a potential mechanism by which FBW7 might regulate detoxification and the cellular response to stress. PMID:26306035

The WIRED Survey. 2; Infrared Excesses in the SDSS DR7 White Dwarf Catalog

NASA Technical Reports Server (NTRS)

Debes, John H.; Hoard, D. W.; Wachter, Stefanie; Leisawitz, David T.; Cohen, Martin

2011-01-01

With the launch of the Wide-field Infrar.ed Survey Explorer (WISE), a new era of detecting planetary debris and brown dwarfs (BDs) around white dwarfs (WDs) has begun with the WISE InfraRed Excesses around Degenerates (WIRED) Survey. The WIRED Survey is sensitive to substellar objects and dusty debris around WDs out to distances exceeding 100 pc, well beyond the completeness level of local WDs. In this paper, we present a cross-correlation of the preliminary Sloan Digital Sky Survey (SDSS) Data Release 7 (DR7) WD catalog between the WISE, Two-Micron All Sky Survey (2MASS), UKIRT Infrared Deep Sky Survey (UKIDSS), and SDSS DR7 photometric catalogs. From -18,000 input targets, there are WISE detections comprising 344 "naked" WDs (detection of the WD photosphere only), 1020 candidate WD+M dwarf binaries, 42 candidate WD+BD systems, 52 candidate WD+dust disk systems, and 69 targets with indeterminate infrared excess. We classified all of the detected targets through spectral energy distribution model fitting of the merged optical, near-IR, and WISE photometry. Some of these detections could be the result of contaminating sources within the large (approx. 6") WISE point-spread function; we make a preliminary estimate for the rates of contamination for our WD+BD and WD+disk candidates and provide notes for each target of interest. Each candidate presented here should be confirmed with higher angular resolution infrared imaging or infrared spectroscopy. We also present an overview of the observational characteristics of the detected WDs in the WISE photometric bands, including the relative frequencies of candidate WD+M, WD+BD, and WD+disk systems.

Mapping wood density globally using remote sensing and climatological data

NASA Astrophysics Data System (ADS)

Moreno, A.; Camps-Valls, G.; Carvalhais, N.; Kattge, J.; Robinson, N.; Reichstein, M.; Allred, B. W.; Running, S. W.

2017-12-01

Wood density (WD) is defined as the oven-dry mass divided by fresh volume, varies between individuals, and describes the carbon investment per unit volume of stem. WD has been proven to be a key functional trait in carbon cycle research and correlates with numerous morphological, mechanical, physiological, and ecological properties. In spite of the utility and importance of this trait, there is a lack of an operational framework to spatialize plant WD measurements at a global scale. In this work, we present a consistent modular processing chain to derive global maps (500 m) of WD using modern machine learning techniques along with optical remote sensing data (MODIS/Landsat) and climate data using the Google Earth Engine platform. The developed approach uses a hierarchical Bayesian approach to fill in gaps in the plant measured WD data set to maximize its global representativeness. WD plant species are then aggregated to Plant Functional Types (PFT). The spatial abundance of PFT at 500 m spatial resolution (MODIS) is calculated using a high resolution (30 m) PFT map developed using Landsat data. Based on these PFT abundances, representative WD values are estimated for each MODIS pixel with nearby measured data. Finally, random forests are used to globally estimate WD from these MODIS pixels using remote sensing and climate. The validation and assessment of the applied methods indicate that the model explains more than 72% of the spatial variance of the calculated community aggregated WD estimates with virtually unbiased estimates and low RMSE (<15%). The maps thus offer new opportunities to study and analyze the global patterns of variation of WD at an unprecedented spatial coverage and spatial resolution.

Enhancing seismic P phase arrival picking based on wavelet denoising and kurtosis picker

NASA Astrophysics Data System (ADS)

Shang, Xueyi; Li, Xibing; Weng, Lei

2018-01-01

P phase arrival picking of weak signals is still challenging in seismology. A wavelet denoising is proposed to enhance seismic P phase arrival picking, and the kurtosis picker is applied on the wavelet-denoised signal to identify P phase arrival. It has been called the WD-K picker. The WD-K picker, which is different from those traditional wavelet-based pickers on the basis of a single wavelet component or certain main wavelet components, takes full advantage of the reconstruction of main detail wavelet components and the approximate wavelet component. The proposed WD-K picker considers more wavelet components and presents a better P phase arrival feature. The WD-K picker has been evaluated on 500 micro-seismic signals recorded in the Chinese Yongshaba mine. The comparison between the WD-K pickings and manual pickings shows the good picking accuracy of the WD-K picker. Furthermore, the WD-K picking performance has been compared with the main detail wavelet component combining-based kurtosis (WDC-K) picker, the single wavelet component-based kurtosis (SW-K) picker, and certain main wavelet component-based maximum kurtosis (MMW-K) picker. The comparison has demonstrated that the WD-K picker has better picking accuracy than the other three-wavelet and kurtosis-based pickers, thus showing the enhanced ability of wavelet denoising.

Targeting Wolman Disease and Cholesteryl Ester Storage Disease: Disease Pathogenesis and Therapeutic Development

PubMed Central

Aguisanda, Francis; Thorne, Natasha; Zheng, Wei

2017-01-01

Wolman disease (WD) and cholesteryl ester storage disease (CESD) are lysosomal storage diseases (LSDs) caused by a deficiency in lysosomal acid lipase (LAL) due to mutations in the LIPA gene. This enzyme is critical to the proper degradation of cholesterol in the lysosome. LAL function is completely lost in WD while some residual activity remains in CESD. Both are rare diseases with an incidence rate of less than 1/100,000 births for WD and approximate 2.5/100,000 births for CESD. Clinical manifestation of WD includes hepatosplenomegaly, calcified adrenal glands, severe malabsorption and a failure to thrive. As in CESD, histological analysis of WD tissues reveals the accumulation of triglycerides (TGs) and esterified cholesterol (EC) in cellular lysosomes. However, the clinical presentation of CESD is less severe and more variable than WD. This review is to provide an overview of the disease pathophysiology and the current state of therapeutic development for both of WD and CESD. The review will also discuss the application of patient derived iPSCs for further drug discovery. PMID:28401034

A hybrid wavelet de-noising and Rank-Set Pair Analysis approach for forecasting hydro-meteorological time series.

PubMed

Wang, Dong; Borthwick, Alistair G; He, Handan; Wang, Yuankun; Zhu, Jieyu; Lu, Yuan; Xu, Pengcheng; Zeng, Xiankui; Wu, Jichun; Wang, Lachun; Zou, Xinqing; Liu, Jiufu; Zou, Ying; He, Ruimin

2018-01-01

Accurate, fast forecasting of hydro-meteorological time series is presently a major challenge in drought and flood mitigation. This paper proposes a hybrid approach, wavelet de-noising (WD) and Rank-Set Pair Analysis (RSPA), that takes full advantage of a combination of the two approaches to improve forecasts of hydro-meteorological time series. WD allows decomposition and reconstruction of a time series by the wavelet transform, and hence separation of the noise from the original series. RSPA, a more reliable and efficient version of Set Pair Analysis, is integrated with WD to form the hybrid WD-RSPA approach. Two types of hydro-meteorological data sets with different characteristics and different levels of human influences at some representative stations are used to illustrate the WD-RSPA approach. The approach is also compared to three other generic methods: the conventional Auto Regressive Integrated Moving Average (ARIMA) method, Artificial Neural Networks (ANNs) (BP-error Back Propagation, MLP-Multilayer Perceptron and RBF-Radial Basis Function), and RSPA alone. Nine error metrics are used to evaluate the model performance. Compared to three other generic methods, the results generated by WD-REPA model presented invariably smaller error measures which means the forecasting capability of the WD-REPA model is better than other models. The results show that WD-RSPA is accurate, feasible, and effective. In particular, WD-RSPA is found to be the best among the various generic methods compared in this paper, even when the extreme events are included within a time series. Copyright © 2017 Elsevier Inc. All rights reserved.

Transgenic tomatoes expressing the 6F peptide and ezetimibe prevent diet-induced increases of IFN-β and cholesterol 25-hydroxylase in jejunum

PubMed Central

Mukherjee, Pallavi; Hough, Greg; Chattopadhyay, Arnab; Navab, Mohamad; Fogelman, Hannah R.; Meriwether, David; Williams, Kevin; Bensinger, Steven; Moller, Travis; Faull, Kym F.; Lusis, Aldons J.; Iruela-Arispe, M. Luisa; Bostrom, Kristina I.; Tontonoz, Peter; Reddy, Srinivasa T.; Fogelman, Alan M.

2017-01-01

Feeding LDL receptor (LDLR)-null mice a Western diet (WD) increased the expression of IFN-β in jejunum as determined by quantitative RT-PCR (RT-qPCR), immunohistochemistry (IHC), and ELISA (all P < 0.0001). WD also increased the expression of cholesterol 25-hydroxylase (CH25H) as measured by RT-qPCR (P < 0.0001), IHC (P = 0.0019), and ELISA (P < 0.0001), resulting in increased levels of 25-hydroxycholesterol (25-OHC) in jejunum as determined by LC-MS/MS (P < 0.0001). Adding ezetimibe at 10 mg/kg/day or adding a concentrate of transgenic tomatoes expressing the 6F peptide (Tg6F) at 0.06% by weight of diet substantially ameliorated these changes. Adding either ezetimibe or Tg6F to WD also ameliorated WD-induced changes in plasma lipids, serum amyloid A, and HDL cholesterol. Adding the same doses of ezetimibe and Tg6F together to WD (combined formulation) was generally more efficacious compared with adding either agent alone. Surprisingly, adding ezetimibe during the preparation of Tg6F, but before addition to WD, was more effective than the combined formulation for all parameters measured in jejunum (P = 0.0329 to P < 0.0001). We conclude the following: i) WD induces IFN-β, CH25H, and 25-OHC in jejunum; and ii) Tg6F and ezetimibe partially ameliorate WD-induced inflammation by preventing WD-induced increases in IFN-β, CH25H, and 25-OHC. PMID:28592401

Transgenic tomatoes expressing the 6F peptide and ezetimibe prevent diet-induced increases of IFN-β and cholesterol 25-hydroxylase in jejunum.

PubMed

Mukherjee, Pallavi; Hough, Greg; Chattopadhyay, Arnab; Navab, Mohamad; Fogelman, Hannah R; Meriwether, David; Williams, Kevin; Bensinger, Steven; Moller, Travis; Faull, Kym F; Lusis, Aldons J; Iruela-Arispe, M Luisa; Bostrom, Kristina I; Tontonoz, Peter; Reddy, Srinivasa T; Fogelman, Alan M

2017-08-01

Feeding LDL receptor (LDLR)-null mice a Western diet (WD) increased the expression of IFN-β in jejunum as determined by quantitative RT-PCR (RT-qPCR), immunohistochemistry (IHC), and ELISA (all P < 0.0001). WD also increased the expression of cholesterol 25-hydroxylase (CH25H) as measured by RT-qPCR ( P < 0.0001), IHC ( P = 0.0019), and ELISA ( P < 0.0001), resulting in increased levels of 25-hydroxycholesterol (25-OHC) in jejunum as determined by LC-MS/MS ( P < 0.0001). Adding ezetimibe at 10 mg/kg/day or adding a concentrate of transgenic tomatoes expressing the 6F peptide (Tg6F) at 0.06% by weight of diet substantially ameliorated these changes. Adding either ezetimibe or Tg6F to WD also ameliorated WD-induced changes in plasma lipids, serum amyloid A, and HDL cholesterol. Adding the same doses of ezetimibe and Tg6F together to WD (combined formulation) was generally more efficacious compared with adding either agent alone. Surprisingly, adding ezetimibe during the preparation of Tg6F, but before addition to WD, was more effective than the combined formulation for all parameters measured in jejunum ( P = 0.0329 to P < 0.0001). We conclude the following: i ) WD induces IFN-β, CH25H, and 25-OHC in jejunum; and ii ) Tg6F and ezetimibe partially ameliorate WD-induced inflammation by preventing WD-induced increases in IFN-β, CH25H, and 25-OHC. Copyright © 2017 by the American Society for Biochemistry and Molecular Biology, Inc.

SOVRaD - A Digest of Recent Soviet R and D Articles. Volume 1, Numbers 5-6, May-June 1975

DTIC Science & Technology

1975-06-01

oreoared bv nnW i ^ • y^ ! . S^ aryl.b.s.(cYanamid^ P ulN ^Tu^^Y^Tml^T "’ lleterojunction Solar Cell (verbatim^ forward segment of...Wolf numbers for 1920 -- 1965; Wolf number R = ’’(lOg + f), where f = the number of spots in the solar disc, g = tie numbo’" of soot groups...an increase in the intensity of solar activity, as detcrm’^wd by the mean annual Wolf number. The maximum rate of ball lightning repeats

Liver transplantation for Wilson disease.

PubMed

Catana, Andreea M; Medici, Valentina

2012-01-27

The aim of this paper is to review the current status of liver transplantation (LT) for Wilson disease (WD), focusing on indications and controversies, especially in patients with neuropsychiatric disease, and on identification of acute liver failure (ALF) cases related to WD. LT remains the treatment of choice for patients with ALF, as initial presentation of WD or when anti-copper agents are stopped, and for patients with chronic liver disease progressed to cirrhosis, unresponsive to chelating medications or not timely treated with copper chelating agents. The indication for LT in WD remains highly debated in patients with progressive neurological deterioration and failure to improve with appropriate medical treatment. In case of Wilsonian ALF, early identification is key as mortality is 100% without emergency LT. As many of the copper metabolism parameters are believed to be less reliable in ALF, simple biochemical tests have been proposed for diagnosis of acute WD with good sensitivity and specificity. LT corrects copper metabolism and complications resulting from WD with excellent 1 and 5 year survival. Living related liver transplantation represents an alternative to deceased donor LT with excellent long-term survival, without disease recurrence. Future options may include hepatocyte transplantation and gene therapy. Although both of these have shown promising results in animal models of WD, prospective human studies are much needed to demonstrate their long-term beneficial effects and their potential to replace the need for medical therapy and LT in patients with WD.

Compact Binary Mergers and the Event Rate of Fast Radio Bursts

NASA Astrophysics Data System (ADS)

Cao, Xiao-Feng; Yu, Yun-Wei; Zhou, Xia

2018-05-01

Fast radio bursts (FRBs) are usually suggested to be associated with mergers of compact binaries consisting of white dwarfs (WDs), neutron stars (NSs), or black holes (BHs). We test these models by fitting the observational distributions in both redshift and isotropic energy of 22 Parkes FRBs, where, as usual, the rates of compact binary mergers (CBMs) are connected with cosmic star formation rates by a power-law distributed time delay. It is found that the observational distributions can well be produced by the CBM model with a characteristic delay time from several tens to several hundreds of megayears and an energy function index 1.2 ≲ γ ≲ 1.7, where a tentative fixed spectral index β = 0.8 is adopted for all FRBs. Correspondingly, the local event rate of FRBs is constrained to {(3{--}6)× {10}4{f}{{b}}-1({ \\mathcal T }/270{{s}})}-1{({ \\mathcal A }/2π )}-1 {Gpc}}-3 {yr}}-1 for an adopted minimum FRB energy of E min = 3 × 1039 erg, where f b is the beaming factor of the radiation, { \\mathcal T } is the duration of each pointing observation, and { \\mathcal A } is the sky area of the survey. This event rate, about an order of magnitude higher than the rates of NS–NS/NS–BH mergers, indicates that the most promising origin of FRBs in the CBM scenario could be mergers of WD–WD binaries. Here a massive WD could be produced since no FRB was found to be associated with an SN Ia. Alternatively, if all FRBs can repeat on a timescale much longer than the period of current observations, then they could also originate from a young active NS that forms from relatively rare NS–NS mergers and accretion-induced collapses of WD–WD binaries.

Association of Mumps Virus V Protein with RACK1 Results in Dissociation of STAT-1 from the Alpha Interferon Receptor Complex

PubMed Central

Kubota, Toru; Yokosawa, Noriko; Yokota, Shin-ichi; Fujii, Nobuhiro

2002-01-01

It has been reported that mumps virus protein V or the C-terminal Cys-rich region of protein V (Vsp) is associated with blocking of the interferon (IFN) signal transduction pathway through a decrease in STAT-1 production. The intracellular target of the V protein was investigated by using a two-hybrid screening system with Vsp as bait. Full-length V protein and Vsp were able to bind to RACK1, and the interaction did not require two WD domains, WD1 and WD2, in RACK1. A significant interaction between V protein and RACK1 was also demonstrated in cells persistently infected with mumps virus (FLMT cells), and the formation of the complex was not affected by treatment with IFN. On the other hand, in uninfected cells, STAT-1 was associated with the long form of the β subunit of the alpha IFN receptor, and this association was mediated by the function of RACK1 as an adaptor protein. Immunoprecipitation and glutathione S-transferase pull-down experiments revealed that the association of RACK1 or mumps virus V protein with the IFN receptor was undetectable in mumps virus-infected cells. Furthermore, RACK1 interacted with mumps virus V protein with a higher affinity than STAT-1 did. Therefore, it is suggested that mumps virus V protein has the ability to interact strongly with RACK1 and consequently to bring about the disruption of the complex formed from STAT-1, RACK1, and the IFN receptor. PMID:12438593

Genomic profiling of dedifferentiated liposarcoma compared to matched well-differentiated liposarcoma reveals higher genomic complexity and a common origin

PubMed Central

Beird, Hannah C.; Wu, Chia-Chin; Ingram, Davis R.; Wang, Wei-Lien; Alimohamed, Asrar; Gumbs, Curtis; Little, Latasha; Song, Xingzhi; Feig, Barry W.; Roland, Christina L.; Zhang, Jianhua; Benjamin, Robert S.; Hwu, Patrick; Lazar, Alexander J.; Futreal, P. Andrew; Somaiah, Neeta

2018-01-01

Well-differentiated (WD) liposarcoma is a low-grade mesenchymal tumor with features of mature adipocytes and high propensity for local recurrence. Often, WD patients present with or later progress to a higher-grade nonlipogenic form known as dedifferentiated (DD) liposarcoma. These DD tumors behave more aggressively and can metastasize. Both WD and DD liposarcomas harbor neochromosomes formed from amplifications and rearrangements of Chr 12q that encode oncogenes (MDM2, CDK4, and YEATS2) and adipocytic differentiation factors (HMGA2 and CPM). However, genomic changes associated with progression from WD to DD have not been well-defined. Therefore, we selected patients with matched WD and DD tumors for extensive genomic profiling in order to understand their clonal relationships and to delineate any defining alterations for each entity. Exome and transcriptomic sequencing was performed for 17 patients with both WD and DD diagnoses. Somatic point and copy-number alterations were integrated with transcriptional analyses to determine subtype-associated genomic features and pathways. The results were, on average, that only 8.3% of somatic mutations in WD liposarcoma were shared with their cognate DD component. DD tumors had higher numbers of somatic copy-number losses, amplifications involving Chr 12q, and fusion transcripts than WD tumors. HMGA2 and CPM rearrangements occur more frequently in DD components. The shared somatic mutations indicate a clonal origin for matched WD and DD tumors and show early divergence with ongoing genomic instability due to continual generation and selection of neochromosomes. Stochastic generation and subsequent expression of fusion transcripts from the neochromosome that involve adipogenesis genes such as HMGA2 and CPM may influence the differentiation state of the subsequent tumor. PMID:29610390

Diagnosis of Wilson disease in young children: molecular genetic testing and a paradigm shift from the laboratory diagnosis.

PubMed

Seo, Jeong Kee

2012-12-01

Wilson disease (WD) is an autosomal recessive disorder of copper metabolism that results in accumulation of copper primarily in the liver, brain and cornea. Mutations in the WD gene, ATP7B, cause failure of copper excretion from hepatocyte into bile and a defective synthesis of ceruloplasmin. More than 500 mutations are now recognized, scattered throughout the ATP7B gene. Since WD has protean clinical presentations, awareness of WD in clinical practice is important for the early diagnosis and prevention of accumulated copper toxicity. Molecular genetic testing is playing an increasingly important role in the diagnosis of WD in uncertain cases and family screening. Siblings should be screened for WD once an index case has been diagnosed. Discrimination of heterozygotes from asymptomatic patients is essential to avoid inappropriate lifelong therapy for heterozygotes. Genetic testing, either by haplotype analysis or by mutation analysis, is the only definite solution for differentiating heterozygote carriers from affected asymptomatic patients. Routine genetic testing, because of the multitude of documented mutations, has been thought to be impractical until recently. However, genetic testing is now being more actively applied to the diagnosis of WD, particularly in young children in whom conventional biochemical diagnosis has much limitation and only genetic testing is able to confirm WD. Because advancement of modern biochemical technology now allows more rapid, easier, and less expensive mutation detection, direct DNA sequencing could be actively considered as the primary mode of diagnostic investigation rather than a supplementary test to the conventional biochemical tests. This review will focus on the recent advancement of molecular genetics and genetic diagnosis of WD in very young children on the basis of research data of the Seoul National University Children's Hospital and recent literature.

p.H1069Q mutation in ATP7B and biochemical parameters of copper metabolism and clinical manifestation of Wilson's disease.

PubMed

Gromadzka, Graznya; Schmidt, Harmut H J; Genschel, Janine; Bochow, Bettina; Rodo, M; Tarnacka, Beatek; Litwin, Thomas; Chabik, Grzegorz; Członkowska, Anna

2006-02-01

We compared the effect of the p.H1069Q mutation and other non-p.H1069Q mutations in ATP7B on the phenotypic expression of Wilson's disease (WD), and assessed whether the clinical phenotype of WD in compound heterozygotes depends on the type of mutation coexisting with the p.H1069Q. One hundred forty-two patients with clinically, biochemically, and genetically diagnosed WD were studied. The mutational analysis of ATP7B was performed by direct sequencing. A total number of 26 mutations in ATP7B were identified. The p.His1069Gln was the most common mutation (allelic frequency: 72%). Seventy-three patients were homozygous for this mutation. Of compound heterozygotes, 37 had frameshift/nonsense mutation, and 20 had other missense mutation on one of their ATP7B alleles. Twelve patients had two non-p.H1069Q mutations. Patients homozygous for the p.H1069Q mutation had the less severe disturbances of copper metabolism and the latest presentation of first WD symptoms. The most severely disturbed copper metabolism and the earliest age at initial disease manifestation was noticed in non-p.H1069Q patients. In compound heterozygotes, the type of mutation coexisting with the p.H1069Q to a small extent influenced WD phenotype. The phenotype of WD varied considerably among patients with the same genotype. The p.H1069Q mutation is associated with late WD manifestation and with a mild disruption of copper metabolism. In compound heterozygotes, the phenotype of WD to a small extent depends on the type of mutation coexisting with the p.H1069Q. Besides genotype, additional modifying factors seem to determine WD manifestations. Copyright (c) 2005 Movement Disorder Society.

Prevalence and causes of work disability among working-age U.S. adults, 2011-2013, NHIS.

PubMed

Theis, Kristina A; Roblin, Douglas W; Helmick, Charles G; Luo, Ruiyan

2018-01-01

Chronic conditions are among the major causes of work disability (WD), which is associated with lower employment, less economic activity, and greater dependence on social programs, while limiting access to the benefits of employment participation. We estimated the overall prevalence of WD among working-age (18-64 years) U.S. adults and the most common causes of WD overall and by sex. Next, we estimated the prevalence and most common causes of WD among adults with 12 common chronic conditions by sex and age. We hypothesized that musculoskeletal conditions would be among the most common causes of WD overall and for individuals with other diagnosed chronic conditions. Data were obtained from years 2011, 2012, and 2013 of the National Health Interview Survey. WD was defined by a "yes" response to one or both of: "Does a physical, mental, or emotional problem NOW keep you from working at a job or business?" and "Are you limited in the kind OR amount of work you can do because of a physical, mental or emotional problem?" Overall, 20.1 million adults (10.4% (95% CI = 10.1-10.8) of the working-age population) reported WD. The top three most commonly reported causes of WD were back/neck problems 30.3% (95% CI = 29.1-31.5), depression/anxiety/emotional problems 21.0% (19.9-22.0), and arthritis/rheumatism 18.6 (17.6-19.6). Musculoskeletal conditions were among the three most common causes of WD overall and by age- and sex-specific respondents across diagnosed chronic conditions. Quantifying the prevalence and causes of work disability by age and sex can help prioritize interventions. Published by Elsevier Inc.

PCR analysis is superior to histology for diagnosis of Whipple's disease mimicking seronegative rheumatic diseases.

PubMed

Lehmann, P; Ehrenstein, B; Hartung, W; Dragonas, C; Reischl, U; Fleck, M

2017-03-01

The diagnosis of Whipple's disease (WD) is commonly confirmed by histology demonstrating Periodic Acid Schiff (PAS)-positive macrophages in the duodenal mucosa. Analysis of intestinal tissue or other specimens using polymerase chain reaction (PCR) is a more sensitive method. However, the relevance of positive PCR findings is still controversial. Therefore, we evaluated the relevance of histology and PCR findings to establishing the diagnosis of WD in a series of WD patients initially presenting with suspected rheumatic diseases. Between 2006 and 2014, 20 patients with seronegative rheumatic diseases tested positive for Tropheryma whipplei (Tw) by PCR and/or histology and were enrolled in a retrospective analysis of the diagnostic value of both procedures. Seven of the 20 cases (35%) were diagnosed with 'classic' WD as indicated by PAS-positive macrophages. In the remaining 13 patients, the presence of Tw was detected by intestinal (n = 10) or synovial PCR analysis (n = 3). Two of the 20 patients (10%) with evidence of Tw did not respond to antibiotic therapy. They were not considered to suffer from WD. Therefore, relying only on histological findings of intestinal biopsies would have missed 11 (61%) of the 18 patients with WD in our cohort. In comparison, PCR of intestinal biopsies detected Tw-DNA in 14 (93%) of the 15 WD patients evaluated. Patients with a positive histology did not differ from PCR-positive patients with regard to sex, age, or duration of disease, but more often presented with gastrointestinal symptoms. A substantial number of WD patients present without typical intestinal histology findings. Additional PCR analysis of intestinal tissue or synovial fluid increased the sensitivity of the diagnostic evaluation and should be considered particularly in patients presenting with atypical seronegative rheumatic diseases and a high-risk profile for WD.

Taxonomic distribution, repeats, and functions of the S1 domain-containing proteins as members of the OB-fold family.

PubMed

Deryusheva, Evgeniia I; Machulin, Andrey V; Selivanova, Olga M; Galzitskaya, Oxana V

2017-04-01

Proteins of the nucleic acid-binding proteins superfamily perform such functions as processing, transport, storage, stretching, translation, and degradation of RNA. It is one of the 16 superfamilies containing the OB-fold in protein structures. Here, we have analyzed the superfamily of nucleic acid-binding proteins (the number of sequences exceeds 200,000) and obtained that this superfamily prevalently consists of proteins containing the cold shock DNA-binding domain (ca. 131,000 protein sequences). Proteins containing the S1 domain compose 57% from the cold shock DNA-binding domain family. Furthermore, we have found that the S1 domain was identified mainly in the bacterial proteins (ca. 83%) compared to the eukaryotic and archaeal proteins, which are available in the UniProt database. We have found that the number of multiple repeats of S1 domain in the S1 domain-containing proteins depends on the taxonomic affiliation. All archaeal proteins contain one copy of the S1 domain, while the number of repeats in the eukaryotic proteins varies between 1 and 15 and correlates with the protein size. In the bacterial proteins, the number of repeats is no more than 6, regardless of the protein size. The large variation of the repeat number of S1 domain as one of the structural variants of the OB-fold is a distinctive feature of S1 domain-containing proteins. Proteins from the other families and superfamilies have either one OB-fold or change slightly the repeat numbers. On the whole, it can be supposed that the repeat number is a vital for multifunctional activity of the S1 domain-containing proteins. Proteins 2017; 85:602-613. © 2016 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Liver transplantation for Wilson disease

PubMed Central

Catana, Andreea M; Medici, Valentina

2012-01-01

The aim of this paper is to review the current status of liver transplantation (LT) for Wilson disease (WD), focusing on indications and controversies, especially in patients with neuropsychiatric disease, and on identification of acute liver failure (ALF) cases related to WD. LT remains the treatment of choice for patients with ALF, as initial presentation of WD or when anti-copper agents are stopped, and for patients with chronic liver disease progressed to cirrhosis, unresponsive to chelating medications or not timely treated with copper chelating agents. The indication for LT in WD remains highly debated in patients with progressive neurological deterioration and failure to improve with appropriate medical treatment. In case of Wilsonian ALF, early identification is key as mortality is 100% without emergency LT. As many of the copper metabolism parameters are believed to be less reliable in ALF, simple biochemical tests have been proposed for diagnosis of acute WD with good sensitivity and specificity. LT corrects copper metabolism and complications resulting from WD with excellent 1 and 5 year survival. Living related liver transplantation represents an alternative to deceased donor LT with excellent long-term survival, without disease recurrence. Future options may include hepatocyte transplantation and gene therapy. Although both of these have shown promising results in animal models of WD, prospective human studies are much needed to demonstrate their long-term beneficial effects and their potential to replace the need for medical therapy and LT in patients with WD. PMID:22312450

BEER ANALYSIS OF KEPLER AND CoRoT LIGHT CURVES. IV. DISCOVERY OF FOUR NEW LOW-MASS WHITE DWARF COMPANIONS IN THE KEPLER DATA

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

Faigler, S.; Kull, I.; Mazeh, T.

We report the discovery of four short-period eclipsing systems in the Kepler light curves, consisting of an A-star primary and a low-mass white dwarf (WD) secondary (dA+WD)—KIC 4169521, KOI-3818, KIC 2851474, and KIC 9285587. The systems show BEaming, Ellipsoidal and Reflection (BEER) phase modulations together with primary and secondary eclipses. These add to the 6 Kepler and 18 WASP short-period eclipsing dA+WD binaries that were previously known. The light curves, together with follow-up spectroscopic observations, allow us to derive the masses, radii, and effective temperatures of the two components of the four systems. The orbital periods, of 1.17–3.82 days, andmore » WD masses, of 0.19–0.22 M{sub ⊙}, are similar to those of the previously known systems. The WD radii of KOI-3818, KIC 2851474, and KIC 9285587 are 0.026, 0.035, and 0.026 R{sub ⊙}, respectively, the smallest WD radii derived so far for short-period eclipsing dA+WD binaries. These three binaries extend the previously known population to older systems with cooler and smaller WD secondaries. KOI-3818 displays evidence for a fast-rotating primary and a minute but significant eccentricity, ∼1.5 × 10{sup −3}. These features are probably the outcome of the mass-transfer process.« less

Evolving ONe WD+He star systems to intermediate-mass binary pulsars

NASA Astrophysics Data System (ADS)

Liu, D.; Wang, B.; Chen, W.; Zuo, Z.; Han, Z.

2018-06-01

It has been suggested that accretion-induced collapse (AIC) is a non-negligible path for the formation of the observed neutron stars (NSs). An ONe white dwarf (WD) that accretes material from a He star may experience AIC process and eventually produce intermediate-mass binary pulsars (IMBPs), named as the ONe WD+He star scenario. Note that previous studies can only account for part of the observed IMBPs with short orbital periods. In this work, we investigate the evolution of about 900 ONe WD+He star binaries to explore the distribution of IMBPs. We found that the ONe WD+He star scenario could form IMBPs including pulsars with 5-340 ms spin periods and 0.75-1.38 M_{⊙} WD companions, in which the orbital periods range from 0.04 to 900 d. Compared with the 20 observed IMBPs, this scenario can cover the parameters of 13 sources in the final orbital period-WD mass plane and the Corbet diagram, most of which have short orbital periods. We found that the ONe WD+He star scenario can explain almost all the observed IMBPs with short orbital periods. This work can well match the observed parameters of PSR J1802-2124 (one of the two precisely observed IMBPs), providing a possible evolutional path for its formation. We also speculate that the compact companion of HD 49798 (a hydrogen depleted sdO6 star) may be not a NS based on this work.

A strange dwarf scenario for the formation of the peculiar double white dwarf binary SDSS J125733.63+542850.5

NASA Astrophysics Data System (ADS)

Jiang, Long; Chen, Wen-Cong; Li, Xiang-Dong

2018-05-01

The Hubble Space Telescope observation of the double white dwarf (WD) binary SDSS J125733.63+542850.5 reveals that the massive WD has a surface gravity log g1 ˜ 8.7 (which implies a mass of M1 ˜ 1.06 M⊙) and an effective temperature T1 ˜ 13 000 K, while the effective temperature of the low-mass WD (M2 < 0.24 M⊙) is T2 ˜ 6400K. Therefore, the massive and the low-mass WDs have a cooling age τ1 ˜ 1 Gyr and τ2 ≥ 5 Gyr, respectively. This is in contradiction with traditional binary evolution theory. In this paper, we propose a strange dwarf (SD) scenario to explain the formation of this double WD binary. We assume that the massive WD is a SD originating from a phase transition (PT) in a ˜1.1 M⊙ WD, which has experienced accretion and spin-down processes. Its high effective temperature could arise from the heating process during the PT. Our simulations suggest that the progenitor of SDSS J125733.63+542850.5 can be a binary system consisting of a 0.65 M⊙ WD and a 1.5 M⊙ main-sequence star in a 1.492 d orbit. Especially, the secondary star (i.e. the progenitor of the low-mass WD) is likely to have an ultra-low metallicity of Z = 0.0001.

Maternal exposure to Western diet affects adult body composition and voluntary wheel running in a genotype-specific manner in mice.

PubMed

Hiramatsu, Layla; Kay, Jarren C; Thompson, Zoe; Singleton, Jennifer M; Claghorn, Gerald C; Albuquerque, Ralph L; Ho, Brittany; Ho, Brett; Sanchez, Gabriela; Garland, Theodore

2017-10-01

Some human diseases, including obesity, Type II diabetes, and numerous cancers, are thought to be influenced by environments experienced in early life, including in utero. Maternal diet during the perinatal period may be especially important for adult offspring energy balance, potentially affecting both body composition and physical activity. This effect may be mediated by the genetic background of individuals, including, for example, potential "protective" mechanisms for individuals with inherently high levels of physical activity or high basal metabolic rates. To examine some of the genetic and environmental factors that influence adult activity levels, we used an ongoing selection experiment with 4 replicate lines of mice bred for high voluntary wheel running (HR) and 4 replicate, non-selected control lines (C). Dams (half HR and half C) were fed a "Western" diet (WD, high in fat and sucrose) or a standard diet (SD) from 2weeks prior to mating until their pups could feed on solid food (14days of age). We analyzed dam and litter characteristics from birth to weaning, and offspring mass and physical activity into adulthood. One male offspring from each litter received additional metabolic and behavioral tests. Maternal WD caused pups to eat solid food significantly earlier for C litters, but not for HR litters (interaction of maternal environment and genotype). With dam mass as a covariate, mean pup mass was increased by maternal WD but litter size was unaffected. HR dams had larger litters and tended to have smaller pups than C dams. Home-cage activity of juvenile focal males was increased by maternal WD. Juvenile lean mass, fat mass, and fat percent were also increased by maternal WD, but food consumption (with body mass as a covariate) was unaffected (measured only for focal males). Behavior in an elevated plus maze, often used to indicate anxiety, was unaffected by maternal WD. Maximal aerobic capacity (VO 2 max) was also unaffected by maternal WD, but HR had higher VO 2 max than C mice. Adult lean, fat, and total body masses were significantly increased by maternal WD, with greater increase for fat than for lean mass. Overall, no aspect of adult wheel running (total distance, duration, average running speed, maximum speed) or home-cage activity was statistically affected by maternal WD. However, analysis of the 8 individual lines revealed that maternal WD significantly increased wheel running in one of the 4 HR lines. On average, all groups lost fat mass after 6days of voluntary wheel running, but the absolute amount lost was greater for mice with maternal WD resulting in no effect of maternal WD on absolute or % body fat after wheel access. All groups gained lean and total body mass during wheel access, regardless of maternal WD or linetype. Measured after wheel access, circulating leptin, adiponectin, and corticosterone concentrations were unaffected by maternal WD and did not differ between HR and C mice. With body mass as a covariate, heart ventricle mass was increased by maternal WD in both HR and C mice, but fat pads, liver, spleen, and brain masses were unaffected. As found previously, HR mice had larger brains than C mice. Body mass of grand-offspring was unaffected by grand-maternal WD, but grand-offspring wheel running was significantly increased for one HR line and decreased for another HR line by grand-maternal WD. In summary, maternal Western diet had long-lasting and general effects on offspring adult morphology, but effects on adult behavior were limited and contingent on sex and genetic background. Copyright © 2017 Elsevier Inc. All rights reserved.

Enhanced Expression of WD Repeat-Containing Protein 35 via CaMKK/AMPK Activation in Bupivacaine-Treated Neuro2a Cells

PubMed Central

Huang, Lei; Kondo, Fumio; Gosho, Masahiko; Feng, Guo-Gang; Harato, Misako; Xia, Zhong-yuan; Ishikawa, Naohisa; Fujiwara, Yoshihiro; Okada, Shoshiro

2014-01-01

We previously reported that bupivacaine induces reactive oxygen species (ROS) generation, p38 mitogen-activated protein kinase (MAPK) activation and nuclear factor-kappa B activation, resulting in an increase in expression of WD repeat-containing protein 35 (WDR35) in mouse neuroblastoma Neuro2a cells. However, the identity of signaling upstream of p38 MAPK pathways to WDR35 expression remains unclear. It has been shown that AMP-activated protein kinase (AMPK) can activate p38 MAPK through diverse mechanisms. In addition, several kinases acting upstream of AMPK have been identified including Ca2+/calmodulin-dependent protein kinase kinase (CaMKK). Recent studies reported that AMPK may be involved in bupivacaine-induced cytotoxicity in Schwann cells and in human neuroblastoma SH-SY5Y cells. The present study was undertaken to test whether CaMKK and AMPK are involved in bupivacaine-induced WDR35 expression in Neuro2a cells. Our results showed that bupivacaine induced activation of AMPK and p38 MAPK in Neuro2a cells. The AMPK inhibitors, compound C and iodotubercidin, attenuated the bupivacaine-induced activation of AMPK and p38 MAPK, resulting in an inhibition of the bupivacaine-induced increase in WDR35 expression. Treatment with the CaMKK inhibitor STO-609 also attenuated the bupivacaine-induced activation of AMPK and p38 MAPK, resulting in an inhibition of the bupivacaine-induced increase in WDR35 expression. These results suggest that bupivacaine activates AMPK and p38 MAPK via CaMKK in Neuro2a cells, and that the CaMKK/AMPK/p38 MAPK pathway is involved in regulating WDR35 expression. PMID:24859235

Effects of short-term Western diet on cerebral oxidative stress and diabetes related factors in APP x PS1 knock-in mice.

PubMed

Studzinski, Christa M; Li, Feng; Bruce-Keller, Annadora J; Fernandez-Kim, Sun Ok; Zhang, Le; Weidner, Adam M; Markesbery, William R; Murphy, M Paul; Keller, Jeffrey N

2009-02-01

A chronic high fat Western diet (WD) promotes a variety of morbidity factors although experimental evidence for short-term WD mediating brain dysfunction remains to be elucidated. The amyloid precursor protein and presenilin-1 (APP x PS1) knock-in mouse model has been demonstrated to recapitulate some key features of Alzheimer's disease pathology, including amyloid-beta (Abeta) pathogenesis. In this study, we placed 1-month-old APP x PS1 mice and non-transgenic littermates on a WD for 4 weeks. The WD resulted in a significant elevation in protein oxidation and lipid peroxidation in the brain of APP x PS1 mice relative to non-transgenic littermates, which occurred in the absence of increased Abeta levels. Altered adipokine levels were also observed in APP x PS1 mice placed on a short-term WD, relative to non-transgenic littermates. Taken together, these data indicate that short-term WD is sufficient to selectively promote cerebral oxidative stress and metabolic disturbances in APP x PS1 knock-in mice, with increased oxidative stress preceding alterations in Abeta. These data have important implications for understanding how WD may potentially contribute to brain dysfunction and the development of neurodegenerative disorders such as Alzheimer's disease.

Hybrid Wavelet De-noising and Rank-Set Pair Analysis approach for forecasting hydro-meteorological time series

NASA Astrophysics Data System (ADS)

WANG, D.; Wang, Y.; Zeng, X.

2017-12-01

Accurate, fast forecasting of hydro-meteorological time series is presently a major challenge in drought and flood mitigation. This paper proposes a hybrid approach, Wavelet De-noising (WD) and Rank-Set Pair Analysis (RSPA), that takes full advantage of a combination of the two approaches to improve forecasts of hydro-meteorological time series. WD allows decomposition and reconstruction of a time series by the wavelet transform, and hence separation of the noise from the original series. RSPA, a more reliable and efficient version of Set Pair Analysis, is integrated with WD to form the hybrid WD-RSPA approach. Two types of hydro-meteorological data sets with different characteristics and different levels of human influences at some representative stations are used to illustrate the WD-RSPA approach. The approach is also compared to three other generic methods: the conventional Auto Regressive Integrated Moving Average (ARIMA) method, Artificial Neural Networks (ANNs) (BP-error Back Propagation, MLP-Multilayer Perceptron and RBF-Radial Basis Function), and RSPA alone. Nine error metrics are used to evaluate the model performance. The results show that WD-RSPA is accurate, feasible, and effective. In particular, WD-RSPA is found to be the best among the various generic methods compared in this paper, even when the extreme events are included within a time series.

Serial analysis of gene expression (SAGE) in normal human trabecular meshwork.

PubMed

Liu, Yutao; Munro, Drew; Layfield, David; Dellinger, Andrew; Walter, Jeffrey; Peterson, Katherine; Rickman, Catherine Bowes; Allingham, R Rand; Hauser, Michael A

2011-04-08

To identify the genes expressed in normal human trabecular meshwork tissue, a tissue critical to the pathogenesis of glaucoma. Total RNA was extracted from human trabecular meshwork (HTM) harvested from 3 different donors. Extracted RNA was used to synthesize individual SAGE (serial analysis of gene expression) libraries using the I-SAGE Long kit from Invitrogen. Libraries were analyzed using SAGE 2000 software to extract the 17 base pair sequence tags. The extracted sequence tags were mapped to the genome using SAGE Genie map. A total of 298,834 SAGE tags were identified from all HTM libraries (96,842, 88,126, and 113,866 tags, respectively). Collectively, there were 107,325 unique tags. There were 10,329 unique tags with a minimum of 2 counts from a single library. These tags were mapped to known unique Unigene clusters. Approximately 29% of the tags (orphan tags) did not map to a known Unigene cluster. Thirteen percent of the tags mapped to at least 2 Unigene clusters. Sequence tags from many glaucoma-related genes, including myocilin, optineurin, and WD repeat domain 36, were identified. This is the first time SAGE analysis has been used to characterize the gene expression profile in normal HTM. SAGE analysis provides an unbiased sampling of gene expression of the target tissue. These data will provide new and valuable information to improve understanding of the biology of human aqueous outflow.

A study of oxidative stress, cytokines and glutamate in Wilson disease and their asymptomatic siblings.

PubMed

Kalita, Jayantee; Kumar, Vijay; Misra, Usha K; Ranjan, Abhay; Khan, Hamidullah; Konwar, Rituraj

2014-09-15

Free copper in Wilson disease (WD) is toxic and may reduce antioxidant, increase oxidative stress marker and thereby cytokine release and excitotoxic injury, but there is paucity of studies in humans. We report oxidative stress markers, cytokines and glutamate in neurologic WD and correlate these with their clinical severity, laboratory findings and extent of Magnetic resonance imaging (MRI) changes. 29 patients with neurologic WD and 9 asymptomatic WD siblings were included and their clinical, treatment history, disease severity, biochemical findings and MRI changes were noted. Glutathione (GSH), total antioxidant capacity (TAC) and malonodialdehyde (MDA) were measured by spectrophotometer, cytokines by cytokine bead array and glutamate by the fluorometer. In WD patients, the glutathione (mean±SEM, 2.20±0.06 vs. 2.73±0.04mg/dl, P<0.001) and TAC (1.70±0.03 vs. 2.29±0.02 Trolox_Eq_mmol/l, P<0.001) were reduced, and MDA and glutamate (23.93±0.54 vs. 19.96±0.27μmol/l; P<0.001) were increased (4.7±0.11 vs. 3.03±0.52nmol/ml, P<0.001) compared to controls. The serum IL6 {median (IQRs), 9.42(10.92) vs. 5.2(5.34) pg/ml; P=0.001}, IL8 {12.37(10.92) vs. 5.63(5.52) pg/ml; P<0.001}, IL10 {8.33(8.3) vs. 2.05(1.37) pg/ml; P=0.001} and TNFα {6.14(8.95) vs. 3.61(3.58) pg/ml; P<0.001} were also increased in WD patients compared to controls. These changes were more marked in the neurologic WD compared to asymptomatic WD and in the untreated compared to treated patients. TAC correlated with duration of illness, serum free copper, 24hour urinary copper and serum ceruloplasmin, and glutamate with MDA, TNFα, ceruloplasmin and 24-hour urinary copper. In WD patients, antioxidants are reduced and MDA, cytokines and glutamate are increased which are more marked in symptomatic neurologic WD than asymptomatic patients. Copyright © 2014 Elsevier B.V. All rights reserved.

MONTE CARLO POPULATION SYNTHESIS OF POST-COMMON-ENVELOPE WHITE DWARF BINARIES AND TYPE Ia SUPERNOVA RATE

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

Ablimit, Iminhaji; Maeda, Keiichi; Li, Xiang-Dong

Binary population synthesis (BPS) studies provide a comprehensive way to understand the evolution of binaries and their end products. Close white dwarf (WD) binaries have crucial characteristics for examining the influence of unresolved physical parameters on binary evolution. In this paper, we perform Monte Carlo BPS simulations, investigating the population of WD/main-sequence (WD/MS) binaries and double WD binaries using a publicly available binary star evolution code under 37 different assumptions for key physical processes and binary initial conditions. We considered different combinations of the binding energy parameter ( λ {sub g}: considering gravitational energy only; λ {sub b}: considering bothmore » gravitational energy and internal energy; and λ {sub e}: considering gravitational energy, internal energy, and entropy of the envelope, with values derived from the MESA code), CE efficiency, critical mass ratio, initial primary mass function, and metallicity. We find that a larger number of post-CE WD/MS binaries in tight orbits are formed when the binding energy parameters are set by λ {sub e} than in those cases where other prescriptions are adopted. We also determine the effects of the other input parameters on the orbital periods and mass distributions of post-CE WD/MS binaries. As they contain at least one CO WD, double WD systems that evolved from WD/MS binaries may explode as type Ia supernovae (SNe Ia) via merging. In this work, we also investigate the frequency of two WD mergers and compare it to the SNe Ia rate. The calculated Galactic SNe Ia rate with λ = λ {sub e} is comparable to the observed SNe Ia rate, ∼8.2 × 10{sup 5} yr{sup 1} – ∼4 × 10{sup 3} yr{sup 1} depending on the other BPS parameters, if a DD system does not require a mass ratio higher than ∼0.8 to become an SNe Ia. On the other hand, a violent merger scenario, which requires the combined mass of two CO WDs ≥ 1.6 M {sub ⊙} and a mass ratio >0.8, results in a much lower SNe Ia rate than is observed.« less

Western diet-induced hepatic steatosis and alterations in the liver transcriptome in adult Brown-Norway rats.

PubMed

Roberts, Michael D; Mobley, C Brooks; Toedebush, Ryan G; Heese, Alexander J; Zhu, Conan; Krieger, Anna E; Cruthirds, Clayton L; Lockwood, Christopher M; Hofheins, John C; Wiedmeyer, Charles E; Leidy, Heather J; Booth, Frank W; Rector, R Scott

2015-10-30

The purpose of this study was to investigate the effects of sub-chronic high fat, high sucrose diet (also termed 'Westernized diet' or WD) feeding on the liver transcriptome during early nonalcoholic fatty liver disease (NAFLD) development. Brown Norway male rats (9 months of age) were randomly assigned to receive ad libitum access to a control (CTL; 14 % kcal fat, 1.2 % sucrose by weight) diet or WD (42 % kcal from fat, 34 % sucrose by weight) for 6 weeks. Six weeks of WD feeding caused hepatic steatosis development as evidenced by the 2.25-fold increase in liver triacylglycerol content, but did not induce advanced liver disease (i.e., no overt inflammation or fibrosis) in adult Brown Norway rats. RNA deep sequencing (RNA-seq) revealed that 94 transcripts were altered in liver by WD feeding (46 up-, 48 down-regulated, FDR < 0.05). Specifically, the top differentially regulated gene network by WD feeding was 'Lipid metabolism, small molecular biochemistry, vitamin and mineral metabolism' (Ingenuity Pathway Analysis (IPA) score 61). The top-regulated canonical signaling pathway in WD-fed rats was the 'Superpathway of cholesterol biosynthesis' (10/29 genes regulated, p = 1.68E-17), which coincides with a tendency for serum cholesterol levels to increase in WD-fed rats (p = 0.09). Remarkably, liver stearoyl-CoA desaturase (Scd) mRNA expression was by far the most highly-induced transcript in WD-fed rats (approximately 30-fold, FDR = 0.01) which supports previous literature underscoring this gene as a crucial target during NAFLD development. In summary, sub-chronic WD feeding appears to increase hepatic steatosis development over a 6-week period but only induces select inflammation-related liver transcripts, mostly acute phase response genes. These findings continue to outline the early stages of NAFLD development prior to overt liver inflammation and advanced liver disease.

Regulation of glutamine synthetase isoforms in two differentially drought-tolerant rice (Oryza sativa L.) cultivars under water deficit conditions.

PubMed

Singh, Kamal Krishna; Ghosh, Shilpi

2013-02-01

KEY MESSAGE : The regulation of GS isoforms by WD was organ specific. Two GS isoforms i.e. OsGS1;1 and OsGS2 were differentially regulated in IR-64 (drought-sensitive) and Khitish (drought-tolerant) cultivars of rice. Water deficit (WD) has adverse effect on rice (Oryza sativa L.) and acclimation requires essential reactions of primary metabolism to continue. Rice plants utilize ammonium as major nitrogen source, which is assimilated into glutamine by the reaction of Glutamine synthetase (GS, EC 6.3.1.2). Rice plants possess one gene (OsGS2) for chloroplastic GS2 and three genes (OsGS1;1, OsGS1;2 and OsGS1;3) for cytosolic GS1. Here, we report the effect of WD on regulation of GS isoforms in drought-sensitive (cv. IR-64) and drought-tolerant (cv. Khitish) rice cultivars. Under WD, total GS activity in root and leaf decreased significantly in IR-64 seedlings in comparison to Khitish seedlings. The reduced GS activity in IR-64 leaf was mainly due to decrease in GS2 activity, which correlated with decrease in corresponding transcript and polypeptide contents. GS1 transcript and polypeptide accumulated in leaf during WD, however, GS1 activity was maintained at a constant level. Total GS activity in stem of both the varieties was insensitive to WD. Among GS1 genes, OsGS1;1 expression was differently regulated by WD in the two rice varieties. Its transcript accumulated more abundantly in IR-64 leaf than in Khitish leaf. Following WD, OsGS1;1 mRNA level in stem and root tissues declined in IR-64 and enhanced in Khitish. A steady OsGS1;2 expression patterns were noted in leaf, stem and root of both the cultivars. Results suggest that OsGS2 and OsGS1;1 expression may contribute to drought tolerance of Khitish cultivar under WD conditions.

Dietary calcium and cholecalciferol modulate cyclin D1 expression, apoptosis, and tumorigenesis in intestine of adenomatous polyposis coli1638N/+ mice.

PubMed

Yang, Kan; Lamprecht, Sergio A; Shinozaki, Hiroharu; Fan, Kunhua; Yang, Wancai; Newmark, Harold L; Kopelovich, Levy; Edelmann, Winfried; Jin, Bo; Gravaghi, Claudia; Augenlicht, Leonard; Kucherlapati, Raju; Lipkin, Martin

2008-09-01

Both epidemiological and experimental findings have indicated that components of Western diets influence colonic tumorigenesis. Among dietary constituents, calcium and cholecalciferol have emerged as promising chemopreventive agents. We have demonstrated that a Western-style diet (WD) with low levels of calcium and cholecalciferol and high levels of (n-6) PUFA, increased the incidence of neoplasia in mouse intestine compared with a standard AIN-76A diet; models included wild-type mice and mice with targeted mutations. In the present study, adenomatous polyposis coli (Apc)(1638N/+) mice carrying a heterozygous Apc mutation were fed either an AIN-76A diet, a WD, or a WD supplemented with calcium and cholecalciferol (WD/Ca/VitD3). Diets were fed for 24 wk and effects on cellular and molecular events were assessed by performing immunohistochemistry in colonic epithelium along the crypt-to-surface continuum. Feeding WD to Apc(1638N/+) mice not only enhanced cyclin D1 expression in colonic epithelium compared with AIN-76A treatment as previously reported but also significantly increased the expression of the antiapoptotic protein B-cell lymphoma 2 (Bcl-2) concomitantly with a decrease in the proapoptotic Bcl2-associated X protein and the number of apoptotic epithelial cells. WD treatment enhanced mutant Apc-driven small intestinal carcinogenesis and also resulted in the formation of a small number of colonic adenomas (0.16 +/- 0.09; P < 0.05). By contrast, the WD/Ca/VitD3 diet reversed WD-induced growth, promoting changes in colonic epithelium. Importantly, Apc(1638N/+) mice fed the WD/Ca/VitD3 diet did not develop colonic tumors, further indicating that dietary calcium and cholecalciferol have a key role in the chemoprevention of colorectal neoplasia in this mouse model of human colon cancer.

MET-activating Residues in the B-repeat of the Listeria monocytogenes Invasion Protein InlB*

PubMed Central

Bleymüller, Willem M.; Lämmermann, Nina; Ebbes, Maria; Maynard, Daniel; Geerds, Christina; Niemann, Hartmut H.

2016-01-01

The facultative intracellular pathogen Listeria monocytogenes causes listeriosis, a rare but life-threatening disease. Host cell entry begins with activation of the human receptor tyrosine kinase MET through the bacterial invasion protein InlB, which contains an internalin domain, a B-repeat, and three GW domains. The internalin domain is known to bind MET, but no interaction partner is known for the B-repeat. Adding the B-repeat to the internalin domain potentiates MET activation and is required to stimulate Madin-Darby canine kidney (MDCK) cell scatter. Therefore, it has been hypothesized that the B-repeat may bind a co-receptor on host cells. To test this hypothesis, we mutated residues that might be important for binding an interaction partner. We identified two adjacent residues in strand β2 of the β-grasp fold whose mutation abrogated induction of MDCK cell scatter. Biophysical analysis indicated that these mutations do not alter protein structure. We then tested these mutants in human HT-29 cells that, in contrast to the MDCK cells, were responsive to the internalin domain alone. These assays revealed a dominant negative effect, reducing the activity of a construct of the internalin domain and mutated B-repeat below that of the individual internalin domain. Phosphorylation assays of MET and its downstream targets AKT and ERK confirmed the dominant negative effect. Attempts to identify a host cell receptor for the B-repeat were not successful. We conclude that there is limited support for a co-receptor hypothesis and instead suggest that the B-repeat contributes to MET activation through low affinity homodimerization. PMID:27789707

Complex structure of the fission yeast SREBP-SCAP binding domains reveals an oligomeric organization.

PubMed

Gong, Xin; Qian, Hongwu; Shao, Wei; Li, Jingxian; Wu, Jianping; Liu, Jun-Jie; Li, Wenqi; Wang, Hong-Wei; Espenshade, Peter; Yan, Nieng

2016-11-01

Sterol regulatory element-binding protein (SREBP) transcription factors are master regulators of cellular lipid homeostasis in mammals and oxygen-responsive regulators of hypoxic adaptation in fungi. SREBP C-terminus binds to the WD40 domain of SREBP cleavage-activating protein (SCAP), which confers sterol regulation by controlling the ER-to-Golgi transport of the SREBP-SCAP complex and access to the activating proteases in the Golgi. Here, we biochemically and structurally show that the carboxyl terminal domains (CTD) of Sre1 and Scp1, the fission yeast SREBP and SCAP, form a functional 4:4 oligomer and Sre1-CTD forms a dimer of dimers. The crystal structure of Sre1-CTD at 3.5 Å and cryo-EM structure of the complex at 5.4 Å together with in vitro biochemical evidence elucidate three distinct regions in Sre1-CTD required for Scp1 binding, Sre1-CTD dimerization and tetrameric formation. Finally, these structurally identified domains are validated in a cellular context, demonstrating that the proper 4:4 oligomeric complex formation is required for Sre1 activation.

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

Buckner, Mark A; Bobrek, Miljko; Farquhar, Ethan

Wireless Access Points (WAP) remain one of the top 10 network security threats. This research is part of an effort to develop a physical (PHY) layer aware Radio Frequency (RF) air monitoring system with multi-factor authentication to provide a first-line of defense for network security--stopping attackers before they can gain access to critical infrastructure networks through vulnerable WAPs. This paper presents early results on the identification of OFDM-based 802.11a WiFi devices using RF Distinct Native Attribute (RF-DNA) fingerprints produced by the Fractional Fourier Transform (FRFT). These fingerprints are input to a "Learning from Signals" (LFS) classifier which uses hybrid Differentialmore » Evolution/Conjugate Gradient (DECG) optimization to determine the optimal features for a low-rank model to be used for future predictions. Results are presented for devices under the most challenging conditions of intra-manufacturer classification, i.e., same-manufacturer, same-model, differing only in serial number. The results of Fractional Fourier Domain (FRFD) RF-DNA fingerprints demonstrate significant improvement over results based on Time Domain (TD), Spectral Domain (SD) and even Wavelet Domain (WD) fingerprints.« less

Endocrine and mood responses to two working days in female teachers.

PubMed

Serrano, Miguel Angel; Moya-Albiol, Luís; Salvador, Alicia

2014-01-01

Currently, a considerable amount of work stress is present in school teachers, one of the occupational groups with the highest levels of job strain and burnout. As chronic stress produces significant modifications in emotional adjustment and neuroendocrine functioning, we aimed to investigate the role of these work stress constructs in the endocrine and mood responses of a group of female teachers during two working days (WD) at different moments in the academic year. We studied mood as well as levels of cortisol and testosterone, representative of a predominant catabolic or anabolic balance. Our results showed that higher "control" was associated with higher positive mood (p = .028 on WD1 and p = .057 on WD2) and salivary testosterone (Tsal) (p = .022 on WD1), whereas "demands" and "total job strain" were related to negative mood (p = .011 and p = .015, respectively). Participants with higher scores on "total burnout" and "emotional exhaustion" also had higher negative mood (p < .05 in all cases). Depersonalization correlated positively with negative mood (p = .019 and p = .006 on WD1 and WD2, respectively). Finally, personal accomplishment showed an inverse relationship with negative mood (p = .038 on WD2). These results are useful for job risk prevention and interventions that should focus on the control dimension of the job strain questionnaire and on personal accomplishment from the burnout scale.

CDK4 Amplification Predicts Recurrence of Well-Differentiated Liposarcoma of the Abdomen

PubMed Central

Ha, Sang Yun; Paik, Kwang Yeol; Lee, Seung Eun; Kim, Jong Man; Park, Jae Berm; Kwon, Choon Hyuck David; Joh, Jae-Won; Choi, Yoon-La; Kim, Sung Joo

2014-01-01

Background The absence of CDK4 amplification in liposarcomas is associated with favorable prognosis. We aimed to identify the factors associated with tumor recurrence in patients with well-differentiated (WD) and dedifferentiated (DD) liposarcomas. Methods From 2000 to 2010, surgical resections for 101 WD and DD liposarcomas were performed. Cases in which complete surgical resections with curative intent were carried out were selected. MDM2 and CDK4 gene amplification were analyzed by quantitative real-time polymerase chain reaction (Q-PCR). Results There were 31 WD and 17 DD liposarcomas. Locoregional recurrence was observed in 11 WD and 3 DD liposarcomas. WD liposarcomas showed better patient survival compared to DD liposarcomas (P<0.05). Q-PCR analysis of the liposarcomas revealed the presence of CDK4 amplification in 44 cases (91.7%) and MDM2 amplification in 46 cases (95.8%). WD liposarcomas with recurrence after surgical resection had significantly higher levels of CDK4 amplification compared to those without recurrence (P = 0.041). High level of CDK4 amplification (cases with CDK4 amplification higher than the median 7.54) was associated with poor recurrence-free survival compared to low CDK4 amplification in both univariate (P = 0.012) and multivariate analyses (P = 0.020). Conclusions Level of CDK4 amplification determined by Q-PCR was associated with the recurrence of WD liposarcomas after surgical resection. PMID:25121597

Autism-Like Behaviours and Memory Deficits Result from a Western Diet in Mice.

PubMed

Veniaminova, Ekaterina; Cespuglio, Raymond; Cheung, Chi Wai; Umriukhin, Alexei; Markova, Nataliia; Shevtsova, Elena; Lesch, Klaus-Peter; Anthony, Daniel C; Strekalova, Tatyana

2017-01-01

Nonalcoholic fatty liver disease, induced by a Western diet (WD), evokes central and peripheral inflammation that is accompanied by altered emotionality. These changes can be associated with abnormalities in social behaviour, hippocampus-dependent cognitive functions, and metabolism. Female C57BL/6J mice were fed with a regular chow or with a WD containing 0.2% of cholesterol and 21% of saturated fat for three weeks. WD-treated mice exhibited increased social avoidance, crawl-over and digging behaviours, decreased body-body contacts, and hyperlocomotion. The WD-fed group also displayed deficits in hippocampal-dependent performance such as contextual memory in a fear conditioning and pellet displacement paradigms. A reduction in glucose tolerance and elevated levels of serum cholesterol and leptin were also associated with the WD. The peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1a) mRNA, a marker of mitochondrial activity, was decreased in the prefrontal cortex, hippocampus, hypothalamus, and dorsal raphe, suggesting suppressed brain mitochondrial functions, but not in the liver. This is the first report to show that a WD can profoundly suppress social interactions and induce dominant-like behaviours in naïve adult mice. The spectrum of behaviours that were found to be induced are reminiscent of symptoms associated with autism, and, if paralleled in humans, suggest that a WD might exacerbate autism spectrum disorder.

Autism-Like Behaviours and Memory Deficits Result from a Western Diet in Mice

PubMed Central

Cespuglio, Raymond; Umriukhin, Alexei

2017-01-01

Nonalcoholic fatty liver disease, induced by a Western diet (WD), evokes central and peripheral inflammation that is accompanied by altered emotionality. These changes can be associated with abnormalities in social behaviour, hippocampus-dependent cognitive functions, and metabolism. Female C57BL/6J mice were fed with a regular chow or with a WD containing 0.2% of cholesterol and 21% of saturated fat for three weeks. WD-treated mice exhibited increased social avoidance, crawl-over and digging behaviours, decreased body-body contacts, and hyperlocomotion. The WD-fed group also displayed deficits in hippocampal-dependent performance such as contextual memory in a fear conditioning and pellet displacement paradigms. A reduction in glucose tolerance and elevated levels of serum cholesterol and leptin were also associated with the WD. The peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1a) mRNA, a marker of mitochondrial activity, was decreased in the prefrontal cortex, hippocampus, hypothalamus, and dorsal raphe, suggesting suppressed brain mitochondrial functions, but not in the liver. This is the first report to show that a WD can profoundly suppress social interactions and induce dominant-like behaviours in naïve adult mice. The spectrum of behaviours that were found to be induced are reminiscent of symptoms associated with autism, and, if paralleled in humans, suggest that a WD might exacerbate autism spectrum disorder. PMID:28685102

Caffeine prevents cognitive impairment induced by chronic psychosocial stress and/or high fat-high carbohydrate diet.

PubMed

Alzoubi, K H; Abdul-Razzak, K K; Khabour, O F; Al-Tuweiq, G M; Alzubi, M A; Alkadhi, K A

2013-01-15

Caffeine alleviates cognitive impairment associated with a variety of health conditions. In this study, we examined the effect of caffeine treatment on chronic stress- and/or high fat-high carbohydrate Western diet (WD)-induced impairment of learning and memory in rats. Chronic psychosocial stress, WD and caffeine (0.3 g/L in drinking water) were simultaneously administered for 3 months to adult male Wistar rats. At the conclusion of the 3 months, and while the previous treatments continued, rats were tested in the radial arm water maze (RAWM) for learning, short-term and long-term memory. This procedure was applied on a daily basis to all animals for 5 consecutive days or until the animal reaches days to criterion (DTC) in the 12th learning trial and memory tests. DTC is the number of days that the animal takes to make zero error in two consecutive days. Chronic stress and/or WD groups caused impaired learning, which was prevented by chronic caffeine administration. In the memory tests, chronic caffeine administration also prevented memory impairment during chronic stress conditions and/or WD. Furthermore, DTC value for caffeine treated stress, WD, and stress/WD groups indicated that caffeine normalizes memory impairment in these groups. These results showed that chronic caffeine administration prevented stress and/or WD-induced impairment of spatial learning and memory. Copyright © 2012 Elsevier B.V. All rights reserved.

Improving Assessment of Work Related Mental Health Function Using the Work Disability Functional Assessment Battery (WD-FAB).

PubMed

Marfeo, Elizabeth E; Ni, Pengsheng; McDonough, Christine; Peterik, Kara; Marino, Molly; Meterko, Mark; Rasch, Elizabeth K; Chan, Leighton; Brandt, Diane; Jette, Alan M

2018-03-01

Purpose To improve the mental health component of the Work Disability Functional Assessment Battery (WD-FAB), developed for the US Social Security Administration's (SSA) disability determination process. Specifically our goal was to expand the WD-FAB scales of mood & emotions, resilience, social interactions, and behavioral control to improve the depth and breadth of the current scales and expand the content coverage to include aspects of cognition & communication function. Methods Data were collected from a random, stratified sample of 1695 claimants applying for the SSA work disability benefits, and a general population sample of 2025 working age adults. 169 new items were developed to replenish the WD-FAB scales and analyzed using factor analysis and item response theory (IRT) analysis to construct unidimensional scales. We conducted computer adaptive test (CAT) simulations to examine the psychometric properties of the WD-FAB. Results Analyses supported the inclusion of four mental health subdomains: Cognition & Communication (68 items), Self-Regulation (34 items), Resilience & Sociability (29 items) and Mood & Emotions (34 items). All scales yielded acceptable psychometric properties. Conclusions IRT methods were effective in expanding the WD-FAB to assess mental health function. The WD-FAB has the potential to enhance work disability assessment both within the context of the SSA disability programs as well as other clinical and vocational rehabilitation settings.

Tissue distribution and functional analysis of vitellogenin-6 of Toxocara canis.

PubMed

Zhu, Hong-Hong; Ma, Guang-Xu; Luo, Yong-Fang; Luo, Yong-Li; Yin, Sha-Sha; Xiong, Yi; Zhou, Rong-Qiong

2017-06-01

Toxocara canis is an common intestinal nematode of canids and the principal causative agent of human toxocariasis. Vitellogenin (Vg), a source of amino acids and lipids in the eggs, are considered to play an important role in embryo development of a wide range of organisms. In the present study, the transcriptional levels of Tc-vit-6 gene in male and female adult T. canis were determined by quantitative real-time PCR, which indicated high transcription of Tc-vit-6 in the intestine, reproductive tract and body wall of male and female adult T. canis. The fragment of Tc-vit-6 encoding a vWD domain, was cloned and expressed to produce a rabbit anti-TcvWD polyclonal antibody. Tissue distribution of TcVg6 was detected by immunohistochemical assays, which showed predominant distribution of TcVg6 in the tissues of intestine, as well as reproductive tract (including some of the germ cells) and musculature of male and female adult worms. Collectively, these results indicated multiple biological roles of TcVg6 apart from that in the reproduction of T. canis. Copyright © 2017 Elsevier Inc. All rights reserved.

The Next Generation Virgo Cluster Survey. XXVIII. Characterization of the Galactic White Dwarf Population

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

Fantin, Nicholas J.; Côté, Patrick; Gwyn, S. D. J.

We use three different techniques to identify hundreds of white dwarf (WD) candidates in the Next Generation Virgo Cluster Survey (NGVS) based on photometry from the NGVS and GUViCS, and proper motions derived from the NGVS and the Sloan Digital Sky Survey (SDSS). Photometric distances for these candidates are calculated using theoretical color–absolute magnitude relations, while effective temperatures are measured by fitting their spectral energy distributions. Disk and halo WD candidates are separated using a tangential velocity cut of 200 km s{sup −1} in a reduced proper motion diagram, which leads to a sample of six halo WD candidates. Coolingmore » ages, calculated for an assumed WD mass of 0.6 M {sub ⊙}, range between 60 Myr and 6 Gyr, although these estimates depend sensitively on the adopted mass. Luminosity functions for the disk and halo subsamples are constructed and compared to previous results from the SDSS and SuperCOSMOS survey. We compute a number density of (2.81 ± 0.52) × 10{sup −3} pc{sup −3} for the disk WD population—consistent with previous measurements. We find (7.85 ± 4.55) × 10{sup −6} pc{sup −3} for the halo, or 0.3% of the disk. Observed stellar counts are also compared to predictions made by the TRILEGAL and Besançon stellar population synthesis models. The comparison suggests that the TRILEGAL model overpredicts the total number of WDs. The WD counts predicted by the Besançon model agree with the observations, although a discrepancy arises when comparing the predicted and observed halo WD populations; the difference is likely due to the WD masses in the adopted model halo.« less

Effect of low carbohydrate high protein (LCHP) diet on lipid metabolism, liver and kidney function in rats.

PubMed

Kostogrys, Renata B; Franczyk-Żarów, Magdalena; Maślak, Edyta; Topolska, Kinga

2015-03-01

The objective of this study was to compare effects of Western diet (WD) with low carbohydrate high protein (LCHP) diet on lipid metabolism, liver and kidney function in rats. Eighteen rats were randomly assigned to three experimental groups and fed for the next 2 months. The experimental diets were: Control (7% of soybean oil, 20% protein), WD (21% of butter, 20% protein), and LCHP (21% of butter and 52.4% protein) diet. The LCHP diet significantly decreased the body weight of the rats. Diet consumption was differentiated among groups, however significant changes were observed since third week of the experiment duration. Rats fed LCHP diet ate significantly less (25.2g/animal/day) than those from Control (30.2g/animal/day) and WD (27.8 g/animal/day) groups. Additionally, food efficiency ratio (FER) tended to decrease in LCHP fed rats. Serum homocysteine concentration significantly decreased in rats fed WD and LCHP diets. Liver weights were significantly higher in rats fed WD and LCHP diets. At the end of the experiment (2 months) the triacylglycerol (TAG) was significantly decreased in animals fed LCHP compared to WD. qRT-PCR showed that SCD-1 and FAS were decreased in LCHP fed rats, but WD diet increased expression of lipid metabolism genes. Rats receiving LCHP diet had two fold higher kidney weight and 54.5% higher creatinin level compared to Control and WD diets. In conclusion, LCHP diet decreased animal's body weight and decreased TAG in rat's serum. However, kidney damage in LCHP rats was observed. Copyright © 2015 Elsevier B.V. All rights reserved.

Tidal Disruption of a White Dwarf by a Black Hole: The Diversity of Nucleosynthesis, Explosion Energy, and the Fate of Debris Streams

NASA Astrophysics Data System (ADS)

Kawana, Kojiro; Tanikawa, Ataru; Yoshida, Naoki

2018-03-01

We run a suite of hydrodynamics simulations of tidal disruption events (TDEs) of a white dwarf (WD) by a black hole (BH) with a wide range of WD/BH masses and orbital parameters. We implement nuclear reactions to study nucleosynthesis and its dynamical effect through release of nuclear energy. The released nuclear energy effectively increases the fraction of unbound ejecta. This effect is weaker for a heavy WD with 1.2 M⊙, because the specific orbital energy distribution of the debris is predominantly determined by the tidal force, rather than by the explosive reactions. The elemental yield of a TDE depends critically on the initial composition of a WD, while the BH mass and the orbital parameters also affect the total amount of synthesized elements. Tanikawa et al. (2017) find that simulations of WD-BH TDEs with low resolution suffer from spurious heating and inaccurate nuclear reaction results. In order to examine the validity of our calculations, we compare the amounts of the synthesized elements with the upper limits of them derived in a way where we can avoid uncertainties due to low resolution. The results are largely consistent, and thus support our findings. We find particular TDEs where early self-intersection of a WD occurs during the first pericenter passage, promoting formation of an accretion disk. We expect that relativistic jets and/or winds would form in these cases because accretion rates would be super-Eddington. The WD-BH TDEs result in a variety of events depending on the WD/BH mass and pericenter radius of the orbit.

Study protocol for a group randomized controlled trial of a classroom-based intervention aimed at preventing early risk factors for drug abuse: integrating effectiveness and implementation research.

PubMed

Poduska, Jeanne; Kellam, Sheppard; Brown, C Hendricks; Ford, Carla; Windham, Amy; Keegan, Natalie; Wang, Wei

2009-09-02

While a number of preventive interventions delivered within schools have shown both short-term and long-term impact in epidemiologically based randomized field trials, programs are not often sustained with high-quality implementation over time. This study was designed to support two purposes. The first purpose was to test the effectiveness of a universal classroom-based intervention, the Whole Day First Grade Program (WD), aimed at two early antecedents to drug abuse and other problem behaviors, namely, aggressive, disruptive behavior and poor academic achievement. The second purpose--the focus of this paper--was to examine the utility of a multilevel structure to support high levels of implementation during the effectiveness trial, to sustain WD practices across additional years, and to train additional teachers in WD practices. The WD intervention integrated three components, each previously tested separately: classroom behavior management; instruction, specifically reading; and family-classroom partnerships around behavior and learning. Teachers and students in 12 schools were randomly assigned to receive either the WD intervention or the standard first-grade program of the school system (SC). Three consecutive cohorts of first graders were randomized within schools to WD or SC classrooms and followed through the end of third grade to test the effectiveness of the WD intervention. Teacher practices were assessed over three years to examine the utility of the multilevel structure to support sustainability and scaling-up. The design employed in this trial appears to have considerable utility to provide data on WD effectiveness and to inform the field with regard to structures required to move evidence-based programs into practice. NCT00257088.

Tidal disruption of a white dwarf by a black hole: the diversity of nucleosynthesis, explosion energy, and the fate of debris streams

NASA Astrophysics Data System (ADS)

Kawana, Kojiro; Tanikawa, Ataru; Yoshida, Naoki

2018-07-01

We run a suite of hydrodynamic simulations of tidal disruption events (TDEs) of a white dwarf (WD) by a black hole (BH) with a wide range of WD/BH masses and orbital parameters. We implement nuclear reactions to study nucleosynthesis and its dynamical effect through release of nuclear energy. The released nuclear energy effectively increases the fraction of unbound ejecta. This effect is weaker for a heavy WD with 1.2 M⊙, because the specific orbital energy distribution of the debris is predominantly determined by the tidal force, rather than by the explosive reactions. The elemental yield of a TDE depends critically on the initial composition of a WD, while the BH mass and the orbital parameters also affect the total amount of synthesized elements. Tanikawa et al. (2017) find that simulations of WD-BH TDEs with low resolution suffer from spurious heating and inaccurate nuclear reaction results. In order to examine the validity of our calculations, we compare the amounts of the synthesized elements with the upper limits of them derived in a way where we can avoid uncertainties due to low resolution. The results are largely consistent, and thus support our findings. We find particular TDEs where early self-intersection of a WD occurs during the first pericentre passage, promoting formation of an accretion disc. We expect that relativistic jets and/or winds would form in these cases because accretion rates would be super-Eddington. The WD-BH TDEs result in a variety of events depending on the WD/BH mass and pericentre radius of the orbit.

Analysis of sequence repeats of proteins in the PDB.

PubMed

Mary Rajathei, David; Selvaraj, Samuel

2013-12-01

Internal repeats in protein sequences play a significant role in the evolution of protein structure and function. Applications of different bioinformatics tools help in the identification and characterization of these repeats. In the present study, we analyzed sequence repeats in a non-redundant set of proteins available in the Protein Data Bank (PDB). We used RADAR for detecting internal repeats in a protein, PDBeFOLD for assessing structural similarity, PDBsum for finding functional involvement and Pfam for domain assignment of the repeats in a protein. Through the analysis of sequence repeats, we found that identity of the sequence repeats falls in the range of 20-40% and, the superimposed structures of the most of the sequence repeats maintain similar overall folding. Analysis sequence repeats at the functional level reveals that most of the sequence repeats are involved in the function of the protein through functionally involved residues in the repeat regions. We also found that sequence repeats in single and two domain proteins often contained conserved sequence motifs for the function of the domain. Copyright © 2013 Elsevier Ltd. All rights reserved.

Writing Disabilities and Reading Disabilities in Elementary School Students

ERIC Educational Resources Information Center

Costa, Lara-Jeane C.; Edwards, Crystal N.; Hooper, Stephen R.

2016-01-01

This longitudinal study was conducted to determine (a) the rate of co-occurrence of reading disabilities (RDs) in a writing disability (WD) population of students followed from first grade to fourth grade and (b) the cognitive burden that is assumed by having a WD and a RD (WD + RD). The sample included 137 first-grade students from a single…

System for indicating fuel-efficient aircraft altitude

NASA Technical Reports Server (NTRS)

Gary, B. L. (Inventor)

1984-01-01

A method and apparatus are provided for indicating the altitude at which an aircraft should fly so the W/d ratio (weight of the aircraft divided by the density of air) more closely approaches the optimum W/d for the aircraft. A passive microwave radiometer on the aircraft is directed at different angles with respect to the horizon to determine the air temperature, and therefore the density of the air, at different altitudes. The weight of the aircraft is known. The altitude of the aircraft is changed to fly the aircraft at an altitude at which is W/d ratio more closely approaches the optimum W/d ratio for that aircraft.

Treatment Response and Outcomes of Grade 3 Pancreatic Neuroendocrine Neoplasms Based on Morphology: Well Differentiated Versus Poorly Differentiated.

PubMed

Raj, Nitya; Valentino, Emily; Capanu, Marinela; Tang, Laura H; Basturk, Olca; Untch, Brian R; Allen, Peter J; Klimstra, David S; Reidy-Lagunes, Diane

2017-03-01

Emerging data suggest that not all grade 3 (G3) pancreatic neuroendocrine neoplasms (panNENs) behave the same; tumor differentiation may predict outcome. Patients with G3 panNENs treated at our institution between 1999 and 2014 were identified. Demographics, response to therapy, and overall survival were determined. Forty-five patients were identified, 16 with G3 well differentiated pancreatic neuroendocrine tumors (WD-panNETs) and 29 with poorly differentiated neuroendocrine carcinomas (PDNEC). Median overall survival in G3 WD-panNET patients was 52.2 months (95% confidence interval, 19.3-86.9 months) compared with 10.1 months (95% confidence interval, 6.9-12.4 months) in PDNEC patients (P = 0.0009). Response rate to platinum agents was 10% in G3 WD-panNETs and 37% in PDNEC. Response rate to alkylating agents was 50% in G3 WD-panNETs and 50% in PDNEC. Both G3 WD-panNETs and PDNEC responded to platinum and alkylating agents. Overall survival was significantly greater in G3 WD-panNETs compared with PDNEC. These findings challenge current classification and suggest that G3 panNENs should be classified by morphology.

Exposure to Vinyl Chloride and Its Influence on Western Diet-Induced Cardiac Remodeling.

PubMed

Liang, Yaqin; Lang, Anna L; Zhang, Jian; Chen, Jing; Wang, Kai; Chen, Liya; Beier, Juliane I; Qian, Yan; Cai, Lu

2018-06-18

Obesity, usually caused by high fat diets (HFD), is a major public health issue worldwide, causing obesity associated cardiomyopathy. Moreover, the environmental toxicant vinyl chloride (VC) can exacerbate HFD-induced fatty liver disease. However, whether VC serves to enhance obesity-associated cardiomyopathy remains unclear. This study aims to investigate the interaction of western diet (WD) containing relatively low fat (42%) with VC on cardiac remodeling and its underling mechanisms. Adult male C57BL/6J mice were exposed to WD coinhalation of low-dose VC (<1 ppm/d) for 12 weeks. Results showed that WD feeding for 12 weeks caused slight cardiac systolic dysfunction without significant hypertrophy or fibrosis, even with VC. Nevertheless, WD upregulated NF-κB function and expression of IL-1β and PAI-1, while VC showed no significant impact on these effects. In contrast, WD together with VC significantly increased the expression of CHOP and TGF-β1, key markers for endoplasmic reticulum stress and profibrotic cytokine, respectively. In summary, exposure to low-dose of environmental toxicant VC while a WD is consumed for a relatively short time does not have significant impact on cardiac remodeling except for a mild systolic dysfunction of the heart.

The Solar Neighborhood. XXXIX. Parallax Results from the CTIOPI and NOFS Programs: 50 New Members of the 25 parsec White Dwarf Sample

NASA Astrophysics Data System (ADS)

Subasavage, John P.; Jao, Wei-Chun; Henry, Todd J.; Harris, Hugh C.; Dahn, Conard C.; Bergeron, P.; Dufour, P.; Dunlap, Bart H.; Barlow, Brad N.; Ianna, Philip A.; Lépine, Sébastien; Margheim, Steven J.

2017-07-01

We present 114 trigonometric parallaxes for 107 nearby white dwarf (WD) systems from both the Cerro Tololo Inter-American Observatory Parallax Investigation (CTIOPI) and the U. S. Naval Observatory Flagstaff Station (NOFS) parallax programs. Of these, 76 parallaxes for 69 systems were measured by the CTIOPI program and 38 parallaxes for as many systems were measured by the NOFS program. A total of 50 systems are confirmed to be within the 25-pc horizon of interest. Coupled with a spectroscopic confirmation of a common proper-motion companion to a Hipparcos star within 25 pc as well as confirmation parallax determinations for two WD systems included in the recently released Tycho Gaia Astrometric Solution catalog, we add 53 new systems to the 25-pc WD sample—a 42% increase. Our sample presented here includes four strong candidate halo systems, a new metal-rich DAZ WD, a confirmation of a recently discovered nearby short-period (P = 2.85 hr) double degenerate, a WD with a new astrometric perturbation (long period, unconstrained with our data), and a new triple system where the WD companion main-sequence star has an astrometric perturbation (P ˜ 1.6 year).

Sub-Chandrasekhar-mass White Dwarf Detonations Revisited

NASA Astrophysics Data System (ADS)

Shen, Ken J.; Kasen, Daniel; Miles, Broxton J.; Townsley, Dean M.

2018-02-01

The detonation of a sub-Chandrasekhar-mass white dwarf (WD) has emerged as one of the most promising Type Ia supernova (SN Ia) progenitor scenarios. Recent studies have suggested that the rapid transfer of a very small amount of helium from one WD to another is sufficient to ignite a helium shell detonation that subsequently triggers a carbon core detonation, yielding a “dynamically driven double-degenerate double-detonation” SN Ia. Because the helium shell that surrounds the core explosion is so minimal, this scenario approaches the limiting case of a bare C/O WD detonation. Motivated by discrepancies in previous literature and by a recent need for detailed nucleosynthetic data, we revisit simulations of naked C/O WD detonations in this paper. We disagree to some extent with the nucleosynthetic results of previous work on sub-Chandrasekhar-mass bare C/O WD detonations; for example, we find that a median-brightness SN Ia is produced by the detonation of a 1.0 {M}ȯ WD instead of a more massive and rarer 1.1 {M}ȯ WD. The neutron-rich nucleosynthesis in our simulations agrees broadly with some observational constraints, although tensions remain with others. There are also discrepancies related to the velocities of the outer ejecta and light curve shapes, but overall our synthetic light curves and spectra are roughly consistent with observations. We are hopeful that future multidimensional simulations will resolve these issues and further bolster the dynamically driven double-degenerate double-detonation scenario’s potential to explain most SNe Ia.

Structure and stability of the ankyrin domain of the Drosophila Notch receptor.

PubMed

Zweifel, Mark E; Leahy, Daniel J; Hughson, Frederick M; Barrick, Doug

2003-11-01

The Notch receptor contains a conserved ankyrin repeat domain that is required for Notch-mediated signal transduction. The ankyrin domain of Drosophila Notch contains six ankyrin sequence repeats previously identified as closely matching the ankyrin repeat consensus sequence, and a putative seventh C-terminal sequence repeat that exhibits lower similarity to the consensus sequence. To better understand the role of the Notch ankyrin domain in Notch-mediated signaling and to examine how structure is distributed among the seven ankyrin sequence repeats, we have determined the crystal structure of this domain to 2.0 angstroms resolution. The seventh, C-terminal, ankyrin sequence repeat adopts a regular ankyrin fold, but the first, N-terminal ankyrin repeat, which contains a 15-residue insertion, appears to be largely disordered. The structure reveals a substantial interface between ankyrin polypeptides, showing a high degree of shape and charge complementarity, which may be related to homotypic interactions suggested from indirect studies. However, the Notch ankyrin domain remains largely monomeric in solution, demonstrating that this interface alone is not sufficient to promote tight association. Using the structure, we have classified reported mutations within the Notch ankyrin domain that are known to disrupt signaling into those that affect buried residues and those restricted to surface residues. We show that the buried substitutions greatly decrease protein stability, whereas the surface substitutions have only a marginal affect on stability. The surface substitutions are thus likely to interfere with Notch signaling by disrupting specific Notch-effector interactions and map the sites of these interactions.

A Metabolomic Analysis of Omega-3 Fatty Acid-Mediated Attenuation of Western Diet-Induced Nonalcoholic Steatohepatitis in LDLR -/- Mice

PubMed Central

Depner, Christopher M.; Traber, Maret G.; Bobe, Gerd; Kensicki, Elizabeth; Bohren, Kurt M.; Milne, Ginger; Jump, Donald B.

2013-01-01

Background Nonalcoholic steatohepatitis (NASH) is a progressive form of nonalcoholic fatty liver disease and a risk factor for cirrhosis, hepatocellular carcinoma and liver failure. Previously, we reported that dietary docosahexaenoic acid (DHA, 22:6,n-3) was more effective than eicosapentaenoic acid (EPA, 20:5,n-3) at reversing western diet (WD) induced NASH in LDLR-/- mice. Methods Using livers from our previous study, we carried out a global non-targeted metabolomic approach to quantify diet-induced changes in hepatic metabolism. Results Livers from WD + olive oil (WD + O)-fed mice displayed histological and gene expression features consistent with NASH. The metabolomic analysis of 320 metabolites established that the WD and n-3 polyunsaturated fatty acid (PUFA) supplementation had broad effects on all major metabolic pathways. Livers from WD + O-fed mice were enriched in saturated (SFA) and monounsaturated fatty acids (MUFA), palmitoyl-sphingomyelin, cholesterol, n-6 PUFA, n-6 PUFA-containing phosphoglycerolipids, n-6 PUFA-derived oxidized lipids (12-HETE) and depleted of C20-22 n-3 PUFA-containing phosphoglycerolipids, C20-22 n-3 PUFA-derived oxidized lipids (18-HEPE, 17,18-DiHETE) and S-lactoylglutathione, a methylglyoxal detoxification product. WD + DHA was more effective than WD + EPA at attenuating WD + O-induced changes in NASH gene expression markers, n-6 PUFA and oxidized lipids, citrate and S-lactosyl glutathione. Diet-induced changes in hepatic MUFA and sphingolipid content were associated with changes in expression of enzymes involved in MUFA and sphingolipid synthesis. Changes in hepatic oxidized fatty acids and S-lactoylglutathione, however, correlated with hepatic n-3 and n-6 C20-22 PUFA content. Hepatic C20-22 n-3 PUFA content was inversely associated with hepatic α-tocopherol and ascorbate content and positively associated with urinary F2- and F3-isoprostanes, revealing diet effects on whole body oxidative stress. Conclusion DHA regulation of hepatic SFA, MUFA, PUFA, sphingomyelin, PUFA-derived oxidized lipids and S-lactoylglutathione may explain the protective effects of DHA against WD-induced NASH in LDLR-/- mice. PMID:24358308

A metabolomic analysis of omega-3 fatty acid-mediated attenuation of western diet-induced nonalcoholic steatohepatitis in LDLR-/- mice.

PubMed

Depner, Christopher M; Traber, Maret G; Bobe, Gerd; Kensicki, Elizabeth; Bohren, Kurt M; Milne, Ginger; Jump, Donald B

2013-01-01

Nonalcoholic steatohepatitis (NASH) is a progressive form of nonalcoholic fatty liver disease and a risk factor for cirrhosis, hepatocellular carcinoma and liver failure. Previously, we reported that dietary docosahexaenoic acid (DHA, 22:6,n-3) was more effective than eicosapentaenoic acid (EPA, 20:5,n-3) at reversing western diet (WD) induced NASH in LDLR(-/-) mice. Using livers from our previous study, we carried out a global non-targeted metabolomic approach to quantify diet-induced changes in hepatic metabolism. Livers from WD + olive oil (WD + O)-fed mice displayed histological and gene expression features consistent with NASH. The metabolomic analysis of 320 metabolites established that the WD and n-3 polyunsaturated fatty acid (PUFA) supplementation had broad effects on all major metabolic pathways. Livers from WD + O-fed mice were enriched in saturated (SFA) and monounsaturated fatty acids (MUFA), palmitoyl-sphingomyelin, cholesterol, n-6 PUFA, n-6 PUFA-containing phosphoglycerolipids, n-6 PUFA-derived oxidized lipids (12-HETE) and depleted of C20-22 n-3 PUFA-containing phosphoglycerolipids, C20-22 n-3 PUFA-derived oxidized lipids (18-HEPE, 17,18-DiHETE) and S-lactoylglutathione, a methylglyoxal detoxification product. WD + DHA was more effective than WD + EPA at attenuating WD + O-induced changes in NASH gene expression markers, n-6 PUFA and oxidized lipids, citrate and S-lactosyl glutathione. Diet-induced changes in hepatic MUFA and sphingolipid content were associated with changes in expression of enzymes involved in MUFA and sphingolipid synthesis. Changes in hepatic oxidized fatty acids and S-lactoylglutathione, however, correlated with hepatic n-3 and n-6 C20-22 PUFA content. Hepatic C20-22 n-3 PUFA content was inversely associated with hepatic α-tocopherol and ascorbate content and positively associated with urinary F2- and F3-isoprostanes, revealing diet effects on whole body oxidative stress. DHA regulation of hepatic SFA, MUFA, PUFA, sphingomyelin, PUFA-derived oxidized lipids and S-lactoylglutathione may explain the protective effects of DHA against WD-induced NASH in LDLR(-/-) mice.

Molecular mapping of qBK1 WD , a major QTL for bakanae disease resistance in rice.

PubMed

Lee, Sais-Beul; Hur, Yeon-Jae; Cho, Jun-Hyeon; Lee, Jong-Hee; Kim, Tae-Heon; Cho, Soo-Min; Song, You-Chun; Seo, Young-Su; Lee, Jungkwan; Kim, Tae-Sung; Park, Yong-Jin; Oh, Myung-Kyu; Park, Dong-Soo

2018-01-10

Bakanae or foot rot disease is a prominent disease of rice caused by Gibberella fujikuroi. This disease may infect rice plants from the pre-emergence stage to the mature stage. In recent years, raising rice seedlings in seed boxes for mechanical transplanting has increased the incidence of many seedling diseases; only a few rice varieties have been reported to exhibit resistance to bakanae disease. In this study, we attempted to identify quantitative trait loci (QTLs) conferring bakanae disease resistance from the highly resistant japonica variety Wonseadaesoo. A primary QTL study using the genotypes/phenotypes of the recombinant inbred lines (RILs) indicated that the locus qBK1 WD conferring resistance to bakanae disease from Wonseadaesoo was located in a 1.59 Mb interval delimited on the physical map between chr01_13542347 (13.54 Mb) and chr01_15132528 (15.13 Mb). The log of odds (LOD) score of qBK1 WD was 8.29, accounting for 20.2% of the total phenotypic variation. We further identified a gene pyramiding effect of two QTLs, qBK WD and previously developed qBK1. The mean proportion of healthy plant for 31 F 4 RILs that had no resistance genes was 35.3%, which was similar to that of the susceptible check variety Ilpum. The proportion of healthy plants for the lines with only qBK WD or qBK1 was 66.1% and 55.5%, respectively, which was significantly higher than that of the lines without resistance genes and that of Ilpum. The mean proportion of the healthy plant for 15 F 4 RILs harboring both qBK WD and qBK1 was 80.2%, which was significantly higher than that of the lines with only qBK WD or qBK1. Introducing qBK WD or pyramiding the QTLs qBK WD and qBK1 could provide effective tools for breeding rice with bakanae disease resistance. To our knowledge, this is the first report on a gene pyramiding effect that provides higher resistance against bakanae disease.

Nitrogen fixation system of tungsten-resistant mutants of Azotobacter vinelandii.

PubMed Central

Riddle, G D; Simonson, J G; Hales, B J; Braymer, H D

1982-01-01

Mutants of Azotobacter vinelandii ATCC 12837 were isolated which could fix N2 in the presence of high tungsten concentrations. The most studied of these mutants (WD2) grew well in N-free modified Burk broth containing 10 mM W, whereas the wild type would not grow in this medium. WD2 would also grow in Burk N-free broth at about the same rate as the wild type. WD2 in broth containing W exhibited 22% of the whole cell acetylene reduction activity of the wild type in broth containing Mo and showed a lowered affinity for acetylene. Two-dimensional gel electrophoresis experiments showed that N2-fixing cells of WD2 from broth containing W or Mo did not produce significant amounts of component I of native nitrogenase protein. Electron spin resonance spectra of whole cells and cell-free extracts of WD2 from broth containing W lacked any trace of the g = 3.6 resonance associated with FeMoCo. Images PMID:6956567

New Insights on the White Dwarf Luminosity and Mass Functions from the LSS-GAC Survey

NASA Astrophysics Data System (ADS)

Rebassa-Mansergas, Alberto; Liu, Xiaowei; Cojocaru, Ruxandra; Torres, Santiago; García–Berro, Enrique; Yuan, Haibo; Huang, Yang; Xiang, Maosheng

2015-06-01

The white dwarf (WD) population observed in magnitude-limited surveys can be used to derive the luminosity function (LF) and mass function (MF), once the corresponding volume corrections are employed. However, the WD samples from which the observational LFs and MFs are built are the result of complicated target selection algorithms. Thus, it is difficult to quantify the effects of the observational biases on the observed functions. The LAMOST (Large sky Area Multi-Object fiber Spectroscopic Telescope) spectroscopic survey of the Galactic anti-center (LSS-GAC) has well-defined selection criteria. This is a noticeable advantage over previous surveys. Here we derive the WD LF and MF of the LSS-GAC, and use a Monte Carlo code to simulate the WD population in the Galactic anti-center. We apply the well-defined LSS-GAC selection criteria to the simulated populations, taking into account all observational biases, and perform the first meaningful comparison between the simulated WD LFs and MFs and the observed ones.

The Solar Neighborhood. XXXIX. Parallax Results from the CTIOPI and NOFS Programs: 50 New Members of the 25 parsec White Dwarf Sample

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

Subasavage, John P.; Harris, Hugh C.; Dahn, Conard C.

We present 114 trigonometric parallaxes for 107 nearby white dwarf (WD) systems from both the Cerro Tololo Inter-American Observatory Parallax Investigation (CTIOPI) and the U. S. Naval Observatory Flagstaff Station (NOFS) parallax programs. Of these, 76 parallaxes for 69 systems were measured by the CTIOPI program and 38 parallaxes for as many systems were measured by the NOFS program. A total of 50 systems are confirmed to be within the 25-pc horizon of interest. Coupled with a spectroscopic confirmation of a common proper-motion companion to a Hipparcos star within 25 pc as well as confirmation parallax determinations for two WD systems included inmore » the recently released Tycho Gaia Astrometric Solution catalog, we add 53 new systems to the 25-pc WD sample—a 42% increase. Our sample presented here includes four strong candidate halo systems, a new metal-rich DAZ WD, a confirmation of a recently discovered nearby short-period ( P  = 2.85 hr) double degenerate, a WD with a new astrometric perturbation (long period, unconstrained with our data), and a new triple system where the WD companion main-sequence star has an astrometric perturbation ( P  ∼ 1.6 year).« less

The double-degenerate model for the progenitors of Type Ia supernovae

NASA Astrophysics Data System (ADS)

Liu, D.; Wang, B.; Han, Z.

2018-02-01

The double-degenerate (DD) model, involving the merging of massive double carbon-oxygen white dwarfs (CO WDs) driven by gravitational wave radiation, is one of the classical pathways for the formation of Type Ia supernovae (SNe Ia). Recently, it has been proposed that the WD+He subgiant channel has a significant contribution to the production of massive double WDs, in which the primary WD accumulates mass by accreting He-rich matter from an He subgiant. We evolved about 1800 CO WD+He star systems and obtained a large and dense grid for producing SNe Ia through the DD model. We then performed a series of binary population synthesis simulations for the DD model, in which the WD+He subgiant channel is calculated by interpolations in the SN Ia production grid. According to our standard model, the Galactic birth rate of SNe Ia is about 2.4 × 10- 3 yr- 1 for the WD+He subgiant channel of the DD model; the total birth rate is about 3.7 × 10- 3 yr- 1 for all channels, reproducing that of observations. Previous theoretical models still have deficit with the observed SNe Ia with delay times < 1 Gyr and > 8 Gyr. After considering the WD+He subgiant channel, we found that the delay time distributions are comparable with the observed results. Additionally, some recent studies proposed that the violent WD mergers are more likely to produce SNe Ia based on the DD model. We estimated that the violent mergers through the DD model may contribute to at most 16 per cent of all SNe Ia.

Endothelial Estrogen Receptor-α Does Not Protect Against Vascular Stiffness Induced by Western Diet in Female Mice.

PubMed

Manrique, Camila; Lastra, Guido; Ramirez-Perez, Francisco I; Haertling, Dominic; DeMarco, Vincent G; Aroor, Annayya R; Jia, Guanghong; Chen, Dongqing; Barron, Brady J; Garro, Mona; Padilla, Jaume; Martinez-Lemus, Luis A; Sowers, James R

2016-04-01

Consumption of a diet high in fat and refined carbohydrates (Western diet [WD]) is associated with obesity and insulin resistance, both major risk factors for cardiovascular disease (CVD). In women, obesity and insulin resistance abrogate the protection against CVD likely afforded by estrogen signaling through estrogen receptor (ER)α. Indeed, WD in females results in increased vascular stiffness, which is independently associated with CVD. We tested the hypothesis that loss of ERα signaling in the endothelium exacerbates WD-induced vascular stiffening in female mice. We used a novel model of endothelial cell (EC)-specific ERα knockout (EC-ERαKO), obtained after sequential crossing of the ERα double floxed mice and VE-Cadherin Cre-recombinase mice. Ten-week-old females, EC-ERαKO and aged-matched genopairs were fed either a regular chow diet (control diet) or WD for 8 weeks. Vascular stiffness was measured in vivo by pulse wave velocity and ex vivo in aortic explants by atomic force microscopy. In addition, vascular reactivity was assessed in isolated aortic rings. Initial characterization of the model fed a control diet did not reveal changes in whole-body insulin sensitivity, aortic vasoreactivity, or vascular stiffness in the EC-ERαKO mice. Interestingly, ablation of ERα in ECs reduced WD-induced vascular stiffness and improved endothelial-dependent dilation. In the setting of a WD, endothelial ERα signaling contributes to vascular stiffening in females. The precise mechanisms underlying the detrimental effects of endothelial ERα in the setting of a WD remain to be elucidated.

Differentiating oral lesions in different carcinogenesis stages with optical coherence tomography

NASA Astrophysics Data System (ADS)

Tsai, Meng-Tsan; Lee, Cheng-Kuang; Lee, Hsiang-Chieh; Chen, Hsin-Ming; Chiang, Chun-Pin; Wang, Yih-Ming; Yang, Chih-Chung

2009-07-01

A swept-source optical coherence tomography (SS-OCT) system is used to clinically scan oral lesions in different oral carcinogenesis stages, including normal oral mucosa control, mild dysplasia (MiD), moderate dysplasia (MoD), early-stage squamous cell carcinoma (ES-SCC), and well-developed SCC (WD-SCC), for diagnosis purpose. On the basis of the analyses of the SS-OCT images, the stages of dysplasia (MiD and MoD), and SCC (ES-SCC and WD-SCC) can be differentiated from normal control by evaluating the depth-dependent standard deviation (SD) values of lateral variations. In the dysplasia stage, the boundary between the epithelium (EP) and lamina propria (LP) layers can still be identified and the EP layer becomes significantly thicker than that of normal control. Also, in a certain range of the EP layer above the EP/LP boundary, the SD value becomes larger than a certain percentage of the maximum level, which is observed around the EP/LP boundary. On the other hand, in the ES-SCC and WD-SCC stages, the EP/LP boundary disappears. Because of the higher density of connective tissue papillae in the ES-SCC stage, the SD values of the slowly varying lateral scan profiles in the ES-SCC samples are significantly larger than those in the WD-SCC sample. Also, ES-SCC can be differentiated from WD-SCC by comparing the exponential decay constants of averaged A-mode scan profiles. Because of the higher tissue absorption in the WD-SCC lesion, the decay constants in the WD-SCC samples are significantly higher than those in the ES-SCC samples.

Modification of Turbulent Pipe Flow Equations to Estimate the Vertical Velocity Profiles Under Woody Debris Jams

NASA Astrophysics Data System (ADS)

Cervania, A.; Knack, I. M. W.

2017-12-01

The presence of woody debris (WD) jams in rivers and streams increases the risk of backwater flooding and reduces the navigability of a channel, but adds fish and macroinvertebrate habitat to the stream. When designing river engineering projects engineers use hydraulic models to predict flow behavior around these obstructions. However, the complexities of flow through and beneath WD jams are still poorly understood. By increasing the ability to predict flow behavior around WD jams, landowners and engineers are empowered to develop sustainable practices regarding the removal or placement of WD in rivers and flood plains to balance the desirable and undesirable effects to society and the environment. The objective of this study is to address some of this knowledge gap by developing a method to estimate the vertical velocity profile of flow under WD jams. When flow passes under WD jams, it becomes affected by roughness elements on all sides, similar to turbulent flows in pipe systems. Therefore, the method was developed using equations that define the velocity profiles of turbulent pipe flows: the law of the wall, the logarithmic law, and the velocity defect law. Flume simulations of WD jams were conducted and the vertical velocity profiles were measured along the centerline. A calculated velocity profile was fit to the measured profile through the calibration of eight parameters. An optimal value or range of values have been determined for several of these parameters using cross-validation techniques. The results indicate there may be some promise to using this method in hydraulic models.

Formation of Extremely Low-mass White Dwarf Binaries

NASA Astrophysics Data System (ADS)

Sun, M.; Arras, P.

2018-05-01

Motivated by the discovery of several pulsating, extremely low-mass white dwarfs (ELM WDs, mass M ≲ 0.18 M ⊙) that likely have WD companions, this paper discusses binary formation models for these systems. ELM WDs are formed using angular momentum losses by magnetic braking. Evolutionary models are constructed using the Modules for Experiments in Stellar Astrophysics (MESA), with ELM WD progenitors in the range 1.0 ≲ M d/M ⊙ ≲ 1.5 and WD companions in the range 0.4 ≲ M a/M ⊙ ≲ 0.9. A prescription to reduce magnetic braking for thin surface convection zones is included. Upon the thinning of the evolved donor envelope, the donor star shrinks out of contact and mass transfer (MT) ceases, revealing the ELM WD. Systems with low masses have previously been suggested as possible AM CVNs. Systems with high masses, up to the limit M ≃ 0.18 M ⊙ at which shell flashes occur on the WD cooling track, tend to expand out to orbital periods P orb ≳ 15 hr. In between this range, ELM WDs may become pulsators both as pre-WDs and on the WD cooling track. Brickhill’s criterion for convective mode driving is used to estimate the location of the blue edge of the g-mode instability strip. In the appendix, we show that the formation of an ELM WD by unstable MT or a common-envelope event is unlikely. Stable Roche-lobe overflow with conservative MT produces only M ≳ 0.2 M ⊙.

The response of the natriuretic peptide system to water deprivation in the desert rodent, Notomys alexis.

PubMed

Heimeier, Rachel A; Donald, John A

2006-02-01

Natriuretic peptides (NPs) are regulatory molecules that cause cGMP-mediated diuresis and natriuresis in mammals. Accordingly, it is interesting to consider their role in desert-adapted animals in which water is often limited. This study investigated the response of the natriuretic peptide (NP) system to varying periods of water deprivation (WD) in the Australian desert rodent species, Notomys alexis. It was hypothesised that the expression of the NP system will be down-regulated in water-deprived N. alexis compared to water-replete animals. The plasma levels of ANP were significantly reduced after 3 days of WD, but were unaffected by 7, 14 and 28 days of WD. Water deprivation for 3, 7, 14 days had a variable effect on the mRNA expression of ANP, CNP, NPR-A, NPR-B, and NPR-C, and a uniform down-regulation was not observed. However, after 28 days of WD, mRNA expression was similar to water-replete animals, except for NPR-A. Surprisingly, 7 and 14 days of WD caused an up-regulation in the ability of ANP to stimulate cGMP; this also occurred at 14 days for CNP. Taken together, the mRNA expression and peptide mediated guanylyl cyclase activity data after WD were in the opposite direction to what was predicted. Interestingly, after 28 days of WD, most parameters were similar to those of water-replete animals, which indicates that a down-regulation of the NP system is not part of the physiological response to an absence of free water in N. alexis.

Erectile Dysfunction Precedes Coronary Artery Endothelial Dysfunction in Rats Fed a High-Fat, High-Sucrose, Western Pattern Diet

PubMed Central

La Favor, Justin D.; Anderson, Ethan J.; Hickner, Robert C.; Wingard, Christopher J.

2016-01-01

Introduction It is suggested that erectile dysfunction (ED) may be an early risk factor for cardiovascular disease. Aim The goal of this study was to determine whether development of ED precedes the onset of coronary artery endothelial dysfunction in response to a Western diet (WD), thereby establishing whether the WD differentially impacts the endothelium in a time-dependent manner. Additionally, a goal was to determine if diet-induced ED is reversible with intracavernosal sepiapterin treatment. Methods Male Sprague-Dawley rats were fed a WD for 4, 8, or 12 weeks, or a control diet for 8 weeks. Erectile function was evaluated by measuring the mean arterial pressure (MAP) and intracavernosal pressure (ICP) in response to electrical field stimulation of the cavernosal nerve near the major pelvic ganglion, in the absence and presence of sepiapterin. Coronary artery endothelial function was evaluated ex vivo with cumulative doses of acetylcholine (ACh) applied to segments of the left anterior descending coronary artery preconstricted with serotonin. Main Outcome Measures Erectile function was assessed as the ICP response to electrical field stimulation (EFS), normalized to MAP. Coronary artery endothelial function was assessed as the effective concentration producing 50% of a maximal response (EC50) of the ACh response. Results The ICP/MAP response to EFS was significantly attenuated following both 8 and 12 weeks of the WD compared with the control diet (P < 0.05). Sepiapterin treatment augmented the ICP/MAP response in all WD groups (P < 0.05). The coronary artery EC50 of the ACh response was not different from control following 4 or 8 weeks but was significantly elevated following 12 weeks of the WD (P < 0.01). Conclusions These data suggest that erectile function is reduced prior to coronary artery endothelial function in response to the WD. Improvement of erectile function with sepiapterin in WD rats indicates that nitric oxide synthase uncoupling is a key mechanism in diet-induced ED. PMID:23170997

The plant decapeptide OSIP108 prevents copper-induced toxicity in various models for Wilson disease

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

Spincemaille, Pieter; Pham, Duc-Hung; Chandhok, Gursimran

2014-10-15

Background: Wilson disease (WD) is caused by accumulation of excess copper (Cu) due to a mutation in the gene encoding the liver Cu transporter ATP7B, and is characterized by acute liver failure or cirrhosis and neuronal cell death. We investigated the effect of OSIP108, a plant derived decapeptide that prevents Cu-induced apoptosis in yeast and human cells, on Cu-induced toxicity in various mammalian in vitro models relevant for WD and in a Cu-toxicity zebrafish larvae model applicable to WD. Methods: The effect of OSIP108 was evaluated on viability of various cell lines in the presence of excess Cu, on livermore » morphology of a Cu-treated zebrafish larvae strain that expresses a fluorescent reporter in hepatocytes, and on oxidative stress levels in wild type AB zebrafish larvae. Results: OSIP108 increased not only viability of Cu-treated CHO cells transgenically expressing ATP7B and the common WD-causing mutant ATP7B{sup H1069Q}, but also viability of Cu-treated human glioblastoma U87 cells. Aberrancies in liver morphology of Cu-treated zebrafish larvae were observed, which were further confirmed as Cu-induced hepatotoxicity by liver histology. Injections of OSIP108 into Cu-treated zebrafish larvae significantly increased the amount of larvae with normal liver morphology and decreased Cu-induced production of reactive oxygen species. Conclusions: OSIP108 prevents Cu-induced toxicity in in vitro models and in a Cu-toxicity zebrafish larvae model applicable to WD. General significance: All the above data indicate the potential of OSIP108 as a drug lead for further development as a novel WD treatment. - Highlights: • Wilson disease (WD) is characterized by accumulation of toxic copper (Cu). • OSIP108 increases viability of Cu-treated cellular models applicable to WD. • OSIP108 injections preserve liver morphology of Cu-treated zebrafish larvae. • OSIP108 injections into zebrafish larvae abrogates Cu-induced oxidative stress.« less

Light-curve Analysis of Neon Novae

NASA Astrophysics Data System (ADS)

Hachisu, Izumi; Kato, Mariko

2016-01-01

We analyzed light curves of five neon novae, QU Vul, V351 Pup, V382 Vel, V693 CrA, and V1974 Cyg, and determined their white dwarf (WD) masses and distance moduli on the basis of theoretical light curves composed of free-free and photospheric emission. For QU Vul, we obtained a distance of d ˜ 2.4 kpc, reddening of E(B - V) ˜ 0.55, and WD mass of MWD = 0.82-0.96 {M}⊙ . This suggests that an oxygen-neon WD lost a mass of more than ˜ 0.1 {M}⊙ since its birth. For V351 Pup, we obtained d˜ 5.5 {{kpc}}, E(B-V)˜ 0.45, and {M}{{WD}}=0.98-1.1 {M}⊙ . For V382 Vel, we obtained d˜ 1.6 {{kpc}}, E(B-V)˜ 0.15, and {M}{{WD}}=1.13-1.28 {M}⊙ . For V693 CrA, we obtained d˜ 7.1 {{kpc}}, E(B-V)˜ 0.05, and {M}{{WD}}=1.15-1.25 {M}⊙ . For V1974 Cyg, we obtained d˜ 1.8 {{kpc}}, E(B-V)˜ 0.30, and {M}{{WD}}=0.95-1.1 {M}⊙ . For comparison, we added the carbon-oxygen nova V1668 Cyg to our analysis and obtained d˜ 5.4 {{kpc}}, E(B-V)˜ 0.30, and {M}{{WD}}=0.98-1.1 {M}⊙ . In QU Vul, photospheric emission contributes 0.4-0.8 mag at most to the optical light curve compared with free-free emission only. In V351 Pup and V1974 Cyg, photospheric emission contributes very little (0.2-0.4 mag at most) to the optical light curve. In V382 Vel and V693 CrA, free-free emission dominates the continuum spectra, and photospheric emission does not contribute to the optical magnitudes. We also discuss the maximum magnitude versus rate of decline relation for these novae based on the universal decline law.

Uric acid promotes vascular stiffness, maladaptive inflammatory responses and proteinuria in western diet fed mice.

PubMed

Aroor, Annayya R; Jia, Guanghong; Habibi, Javad; Sun, Zhe; Ramirez-Perez, Francisco I; Brady, Barron; Chen, Dongqing; Martinez-Lemus, Luis A; Manrique, Camila; Nistala, Ravi; Whaley-Connell, Adam T; Demarco, Vincent G; Meininger, Gerald A; Sowers, James R

2017-09-01

Aortic vascular stiffness has been implicated in the development of cardiovascular disease (CVD) and chronic kidney disease (CKD) in obese individuals. However, the mechanism promoting these adverse effects are unclear. In this context, promotion of obesity through consumption of a western diet (WD) high in fat and fructose leads to excess circulating uric acid. There is accumulating data implicating elevated uric acid in the promotion of CVD and CKD. Accordingly, we hypothesized that xanthine oxidase(XO) inhibition with allopurinol would prevent a rise in vascular stiffness and proteinuria in a translationally relevant model of WD-induced obesity. Four-week-old C57BL6/J male mice were fed a WD with excess fat (46%) and fructose (17.5%) with or without allopurinol (125mg/L in drinking water) for 16weeks. Aortic endothelial and extracellular matrix/vascular smooth muscle stiffness was evaluated by atomic force microscopy. Aortic XO activity, 3-nitrotyrosine (3-NT) and aortic endothelial sodium channel (EnNaC) expression were evaluated along with aortic expression of inflammatory markers. In the kidney, expression of toll like receptor 4 (TLR4) and fibronectin were assessed along with evaluation of proteinuria. XO inhibition significantly attenuated WD-induced increases in plasma uric acid, vascular XO activity and oxidative stress, in concert with reductions in proteinuria. Further, XO inhibition prevented WD-induced increases in aortic EnNaC expression and associated endothelial and subendothelial stiffness. XO inhibition also reduced vascular pro-inflammatory and maladaptive immune responses induced by consumption of a WD. XO inhibition also decreased WD-induced increases in renal TLR4 and fibronectin that associated proteinuria. Consumption of a WD leads to elevations in plasma uric acid, increased vascular XO activity, oxidative stress, vascular stiffness, and proteinuria all of which are attenuated with allopurinol administration. Copyright © 2017 Elsevier Inc. All rights reserved.

TRANSPARENT TESTA GLABRA 1-Dependent Regulation of Flavonoid Biosynthesis

PubMed Central

Zhang, Bipei

2017-01-01

The flavonoid composition of various tissues throughout plant development is of biological relevance and particular interest for breeding. Arabidopsis thaliana TRANSPARENT TESTA GLABRA 1 (AtTTG1) is an essential regulator of late structural genes in flavonoid biosynthesis. Here, we provide a review of the regulation of the pathway’s core enzymes through AtTTG1-containing R2R3-MYELOBLASTOSIS-basic HELIX-LOOP-HELIX-WD40 repeat (MBW(AtTTG1)) complexes embedded in an evolutionary context. We present a comprehensive collection of A. thaliana ttg1 mutants and AtTTG1 orthologs. A plethora of MBW(AtTTG1) mechanisms in regulating the five major TTG1-dependent traits is highlighted. PMID:29261137

STAND, a class of P-loop NTPases including animal and plant regulators of programmed cell death: multiple, complex domain architectures, unusual phyletic patterns, and evolution by horizontal gene transfer.

PubMed

Leipe, Detlef D; Koonin, Eugene V; Aravind, L

2004-10-08

Using sequence profile analysis and sequence-based structure predictions, we define a previously unrecognized, widespread class of P-loop NTPases. The signal transduction ATPases with numerous domains (STAND) class includes the AP-ATPases (animal apoptosis regulators CED4/Apaf-1, plant disease resistance proteins, and bacterial AfsR-like transcription regulators) and NACHT NTPases (e.g. NAIP, TLP1, Het-E-1) that have been studied extensively in the context of apoptosis, pathogen response in animals and plants, and transcriptional regulation in bacteria. We show that, in addition to these well-characterized protein families, the STAND class includes several other groups of (predicted) NTPase domains from diverse signaling and transcription regulatory proteins from bacteria and eukaryotes, and three Archaea-specific families. We identified the STAND domain in several biologically well-characterized proteins that have not been suspected to have NTPase activity, including soluble adenylyl cyclases, nephrocystin 3 (implicated in polycystic kidney disease), and Rolling pebble (a regulator of muscle development); these findings are expected to facilitate elucidation of the functions of these proteins. The STAND class belongs to the additional strand, catalytic E division of P-loop NTPases together with the AAA+ ATPases, RecA/helicase-related ATPases, ABC-ATPases, and VirD4/PilT-like ATPases. The STAND proteins are distinguished from other P-loop NTPases by the presence of unique sequence motifs associated with the N-terminal helix and the core strand-4, as well as a C-terminal helical bundle that is fused to the NTPase domain. This helical module contains a signature GxP motif in the loop between the two distal helices. With the exception of the archaeal families, almost all STAND NTPases are multidomain proteins containing three or more domains. In addition to the NTPase domain, these proteins typically contain DNA-binding or protein-binding domains, superstructure-forming repeats, such as WD40 and TPR, and enzymatic domains involved in signal transduction, including adenylate cyclases and kinases. By analogy to the AAA+ ATPases, it can be predicted that STAND NTPases use the C-terminal helical bundle as a "lever" to transmit the conformational changes brought about by NTP hydrolysis to effector domains. STAND NTPases represent a novel paradigm in signal transduction, whereby adaptor, regulatory switch, scaffolding, and, in some cases, signal-generating moieties are combined into a single polypeptide. The STAND class consists of 14 distinct families, and the evolutionary history of most of these families is riddled with dramatic instances of lineage-specific expansion and apparent horizontal gene transfer. The STAND NTPases are most abundant in developmentally and organizationally complex prokaryotes and eukaryotes. Transfer of genes for STAND NTPases from bacteria to eukaryotes on several occasions might have played a significant role in the evolution of eukaryotic signaling systems.

Is WD 1437-008 a cataclysmic variable?

NASA Astrophysics Data System (ADS)

Shimansky, V. V.; Nurtdinova, D. N.; Borisov, N. V.; Spiridonova, O. I.

2011-10-01

Comprehensive observations of a close binary candidate WD 1437-008 are performed. The shape and amplitude of the observed brightness variations are shown to be inconsistent with the hypothesis of reflection effects, and the photometric period of the system, P phot = 0. d 2775, is found to differ from the period of spectral variations, P sp = 0. d 272060. As a result, WD 1437-008 has been preliminarily classified as a low-inclination cataclysmic variable.

Demonstration/Validation of Low Volatile Organic Compound (VOC) Chemical Agent Resistant Coating (CARC)

DTIC Science & Technology

2003-11-25

alkyd resin enamel was 14 Figure 1 -- Test Panels Before Application of WD CARC at MCB Figure 2 -- Test Panels with WD CARC Applied at MCB...WD) Chemical Agent Resistant Coating (CARC) patented (#5,691,410) by the Army Research Laboratory (ARL) has undergone technology Demonstration...Resistant Coating (CARC) patented (#5,691,410) by the Army Research Laboratory (ARL) has undergone technology Demonstration/Validation (Dem/Val) testing

The molecular genetics of von Willebrand disease.

PubMed

Berber, Ergül

2012-12-01

Quantitative and/or qualitative deficiency of von Willebrand factor (vWF) is associated with the most common inherited bleeding disease von Willebrand disease (vWD). vWD is a complex disease with clinical and genetic heterogeneity. Incomplete penetrance and variable expression due to genetic and environmental factors contribute to its complexity. vWD also has a complex molecular pathogenesis. Some vWF gene mutations are associated with the affected vWF biosynthesis and multimerization, whereas others are associated with increased clearance and functional impairment. Moreover, in addition to a particular mutation, type O blood may result in the more severe phenotype. The present review aimed to provide a summary of the current literature on the molecular genetics of vWD. None declared.

Nuclear factor erythroid-2-related factor regulates LRWD1 expression and cellular adaptation to oxidative stress in human embryonal carcinoma cells.

PubMed

Hung, Jui-Hsiang; Wee, Shi-Kae; Omar, Hany A; Su, Chia-Hui; Chen, Hsing-Yi; Chen, Pin-Shern; Chiu, Chien-Chih; Wu, Ming-Syuan; Teng, Yen-Ni

2018-05-01

Leucine-rich repeats and WD repeat domain-containing protein 1 (LRWD1) is implicated in the regulation of signal transduction, transcription, RNA processing and tumor development. However, LRWD1 transcriptional regulation is not fully understood. This study aimed to investigate the relationship between LRWD1 expression and reactive oxygen species (ROS) level in human embryonal carcinoma cell line, NT2/D1 cells, which will help in understanding the transcriptional regulatory role of ROS in cells. Results showed that the exposure of NT2/D1 cells to various concentrations of hydrogen peroxide (H 2 O 2 ) and the nitric oxide (NO) donor sodium nitroprusside (SNP) caused a significant increase in the mRNA and protein expression of LRWD1. In addition, LRWD1 promoter luciferase reporter assay, and Chromatin Immunoprecipitation assay (CHIP assay) showed that nuclear factor erythroid-2-related factor (Nrf2) was involved in the regulation of LRWD1 expression in response to oxidative stress. The involvement of Nrf2 was confirmed by shRNA-mediated knockdown of Nrf2 in NT2/D1 cells, which caused a significant decrease in LRWD1 expression in response to oxidative stress. Similarly, LRWD1 knockdown resulted in the accumulation of H 2 O 2 and superoxide anion radical (O2-). Blocking ROS production by N-acetyl cysteine (NAC) protected NT2/D1 shLRWD1cells from H 2 O 2 -induced cell death. Collectively, oxidative stress increased LRWD1 expression through a Nrf2-dependent mechanism, which plays an important role in cellular adaptation to oxidative stress. These results highlight an evidence, on the molecular level, about LRWD1 transcriptional regulation under oxidative stress. Copyright © 2018 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

The central domain of bovine submaxillary mucin consists of over 50 tandem repeats of 329 amino acids. Chromosomal localization of the BSM1 gene and relations to ovine and porcine counterparts.

PubMed

Jiang, W; Gupta, D; Gallagher, D; Davis, S; Bhavanandan, V P

2000-04-01

We previously elucidated five distinct protein domains (I-V) for bovine submaxillary mucin, which is encoded by two genes, BSM1 and BSM2. Using Southern blot analysis, genomic cloning and sequencing of the BSM1 gene, we now show that the central domain (V) consists of approximately 55 tandem repeats of 329 amino acids and that domains III-V are encoded by a 58.4-kb exon, the largest exon known for all genes to date. The BSM1 gene was mapped by fluorescence in situ hybridization to the proximal half of chromosome 5 at bands q2. 2-q2.3. The amino-acid sequence of six tandem repeats (two full and four partial) were found to have only 92-94% identities. We propose that the variability in the amino-acid sequences of the mucin tandem repeat is important for generating the combinatorial library of saccharides that are necessary for the protective function of mucins. The deduced peptide sequences of the central domain match those determined from the purified bovine submaxillary mucin and also show 68-94% identity to published peptide sequences of ovine submaxillary mucin. This indicates that the core protein of ovine submaxillary mucin is closely related to that of bovine submaxillary mucin and contains similar tandem repeats in the central domain. In contrast, the central domain of porcine submaxillary mucin is reported to consist of 81-amino-acid tandem repeats. However, both bovine submaxillary mucin and porcine submaxillary mucin contain similar N-terminal and C-terminal domains and the corresponding genes are in the conserved linkage regions of the respective genomes.

Highly sensitive detection of individual HEAT and ARM repeats with HHpred and COACH.

PubMed

Kippert, Fred; Gerloff, Dietlind L

2009-09-24

HEAT and ARM repeats occur in a large number of eukaryotic proteins. As these repeats are often highly diverged, the prediction of HEAT or ARM domains can be challenging. Except for the most clear-cut cases, identification at the individual repeat level is indispensable, in particular for determining domain boundaries. However, methods using single sequence queries do not have the sensitivity required to deal with more divergent repeats and, when applied to proteins with known structures, in some cases failed to detect a single repeat. Testing algorithms which use multiple sequence alignments as queries, we found two of them, HHpred and COACH, to detect HEAT and ARM repeats with greatly enhanced sensitivity. Calibration against experimentally determined structures suggests the use of three score classes with increasing confidence in the prediction, and prediction thresholds for each method. When we applied a new protocol using both HHpred and COACH to these structures, it detected 82% of HEAT repeats and 90% of ARM repeats, with the minimum for a given protein of 57% for HEAT repeats and 60% for ARM repeats. Application to bona fide HEAT and ARM proteins or domains indicated that similar numbers can be expected for the full complement of HEAT/ARM proteins. A systematic screen of the Protein Data Bank for false positive hits revealed their number to be low, in particular for ARM repeats. Double false positive hits for a given protein were rare for HEAT and not at all observed for ARM repeats. In combination with fold prediction and consistency checking (multiple sequence alignments, secondary structure prediction, and position analysis), repeat prediction with the new HHpred/COACH protocol dramatically improves prediction in the twilight zone of fold prediction methods, as well as the delineation of HEAT/ARM domain boundaries. A protocol is presented for the identification of individual HEAT or ARM repeats which is straightforward to implement. It provides high sensitivity at a low false positive rate and will therefore greatly enhance the accuracy of predictions of HEAT and ARM domains.

Highly Sensitive Detection of Individual HEAT and ARM Repeats with HHpred and COACH

PubMed Central

Kippert, Fred; Gerloff, Dietlind L.

2009-01-01

Background HEAT and ARM repeats occur in a large number of eukaryotic proteins. As these repeats are often highly diverged, the prediction of HEAT or ARM domains can be challenging. Except for the most clear-cut cases, identification at the individual repeat level is indispensable, in particular for determining domain boundaries. However, methods using single sequence queries do not have the sensitivity required to deal with more divergent repeats and, when applied to proteins with known structures, in some cases failed to detect a single repeat. Methodology and Principal Findings Testing algorithms which use multiple sequence alignments as queries, we found two of them, HHpred and COACH, to detect HEAT and ARM repeats with greatly enhanced sensitivity. Calibration against experimentally determined structures suggests the use of three score classes with increasing confidence in the prediction, and prediction thresholds for each method. When we applied a new protocol using both HHpred and COACH to these structures, it detected 82% of HEAT repeats and 90% of ARM repeats, with the minimum for a given protein of 57% for HEAT repeats and 60% for ARM repeats. Application to bona fide HEAT and ARM proteins or domains indicated that similar numbers can be expected for the full complement of HEAT/ARM proteins. A systematic screen of the Protein Data Bank for false positive hits revealed their number to be low, in particular for ARM repeats. Double false positive hits for a given protein were rare for HEAT and not at all observed for ARM repeats. In combination with fold prediction and consistency checking (multiple sequence alignments, secondary structure prediction, and position analysis), repeat prediction with the new HHpred/COACH protocol dramatically improves prediction in the twilight zone of fold prediction methods, as well as the delineation of HEAT/ARM domain boundaries. Significance A protocol is presented for the identification of individual HEAT or ARM repeats which is straightforward to implement. It provides high sensitivity at a low false positive rate and will therefore greatly enhance the accuracy of predictions of HEAT and ARM domains. PMID:19777061

THE URINE PROTEOME FOR RADIATION BIODOSIMETRY: EFFECT OF TOTAL BODY VERSUS LOCAL KIDNEY IRRADIATION

PubMed Central

Sharma, Mukut; Halligan, Brian D.; Wakim, Bassam T.; Savin, Virginia J.; Cohen, Eric P.; Moulder, John E.

2009-01-01

Victims of nuclear accidents or radiological terrorism are likely to receive varying doses of ionizing radiation inhomogeneously distributed over the body. Early biomarkers may be useful in determining organ-specific doses due to total body irradiation (TBI) or partial body irradiation. We used liquid chromatography and mass spectrometry to compare the effect of TBI and local kidney irradiation (LKI) on the rat urine proteome using a single 10 Gy dose of X-rays. Both TBI and LKI altered the urinary protein profile within 24 hours with noticeable differences in Gene Ontology categories. Some proteins including fetuin-B, tissue kallikrein, beta-glucuronidase, vitamin D-dependent calcium binding protein and chondroitin sulfate proteoglycan NG2 were detected only in the TBI group. Some other proteins including major urinary protein-1, RNA binding protein 19, neuron navigator, Dapper homolog 3, WD repeat and FYVE domain containing protein 3, sorting nexin-8, ankycorbin and aquaporin were detected only in the LKI group. Protease inhibitors and kidney proteins were more abundant (fraction of total scans) in the LKI group. Up/Uc ratio and urinary albumin abundance decreased in both TBI and LKI groups. Several markers of acute kidney injury were not detectable in either irradiated group. Present data indicate that abundance and number of proteins may follow opposite trends. These novel findings demonstrate intriguing differences between TBI and LKI, and suggest that urine proteome may be useful in determining organ-specific changes caused by partial body irradiation. PMID:20065682

Familial temporal lobe epilepsy with psychic auras associated with a novel LGI1 mutation.

PubMed

Striano, P; Busolin, G; Santulli, L; Leonardi, E; Coppola, A; Vitiello, L; Rigon, L; Michelucci, R; Tosatto, S C E; Striano, S; Nobile, C

2011-03-29

Autosomal dominant lateral temporal epilepsy (ADLTE) is characterized by focal seizures with auditory features or aphasia. Mutations in the LGI1 gene have been reported in up to 50% of ADLTE pedigrees. We report a family with temporal lobe epilepsy characterized by psychic symptoms associated with a novel LGI1 mutation. All participants were personally interviewed and underwent neurologic examination and video-EEG recordings. LGI1 exons were sequenced by standard methods. Mutant cDNA was transfected into human embryonic kidney 293 cells; both cell lysates and media were analyzed by Western blot. In silico modeling of the Lgi1 protein EPTP domain was carried out using the structure of WD repeat protein and manually refined. Three affected family members were ascertained, 2 of whom had temporal epilepsy with psychic symptoms (déjà vu, fear) but no auditory or aphasic phenomena, while the third had complex partial seizures without any aura. In all patients, we found a novel LGI1 mutation, Arg407Cys, which did not hamper protein secretion in vitro. Mapping of the mutation on a 3-dimensional protein model showed that this mutation does not induce large structural rearrangements but could destabilize interactions of Lgi1 with target proteins. The Arg407Cys is the first mutation with no effect on Lgi1 protein secretion. The uncommon, isolated psychic symptoms associated with it suggests that ADLTE encompasses a wider range of auras of temporal origin than hitherto reported.

Target gene analyses of 39 amelogenesis imperfecta kindreds

PubMed Central

Chan, Hui-Chen; Estrella, Ninna M. R. P.; Milkovich, Rachel N.; Kim, Jung-Wook; Simmer, James P.; Hu, Jan C-C.

2012-01-01

Previously, mutational analyses identified six disease-causing mutations in 24 amelogenesis imperfecta (AI) kindreds. We have since expanded the number of AI kindreds to 39, and performed mutation analyses covering the coding exons and adjoining intron sequences for the six proven AI candidate genes [amelogenin (AMELX), enamelin (ENAM), family with sequence similarity 83, member H (FAM83H), WD repeat containing domain 72 (WDR72), enamelysin (MMP20), and kallikrein-related peptidase 4 (KLK4)] and for ameloblastin (AMBN) (a suspected candidate gene). All four of the X-linked AI families (100%) had disease-causing mutations in AMELX, suggesting that AMELX is the only gene involved in the aetiology of X-linked AI. Eighteen families showed an autosomal-dominant pattern of inheritance. Disease-causing mutations were identified in 12 (67%): eight in FAM83H, and four in ENAM. No FAM83H coding-region or splice-junction mutations were identified in three probands with autosomal-dominant hypocalcification AI (ADHCAI), suggesting that a second gene may contribute to the aetiology of ADHCAI. Six families showed an autosomal-recessive pattern of inheritance, and disease-causing mutations were identified in three (50%): two in MMP20, and one in WDR72. No disease-causing mutations were found in 11 families with only one affected member. We conclude that mutation analyses of the current candidate genes for AI have about a 50% chance of identifying the disease-causing mutation in a given kindred. PMID:22243262

The urine proteome for radiation biodosimetry: effect of total body vs. local kidney irradiation.

PubMed

Sharma, Mukut; Halligan, Brian D; Wakim, Bassam T; Savin, Virginia J; Cohen, Eric P; Moulder, John E

2010-02-01

Victims of nuclear accidents or radiological terrorism are likely to receive varying doses of ionizing radiation inhomogeneously distributed over the body. Early biomarkers may be useful in determining organ-specific doses due to total body irradiation (TBI) or partial body irradiation. The authors used liquid chromatography and mass spectrometry to compare the effect of TBI and local kidney irradiation (LKI) on the rat urine proteome using a single 10-Gy dose of x-rays. Both TBI and LKI altered the urinary protein profile within 24 h with noticeable differences in gene ontology categories. Some proteins, including fetuin-B, tissue kallikrein, beta-glucuronidase, vitamin D-dependent calcium binding protein and chondroitin sulfate proteoglycan NG2, were detected only in the TBI group. Some other proteins, including major urinary protein-1, RNA binding protein 19, neuron navigator, Dapper homolog 3, WD repeat and FYVE domain containing protein 3, sorting nexin-8, ankycorbin and aquaporin were detected only in the LKI group. Protease inhibitors and kidney proteins were more abundant (fraction of total scans) in the LKI group. Urine protein (Up) and creatinine (Uc) (Up/Uc) ratios and urinary albumin abundance decreased in both TBI and LKI groups. Several markers of acute kidney injury were not detectable in either irradiated group. Present data indicate that abundance and number of proteins may follow opposite trends. These novel findings demonstrate intriguing differences between TBI and LKI, and suggest that urine proteome may be useful in determining organ-specific changes caused by partial body irradiation.

Impaired gait pattern as a sensitive tool to assess hypoxic brain damage in a novel mouse model of atherosclerotic plaque rupture.

PubMed

Roth, Lynn; Van Dam, Debby; Van der Donckt, Carole; Schrijvers, Dorien M; Lemmens, Katrien; Van Brussel, Ilse; De Deyn, Peter P; Martinet, Wim; De Meyer, Guido R Y

2015-02-01

Apolipoprotein E deficient (ApoE(-/-)) mice with a heterozygous mutation in the fibrillin-1 gene (Fbn1(C1039G+/-)) show spontaneous atherosclerotic plaque ruptures, disturbances in cerebral flow and sudden death when fed a Western-type diet (WD). The present study focused on motor coordination and spatial learning of ApoE(-/-) Fbn1(C1039G+/-) mice on WD for 20 weeks (n=21). ApoE(-/-) mice on WD (n=24) and ApoE(-/-) Fbn1(C1039G+/-) mice on normal diet (ND, n=21) served as controls. Starting from 10 weeks of diet, coordination was assessed every two weeks by the following tests: gait analysis, stationary beam, wire suspension and accelerating rotarod. The Morris water maze test was performed after 13 weeks of diet to study spatial learning. At the end of the experiment (20 weeks of WD), the mice were sacrificed and the brachiocephalic artery and brain were isolated. From 12 weeks onward, gait analysis of ApoE(-/-) Fbn1(C1039G+/-) mice on WD revealed a progressive increase in track width as compared to ApoE(-/-) mice on WD and ApoE(-/-) Fbn1(C1039G+/-) mice on ND (at 20 weeks: 29.8±0.6 mm vs. 25.8±0.4 mm and 26.0±0.5 mm). Moreover, the stationary beam test showed a decrease in motor coordination of ApoE(-/-) Fbn1(C1039G+/-) mice on WD at 18 and 20 weeks. The wire suspension test and accelerating rotarod could not detect signs of motor impairment. Spatial learning was also not affected. Histological analysis of the brachiocephalic artery showed larger and more stenotic plaques in ApoE(-/-) Fbn1(C1039G+/-) mice on WD. Furthermore, the parietal cortex of ApoE(-/-) Fbn1(C1039G+/-) mice on WD showed pyknotic nuclei as a sign of hypoxia and the percentage of pyknosis correlated with track width. In conclusion, gait analysis may be an efficient method for analyzing hypoxic brain damage in the ApoE(-/-) Fbn1(C1039G+/-) mouse model. This test could be of value to assess the effect of potential anti-atherosclerotic therapies in mice. Copyright © 2014 Elsevier Inc. All rights reserved.

Peripheral endocannabinoid signaling controls hyperphagia in western diet-induced obesity

PubMed Central

Argueta, Donovan A.; DiPatrizio, Nicholas V.

2017-01-01

The endocannabinoid system in the brain and periphery plays a major role in controlling food intake and energy balance. We reported that tasting dietary fats was met with increased levels of the endocannabinoids, 2-arachidonoyl-sn-glycerol (2-AG) and anandamide, in the rat upper small intestine, and pharmacological inhibition of this local signaling event dose-dependently blocked sham feeding of fats. We now investigated the contribution of peripheral endocannabinoid signaling in hyperphagia associated with chronic consumption of a western-style diet in mice ([WD] i.e., high fat and sucrose). Feeding patterns were assessed in male C57BL/6Tac mice maintained for 60 days on WD or a standard rodent chow (SD), and the role for peripheral endocannabinoid signaling at CB1Rs in controlling food intake was investigated via pharmacological interventions. In addition, levels of the endocannabinoids, 2-AG and anandamide, in the upper small intestine and circulation of mice were analyzed via liquid chromatography coupled to tandem mass spectrometry to evaluate diet-related changes in endocannabinoid signaling and the potential impact on food intake. Mice fed WD for 60 days exhibited large increases in body weight, daily caloric intake, average meal size, and rate of feeding when compared to control mice fed SD. Inhibiting peripheral CB1Rs with the peripherally-restricted neutral cannabinoid CB1 receptor antagonist, AM6545 (10mg/kg), significantly reduced intake of WD during a 6 h test, but failed to modify intake of SD in mice. AM6545 normalized intake of WD, average meal size, and rate of feeding to levels found in SD control mice. These results suggest that endogenous activity at peripheral CB1Rs in WD mice is critical for driving hyperphagia. In support of this hypothesis, levels of 2-AG and anandamide in both, jejunum mucosa and plasma, of ad-libitum fed WD mice increased when compared to SC mice. Furthermore, expression of genes for primary components of the endocannabinoid system (i.e., cannabinoid receptors, and endocannabinoid biosynthetic and degradative enzymes) was dysregulated in WD mice when compared to SC mice. Our results suggest that hyperphagia associated with WD-induced obesity is driven by enhanced endocannabinoid signaling at peripheral CB1Rs. PMID:28065722

Peripheral endocannabinoid signaling controls hyperphagia in western diet-induced obesity.

PubMed

Argueta, Donovan A; DiPatrizio, Nicholas V

2017-03-15

The endocannabinoid system in the brain and periphery plays a major role in controlling food intake and energy balance. We reported that tasting dietary fats was met with increased levels of the endocannabinoids, 2-arachidonoyl-sn-glycerol (2-AG) and anandamide, in the rat upper small intestine, and pharmacological inhibition of this local signaling event dose-dependently blocked sham feeding of fats. We now investigated the contribution of peripheral endocannabinoid signaling in hyperphagia associated with chronic consumption of a western-style diet in mice ([WD] i.e., high fat and sucrose). Feeding patterns were assessed in male C57BL/6Tac mice maintained for 60days on WD or a standard rodent chow (SD), and the role for peripheral endocannabinoid signaling at CB 1 Rs in controlling food intake was investigated via pharmacological interventions. In addition, levels of the endocannabinoids, 2-AG and anandamide, in the upper small intestine and circulation of mice were analyzed via liquid chromatography coupled to tandem mass spectrometry to evaluate diet-related changes in endocannabinoid signaling and the potential impact on food intake. Mice fed WD for 60days exhibited large increases in body weight, daily caloric intake, average meal size, and rate of feeding when compared to control mice fed SD. Inhibiting peripheral CB 1 Rs with the peripherally-restricted neutral cannabinoid CB 1 receptor antagonist, AM6545 (10mg/kg), significantly reduced intake of WD during a 6h test, but failed to modify intake of SD in mice. AM6545 normalized intake of WD, average meal size, and rate of feeding to levels found in SD control mice. These results suggest that endogenous activity at peripheral CB 1 Rs in WD mice is critical for driving hyperphagia. In support of this hypothesis, levels of 2-AG and anandamide in both, jejunum mucosa and plasma, of ad-libitum fed WD mice increased when compared to SC mice. Furthermore, expression of genes for primary components of the endocannabinoid system (i.e., cannabinoid receptors, and endocannabinoid biosynthetic and degradative enzymes) was dysregulated in WD mice when compared to SC mice. Our results suggest that hyperphagia associated with WD-induced obesity is driven by enhanced endocannabinoid signaling at peripheral CB 1 Rs. Copyright © 2017 Elsevier Inc. All rights reserved.

Roles of CUB and LDL receptor class A domain repeats of a transmembrane serine protease matriptase in its zymogen activation

PubMed Central

Inouye, Kuniyo; Tomoishi, Marie; Yasumoto, Makoto; Miyake, Yuka; Kojima, Kenji; Tsuzuki, Satoshi; Fushiki, Tohru

2013-01-01

Matriptase is a type II transmembrane serine protease containing two complement proteases C1r/C1s–urchin embryonic growth factor–bone morphogenetic protein domains (CUB repeat) and four low-density lipoprotein receptor class A domains (LDLRA repeat). The single-chain zymogen of matriptase has been found to exhibit substantial protease activity, possibly causing its own activation (i.e. conversion to a disulfide-linked two-chain fully active form), although the activation seems to be mediated predominantly by two-chain molecules. Our aim was to assess the roles of CUB and LDLRA repeats in zymogen activation. Transient expression studies of soluble truncated constructs of recombinant matriptase in COS-1 cells showed that the CUB repeat had an inhibitory effect on zymogen activation, possibly because it facilitated the interaction of two-chain molecules with a matriptase inhibitor, hepatocyte growth factor activator inhibitor type-1. By contrast, the LDLRA repeat had a promoting effect on zymogen activation. The effect of the LDLRA repeat seems to reflect its ability to increase zymogen activity. The proteolytic activities were higher in pseudozymogen forms of recombinant matriptase containing the LDLRA repeat than in a pseudozymogen without the repeat. Our findings provide new insights into the roles of these non-catalytic domains in the generation of active matriptase. PMID:23038671

On the resonant detonation of sub-Chandrasekhar mass white dwarfs during binary inspiral

NASA Astrophysics Data System (ADS)

McKernan, B.; Ford, K. E. S.

2016-12-01

White dwarfs (WDs) are believed to detonate via explosive Carbon-fusion in a Type Ia supernova (SN) when their temperature and/or density reach the point where Carbon is ignited in a runaway reaction. Observations of the Type Ia SN rate imply that all WD binaries that merge through the emission of gravitational radiation within a Hubble time should result in SNe, regardless of total mass. Here we investigate the conditions under which a single WD in a binary system might extract energy from its orbit, depositing enough energy into a resonant mode such that it detonates before merger. We show that, ignoring non-linear effects in a WD binary in tidal lock at small binary separations, the sustained tidal forcing of a low-order quadrupolar g mode or a harmonic of a low-order quadrupolar p mode could, in principle, drive the average temperature of Carbon nuclei in the mode over the runaway fusion threshold. If growing mode energy is thermalized at a core/atmosphere boundary, rapid Helium burning and inwards-travelling p-waves may result in core detonation. Thermalization at a boundary in the core can also result in detonation. If energy can be efficiently transferred from the orbit to modes as the WD binary passes through resonances, the WD merger time-scale will be shortened by Myr-Gyr compared to expected time-scales from gravitational wave (GW)-emission alone and GW detectors will observe deviations from predicted chirp profiles in resolved WD binaries. Future work in this area should focus on whether tidal locking in WD binaries is naturally driven towards low-order mode frequencies.

Using Close White Dwarf + M Dwarf Stellar Pairs to Constrain the Flare Rates in Close Stellar Binaries

NASA Astrophysics Data System (ADS)

Morgan, Dylan P.; West, Andrew A.; Becker, Andrew C.

2016-05-01

We present a study of the statistical flare rates of M dwarfs (dMs) with close white dwarf (WD) companions (WD+dM; typical separations <1 au). Our previous analysis demonstrated that dMs with close WD companions are more magnetically active than their field counterparts. One likely implication of having a close binary companion is increased stellar rotation through disk-disruption, tidal effects, and/or angular momentum exchange; increased stellar rotation has long been associated with an increase in stellar activity. Previous studies show a strong correlation between dMs that are magnetically active (showing Hα in emission) and the frequency of stellar flare rates. We examine the difference between the flare rates observed in close WD+dM binary systems and field dMs. Our sample consists of a subset of 181 close WD+dM pairs from Morgan et al. observed in the Sloan Digital Sky Survey Stripe 82, where we obtain multi-epoch observations in the Sloan ugriz-bands. We find an increase in the overall flaring fraction in the close WD+dM pairs (0.09 ± 0.03%) compared to the field dMs (0.0108 ± 0.0007%) and a lower flaring fraction for active WD+dMs (0.05 ± 0.03%) compared to active dMs (0.28 ± 0.05%). We discuss how our results constrain both the single and binary dM flare rates. Our results also constrain dM multiplicity, our knowledge of the Galactic transient background, and may be important for the habitability of attending planets around dMs with close companions.

Fast and Luminous Transients from the Explosions of Long-lived Massive White Dwarf Merger Remnants

NASA Astrophysics Data System (ADS)

Brooks, Jared; Schwab, Josiah; Bildsten, Lars; Quataert, Eliot; Paxton, Bill; Blinnikov, Sergei; Sorokina, Elena

2017-12-01

We study the evolution and final outcome of long-lived (≈ {10}5 years) remnants from the merger of an He white dwarf (WD) with a more massive C/O or O/Ne WD. Using Modules for Experiments in Stellar Astrophysics ({\\mathtt{MESA}}), we show that these remnants have a red giant configuration supported by steady helium burning, adding mass to the WD core until it reaches {M}{core}≈ 1.12{--}1.20 {M}⊙ . At that point, the base of the surface convection zone extends into the burning layer, mixing the helium-burning products (primarily carbon and magnesium) throughout the convective envelope. Further evolution depletes the convective envelope of helium and dramatically slows the mass increase of the underlying WD core. The WD core mass growth re-initiates after helium depletion, as then an uncoupled carbon-burning shell is ignited and proceeds to burn the fuel from the remaining metal-rich extended envelope. For large enough initial total merger masses, O/Ne WD cores would experience electron-capture triggered collapse to neutron stars (NSs) after growing to near Chandrasekhar mass ({M}{Ch}). Massive C/O WD cores could suffer the same fate after a carbon-burning flame converts them to ONe. The NS formation would release ≈ {10}50 erg into the remaining extended low mass envelope. Using the STELLA radiative transfer code, we predict the resulting optical light curves from these exploded envelopes. Reaching absolute magnitudes of {M}V≈ -17, these transients are bright for about one week and have many features of the class of luminous, rapidly evolving transients studied by Drout and collaborators.

Fish oil alleviated high-fat diet-induced non-alcoholic fatty liver disease via regulating hepatic lipids metabolism and metaflammation: a transcriptomic study.

PubMed

Yuan, Fahu; Wang, Hualin; Tian, Yu; Li, Qi; He, Lei; Li, Na; Liu, Zhiguo

2016-02-01

Intake of fish oil rich in n-3 polyunsaturated fatty acids (PUFAs) is believed to be beneficial against development of non-alcoholic fatty liver disease (NAFLD). However, the underlying mechanisms remain unclear. This study was to gain further understanding of the potential mechanisms of the protective effects of fish oil against NAFLD. Ten male Sprague-Dawley rats were fed a control diet (CON), a Western style high-fat and high-cholesterol diet (WD), or a WD diet containing fish oil (FOH) for 16 weeks respectively. The development of liver steatosis and fibrosis were verified by histological and biochemical examination. Hepatic transcriptome were extracted for RNA-seq analysis, and particular results were confirmed by real-time polymerase chain reaction (PCR). The consumption of fish oil significantly ameliorated WD-induced dyslipidemia, transaminase elevation, hepatic steatosis, inflammatory infiltration, and fibrosis. Hepatic RNA-Seq analysis showed that long-term intake of fish oil restored the expression of circadian clock-related genes per2 and per3, which were reduced in WD fed animals. Fish oil consumption also corrected the expression levels of genes involved in fatty acid and cholesterol metabolism, such as Srebf1, Fasn, Scd1, Insig2, Cd36, Cyp7a1, Abcg5, Abcg8 and Pcsk9. Moreover, the expression levels of pro-inflammation genes Mcp1, Socs2, Sema4a, and Cd44 in the FOH group were lower than that of WD group, implying that fish oil protects the liver against WD-induced hepatic inflammation. The present study demonstrates fish oil protects against WD-induced NALFD via improving lipid metabolism and ameliorating hepatic inflammation. Our findings add to the current understanding on the benefits of n-3 PUFAs against NAFLD.

Western High-Fat Diet Consumption during Adolescence Increases Susceptibility to Traumatic Stress while Selectively Disrupting Hippocampal and Ventricular Volumes

PubMed Central

Kalyan-Masih, Priya; Vega-Torres, Julio David; Haddad, Elizabeth; Rainsbury, Sabrina; Baghchechi, Mohsen

2016-01-01

Abstract Psychological trauma and obesity co-occur frequently and have been identified as major risk factors for psychiatric disorders. Surprisingly, preclinical studies examining how obesity disrupts the ability of the brain to cope with psychological trauma are lacking. The objective of this study was to determine whether an obesogenic Western-like high-fat diet (WD) predisposes rats to post-traumatic stress responsivity. Adolescent Lewis rats (postnatal day 28) were fed ad libitum for 8 weeks with either the experimental WD diet (41.4% kcal from fat) or the control diet (16.5% kcal from fat). We modeled psychological trauma by exposing young adult rats to a cat odor threat. The elevated plus maze and the open field test revealed increased psychological trauma-induced anxiety-like behaviors in the rats that consumed the WD when compared with control animals 1 week after undergoing traumatic stress (p < 0.05). Magnetic resonance imaging showed significant hippocampal atrophy (20% reduction) and lateral ventricular enlargement (50% increase) in the animals fed the WD when compared with controls. These volumetric abnormalities were associated with behavioral indices of anxiety, increased leptin and FK506-binding protein 51 (FKBP51) levels, and reduced hippocampal blood vessel density. We found asymmetric structural vulnerabilities to the WD, particularly the ventral and left hippocampus and lateral ventricle. This study highlights how WD consumption during adolescence impacts key substrates implicated in post-traumatic stress disorder. Understanding how consumption of a WD affects the developmental trajectories of the stress neurocircuitry is critical, as stress susceptibility imposes a marked vulnerability to neuropsychiatric disorders. PMID:27844058

Transcriptional Profiling of Foam Cells Reveals Induction of Guanylate-Binding Proteins Following Western Diet Acceleration of Atherosclerosis in the Absence of Global Changes in Inflammation.

PubMed

Goo, Young-Hwa; Son, Se-Hee; Yechoor, Vijay K; Paul, Antoni

2016-04-18

Foam cells are central to two major pathogenic processes in atherogenesis: cholesterol buildup in arteries and inflammation. The main underlying cause of cholesterol deposition in arteries is hypercholesterolemia. This study aimed to assess, in vivo, whether elevated plasma cholesterol also alters the inflammatory balance of foam cells. Apolipoprotein E-deficient mice were fed regular mouse chow through the study or were switched to a Western-type diet (WD) 2 or 14 weeks before death. Consecutive sections of the aortic sinus were used for lesion quantification or to isolate RNA from foam cells by laser-capture microdissection (LCM) for microarray and quantitative polymerase chain reaction analyses. WD feeding for 2 or 14 weeks significantly increased plasma cholesterol, but the size of atherosclerotic lesions increased only in the 14-week WD group. Expression of more genes was affected in foam cells of mice under prolonged hypercholesterolemia than in mice fed WD for 2 weeks. However, most transcripts coding for inflammatory mediators remained unchanged in both WD groups. Among the main players in inflammatory or immune responses, chemokine (C-X-C motif) ligand 13 was induced in foam cells of mice under WD for 2 weeks. The interferon-inducible GTPases, guanylate-binding proteins (GBP)3 and GBP6, were induced in the 14-week WD group, and other GBP family members were moderately increased. Our results indicate that acceleration of atherosclerosis by hypercholesterolemia is not linked to global changes in the inflammatory balance of foam cells. However, induction of GBPs uncovers a novel family of immune modulators with a potential role in atherogenesis. © 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Western-diet consumption induces alteration of barrier function mechanisms in the ileum that correlates with metabolic endotoxemia in rats.

PubMed

Guerville, Mathilde; Leroy, Anaïs; Sinquin, Annaëlle; Laugerette, Fabienne; Michalski, Marie-Caroline; Boudry, Gaëlle

2017-08-01

Obesity and its related disorders have been associated with the presence in the blood of gut bacteria-derived lipopolysaccharides (LPS). However, the factors underlying this low-grade elevation in plasma LPS, so-called metabolic endotoxemia, are not fully elucidated. We aimed to investigate the effects of Western diet (WD) feeding on intestinal and hepatic LPS handling mechanisms in a rat model of diet-induced obesity (DIO). Rats were fed either a standard chow diet (C) or a Western Diet (WD, 45% fat) for 6 wk. They were either fed ad libitum or pair-fed to match the caloric intake of C rats for the first week, then fed ad libitum for the remaining 5 wk. Six-week WD feeding led to a mild obese phenotype with increased adiposity and elevated serum LPS-binding protein (LBP) levels relative to C rats, irrespective of initial energy intake. Serum LPS was not different between dietary groups but exhibited strong variability. Disrupted ileal mucus secretion and decreased ileal Reg3-γ and -β gene expression along with high ileal permeability to LPS were observed in WD compared with C-fed rats. Ileal and cecal intestinal alkaline phosphatase (IAP) activity as well as Verrucomicrobia and Bifidobacterium cecal levels were increased in WD-fed rats compared with C-fed rats. WD consumption did not impact mRNA levels of LPS-handling hepatic enzymes. Correlation analysis revealed that ileal passage of LPS, IAP activity, Proteobacteria levels and hepatic aoah gene expression correlated with serum LPS and LBP, suggesting that ileal mucosal defense impairment induced by WD feeding contribute to metabolic endotoxemia. Copyright © 2017 the American Physiological Society.

Hepatic inflammation caused by dysregulated bile acid synthesis is reversible by butyrate supplementation.

PubMed

Sheng, Lili; Jena, Prasant Kumar; Hu, Ying; Liu, Hui-Xin; Nagar, Nidhi; Kalanetra, Karen M; French, Samuel William; French, Samuel Wheeler; Mills, David A; Wan, Yu-Jui Yvonne

2017-12-01

Dysregulated bile acid (BA) synthesis or reduced farnesoid X receptor (FXR) levels are found in patients having metabolic diseases, autoimmune hepatitis, and liver cirrhosis or cancer. The objective of this study was to establish the relationship between butyrate and dysregulated BA synthesis-induced hepatitis as well as the effect of butyrate in reversing the liver pathology. Wild-type (WT) and FXR knockout (KO) male mice were placed on a control (CD) or western diet (WD) for 15 months. In the presence or absence of butyrate supplementation, feces obtained from 15-month-old WD-fed FXR KO mice, which had severe hepatitis and liver tumors, were transplanted to 7-month-old WD-fed FXR KO for 3 months. Hepatic phenotypes, microbiota profile, and BA composition were analyzed. Butyrate-generating bacteria and colonic butyrate concentration were reduced due to FXR inactivation and further reduced by WD intake. In addition, WD-fed FXR KO male mice had the highest concentration of hepatic β-muricholic acid (β-MCA) and bacteria-generated deoxycholic acid (DCA) accompanied by serious hepatitis. Moreover, dysregulated BA and reduced SCFA signaling co-existed in both human liver cancers and WD-fed FXR KO mice. Microbiota transplantation using butyrate-deficient feces derived from 15-month-old WD-fed FXR KO mice increased hepatic lymphocyte numbers as well as hepatic β-MCA and DCA concentrations. Furthermore, butyrate supplementation reduced hepatic β-MCA as well as DCA and eliminated hepatic lymphocyte infiltration. In conclusion, reduced butyrate contributes to the development of hepatitis in the FXR KO mouse model. In addition, butyrate reverses dysregulated BA synthesis and its associated hepatitis. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

IMPLICATIONS FOR THE FORMATION OF BLUE STRAGGLER STARS FROM HST ULTRAVIOLET OBSERVATIONS OF NGC 188

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

Gosnell, Natalie M.; Mathieu, Robert D.; Geller, Aaron M.

We present results of a Hubble Space Telescope (HST) far-ultraviolet (FUV) survey searching for white dwarf (WD) companions to blue straggler stars (BSSs) in open cluster NGC 188. The majority of NGC 188 BSSs (15 of 21) are single-lined binaries with properties suggestive of mass-transfer formation via Roche lobe overflow, specifically through an asymptotic giant branch star transferring mass to a main sequence secondary, yielding a BSS binary with a WD companion. In NGC 188, a BSS formed by this mechanism within the past 400 Myr will have a WD companion that is hot and luminous enough to be directlymore » detected as a FUV photometric excess with HST. Comparing expected BSS FUV emission to observed photometry reveals four BSSs with WD companions above 12,000 K (younger than 250 Myr) and three WD companions with temperatures between 11,000 and 12,000 K. These BSS+WD binaries all formed through recent mass transfer. The location of the young BSSs in an optical color–magnitude diagram (CMD) indicates that distance from the zero-age main sequence does not necessarily correlate with BSS age. There is no clear CMD separation between mass transfer-formed BSSs and those likely formed through other mechanisms, such as collisions. The seven detected WD companions place a lower limit on the mass-transfer formation frequency of 33%. We consider other possible formation mechanisms by comparing properties of the BSS population to theoretical predictions. We conclude that 14 BSS binaries likely formed from mass transfer, resulting in an inferred mass-transfer formation frequency of approximately 67%.« less

Effects of disrupting the polyketide synthase gene WdPKS1 in Wangiella [Exophiala] dermatitidis on melanin production and resistance to killing by antifungal compounds, enzymatic degradation, and extremes in temperature

PubMed Central

Paolo, William F; Dadachova, Ekaterina; Mandal, Piyali; Casadevall, Arturo; Szaniszlo, Paul J; Nosanchuk, Joshua D

2006-01-01

Background Wangiella dermatitidis is a human pathogenic fungus that is an etiologic agent of phaeohyphomycosis. W. dermatitidis produces a black pigment that has been identified as a dihydroxynaphthalene melanin and the production of this pigment is associated with its virulence. Cell wall pigmentation in W. dermatitidis depends on the WdPKS1 gene, which encodes a polyketide synthase required for generating the key precursor for dihydroxynaphthalene melanin biosynthesis. Results We analyzed the effects of disrupting WdPKS1 on dihydroxynaphthalene melanin production and resistance to antifungal compounds. Transmission electron microscopy revealed that wdpks1Δ-1 yeast had thinner cell walls that lacked an electron-opaque layer compared to wild-type cells. However, digestion of the wdpks1Δ-1 yeast revealed small black particles that were consistent with a melanin-like compound, because they were acid-resistant, reacted with melanin-binding antibody, and demonstrated a free radical signature by electron spin resonance analysis. Despite lacking the WdPKS1 gene, the mutant yeast were capable of catalyzing the formation of melanin from L-3,4-dihyroxyphenylalanine. The wdpks1Δ-1 cells were significantly more susceptible to killing by voriconazole, amphotericin B, NP-1 [a microbicidal peptide], heat and cold, and lysing enzymes than the heavily melanized parental or complemented strains. Conclusion In summary, W. dermatitidis makes WdPKS-dependent and -independent melanins, and the WdPKS1-dependent deposition of melanin in the cell wall confers protection against antifungal agents and environmental stresses. The biological role of the WdPKS-independent melanin remains unclear. PMID:16784529

Environmental Conditions Affect Botrytis cinerea Infection of Mature Grape Berries More Than the Strain or Transposon Genotype.

PubMed

Ciliberti, Nicola; Fermaud, Marc; Roudet, Jean; Rossi, Vittorio

2015-08-01

Effects of environment, Botrytis cinerea strain, and their interaction on the infection of mature grape berries were investigated. The combined effect of temperature (T) of 15, 20, 25, and 30°C and relative humidity (RH) of 65, 80, 90, and 100% was studied by inoculating berries with mycelium plugs. Regardless of the T, no disease occurred at 65% RH, and both disease incidence and severity increased with increasing RH. The combined effect of T (5 to 30°C) and wetness duration (WD) of 3, 6, 12, 24, and 36 h was studied by inoculating berries with conidia. At WD of 36 h, disease incidence was approximately 75% of affected berries at 20 or 25°C, 50% at 15°C, and 30 to 20% at 30 and 10°C; no infection occurred at 5°C. Under favorable conditions (100% RH or 36 h of WD) and unfavorable conditions (65% RH or 3 h of WD), berry wounding did not significantly affect disease incidence; under moderately favorable conditions (80% RH or 6 to 12 h of WD), disease incidence was approximately 1.5 to 5 times higher in wounded than in intact berries. Our data collectively showed that (i) T and RH or WD were more important than strain for mature berry infection by either mycelium or conidia and (ii) the effect of the environment on the different strains was similar. Two equations were developed describing the combined effect of T and RH, or T and WD, on disease incidence following inoculation by mycelium (R2=0.99) or conidia (R2=0.96), respectively. These equations may be useful in the development of models used to predict and control Botrytis bunch rot during berry ripening.

The Sodium-Glucose Cotransporter 2 Inhibitor Dapagliflozin Prevents Renal and Liver Disease in Western Diet Induced Obesity Mice

PubMed Central

Wang, Dong; Luo, Yuhuan; Wang, Xiaoxin; Orlicky, David J.; Myakala, Komuraiah; Yang, Pengyuan; Levi, Moshe

2018-01-01

Obesity and obesity related kidney and liver disease have become more prevalent over the past few decades, especially in the western world. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a new class of antidiabetic agents with promising effects on cardiovascular and renal function. Given SGLT2 inhibitors exert both anti-diabetic and anti-obesity effects by promoting urinary excretion of glucose and subsequent caloric loss, we investigated the effect of the highly selective renal SGLT2 inhibitor dapagliflozin in mice with Western diet (WD) induced obesity. Low fat (LF) diet or WD-fed male C57BL/6J mice were treated with dapagliflozin for 26 weeks. Dapagliflozin attenuated the WD-mediated increases in body weight, plasma glucose and plasma triglycerides. Treatment with dapagliflozin prevented podocyte injury, glomerular pathology and renal fibrosis determined by second harmonic generation (SHG), nephrin, synaptopodin, collagen IV, and fibronectin immunofluorescence microscopy. Oil Red O staining showed dapagliflozin also decreased renal lipid accumulation associated with decreased SREBP-1c mRNA abundance. Moreover, renal inflammation and oxidative stress were lower in the dapagliflozin-treated WD-fed mice than in the untreated WD-fed mice. In addition, dapagliflozin decreased serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), hepatic lipid accumulation as determined by H&E and Oil Red O staining, and Coherent Anti-Stokes Raman Scattering (CARS) microscopy, and hepatic fibrosis as determined by picrosirius red (PSR) staining and TPE-SHG microscopy in WD-fed mice. Thus, our study demonstrated that the co-administration of the SGLT2 inhibitor dapagliflozin attenuates renal and liver disease during WD feeding of mice. PMID:29301371

The Sodium-Glucose Cotransporter 2 Inhibitor Dapagliflozin Prevents Renal and Liver Disease in Western Diet Induced Obesity Mice.

PubMed

Wang, Dong; Luo, Yuhuan; Wang, Xiaoxin; Orlicky, David J; Myakala, Komuraiah; Yang, Pengyuan; Levi, Moshe

2018-01-03

Obesity and obesity related kidney and liver disease have become more prevalent over the past few decades, especially in the western world. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a new class of antidiabetic agents with promising effects on cardiovascular and renal function. Given SGLT2 inhibitors exert both anti-diabetic and anti-obesity effects by promoting urinary excretion of glucose and subsequent caloric loss, we investigated the effect of the highly selective renal SGLT2 inhibitor dapagliflozin in mice with Western diet (WD) induced obesity. Low fat (LF) diet or WD-fed male C57BL/6J mice were treated with dapagliflozin for 26 weeks. Dapagliflozin attenuated the WD-mediated increases in body weight, plasma glucose and plasma triglycerides. Treatment with dapagliflozin prevented podocyte injury, glomerular pathology and renal fibrosis determined by second harmonic generation (SHG), nephrin, synaptopodin, collagen IV, and fibronectin immunofluorescence microscopy. Oil Red O staining showed dapagliflozin also decreased renal lipid accumulation associated with decreased SREBP-1c mRNA abundance. Moreover, renal inflammation and oxidative stress were lower in the dapagliflozin-treated WD-fed mice than in the untreated WD-fed mice. In addition, dapagliflozin decreased serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), hepatic lipid accumulation as determined by H&E and Oil Red O staining, and Coherent Anti-Stokes Raman Scattering (CARS) microscopy, and hepatic fibrosis as determined by picrosirius red (PSR) staining and TPE-SHG microscopy in WD-fed mice. Thus, our study demonstrated that the co-administration of the SGLT2 inhibitor dapagliflozin attenuates renal and liver disease during WD feeding of mice.

Dyadic Concordance in Mother and Preschooler Resting Cardiovascular Function Varies by Risk Status

PubMed Central

Skowron, Elizabeth A.; Hughes, Brian M.; Howard, Siobhán; Loken, Eric

2014-01-01

This study examined concordance in heart rate (HR) and respiratory sinus arrhythmia (RSA) in a sample of 104 child-maltreating (CM) and nonCM mother–preschooler dyads (208 individuals). In a laboratory setting, mother and child cardiac physiology was simultaneously monitored via ECG in a 5-min resting period. Mothers ranged in age from 20 to 49 years; children ranged in age from 3 to 5 years. Significant within-dyad (WD) and between-dyad (BD) associations were observed for mother HR and both child HR and RSA, and the associations were moderated by CM status. Only CM dyads exhibited BD associations: Higher average maternal HR was associated with higher child HR and lower child RSA. By contrast, when the time interval was divided into 30 s epochs, nonCM dyads exhibited positive WD (dynamic) associations in mother and child HR, and both CM and nonCM dyads showed negative WD associations in mother HR and child RSA. Further, mothers’ mean HR levels moderated the extent of epoch-by-epoch WD concordance observed in mother and child, such that elevated average maternal HR was associated with lower levels of WD (dynamic) concordance. No BD or WD concordance in maternal and child RSA was observed. The findings suggest that measures of intraindividual variation provide useful, alternate perspectives in the study of dyadic processes in at-risk families. PMID:24022469

Western Diet-Induced Dysbiosis in Farnesoid X Receptor Knockout Mice Causes Persistent Hepatic Inflammation after Antibiotic Treatment.

PubMed

Jena, Prasant K; Sheng, Lili; Liu, Hui-Xin; Kalanetra, Karen M; Mirsoian, Annie; Murphy, William J; French, Samuel W; Krishnan, Viswanathan V; Mills, David A; Wan, Yu-Jui Yvonne

2017-08-01

Patients who have liver cirrhosis and liver cancer also have reduced farnesoid X receptor (FXR). The current study analyzes the effect of diet through microbiota that affect hepatic inflammation in FXR knockout (KO) mice. Wild-type and FXR KO mice were on a control (CD) or Western diet (WD) for 10 months. In addition, both CD- and WD-fed FXR KO male mice, which had hepatic lymphocyte and neutrophil infiltration, were treated by vancomycin, polymyxin B, and Abx (ampicillin, neomycin, metronidazole, and vancomycin). Mice were subjected to morphological analysis as well as gut microbiota and bile acid profiling. Male WD-fed FXR KO mice had the most severe steatohepatitis. FXR KO also had reduced Firmicutes and increased Proteobacteria, which could be reversed by Abx. In addition, Abx eliminated hepatic neutrophils and lymphocytes in CD-fed, but not WD-fed, FXR KO mice. Proteobacteria and Bacteroidetes persisted in WD-fed FXR KO mice even after Abx treatment. Only polymyxin B could reduce hepatic lymphocytes in WD-fed FXR KO mice. The reduced hepatic inflammation by antibiotics was accompanied by decreased free and conjugated secondary bile acids as well as changes in gut microbiota. Our data revealed that Lactococcus, Lactobacillus, and Coprococcus protect the liver from inflammation. Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Molecular pathology and haplotype analysis of Wilson disease in Mediterranean populations

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

Figus, A.; Farcia, A.M.G.; Nurchi, A.

1995-12-01

We analyzed mutations and defined the chromosomal haplotype in 127 patients of Mediterranean descent who were affected in Wilson disease (WD): 39 Sardinians, 49 Italians, 33 Turks, and 6 Albanians. Haplotypes were derived by use of the microsatellite markers D13S301, D13S296, D13S297, and D13S298, which are linked to the WD locus. There were five common haplotypes in Sardinians, three in Italians, and two in Turks, which accounted for 85%, 32%, and 30% of the WD chromosomes, respectively. We identified 16 novel mutations: 8 frameshifts, 7 missense mutations, and 1 splicing defect. In addition, we detected the previously described mutations: 2302insC,more » 3404delC, Arg1320ter, Gly944Ser, and His1070Gin. Of the new mutations detected, two, the 1515insT on haplotype I and 2464delC on haplotype XVI, accounted for 6% and 13%, respectively, of the mutations in WD chromsomes in the Sardinian populations. Mutations H1070Q, 2302insC, and 2533delA represented 13%, 8%, and 8%, respectively, of the mutations in WD chromsomes in other Mediterranean populations. The remaining mutations were rare and limited to one or two patients from different populations. Thus, WD results from some frequent mutations and many rare defects. 28 refs., 1 fig., 3 tabs.« less

Wallerian Degeneration Beyond the Corticospinal Tracts: Conventional and Advanced MRI Findings.

PubMed

Chen, Yin Jie; Nabavizadeh, Seyed Ali; Vossough, Arastoo; Kumar, Sunil; Loevner, Laurie A; Mohan, Suyash

2017-05-01

Wallerian degeneration (WD) is defined as progressive anterograde disintegration of axons and accompanying demyelination after an injury to the proximal axon or cell body. Since the 1980s and 1990s, conventional magnetic resonance imaging (MRI) sequences have been shown to be sensitive to changes of WD in the subacute to chronic phases. More recently, advanced MRI techniques, such as diffusion-weighted imaging (DWI) and diffusion tensor imaging (DTI), have demonstrated some of earliest changes attributed to acute WD, typically on the order of days. In addition, there is increasing evidence on the value of advanced MRI techniques in providing important prognostic information related to WD. This article reviews the utility of conventional and advanced MRI techniques for assessing WD, by focusing not only on the corticospinal tract but also other neural tracts less commonly thought of, including corticopontocerebellar tract, dentate-rubro-olivary pathway, posterior column of the spinal cord, corpus callosum, limbic circuit, and optic pathway. The basic anatomy of these neural pathways will be discussed, followed by a comprehensive review of existing literature supported by instructive clinical examples. The goal of this review is for readers to become more familiar with both conventional and advanced MRI findings of WD involving important neural pathways, as well as to illustrate increasing utility of advanced MRI techniques in providing important prognostic information for various pathologies. Copyright © 2016 by the American Society of Neuroimaging.

Mechanisms of pseudosubstrate inhibition of the anaphase promoting complex by Acm1

PubMed Central

Burton, Janet L; Xiong, Yong; Solomon, Mark J

2011-01-01

The anaphase promoting complex (APC) is a ubiquitin ligase that promotes the degradation of cell-cycle regulators by the 26S proteasome. Cdc20 and Cdh1 are WD40-containing APC co-activators that bind destruction boxes (DB) and KEN boxes within substrates to recruit them to the APC for ubiquitination. Acm1 is an APCCdh1 inhibitor that utilizes a DB and a KEN box to bind Cdh1 and prevent substrate binding, although Acm1 itself is not a substrate. We investigated what differentiates an APC substrate from an inhibitor. We identified the Acm1 A-motif that interacts with Cdh1 and together with the DB and KEN box is required for APCCdh1 inhibition. A genetic screen identified Cdh1 WD40 domain residues important for Acm1 A-motif interaction and inhibition that appears to reside near Cdh1 residues important for DB recognition. Specific lysine insertion mutations within Acm1 promoted its ubiquitination by APCCdh1 whereas lysine removal from the APC substrate Hsl1 converted it into a potent APCCdh1 inhibitor. These findings suggest that tight Cdh1 binding combined with the inaccessibility of ubiquitinatable lysines contributes to pseudosubstrate inhibition of APCCdh1. PMID:21460798

Tidal double detonation: a new mechanism for the thermonuclear explosion of a white dwarf induced by a tidal disruption event

NASA Astrophysics Data System (ADS)

Tanikawa, Ataru

2018-03-01

We suggest tidal double detonation as a new mechanism for the thermonuclear explosion of a white dwarf (WD) induced by a tidal disruption event (TDE). Tidal detonation is also a WD explosion induced by a TDE. In this case, helium (He) and carbon-oxygen (CO) detonation waves incinerate He WDs and CO WDs, respectively. On the other hand, for tidal double detonation, He detonation is first excited in the He shell of a CO WD, which then drives CO detonation in the CO core. We name this mechanism after the double detonation scenario in the context of type Ia supernovae. In this paper, by performing numerical simulations for CO WDs of mass 0.60 M⊙ with and without a He shell, we show that tidal double detonation occurs in the shallower encounter of a CO WD with an intermediate-mass black hole (IMBH) compared to simple tidal detonation. We expect tidal double detonation will increase the possibility of the occurrence of WD TDEs, which can help us to understand IMBHs.

WD1145+017 (Abstract)

NASA Astrophysics Data System (ADS)

Motta, M.

2017-12-01

(Abstract only) WD1145 is a 17th magnitude white dwarf star 570 light years away in Virgo that was discovered to have a disintegrating planetoid in close orbit by Andrew Vanderburg, a graduate student at Harvard CfA, while data mining the elucidate the nature of its rather bizarre transit light curves. I obtained multiple observations of WD1145 over the course of a year, and found a series of complex transit light curves that could only be interpreted as a ring complex or torus in close orbit around WD1145. Combined with data from other amateur astronomers, professional observations, and satellite data, it became clear that WD1145 has a small planetoid in close orbit at the Roche limit and is breaking apart, forming a ring of debris material that is then raining down on the white dwarf. The surface of the star is "polluted" by heavy metals, determined by spectroscopic data. Given that in the intense gravitational field of a white dwarf any heavy metals could not for long last on the surface, this confirms that we are tracking in real time the destruction of a small planet by its host star.

THE FIRST DISTANCE CONSTRAINT ON THE RENEGADE HIGH-VELOCITY CLOUD COMPLEX WD

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

Peek, J. E. G.; Roman-Duval, Julia; Tumlinson, Jason

2016-09-10

We present medium-resolution, near-ultraviolet Very Large Telescope/FLAMES observations of the star USNO-A0600-15865535. We adapt a standard method of stellar typing to our measurement of the shape of the Balmer ϵ absorption line to demonstrate that USNO-A0600-15865535 is a blue horizontal branch star, residing in the lower stellar halo at a distance of 4.4 kpc from the Sun. We measure the H and K lines of singly ionized calcium and find two isolated velocity components, one originating in the disk, and one associated with the high-velocity cloud complex WD. This detection demonstrated that complex WD is closer than ∼4.4 kpc andmore » is the first distance constraint on the +100 km s{sup −1} Galactic complex of clouds. We find that complex WD is not in corotation with the Galactic disk, which has been assumed for decades. We examine a number of scenarios and find that the most likely scenario is that complex WD was ejected from the solar neighborhood and is only a few kiloparsecs from the Sun.« less

A biopsychosocial approach to liver transplant evaluation in two patients with Wilson's disease.

PubMed

Boeka, Abbe G; Solomon, Andrea C; Lokken, Kristine; McGuire, Brendan M; Bynon, J Steve

2011-05-01

Wilson's disease (WD) is characterized by hepatic, neurological, and/or psychiatric disturbances. In some cases, liver transplantation is indicated. Because psychologists and other health care workers play an increasing role in the evaluation of individuals presenting for transplant, an understanding of the heterogeneous phenotype of WD is important for mental health professionals working in medical settings. This article reviews two cases of patients with WD (one probable, one confirmed) presenting for liver transplantation and a biopsychosocial assessment approach is demonstrated. Patients are presented in terms of medical, psychiatric, and psychosocial history, neuropsychological examination results, and the subsequent indications for liver transplantation. Both patients exhibited neurocognitive and psychiatric symptoms. One patient was determined to be a marginally suitable candidate for transplantation, whereas the other was considered at high risk for negative outcome post-transplant. This article demonstrates the importance of considering phenotypic presentation, neurocognitive function, psychiatric status, and psychosocial circumstances in assessing transplant readiness in patients with WD. A comprehensive and integrative biopsychosocial assessment approach is appropriate for evaluating patients with WD presenting for liver transplantation. © 2011 Taylor & Francis

WDR5 Facilitates Human Cytomegalovirus Replication by Promoting Capsid Nuclear Egress.

PubMed

Yang, Bo; Liu, Xi-Juan; Yao, Yongxuan; Jiang, Xuan; Wang, Xian-Zhang; Yang, Hong; Sun, Jin-Yan; Miao, Yun; Wang, Wei; Huang, Zhen-Li; Wang, Yanyi; Tang, Qiyi; Rayner, Simon; Britt, William J; McVoy, Michael A; Luo, Min-Hua; Zhao, Fei

2018-05-01

WD repeat-containing protein 5 (WDR5) is essential for assembling the VISA-associated complex to induce a type I interferon antiviral response to Sendai virus infection. However, the roles of WDR5 in DNA virus infections are not well described. Here, we report that human cytomegalovirus exploits WDR5 to facilitate capsid nuclear egress. Overexpression of WDR5 in fibroblasts slightly enhanced the infectious virus yield. However, WDR5 knockdown dramatically reduced infectious virus titers with only a small decrease in viral genome replication or gene expression. Further investigation of late steps of viral replication found that WDR5 knockdown significantly impaired formation of the viral nuclear egress complex and induced substantially fewer infoldings of the inner nuclear membrane. In addition, fewer capsids were associated with these infoldings, and there were fewer capsids in the cytoplasm. Restoration of WDR5 partially reversed these effects. These results suggest that WDR5 knockdown impairs the nuclear egress of capsids, which in turn decreases virus titers. These findings reveal an important role for a host factor whose function(s) is usurped by a viral pathogen to promote efficient replication. Thus, WDR5 represents an interesting regulatory mechanism and a potential antiviral target. IMPORTANCE Human cytomegalovirus (HCMV) has a large (∼235-kb) genome with over 170 open reading frames and exploits numerous cellular factors to facilitate its replication. HCMV infection increases protein levels of WD repeat-containing protein 5 (WDR5) during infection, overexpression of WDR5 enhances viral replication, and knockdown of WDR5 dramatically attenuates viral replication. Our results indicate that WDR5 promotes the nuclear egress of viral capsids, the depletion of WDR5 resulting in a significant decrease in production of infectious virions. This is the first report that WDR5 favors HCMV, a DNA virus, replication and highlights a novel target for antiviral therapy. Copyright © 2018 American Society for Microbiology.

Novel POC1A mutation in primordial dwarfism reveals new insights for centriole biogenesis.

PubMed

Koparir, Asuman; Karatas, Omer F; Yuceturk, Betul; Yuksel, Bayram; Bayrak, Ali O; Gerdan, Omer F; Sagiroglu, Mahmut S; Gezdirici, Alper; Kirimtay, Koray; Selcuk, Ece; Karabay, Arzu; Creighton, Chad J; Yuksel, Adnan; Ozen, Mustafa

2015-10-01

POC1A encodes a WD repeat protein localizing to centrioles and spindle poles and is associated with short stature, onychodysplasia, facial dysmorphism and hypotrichosis (SOFT) syndrome. These main features are related to the defect in cell proliferation of chondrocytes in growth plate. In the current study, we aimed at identifying the molecular basis of two patients with primordial dwarfism (PD) in a single family through utilization of whole-exome sequencing. A novel homozygous p.T120A missense mutation was detected in POC1A in both patients, a known causative gene of SOFT syndrome, and confirmed using Sanger sequencing. To test the pathogenicity of the detected mutation, primary fibroblast cultures obtained from the patients and a control individual were used. For evaluating the global gene expression profile of cells carrying p.T120A mutation in POC1A, we performed the gene expression array and compared their expression profiles to those of control fibroblast cells. The gene expression array analysis showed that 4800 transcript probes were significantly deregulated in cells with p.T120A mutation in comparison to the control. GO term association results showed that deregulated genes are mostly involved in the extracellular matrix and cytoskeleton. Furthermore, the p.T120A missense mutation in POC1A caused the formation of abnormal mitotic spindle structure, including supernumerary centrosomes, and changes in POC1A were accompanied by alterations in another centrosome-associated WD repeat protein p80-katanin. As a result, we identified a novel mutation in POC1A of patients with PD and showed that this mutation causes the formation of multiple numbers of centrioles and multipolar spindles with abnormal chromosome arrangement. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Upon Infection the Cellular WD Repeat-containing Protein 5 (WDR5) Localizes to Cytoplasmic Inclusion Bodies and Enhances Measles Virus Replication.

PubMed

Ma, Dzwokai; George, Cyril X; Nomburg, Jason; Pfaller, Christian K; Cattaneo, Roberto; Samuel, Charles E

2017-12-13

Replication of negative-strand RNA viruses occurs in association with discrete cytoplasmic foci called inclusion bodies. Whereas inclusion bodies represent a prominent subcellular structure induced by viral infection, our knowledge of the cellular protein components involved in inclusion body formation and function is limited. Using measles virus-infected HeLa cells, we found that the WD repeat-containing protein 5 (WDR5), a subunit of histone H3 lysine 4 methyltransferases, was selectively recruited to virus-induced inclusion bodies. Furthermore, WDR5 was found in complexes containing viral proteins associated with RNA replication. WDR5 was not detected with mitochondria, stress granules, or other known secretory or endocytic compartments of infected cells. WDR5 deficiency decreased both viral protein production and infectious virus yields. Interferon production was modestly increased in WDR5 deficient cells. Thus, our study identifies WDR5 as a novel viral inclusion body-associated cellular protein and suggests a role for WDR5 in promoting viral replication. IMPORTANCE Measles virus is a human pathogen that remains a global concern with more than 100,000 measles-related deaths annually despite the availability of an effective vaccine. As measles continues to cause significant morbidity and mortality, understanding the virus-host interactions at the molecular level that affect virus replication efficiency is important for development and optimization of treatment procedures. Measles virus is an RNA virus that encodes six genes and replicates in the cytoplasm of infected cells in discrete cytoplasmic replication bodies, though little is known of the biochemical nature of these structures. Here we show that the cellular protein WDR5 is enriched in the cytoplasmic viral replication factories and enhances virus growth. WDR5-containing protein complex includes viral proteins responsible for viral RNA replication. Thus, we have identified WDR5 as a host factor that enhances the replication of measles virus. Copyright © 2017 American Society for Microbiology.

Expanding RNA binding specificity and affinity of engineered PUF domains.

PubMed

Zhao, Yang-Yang; Mao, Miao-Wei; Zhang, Wen-Jing; Wang, Jue; Li, Hai-Tao; Yang, Yi; Wang, Zefeng; Wu, Jia-Wei

2018-05-18

Specific manipulation of RNA is necessary for the research in biotechnology and medicine. The RNA-binding domains of Pumilio/fem-3 mRNA binding factors (PUF domains) are programmable RNA binding scaffolds used to engineer artificial proteins that specifically modulate RNAs. However, the native PUF domains generally recognize 8-nt RNAs, limiting their applications. Here, we modify the PUF domain of human Pumilio1 to engineer PUFs that recognize RNA targets of different length. The engineered PUFs bind to their RNA targets specifically and PUFs with more repeats have higher binding affinity than the canonical eight-repeat domains; however, the binding affinity reaches the peak at those with 9 and 10 repeats. Structural analysis on PUF with nine repeats reveals a higher degree of curvature, and the RNA binding unexpectedly and dramatically opens the curved structure. Investigation of the residues positioned in between two RNA bases demonstrates that tyrosine and arginine have favored stacking interactions. Further tests on the availability of the engineered PUFs in vitro and in splicing function assays indicate that our engineered PUFs bind RNA targets with high affinity in a programmable way.

Expanding RNA binding specificity and affinity of engineered PUF domains

PubMed Central

Zhao, Yang-Yang; Zhang, Wen-Jing; Wang, Jue; Li, Hai-Tao; Yang, Yi; Wang, Zefeng; Wu, Jia-Wei

2018-01-01

Abstract Specific manipulation of RNA is necessary for the research in biotechnology and medicine. The RNA-binding domains of Pumilio/fem-3 mRNA binding factors (PUF domains) are programmable RNA binding scaffolds used to engineer artificial proteins that specifically modulate RNAs. However, the native PUF domains generally recognize 8-nt RNAs, limiting their applications. Here, we modify the PUF domain of human Pumilio1 to engineer PUFs that recognize RNA targets of different length. The engineered PUFs bind to their RNA targets specifically and PUFs with more repeats have higher binding affinity than the canonical eight-repeat domains; however, the binding affinity reaches the peak at those with 9 and 10 repeats. Structural analysis on PUF with nine repeats reveals a higher degree of curvature, and the RNA binding unexpectedly and dramatically opens the curved structure. Investigation of the residues positioned in between two RNA bases demonstrates that tyrosine and arginine have favored stacking interactions. Further tests on the availability of the engineered PUFs in vitro and in splicing function assays indicate that our engineered PUFs bind RNA targets with high affinity in a programmable way. PMID:29490074

The crystal structure of a partial mouse Notch-1 ankyrin domain: Repeats 4 through 7 preserve an ankyrin fold

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

Lubman, Olga Y.; Kopan, Raphael; Waksman, Gabriel

Folding and stability of proteins containing ankyrin repeats (ARs) is of great interest because they mediate numerous protein-protein interactions involved in a wide range of regulatory cellular processes. Notch, an ankyrin domain containing protein, signals by converting a transcriptional repression complex into an activation complex. The Notch ANK domain is essential for Notch function and contains seven ARs. Here, we present the 2.2 {angstrom} crystal structure of ARs 4-7 from mouse Notch 1 (m1ANK). These C-terminal repeats were resistant to degradation during crystallization, and their secondary and tertiary structures are maintained in the absence of repeats 1-3. The crystallized fragmentmore » adopts a typical ankyrin fold including the poorly conserved seventh AR, as seen in the Drosophila Notch ANK domain (dANK). The structural preservation and stability of the C-terminal repeats shed a new light onto the mechanism of hetero-oligomeric assembly during Notch-mediated transcriptional activation.« less

Mismanagement of Wilson's disease as psychotic disorder.

PubMed

Bidaki, Reza; Zarei, Mina; Mirhosseini, S M Mahdy; Moghadami, Samar; Hejrati, Maral; Kohnavard, Marjan; Shariati, Behnam

2012-01-01

Wilson's disease (WD) or hepatolenticular degeneration is an inherited neurodegenerative disorder of copper metabolism (autosomal recessive, chromosome13). Psychiatric disorders in WD include dementia, characterized by mental slowness, poor concentration, and memory impairment. Symptoms may progress rapidly, especially in younger patients, but are more often gradual in development with periods of remission and exacerbation. Delusional disorder and schizophrenia-like psychosis are rare forms of psychiatric presentation. In this report, the patient with WD presented by psychosis symptoms and treated mistaken as schizophrenia for almost ten years. Although he has treated with antipsychotics, he had periods of remissions and relapses and never was symptoms free. Since psychosis can be the manifestation of medical diseases such as WD, overall view of these patients is necessary and medical diseases should be considered as a differential diagnosis.

Symptomatic treatment of neurologic symptoms in Wilson disease.

PubMed

Litwin, Tomasz; Dušek, Petr; Członkowska, Anna

2017-01-01

Wilson disease (WD) is a potentially treatable neurodegenerative disorder. In the majority of cases, treatment with drugs that induce a negative copper balance (usually chelators or zinc salts) leads to improvements in liver function and neurologic signs. However, some patients show severe neurologic symptoms at diagnosis, such as tremor, dystonia, parkinsonism, and chorea. In this patient group, some neurologic deficits may persist despite adequate treatment, and further neurologic deterioration may be observed after treatment initiation. Such patients may require additional treatment to alleviate neurologic symptoms. Apart from general recommendations for WD anticopper treatment, there are currently no guidelines for managing neurologic symptoms in WD. The aim of this chapter is to summarize possible treatments of neurologic symptoms in WD based on the presently available medical literature. © 2017 Elsevier B.V. All rights reserved.

Transit probabilities for debris around white dwarfs in Kepler/K2 up to C13

NASA Astrophysics Data System (ADS)

Lewis, John Arban; Johnson, John Asher

2018-01-01

WD 1145+017 (Vanderburg et al. 2015), a metal-polluted white dwarf with an infrared-excess and transits confirmed the long held theory that at least some metal-polluted white dwarfs are actively accreting material from crushed up planetesimals. A statistical understanding of WD 1145-like systems would inform us on the various pathways for metal-pollution and the end states of planetary systems around medium- to high-mass stars. At present, there is a single example. We study all white dwarfs observed during the K2 mission to identify white dwarfs with either transits or light curve features similar to WD 1145+017. We correct for contamination using J.J. Hermes' list of high probability white dwarfs (available at k2wd.org ).

Secretion of CyaA-PrtB and HlyA-PrtB fusion proteins in Escherichia coli: involvement of the glycine-rich repeat domain of Erwinia chrysanthemi protease B.

PubMed Central

Létoffé, S; Wandersman, C

1992-01-01

Protease B from Erwinia chrysanthemi was shown previously to have a C-terminal secretion signal located downstream of a domain that contains six glycine-rich repeats. This domain is conserved in all known bacterial proteins secreted by the signal peptide-independent pathway. The role of these repeats in the secretion process is controversial. We compared the secretion processes of various heterologous polypeptides fused either directly to the signal or separated from it by the glycine-rich domain. Although the repeats are not involved in the secretion of small truncated protease B carboxy-terminal peptides, they are required for the secretion of higher-molecular-weight fusion proteins. Secretion efficiency was also dependent on the size of the passenger polypeptide. Images PMID:1629152

A cohort study of the effect of winter dysentery on herd-level milk production.

PubMed

Toftaker, Ingrid; Holmøy, Ingrid; Nødtvedt, Ane; Østerås, Olav; Stokstad, Maria

2017-08-01

Winter dysentery (WD) is a contagious disease caused by bovine coronavirus. It is characterized by acute onset of diarrhea, fever, depression, and reduced milk yield in adult cattle. Although production loss is a well-known consequence of WD, large-scale studies estimating the effect on milk production are lacking. The objective of this study was to estimate the effect of farmer-reported WD on herd-level milk production and milk composition. A cohort study was performed based on reports of herd outbreaks of winter dysentery during a regional epidemic in Norway during the winter of 2011-2012. Reports were made by farmers, and diagnosis was based on a herd outbreak of acute diarrhea in adults. Milk shipment data were retrieved from the dairy company, and information on herd size and milking system were retrieved from the Norwegian Dairy Herd Recording System. We compared milk production in herds with reported outbreaks of WD (n = 224) with all herds in the same area without a reported outbreak (n = 2,093) during the same period. The outcome variable in the analysis was milk volume per cow per day, and the main predictor was whether the herd had a reported outbreak of WD or not. We assessed the effect of WD on milk production by fitting a linear mixed model, adjusting for milk production in the herd before the outbreak. Similarly, we assessed the effect of WD on milk composition using linear regression, adjusting for the levels of milk components before the outbreak. This study estimated a total loss of 51 L/cow during the study period, from 7 d before to 19 d after a reported outbreak. The lowest estimated production was 2 d after the outbreak was reported, when the average milk yield was 19.4 L/cow per day, compared with 23.0 L/cow per day 7 days before notification (i.e., a difference of 3.6 L/cow, or 15%). The effect gradually declined with time. The estimated effect on milk composition was modest, but an increase of 11% in free fatty acids and a small increase in fat/protein ratio indicated that WD might put cows into negative energy balance. Descriptive analysis indicated that herd milk yield was still reduced 4 mo after an outbreak. This cohort study showed that WD causes considerable decreases in milk production, and it alters milk composition. These findings highlight the important negative consequences of WD, and should motivate actions to prevent between-herd spread of bovine coronavirus. Copyright © 2017 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Microemulsion-Type Fire-Resistant Diesel Fuel.

DTIC Science & Technology

1984-12-31

Interface Sci., 42, 381 (1983). (SPEC22.A) 76 V. REFERENCES 1. Weatherford, W.D., Jr.; Fodor, G.E.; Naegeli , D.W.; Owens, E.C.; and Wright, B.R.; and...OO01 and DAAK70-80-C-OOOI, Report AFLRL No. il, December 1979 (Government Accession No. AD A083610). 2. Weatherford, W.D., Jr.; Fodor, G.E.; Naegeli , D.W...130, September 1980 (Government Accession No. AD A090129). 4. Weatherford, W.D., Jr.; Fodor, G.E.; Kanakia, M.D.; Naegeli , D.W.; and Wright, B.R

Computational Identification Raises a Riddle for Distribution of Putative NACHT NTPases in the Genome of Early Green Plants.

PubMed

Arya, Preeti; Acharya, Vishal

2016-01-01

NACHT NTPases and AP-ATPases belongs to STAND (signal transduction ATPases with numerous domain) P-loop NTPase class, which are known to be involved in defense signaling pathways and apoptosis regulation. The AP-ATPases (also known as NB-ARC) and NACHT NTPases are widely spread throughout all kingdoms of life except in plants, where only AP-ATPases have been extensively studied in the scenario of plant defense response against pathogen invasion and in hypersensitive response (HR). In the present study, we have employed a genome-wide survey (using stringent computational analysis) of 67 diverse organisms viz., archaebacteria, cyanobacteria, fungi, animalia and plantae to revisit the evolutionary history of these two STAND P-loop NTPases. This analysis divulged the presence of NACHT NTPases in the early green plants (green algae and the lycophyte) which had not been previously reported. These NACHT NTPases were known to be involved in diverse functional activities such as transcription regulation in addition to the defense signaling cascades depending on the domain association. In Chalmydomonas reinhardtii, a green algae, WD40 repeats found to be at the carboxyl-terminus of NACHT NTPases suggest probable role in apoptosis regulation. Moreover, the genome of Selaginella moellendorffii, an extant lycophyte, intriguingly shows the considerable number of both AP-ATPases and NACHT NTPases in contrast to a large repertoire of AP-ATPases in plants and emerge as an important node in the evolutionary tree of life. The large complement of AP-ATPases overtakes the function of NACHT NTPases and plausible reason behind the absence of the later in the plant lineages. The presence of NACHT NTPases in the early green plants and phyletic patterns results from this study raises a quandary for the distribution of this STAND P-loop NTPase with the apparent horizontal gene transfer from cyanobacteria.

Mutant WDR36 directly affects axon growth of retinal ganglion cells leading to progressive retinal degeneration in mice

PubMed Central

Chi, Zai-Long; Yasumoto, Fumie; Sergeev, Yuri; Minami, Masayoshi; Obazawa, Minoru; Kimura, Itaru; Takada, Yuichiro; Iwata, Takeshi

2010-01-01

Primary open-angle glaucoma (POAG) is one of the three principal subtypes of glaucoma and among the leading cause of blindness worldwide. POAG is defined by cell death of the retinal ganglion cells (RGCs) and surrounding neuronal cells at higher or normal intraocular pressure (IOP). Coded by one of the three genes responsible for POAG, WD repeat-containing protein 36 (WDR36) has two domains with a similar folding. To address whether WDR36 is functionally important in the retina, we developed four transgenic mice strains overexpressing a wild-type (Wt) and three mutant variants of D606G, deletion of amino acids at positions 605–607 (Del605–607) and at 601–640 (Del601–640) equivalent to the location of the D658G mutation observed in POAG patients. A triple amino acid deletion of mouse Wdr36 at positions 605–607 corresponding to the deletion at positions 657–659 in humans developed progressive retinal degeneration at the peripheral retina with normal IOP. RGCs and connecting amacrine cell synapses were affected at the peripheral retina. Axon outgrowth rate of cultured RGC directly isolated from transgenic animal was significantly reduced by the Wdr36 mutation compared with Wt. Molecular modeling of wild and mutant mouse Wdr36 revealed that deletion at positions 605–607 removed three residues and a hydrogen bond, required to stabilize anti-parallel β-sheet of the 6th β-propeller in the second domain. We concluded that WDR36 plays an important functional role in the retina homeostasis and mutation to this gene can cause devastating retinal damage. These data will improve understanding of the functional property of WDR36 in the retina and provide a new animal model for glaucoma therapeutics. PMID:20631153

Elemental analysis of sunflower cataract in Wilson's disease: a study using scanning transmission electron microscopy and energy dispersive spectroscopy.

PubMed

Jang, Hyo Ju; Kim, Joon Mo; Choi, Chul Young

2014-04-01

Signature ophthalmic characteristics of Wilson's disease (WD) are regarded as diagnostically important manifestations of the disease. Previous studies have proved the common occurrence of copper accumulation in the liver of patients with WD. However, in the case of sunflower cataracts, one of the rare diagnostic signs of WD, no study has demonstrated copper accumulation in the lens capsules of sunflower cataracts in WD patients. To investigate the nanostructure and elemental composition of sunflower cataracts in WD, transmission electron microscopy (TEM) was done on the capsulorhexised anterior lens capsule of sunflower cataracts in WD in order to evaluate anatomical variation and elemental changes. We utilized energy dispersive X-ray spectroscopy (EDS) to investigate the elemental composition of the lens capsule using both point and mapping spectroscopy. Quantitative analysis was performed for relative comparison of the elements. TEM showed the presence of granular deposits of varying size (20-350 nm), appearing mainly in the posterior one third of the anterior capsule. The deposits appeared in linear patterns with scattered dots. There were no electron-dense particles in the epithelial cell layer of the lens. Copper and sulfur peaks were consistently revealed in electron-dense granular deposits. In contrast, copper and sulfur peaks were absent in other tissues, including granule-free lens capsules and epithelial tissue. Most copper was exclusively located in clusters of electron-dense particles, and the copper distribution overlapped with sulfur on mapping spectroscopy. Quantitative analysis presented inconsistent ratios of copper to sulfur in each electron-dense granule. The mean ratio of copper to sulfur was about 3.25 (with a range of 2.39-3.78). This is the first elemental analysis of single electron particles in sunflower cataracts using EDS in the ophthalmic area. Sunflower cataracts with WD are assumed to be the result of accumulation of heterogeneous compounds composed of several materials, including copper, sulfur, and/or copper-binding proteins. Linear patterns of copper and sulfur deposition were detected in various sizes and composition ratios with these elements in cases of WD. Copyright © 2014 Elsevier Ltd. All rights reserved.

A maternal Western diet during gestation and lactation modifies offspring's microbiota activity, blood lipid levels, cognitive responses, and hippocampal neurogenesis in Yucatan pigs.

PubMed

Val-Laillet, David; Besson, Marie; Guérin, Sylvie; Coquery, Nicolas; Randuineau, Gwénaëlle; Kanzari, Ameni; Quesnel, Hélène; Bonhomme, Nathalie; Bolhuis, J Elizabeth; Kemp, Bas; Blat, Sophie; Le Huërou-Luron, Isabelle; Clouard, Caroline

2017-05-01

A suboptimal early nutritional environment ( i.e., excess of energy, sugar, and fat intake) can increase susceptibility to diseases and neurocognitive disorders. The purpose of this study was to investigate in nonobese Yucatan minipigs ( Sus scrofa ) the impact of maternal diet [standard diet (SD) vs. Western diet (WD)] during gestation and 25 d of lactation on milk composition, blood metabolism, and microbiota activity of sows ( n = 17) and their piglets ( n = 65), and on spatial cognition ( n = 51), hippocampal plasticity ( n = 17), and food preferences/motivation ( n = 51) in the progeny. Milk dry matter and lipid content, as well as plasma total cholesterol and free fatty acid (FFA) concentrations ( P < 0.05) were higher in WD than in SD sows. Microbiota activity decreased in both WD sows and 100-d-old piglets ( P < 0.05 or P < 0.10, depending on short-chain FAs [SCFAs]). At weaning [postnatal day (PND) 25], WD piglets had increased blood triglyceride and FFA levels ( P < 0.01). Both SD and WD piglets consumed more of a known SD than an unknown high-fat and -sucrose (HFS) diet ( P < 0.0001), but were quicker to obtain HFS rewards compared with SD rewards ( P < 0.01). WD piglets had higher working memory ( P = 0.015) and reference memory ( P < 0.001) scores, which may reflect better cognitive abilities in the task context and a higher motivation for the food rewards. WD piglets had a smaller hippocampal granular cell layer ( P = 0.03) and decreased neurogenesis ( P < 0.005), but increased cell proliferation ( P < 0.001). A maternal WD during gestation and lactation, even in the absence of obesity, has significant consequences for piglets' blood lipid levels, microbiota activity, gut-brain axis, and neurocognitive abilities after weaning.-Val-Laillet, D., Besson, M., Guérin, S., Coquery, N., Randuineau, G., Kanzari, A., Quesnel, H., Bonhomme, N., Bolhuis, J. E., Kemp, B., Blat, S., Le Huërou-Luron, I., Clouard, C. A maternal Western diet during gestation and lactation modifies offspring's microbiota activity, blood lipid levels, cognitive responses, and hippocampal neurogenesis in Yucatan pigs. © FASEB.

The Impacts of Wind Speed Trends and Long-term Variability in Relation to Hydroelectric Reservoir Inflows on Wind Power in the Pacific Northwest

NASA Astrophysics Data System (ADS)

Cross, B.; Kohfeld, K. E.; Cooper, A.; Bailey, H. J.; Rucker, M.

2013-12-01

The use of wind power is growing rapidly in the Pacific Northwest (PNW ) due to environmental concerns, decreasing costs of implementation, strong wind speeds, and a desire to diversify electricity sources to minimize the impacts of streamflow variability on electricity prices and system flexibility. In hydroelectric dominated systems, like the PNW, the benefits of wind power can be maximized by accounting for the relationship between long term variability in wind speeds and reservoir inflows. Clean energy policies in British Columbia make the benefits of increased wind power generation during low streamflow periods particularly large, by preventing the overbuilding of marginal hydroelectric projects. The goal of this work was to quantify long-term relationships between wind speed and streamflow behavior in British Columbia. Wind speed data from the North American Regional Reanalysis (NARR) and cumulative usable inflows (CUI) from BC Hydro were used to analyze 10m wind speed and density (WD) trends, WD-CUI correlations, and WD anomalies during low and high inflow periods in the PNW (40°N to 65°N, 110°W to 135°W) from 1979-2010. Statistically significant positive wind speed and density trends were found for most of the PNW, with the largest increases along the Pacific Coast. CUI-WD correlations were weakly positive for most regions, with the highest values along the US coast (r ~0.55), generally weaker correlations to the north, and negative correlations (r ~ -0.25) along BC's North Coast. When considering seasonal relationships, the Spring freshet was coincident with lower WD anomalies west of the Rocky Mountains and higher WDs to the east. A similar but opposite pattern was observed for low inflow winter months. When considering interannual variability, lowest inflow years experienced positive WD anomalies (up to 40% increases) for the North Coast. In highest inflow years, positive WD anomalies were widespread in the US and for smaller patches of central BC. By accounting for regional and temporal differences in the relationship between wind (WD) and streamflow (CUI) behaviour during wind farm site selection, the benefits of energy diversification can be maximized.

Resistance to Arteriosclerosis in Pigs with von Willebrand's Disease

PubMed Central

Fuster, Valentin; Bowie, E. J. Walter; Lewis, Jon C.; Fass, David N.; Owen, Charles A.; Brown, Arnold L.

1978-01-01

The aortas of 11 pigs (aged 1-3 yr) with homozygous von Willebrand's disease (vWd) were compared with those of 11 normal pigs of the same ages. Six of the controls exhibited multiple arteriosclerotic plaques with intimal thickening of 63-130 μm. In contrast, none of the pigs with vWd had multiple plaques, and only one had a lesion >2 mm in diameter. In a subsequent study, 3-mo-old pigs (11 controls and 7 with homozygous vWd) were placed on a 2% cholesterol diet for up to 6 mo. All of the controls developed arteriosclerotic plaques in the aorta, and in nine of the controls, at least 13% of the entire surface was involved. Intimal thickness ranged up to 390 μm. In contrast, four of the pigs with vWd did not develop such lesions, two developed arteriosclerotic lesions affecting 6 and 7% of the aortic surface, and the seventh had 13% of the aortic surface involved. Most of the pigs with vWd, however, developed flat fatty lesions in contrast to the normal pigs whether on the normal or the high cholesterol diet. There was blue staining of the flat fatty lesions when two pigs with vWd were injected with Evans blue dye antemortem. By electron microscopy, severe endothelial damage was apparent, but there was no intimal proliferation. The coincidence of the impaired platelet-arterial wall interaction and lack of arteriosclerosis in this bleeding disease is discussed. Images PMID:305924

Violent Mergers

NASA Astrophysics Data System (ADS)

Pakmor, Rüdiger

The progenitor systems and explosion scenarios of Type Ia supernovae (SNe Ia) are still heavily debated. The violent merger scenario is a recent addition to explosion scenarios for SNe Ia. Here, two white dwarfs (WDs) in a binary system approach each other owing to the emission of gravitational waves. The interaction between the two WDs preluding or during the merger creates a hotspot on the surface of the primary, more massive, WD that ignites a detonation. If the detonation is a carbon detonation, it completely burns the primary WD leading to a SN Ia. If instead the detonation is a helium detonation in the helium shell of a carbon-oxygen WD, it burns around the primary WD in its helium shell and sends a shock wave into its core that ignites a carbon detonation. Again the primary WD is fully burned. Synthetic observables for explosion models of SNe Ia in the violent merger scenario show good agreement with normal SNe Ia and the subclass of faint, slowly evolving 02es-like SNe Ia for different masses of the primary WD. The violent merger scenario can also explain the delay time distribution and brightness distribution of normal SNe Ia. This chapter discusses in detail the mechanism that leads to ignition in the violent merger scenario, summarizes the properties of explosions in the violent merger scenario and compares to observations. It ends with a summary of the main properties of the population of normal SNe Ia and discusses to which degree they can be explained in the violent merger scenario.

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

Zweifel,M.; Leahy, D.; Barrick, D.

Deltex is a cytosolic effector of Notch signaling thought to bind through its N-terminal domain to the Notch receptor. Here we report the structure of the Drosophila Deltex N-terminal domain, which contains two tandem WWE sequence repeats. The WWE repeats, which adopt a novel fold, are related by an approximate two-fold axis of rotation. Although the WWE repeats are structurally distinct, they interact extensively and form a deep cleft at their junction that appears well suited for ligand binding. The two repeats are thermodynamically coupled; this coupling is mediated in part by a conserved segment that is immediately C-terminal tomore » the second WWE domain. We demonstrate that although the Deltex WWE tandem is monomeric in solution, it forms a heterodimer with the ankyrin domain of the Notch receptor. These results provide structural and functional insight into how Deltex modulates Notch signaling, and how WWE modules recognize targets for ubiquitination.« less

The differential effects of low birth weight and Western diet consumption upon early life hepatic fibrosis development in guinea pig

PubMed Central

Sarr, Ousseynou; Blake, Alexandra; Thompson, Jennifer A.; Zhao, Lin; Rabicki, Katherine; Walsh, Joanna C.; Welch, Ian

2016-01-01

Key points Postnatal intake of a high saturated fat/high sugar diet, the Western diet (WD), is a risk factor for liver fibrosis. Recently, adverse in utero conditions resulting in low birth weight (LBW) have also been associated with postnatal fibrosis development.We demonstrate that suboptimal in utero conditions resulting in LBW are associated with changes in hepatic profibrotic genes in conjunction with minimal liver fibrosis in young non‐overweight adult guinea pigs.Our results also indicate that WD promotes liver steatosis, enhanced expression of hepatic genes and proteins of the proinflammatory, profibrotic, cell death and collagen deposition pathways in conjunction with mild hepatic fibrosis.Our data highlight that pathways responsible for the initiation of a profibrotic state and ultimately hepatic fibrosis appear different depending upon the insult, an in utero‐induced LBW outcome or a postnatal WD exposure. Abstract Postnatal intake of an energy dense diet, the Western diet (WD), is a strong risk factor for liver fibrosis. Recently, adverse in utero conditions resulting in low birth weight (LBW) have also been associated with postnatal fibrosis development. We assessed the independent and possible synergistic effects of placental insufficiency‐induced LBW and postnatal WD consumption on liver fibrosis in early adulthood, with a specific focus on changes in inflammation and apoptosis pathways in association with fibrogenesis. Male LBW (uterine artery ablation) and normal birth weight (NBW) guinea pig pups were fed either a control diet (CD) or WD from weaning to 150 days. Significant steatosis, mild lobular inflammation, apoptosis and mild stage 1 fibrosis (perisinusoidal or portal) were evident in WD‐fed offspring (NBW/WD and LBW/WD). In LBW/CD versus NBW/CD offspring, increased transforming growth factor‐beta 1 and matrix metallopeptidase mRNA and sma‐ and Mad‐related protein 4 (SMAD4) were present in conjunction with minimal stage 1 portal fibrosis. Further, connective tissue growth factor mRNA was increased and miR‐146a expression decreased in LBW offspring, irrespective of diet. Independent of birth weight, WD‐fed offspring exhibited increased expression of fibrotic genes as well as elevated inflammatory and apoptotic markers. Moreover, the augmented expression of collagen, type III, alpha 1 and tumor necrosis factor‐alpha was associated with increased recruitment of RNA polymerase II and enhanced histone acetylation (K9) to their respective promoters. These data support a role for both LBW and postnatal WD as factors contributing to hepatic fibrosis development in offspring through distinct pathways. PMID:26662996

Characteristics of patients with otherwise typical winter depression, but with incomplete summer remission.

PubMed

Lingjaerde, O; Regine Føreland, A

1999-04-01

Seasonal affective disorder, winter depression type (WD-SAD), is characterized by recurring autumn/winter depression with full remission or hypomania/mania in summer. However, some patients have an otherwise typical WD but with incomplete summer remission. We wanted to elucidate in what other respects such patients differ from typical WD-SAD patients. 14 patients meeting DSM-III-R criteria for Seasonal Pattern except for incomplete summer remission (ISR), were compared with 144 patients meeting the full criteria, including complete summer remission (CSR), with regard to demography, illness history, clinical symptoms, and response to light treatment. In comparison with the CSR group, the ISR group had a longer duration of illness, more often used antidepressants, and improved significantly less after treatment with bright light for 6 days, whereas the symptomatology in winter (Montgomery-Asberg Depression Rating Scale plus hypersomnia, hyperphagia, and carbohydrate craving) was similar in the two groups. The ISR group was small, and the severity of their summer depression could only be assessed retrospectively. Patients with otherwise typical WD but with incomplete summer remission respond poorly to light treatment. Full summer remission should be retained as a criterion for WD-SAD.

Discovery of a Detached, Eclipsing 40 Minute Period Double White Dwarf Binary and a Friend: Implications for He+CO White Dwarf Mergers

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

Brown, Warren R.; Kilic, Mukremin; Kosakowski, Alekzander

We report the discovery of two detached double white dwarf (WD) binaries, SDSS J082239.546+304857.19 and SDSS J104336.275+055149.90, with orbital periods of 40 and 46 minutes, respectively. The 40 minute system is eclipsing; it is composed of a 0.30 M {sub ⊙} and a 0.52 M {sub ⊙} WD. The 46 minute system is a likely LISA verification binary. The short 20 ± 2 Myr and ∼34 Myr gravitational-wave merger times of the two binaries imply that many more such systems have formed and merged over the age of the Milky Way. We update the estimated Milky Way He+CO WD binarymore » merger rate and affirm our previously published result: He+CO WD binaries merge at a rate at least 40 times greater than the formation rate of stable mass-transfer AM CVn binaries, and so the majority must have unstable mass-transfer. The implication is that spin–orbit coupling in He+CO WD mergers is weak, or perhaps nova-like outbursts drive He+CO WDs into merger, as proposed by Shen.« less

Post-main-sequence Evolution of Icy Minor Planets. II. Water Retention and White Dwarf Pollution around Massive Progenitor Stars

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

Malamud, Uri; Perets, Hagai B., E-mail: uri.mal@tx.technion.ac.il, E-mail: hperets@physics.technion.ac.il

Most studies suggest that the pollution of white dwarf (WD) atmospheres arises from the accretion of minor planets, but the exact properties of polluting material, and in particular the evidence for water in some cases, are not yet understood. Here we study the water retention of small icy bodies in exo-solar planetary systems, as their respective host stars evolve through and off the main sequence and eventually become WDs. We explore, for the first time, a wide range of star masses and metallicities. We find that the mass of the WD progenitor star is of crucial importance for the retentionmore » of water, while its metallicity is relatively unimportant. We predict that minor planets around lower-mass WD progenitors would generally retain more water and would do so at closer distances from the WD than compared with high-mass progenitors. The dependence of water retention on progenitor mass and other parameters has direct implications for the origin of observed WD pollution, and we discuss how our results and predictions might be tested in the future as more observations of WDs with long cooling ages become available.« less

Local Thermonuclear Runaways in Dwarf Novae?

NASA Astrophysics Data System (ADS)

Shara, Michael

2012-10-01

We have no hope of understanding the structure and evolution of a class of astrophysical objects if we cannot identify the dominant energy source of those objects.The Disk Instability Model {DIM} postulates that Dwarf Nova {DN} outbursts are powered by runaway accretion from an accretion disk onto a White Dwarf {WD} in a red dwarf-WD mass transferring binary. Ominously, HST observations {e.g. Sion et al. 2001} of WD surface abundances hint at a significant shortcoming of the DIM. The data from the present proposal will be able to unequivocally demonstrate if the observed highly Carbon-depleted and Nitrogen-enhanced abundances on WD surfaces {NOT predicted by DIM} vary with binary orbital phase, or throughout a DN quiescence cycle, or from cycle to cycle. These same data will test if predicted {but never observed} Local Thermonuclear Runaways {"Nuclear-powered mini-novas"} occur on the WDs of DN. Such events could trigger or even power DN, providing the long-sought physical mechanism of DN eruptions that DIM lacks. As a "free" bonus, the same data may also directly detect the diffusion of accreted metals in a WD atmosphere for the first time, or provide significant limits on the diffusion rate.

WD+RG systems as the progenitors of type Ia supernovae

NASA Astrophysics Data System (ADS)

Wang, Bo; Han, Zhan-Wen

2010-03-01

Type Ia supernovae (SNe Ia) play an important role in the study of cosmic evolution, especially in cosmology. There are several progenitor models for SNe Ia proposed in the past years. By considering the effect of accretion disk instability on the evolution of white dwarf (WD) binaries, we performed detailed binary evolution calculations for the WD + red-giant (RG) channel of SNe Ia, in which a carbon-oxygen WD accretes material from a RG star to increase its mass to the Chandrasekhar mass limit. According to these calculations, we mapped out the initial and final parameters for SNe Ia in the orbital period-secondary mass (log Pi - Mi2) plane for various WD masses for this channel. We discussed the influence of the variation of the duty cycle value on the regions for producing SNe Ia. Similar to previous studies, this work also indicates that the long-period dwarf novae offer possible ways for producing SNe Ia. Meanwhile, we find that the surviving companion stars from this channel have a low mass after the SN explosion, which may provide a means for the formation of the population of single low-mass WDs (<0.45 Modot).

WD1145+017

NASA Astrophysics Data System (ADS)

Motta, Mario

2017-06-01

WD1145 is a 17th magnitude white dwarf star 570 light years away in Virgo, that was discovered to have a disintegrating planetoid in close orbit by Andrew Vanderburg a graduate student at Harvard CFA, while data mining the Kepler 2 mission. He contacted me to obtain transit data to elucidate the nature of its rather bizarre transit light curves. I obtained multiple observations of WD1145 over the course of a year, and found a series of complex transit light curves that could only be interpreted as a ring complex or torus in close orbit around WD1145. Combined with data from other amateur astronomers, professional observations, and satellite data it became clear that WD1145 has a small planetoid in close orbit at the Roche limit and is breaking apart forming a ring of debris material that is then raining down on the white dwarf. The surface of the star is "polluted" by heavy metals by spectroscopic data. Given that in the intense gravitational field of a white dwarf any heavy metals could not for long last on the surface, this confirms that we are tracking in real time the destruction of a small planet by its host star.

Flexible DNA binding of the BTB/POZ-domain protein FBI-1.

PubMed

Pessler, Frank; Hernandez, Nouria

2003-08-01

POZ-domain transcription factors are characterized by the presence of a protein-protein interaction domain called the POZ or BTB domain at their N terminus and zinc fingers at their C terminus. Despite the large number of POZ-domain transcription factors that have been identified to date and the significant insights that have been gained into their cellular functions, relatively little is known about their DNA binding properties. FBI-1 is a BTB/POZ-domain protein that has been shown to modulate HIV-1 Tat trans-activation and to repress transcription of some cellular genes. We have used various viral and cellular FBI-1 binding sites to characterize the interaction of a POZ-domain protein with DNA in detail. We find that FBI-1 binds to inverted sequence repeats downstream of the HIV-1 transcription start site. Remarkably, it binds efficiently to probes carrying these repeats in various orientations and spacings with no particular rotational alignment, indicating that its interaction with DNA is highly flexible. Indeed, FBI-1 binding sites in the adenovirus 2 major late promoter, the c-fos gene, and the c-myc P1 and P2 promoters reveal variously spaced direct, inverted, and everted sequence repeats with the consensus sequence G(A/G)GGG(T/C)(C/T)(T/C)(C/T) for each repeat.

The Processing and Mechanical Properties of High Temperature/High Performance Composites. Book 1, Section 1: Coatings and Interfaces

DTIC Science & Technology

1989-10-15

Cut Prestressed Film H.M. Jensen on a Substrate J.W. Hutchinson K.S. Kim 8. Measuring the Strength and Stiffness T.P. Weihs of Thin Film Materials by...for Thin Films T.P. Weihs Using Micro-Cantilever Beams J.C. Bravman W.D. Nix 10. Analysis of Elastic and Plastic Deformation A.K. Bhattacharya...Associated with Indentation Testing of Thin W.D. Nix Films on Substrates 11. Finite Elenent Simulidion of Indentation A.K. 13hattacharya Experimnents W.D

White dwarf stars: cosmic chronometers and dark matter probes

NASA Astrophysics Data System (ADS)

Salaris, Maurizio; Cassisi, Santi

2018-04-01

White dwarfs (WD) are the endpoint of the evolution of the large majority of stars formed in our galaxy. In the last two decades observations and theory have improved to a level that makes it possible to employ WD for determining ages of the stellar populations in the disk of the Milky Way and in the nearest star clusters, and constrain the existence and properties of dark matter (DM) candidates. This review is centred on WD models, age-dating, and DM identification methods, recent results and future developments of the field.

Monitoring and modelling of white dwarfs with extremely weak magnetic fields. WD 2047+372 and WD 2359-434

NASA Astrophysics Data System (ADS)

Landstreet, J. D.; Bagnulo, S.; Valyavin, G.; Valeev, A. F.

2017-11-01

Magnetic fields are detected in a few percent of white dwarfs. The number of such magnetic white dwarfs known is now some hundreds. Fields range in strength from a few kG to several hundred MG. Almost all the known magnetic white dwarfs have a mean field modulus ≥1 MG. We are trying to fill a major gap in observational knowledge at the low field limit (≤200 kG) using circular spectro-polarimetry. In this paper we report the discovery and monitoring of strong, periodic magnetic variability in two previously discovered "super-weak field" magnetic white dwarfs, WD 2047+372 and WD 2359-434. WD 2047+372 has a mean longitudinal field that reverses between about -12 and + 15 kG, with a period of 0.243 d, while its mean field modulus appears nearly constant at 60 kG. The observations can be interpreted in terms of a dipolar field tilted with respect to the stellar rotation axis. WD 2359-434 always shows a weak positive longitudinal field with values between about 0 and + 12 kG, varying only weakly with stellar rotation, while the mean field modulus varies between about 50 and 100 kG. The rotation period is found to be 0.112 d using the variable shape of the Hα line core, consistent with available photometry. The field of this star appears to be much more complex than a dipole, and is probably not axisymmetric. Available photometry shows that WD 2359-434 is a light variable with an amplitude of only 0.005 mag; our own photometry shows that if WD 2047+372 is photometrically variable, the amplitude is below about 0.01 mag. These are the first models for magnetic white dwarfs with fields below about 100 kG based on magnetic measurements through the full stellar rotation. They reveal two very different magnetic surface configurations, and that, contrary to simple ohmic decay theory, WD 2359-434 has a much more complex surface field than the much younger WD 2047+372. Based, in part, on observations collected at the European Organisation for Astronomical Research in the Southern Hemisphere, Chile, under observing programmes 095.D-0264 and 097.D-0264, and obtained from the ESO/ST-ECF Science Archive Facility; in part, on observations made with the William Herschel Telescope, operated on the island of La Palma by the Isaac Newton Group in the Spanish Observatorio del Roque de los Muchachos of the Instituto de Astrofisica de Canarias; and in part on observations obtained at the Canada-France-Hawaii Telescope (CFHT) which is operated by the National Research Council of Canada, the Institut National des Sciences de l'Univers of the Centre National de la Recherche Scientifique of France, and the University of Hawaii.

A versatile palindromic amphipathic repeat coding sequence horizontally distributed among diverse bacterial and eucaryotic microbes

PubMed Central

2010-01-01

Background Intragenic tandem repeats occur throughout all domains of life and impart functional and structural variability to diverse translation products. Repeat proteins confer distinctive surface phenotypes to many unicellular organisms, including those with minimal genomes such as the wall-less bacterial monoderms, Mollicutes. One such repeat pattern in this clade is distributed in a manner suggesting its exchange by horizontal gene transfer (HGT). Expanding genome sequence databases reveal the pattern in a widening range of bacteria, and recently among eucaryotic microbes. We examined the genomic flux and consequences of the motif by determining its distribution, predicted structural features and association with membrane-targeted proteins. Results Using a refined hidden Markov model, we document a 25-residue protein sequence motif tandemly arrayed in variable-number repeats in ORFs lacking assigned functions. It appears sporadically in unicellular microbes from disparate bacterial and eucaryotic clades, representing diverse lifestyles and ecological niches that include host parasitic, marine and extreme environments. Tracts of the repeats predict a malleable configuration of recurring domains, with conserved hydrophobic residues forming an amphipathic secondary structure in which hydrophilic residues endow extensive sequence variation. Many ORFs with these domains also have membrane-targeting sequences that predict assorted topologies; others may comprise reservoirs of sequence variants. We demonstrate expressed variants among surface lipoproteins that distinguish closely related animal pathogens belonging to a subgroup of the Mollicutes. DNA sequences encoding the tandem domains display dyad symmetry. Moreover, in some taxa the domains occur in ORFs selectively associated with mobile elements. These features, a punctate phylogenetic distribution, and different patterns of dispersal in genomes of related taxa, suggest that the repeat may be disseminated by HGT and intra-genomic shuffling. Conclusions We describe novel features of PARCELs (Palindromic Amphipathic Repeat Coding ELements), a set of widely distributed repeat protein domains and coding sequences that were likely acquired through HGT by diverse unicellular microbes, further mobilized and diversified within genomes, and co-opted for expression in the membrane proteome of some taxa. Disseminated by multiple gene-centric vehicles, ORFs harboring these elements enhance accessory gene pools as part of the "mobilome" connecting genomes of various clades, in taxa sharing common niches. PMID:20626840

Waking and sleeping following water deprivation in the rat.

PubMed

Martelli, Davide; Luppi, Marco; Cerri, Matteo; Tupone, Domenico; Perez, Emanuele; Zamboni, Giovanni; Amici, Roberto

2012-01-01

Wake-sleep (W-S) states are affected by thermoregulation. In particular, REM sleep (REMS) is reduced in homeotherms under a thermal load, due to an impairment of hypothalamic regulation of body temperature. The aim of this work was to assess whether osmoregulation, which is regulated at a hypothalamic level, but, unlike thermoregulation, is maintained across the different W-S states, could influence W-S occurrence. Sprague-Dawley rats, kept at an ambient temperature of 24°C and under a 12 h∶12 h light-dark cycle, were exposed to a prolonged osmotic challenge of three days of water deprivation (WD) and two days of recovery in which free access to water was restored. Two sets of parameters were determined in order to assess: i) the maintenance of osmotic homeostasis (water and food consumption; changes in body weight and fluid composition); ii) the effects of the osmotic challenge on behavioral states (hypothalamic temperature (Thy), motor activity, and W-S states). The first set of parameters changed in WD as expected and control levels were restored on the second day of recovery, with the exception of urinary Ca(++) that almost disappeared in WD, and increased to a high level in recovery. As far as the second set is concerned, WD was characterized by the maintenance of the daily oscillation of Thy and by a decrease in activity during the dark periods. Changes in W-S states were small and mainly confined to the dark period: i) REMS slightly decreased at the end of WD and increased in recovery; ii) non-REM sleep (NREMS) increased in both WD and recovery, but EEG delta power, a sign of NREMS intensity, decreased in WD and increased in recovery. Our data suggest that osmoregulation interferes with the regulation of W-S states to a much lesser extent than thermoregulation.

The surviving companions in type Ia supernova remnants

NASA Astrophysics Data System (ADS)

Chen, Li-Qing; Meng, Xiang-Cun; Han, Zhan-Wen

2017-08-01

The single-degenerate (SD) model is one of the most popular progenitor models of type Ia supernovae (SNe Ia), in which the companion star can survive after an SN Ia explosion and show peculiar properties. Therefore, searching for the surviving companion in type Ia supernova remnants (SNRs) is a potential method to verify the SD model. In the SN 1604 remnant (Kepler’s SNR), although Chandra X-ray observation suggests that the progenitor is most likely a WD+AGB system, a the surviving companion has not been found. One possible reason is rapid rotation of the white dwarf (WD), causing explosion of the WD to be delayed for a spin-down timescale, and then the companion evolved into a WD before the supernova explosion, so the companion is too dim to be detected. We aim to verify this possible explanation by carrying out binary evolution calculations. In this paper, we use Eggleton’s stellar evolution code to calculate the evolution of binaries consisting of a WD+red giant (RG). We assume that the rapidly rotating WD can continuously increase its mass when its mass exceeds the Chandrasekhar mass limit ({M}{{Ch}}=1.378 {M}⊙ ) until the mass-transfer rate decreases to be lower than a critical value. Eventually, we obtain the final masses of a WD in the range 1.378 M ⊙ to 2.707 M ⊙. We also show that if the spin-down time is less than 106 yr, the companion star will be very bright and easily observed; but if the spin-down time is as long as ˜ 107 yr, the luminosities of the surviving companion would be lower than the detection limit. Our simulation provides guidance in hunting for the surviving companion stars in SNRs, and the fact that no surviving companion has been found in Kepler’s SNR may not be definite evidence disfavoring the SD origin of Kepler’s SN.

Recurrent 3-day cycles of water deprivation for over a month depress mating behaviour but not semen characteristics of adult rams.

PubMed

Khnissi, S; Lassoued, N; Rekik, M; Ben Salem, H

2016-02-01

This study aimed to investigate the effect of water deprivation (WD) on reproductive traits of rams. Ten mature rams were used and allocated to two groups balanced for body weight. Control (C) rams had free access to drinking water, while water-restricted rams (WD) were deprived from water for 3 consecutive days and early on the morning of day 4, they had ad libitum access to water for 24 h, similar to C animals. The experiment lasted 32 days, that is eight 4-day cycles of water deprivation and subsequent watering. Feed and water intake were significantly affected by water deprivation; in comparison with C rams, WD rams reduced their feed intake by 18%. During the watering day of the deprivation cycle, WD rams consumed more water than C rams on the same day (11.8 (SD = 3.37) and 8.4 (SD = 1.92) l respectively; p < 0.05). Glucose, total protein and creatinine were increased as a result of water deprivation. However, testosterone levels were lowered as a result of water deprivation and average values were 10.9 and 6.2 (SEM 1.23) ng/ml for C and WD rams respectively (p < 0.05). Semen traits were less affected by treatment; WD rams consistently had superior sperm concentrations than C animals; and statistical significances were reached in cycles 5 and 8 of water deprivation. Several mating behaviour traits were modified as a result of water deprivation. When compared to controls, WD rams had a more prolonged time to first mount attempt (p < 0.001), their frequency of mount attempts decreased [6.8 vs. 5.2 (SEM 0.1); p < 0.001] and their flehmen reaction intensity was negatively affected (p < 0.05). Water deprivation may have practical implications reducing the libido and therefore the serving capacity of rams under field conditions. Journal of Animal Physiology and Animal Nutrition © 2015 Blackwell Verlag GmbH.

Maternal Western diet during gestation and lactation modifies adult offspring's cognitive and hedonic brain processes, behavior, and metabolism in Yucatan minipigs.

PubMed

Gautier, Yentl; Luneau, Isabelle; Coquery, Nicolas; Meurice, Paul; Malbert, Charles-Henri; Guerin, Sylvie; Kemp, Bas; Bolhuis, J Elizabeth; Clouard, Caroline; Le Huërou-Luron, Isabelle; Blat, Sophie; Val-Laillet, David

2018-06-13

This study explores the long-term effects of exposure to a maternal Western diet (WD) vs. standard diet (SD) in the Yucatan minipig, on the adult progeny at lean status ( n = 32), and then overweight status. We investigated eating behavior, cognitive abilities, brain basal glucose metabolism, dopamine transporter availability, microbiota activity, blood lipids, and glucose tolerance. Although both groups demonstrated similar cognitive abilities in a holeboard test, WD pigs expressed a higher stress level than did SD pigs (immobility, P < 0.05) and lower performance in an alley maze ( P = 0.06). WD pigs demonstrated lower dopamine transporter binding potential in the hippocampus and parahippocampal cortex ( P < 0.05 for both), as well as a trend in putamen ( P = 0.07), associated with lower basal brain activity in the prefrontal cortex and nucleus accumbens ( P < 0.05) compared with lean SD pigs. Lean WD pigs demonstrated a lower glucose tolerance than did SD animals (higher glucose peak, P < 0.05) and a tendency to a higher incremental area under the curve of insulin from 0 to 30 minutes after intravenous glucose injection ( P < 0.1). Both groups developed glucose intolerance with overweight, but WD animals were less impacted than SD animals. These results demonstrate that maternal diet shaped the offspring's brain functions and cognitive responses long term, even after being fed a balanced diet from weaning, but behavioral effects were only revealed in WD pigs under anxiogenic situation; however, WD animals seemed to cope better with the obesogenic diet from a metabolic standpoint.-Gautier, Y., Luneau, I., Coquery, N., Meurice, P., Malbert, C.-H., Guerin, S., Kemp, B., Bolhuis, J. E., Clouard, C., Le Huërou-Luron, I., Blat, S., Val-Laillet, D. Maternal Western diet during gestation and lactation modifies adult offspring's cognitive and hedonic brain processes, behavior, and metabolism in Yucatan minipigs.

X-ray reflection from cold white dwarfs in magnetic cataclysmic variables

NASA Astrophysics Data System (ADS)

Hayashi, Takayuki; Kitaguchi, Takao; Ishida, Manabu

2018-02-01

We model X-ray reflection from white dwarfs (WDs) in magnetic cataclysmic variables (mCVs) using a Monte Carlo simulation. A point source with a power-law spectrum or a realistic post-shock accretion column (PSAC) source irradiates a cool and spherical WD. The PSAC source emits thermal spectra of various temperatures stratified along the column according to the PSAC model. In the point-source simulation, we confirm the following: a source harder and nearer to the WD enhances the reflection; higher iron abundance enhances the equivalent widths (EWs) of fluorescent iron Kα1, 2 lines and their Compton shoulder, and increases the cut-off energy of a Compton hump; significant reflection appears from an area that is more than 90° apart from the position right under the point X-ray source because of the WD curvature. The PSAC simulation reveals the following: a more massive WD basically enhances the intensities of the fluorescent iron Kα1, 2 lines and the Compton hump, except for some specific accretion rate, because the more massive WD makes a hotter PSAC from which higher-energy X-rays are preferentially emitted; a larger specific accretion rate monotonically enhances the reflection because it makes a hotter and shorter PSAC; the intrinsic thermal component hardens by occultation of the cool base of the PSAC by the WD. We quantitatively estimate the influences of the parameters on the EWs and the Compton hump with both types of source. We also calculate X-ray modulation profiles brought about by the WD spin. These depend on the angles of the spin axis from the line of sight and from the PSAC, and on whether the two PSACs can be seen. The reflection spectral model and the modulation model involve the fluorescent lines and the Compton hump and can directly be compared to the data, which allows us to estimate these geometrical parameters with unprecedented accuracy.

Rapid weight gain in professional boxing and correlation with fight decisions: analysis from 71 title fights.

PubMed

Daniele, Gianlorenzo; Weinstein, Richard N; Wallace, Paul Wesley; Palmieri, Vincenzo; Bianco, Massimiliano

2016-11-01

Boxing is a sport where athletes compete in several weight categories. Professional boxers typically dehydrate to cut their weight for the weigh-in (24 h before the contest) and then rehydrate before the fight. The International Boxing Federation (IBF) mandates a second weigh-in 12 h before the fight. Our objectives were: 1) To quantify the weight gain (WG) from the 1st to the 2nd weigh-in; 2) to investigate whether rapid WG affects boxing performance (win/loss rate) and 3) whether weight discrepancy (WD) 15 between boxers exposes them to increased health risks (rate of fights ended before time limit). From official weigh-in reports of 71 IBF fights (142 fighters) the following data were gathered/calculated for each boxer: age, weight division, 1st weight, 2nd weight, WG between weigh-ins (kg and %), WD between opponents, and fight decision. Between the weigh-ins, the average WG was 2.52 ± 1.37 kg (range -0.3/6.4 kg) and 3.8 ± 2.2% of the initial body weight (range -0.4/9.3%) and the average WD 1.94 ± 1.50 kg (maximum 7.10 kg). Both WG and WD did not affect match outcomes. We observed tendencies for higher loss rate among boxers gaining more weight, and for higher victory rate in boxers with larger WD, however without reaching significance. A significant negative correlation was found between the 1st weight and the WG, both in absolute (r = -0.278, p = 0.001) and relative value (r = -0.497, p < 0.0001). Although correlations between WG, WD and boxing performance were not found, single cases with an alarming high WG and WD were noted.

e-Care for heart wellness: a feasibility trial to decrease blood pressure and cardiovascular risk.

PubMed

Green, Beverly B; Anderson, Melissa L; Cook, Andrea J; Catz, Sheryl; Fishman, Paul A; McClure, Jennifer B; Reid, Robert J

2014-04-01

Pharmacist- or nurse-led team care decreases patient blood pressure (BP) and cardiovascular disease (CVD) risk. To evaluate whether a Web-based dietitian-led (WD) team care intervention was feasible and resulted in decreased BP, CVD risk, and weight compared to usual care (UC). Electronic health record (EHR) data identified patients aged 30-69 years with BMI >26, elevated BP, and 10%-25% 10-year Framingham CVD risk who were registered patient website users. Patients with uncontrolled BP at screening were randomized to UC or WD, which included a home BP monitor, scale, and dietitian team care. WD participants had a single in-person dietitian visit to obtain baseline information and create a plan to reduce CVD risk. Planned follow-up occurred via secure messaging to report BP, weight, and fruit and vegetable intake and receive ongoing feedback. If needed, dietitians encouraged patients and their physicians to intensify antihypertensive and lipid-lowering medications. Primary outcomes were change in systolic BP and weight loss ≥4 kg at 6 months. Feasibility outcomes included intervention utilization and satisfaction. Between 2010 and 2011, a total of 90 of 101 participants completed 6-month follow-ups. The WD group had higher rates of secure messaging utilization and patient satisfaction. The WD group lost significantly more weight than the UC group (adjusted net difference=-3.2 kg, 95% CI=-5.0, -1.5, p<0.001) and was more likely to lose ≥4 kg (adjusted relative risk [RRadj]=2.96, 95% CI=1.16, 7.53). BP control and CVD risk reduction were greater in WD than UC, but differences were not statistically significant. WD intervention was feasible and resulted in decreased weight, BP, and CVD risk. A larger trial is justified. Trial Registration Number: NCT01077388. Copyright © 2014 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.

Dose Accuracy and Injection Force of Different Insulin Glargine Pens

PubMed Central

Friedrichs, Arnd; Bohnet, Janine; Korger, Volker; Adler, Steffen; Schubert-Zsilavecz, Manfred; Abdel-Tawab, Mona

2013-01-01

Background Dose accuracy and injection force, representing key parameters of insulin pens, were determined for three pens delivering insulin glargine-based copies, Pen Royale (WR) and DispoPen (WD) for Glaritus® (Wockhardt) and GanLee Pen (GL) for Basalin® (Gan & Lee), compared with pens of the originator, ClikSTAR® (CS) and S o l o S TA R® (SS) for Lantus® (Sanofi) . Methods Using the weighing procedure recommended by DIN EN ISO 11608–1:2000, dose accuracy was evaluated based on nonrandomized delivery of low (5 U), mid (30 U), and high (60 U) dosage levels. Injection force was measured by dispensing the maximum dose of insulin (60 U for the GL, WR, and WD; 80 U for the SS and CS) at dose speeds of 6 and 10 U/s. Results All tested pens delivered comparable average doses within the DIN EN ISO 11608–1:2000 limits at all dosage levels. The GL revealed a higher coefficient of variation (CV) at 5 U, and the WR and WD had higher CVs at all dosage levels compared with the CS and SS. Injection force was higher for the WR, WD, and GL compared with the CS and SS at both dose speeds. In contrast to the CS and SS with an end-of-content feature, doses exceeding the remaining insulin could be dialed with the WR, GL, and WD and, apparently, dispensed with the WD. Conclusions All pens fulfilled the dose accuracy requirements defined by DIN EN ISO 11608–1:2000 standards at all three dosage levels, with the WR, WD, and GL showing higher dosage variability and injection force compared with the SS and CS. Thus, the devices that deliver insulin glargine copies show different performance characteristics compared with the originator. J Diabetes Sci Technol 2013;7(5):1346–1353 PMID:24124963

A short history of diagnostic tests for von Willebrand disease: in memory of Barry Firkin (1930 to 2001) and Ted Zimmerman (1937 to 1988).

PubMed

Koutts, Jerry

2006-07-01

By the end of the 1960s, von Willebrand disease (vWD) was accepted as a combined deficiency of factor (F) VIII coagulation and a plasma factor responsible for normal platelet adhesion. Just how these two functions related to each other was unclear, and the diagnostic tests available at the time were poorly reproducible, cumbersome, and unreliable. As a consequence, the condition was poorly delineated from other coagulation and platelet disorders. In the early 1970s, ristocetin-induced platelet aggregation was described and formed the basis of the first consistent and reliable test that quantified the platelet adhesive function missing in vWD. Immunoprecipitating techniques specific for the molecule missing in vWD were defined. The application of these technologies allowed a clearer understanding of the heterogeneity of vWD and continues to form a basis for the diagnosis of this condition. Concurrently, exploration of the structure and function of von Willebrand factor (vWF) has contributed greatly to the understanding of platelet physiology, ligand receptor interaction, and pathways of cellular interaction and activation. Despite all of the progress during the last 35 years, including extensive developments in the field of molecular biology and genetics of vWD, the diagnosis of this condition in many, if not most cases, remains controversial. The final plasma level of vWF is influenced substantially by epigenetic and environmental factors. This natural heterogeneity is further compounded by significant imprecision of existing tests. As a consequence, defining vWD on the basis of a variation from the normal range alone is more than likely to be incorrect. The high frequency of a positive bleeding disorder in the normal population does not assist discrimination. It has been suggested that the diagnosis of mild type 1 vWD be discarded because it does not exhibit consistent linkage to the VWF gene and does not predict bleeding.

Global Liver Gene Expression Analysis on a Murine Metabolic Syndrome Model Treated by Low-molecular-weight Lychee Fruit Polyphenol (Oligonol®).

PubMed

Uchiyama, Hironobu; Uehara, Kaori; Nagashima, Takayuki; Nakata, Akifumi; Sato, Keisuke; Mihara, Yoshihiro; Komatsu, Ken-Ich; Takanari, Jun; Shimizu, Shigeomi; Wakame, Koji

2016-07-01

Oligonol® (OLG) is a low-molecular-weight lychee fruit polyphenol mainly containing catechin-type monomers and oligomers of proanthocyanidins. Dietary OLG supplementation reportedly improves lipid metabolism disorder and lowers the visceral fat level in animal and human studies. Thus, we investigated the mechanism behind the protective and beneficial effects of OLG on a Western diet (WD)-induced metabolic syndrome (MetS) of a murine model. Using the C57BL/6J mouse for the MetS model, mice were divided into three groups: control (normal diet: ND), Western diet (WD) and WD + 0.5% OLG (OLG) groups. The WD group was fed a high-calorie (high fructose plus high fat) diet for 12 weeks to develop MetS. At week 12, all mice were sacrificed and the blood and liver were obtained for histological and biological examinations and RNA sequencing (RNA-Seq). Body weight, liver weight, plasma triglycerides (TG), total cholesterol (T-Cho) and alanine aminotransferase (ATS) levels of both OLG groups were significantly lower than those of the WD group. On histological examination of the liver, the area of fatty deposits was shown to be suppressed by OLG administration. Expression gene analysis in the liver of WD- versus OLG-fed mice by RNA-Seq showed that 464/45,706 genes exhibited a significant change of expression (corrected p-value <0.05, absolute value of fold change (FC) ≥2). Gene network analysis showed that genes related to hepatic steatosis, liver inflammation and tumor invasion were inactivated in the OLG group. In particular, the lipid metabolism-related genes Lpin1, Adig and Cidea were regulated by OLG administration. OLG may function to suppress MetS and the progression of geriatric diseases in WD-fed mice by regulating the expression of lipid metabolism, inflammation and tumor-related genes in the liver. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Laser therapy

MedlinePlus

... Remove tumors Lasers are also often used during skin surgery . ... 4. James WD, Berger TG, Elston DM. Cutaneous laser surgery. In: James WD, Berger TG, Elston DM, eds. Andrews' Diseases of the Skin: Clinical Dermatology. 12th ed. Philadelphia, PA: Elsevier; 2016: ...

Discovery of Three Self-lensing Binaries from Kepler

NASA Astrophysics Data System (ADS)

Kawahara, Hajime; Masuda, Kento; MacLeod, Morgan; Latham, David W.; Bieryla, Allyson; Benomar, Othman

2018-03-01

We report the discovery of three edge-on binaries with white dwarf (WD) companions that gravitationally magnify (instead of eclipsing) the light of their stellar primaries, as revealed by a systematic search for pulses with long periods in the Kepler photometry. We jointly model the self-lensing light curves and radial-velocity orbits to derive the WD masses, all of which are close to 0.6 solar masses. The orbital periods are long, ranging from 419 to 728 days, and the eccentricities are low, all less than 0.2. These characteristics are reminiscent of the orbits found for many blue stragglers in open clusters and the field, for which stable mass transfer due to Roche-lobe overflow from an evolving primary (now a WD) has been proposed as the formation mechanism. Because the actual masses for our three WD companions have been accurately determined, these self-lensing systems would provide excellent tests for models of interacting binaries.

Explosive nucleosynthesis in tidal disruption events of massive white dwarfs, and their debris

NASA Astrophysics Data System (ADS)

Tanikawa, Ataru; Sato, Yushi; Nomoto, Ken'Ichi; Maeda, Keiichi; Nakasato, Naohito; Hachisu, Izumi

We perform SPH simulations coupled with nuclear reactions to follow tidal disruption events (TDEs) of white dwarfs (WDs) by intermediate mass black holes (IMBHs). We consider an oxygen-neon-magnesium (ONeMg) WD with 1.2M ⊙ as well as a helium (He) WD with 0.3M ⊙, and a carbon-oxygen (CO) WD with 0.6M ⊙. Our WD models have different numbers of SPH particles, N, up to a few 10 million. We find that nucleosynthesis does not converge against N even for N > 107. For all the WDs, the amount of radioactive nuclei, such as 56Ni, decreases with increasing N. Nuclear reactions might be extinguished for infinitely large N. Our results show that these kinds of TDEs, if solely powered by radioactive decays, are much dimmer optical transients similar to Type Ia supernovae as previously suggested.

CAN HELIUM ENVELOPES CHANGE THE OUTCOME OF DIRECT WHITE DWARF COLLISIONS?

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

Holcomb, Cole; Kushnir, Doron

2016-08-01

A pivotal feature for the viability of white dwarf (WD) collisions as SN Ia progenitors is that a significant fraction of the mass is highly compressed to the densities required for efficient {sup 56}Ni production before the ignition of the detonation wave. Previous studies have employed model WDs composed of carbon–oxygen (CO), whereas WDs typically have a non-negligible helium envelope. Given that helium is more susceptible to explosive burning than CO under the conditions of WD collision, a legitimate concern is whether or not early time He detonation ignition can lead to early time CO detonation, drastically reducing {sup 56}Nimore » synthesis. We investigate the role of He in determining the fate of WD collisions by performing a series of two-dimensional hydrodynamics calculations. We find that a necessary condition for non-trivial reduction of the CO ignition time is that the He detonation birthed in the contact region successfully propagates into the unshocked shell. We determine the minimal He shell mass as a function of the total WD mass that upholds this condition. Although we utilize a simplified reaction network similar to those used in previous studies, our findings are in good agreement with detailed investigations concerning the impact of network size on He shell detonations. This allows us to extend our results to the case with more realistic burning physics. Based on the comparison of these findings against evolutionary calculations of WD compositions, we conclude that most, if not all, WD collisions will not be drastically impacted by their intrinsic He components.« less

Western diets induce blood-brain barrier leakage and alter spatial strategies in rats.

PubMed

Hargrave, Sara L; Davidson, Terry L; Zheng, Wei; Kinzig, Kimberly P

2016-02-01

Western diet (WD) intake induces obesity and metabolic dysfunction. The present study examined the effects of WD on hippocampal-dependent cognitive functioning and blood-brain barrier (BBB) permeability as a function of exposure duration, obesity phenotype, and peripheral markers of energy regulation. The use of hippocampal-dependent "place" or hippocampal-independent "response" strategies in a Y maze was assessed in male rats following 10, 40, and 90 days of WD exposure in diet-induced obese (DIO) rats, in diet resistant (DR) rats that are relatively insensitive to the obesogenic properties of WD, and in chow-fed controls. Insulin, glucose, and BBB permeability throughout several loci in the hippocampus, striatum, and cerebellum were evaluated in relation to duration of WD exposure, obesity phenotype, and type of strategy used. DIO rats had increased body weight and adiposity throughout the study, and elevated 10-day glucose and 90-day insulin levels. Throughout the study, chow-fed and DR rats reliably relied on a place strategy. DIO rats, in contrast, favored a response strategy at the 10- and 90-day time points. BBB leakage was observed in the dorsal striatum and multiple subregions of the hippocampus of DIO, but not DR or chow-fed rats. Increased ventral hippocampal BBB permeability and blood glucose levels were associated with reduced place strategy use. These data indicate that WD-induced BBB leakage is dependent on duration of diet exposure as well as obesity phenotype, and implicates BBB leakage and impaired glucoregulation in behavioral strategy and cognitive performance. (c) 2016 APA, all rights reserved).

Reconciling Optical and Radio Observations of the Binary Millisecond Pulsar PSR J1640+2224

NASA Astrophysics Data System (ADS)

Vigeland, Sarah J.; Deller, Adam T.; Kaplan, David L.; Istrate, Alina G.; Stappers, Benjamin W.; Tauris, Thomas M.

2018-03-01

Previous optical and radio observations of the binary millisecond pulsar PSR J1640+2224 have come to inconsistent conclusions about the identity of its companion, with some observations suggesting that the companion is a low-mass helium-core (He-core) white dwarf (WD), while others indicate that it is most likely a high-mass carbon–oxygen (CO) WD. Binary evolution models predict PSR J1640+2224 most likely formed in a low-mass X-ray binary based on the pulsar’s short spin period and long-period, low-eccentricity orbit, in which case its companion should be a He-core WD with mass about 0.35–0.39 M ⊙, depending on metallicity. If instead it is a CO WD, it would suggest that the system has an unusual formation history. In this paper we present the first astrometric parallax measurement for this system from observations made with the Very Long Baseline Array (VLBA), from which we determine the distance to be {1520}-150+170 {pc}. We use this distance and a reanalysis of archival optical observations originally taken in 1995 with the Wide Field Planetary Camera 2 on the Hubble Space Telescope (HST) to measure the WD’s mass. We also incorporate improvements in calibration, extinction model, and WD cooling models. We find that the existing observations are not sufficient to tightly constrain the companion mass, but we conclude the WD mass is >0.4 M ⊙ with >90% confidence. The limiting factor in our analysis is the low signal-to-noise ratio of the original HST observations.

Comparison of Validated Assessment Scales and 3D digital fringe projection method to assess lifetime development of wrinkles in men.

PubMed

Luebberding, Stefanie; Krueger, Nils; Kerscher, Martina

2014-02-01

The assessment of wrinkle severity is an important evaluation criterion to determine the efficacy of aesthetic treatments. Aim of the present study was to compare Validated Assessment Scales (VAS) and 3D fringe projection (PRIMOS(®) ) for the evaluation of facial wrinkles in men and to determine standard values for each level of the VAS. 150 male subjects (20 to 70 years) were selected following strict criteria. Wrinkle severity at periorbital, glabella and forehead lines was evaluated using the 3D fringe projection and 5-point photonumeric VAS. The results of both methods were matched by determining quantitative values for each level of the clinical rating scale. High average correlation with age was found for VAS, Wd, maxWd, lWd, Wv, aWa and pWa. With a Wd of 60 to 70μm crow's feet and forehead lines are pronounced first, whereas glabella lines develop in subject's mid-forties, by an Wd of 180μm. Wrinkle severity increases at all locations every 10 years of age by one level of the VAS. This increase corresponds to an increase of Wd about 100 μm at glabella and forehead lines, and about 50 μm at crow's feet. The presented reference values for the Validated Assessment Scale are an important step towards an optimized assessment of skin aging and aesthetic dermatological treatments. The data helps to combine the precession of a biophysical measurement with the practical relevance of a clinical rating. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Docosahexaenoic acid attenuates Western diet-induced hepatic fibrosis in Ldlr−/− mice by targeting the TGFβ-Smad3 pathway[S

PubMed Central

Lytle, Kelli A.; Depner, Christopher M.; Wong, Carmen P.; Jump, Donald B.

2015-01-01

DHA (22:6,ω3), but not EPA (20:5,ω3), attenuates Western diet (WD)-induced hepatic fibrosis in a Ldlr−/− mouse model of nonalcoholic steatohepatitis. We examined the molecular basis for the differential effect of dietary EPA and DHA on WD-induced hepatic fibrosis. DHA was more effective than EPA at preventing WD-induced effects on hepatic transcripts linked to fibrosis, including collagen 1A1 (Col1A1), transforming growth factor-β (TGFβ) signaling and proteins involved in remodeling the extracellular matrix, including metalloproteases, tissue inhibitors of metalloproteases, and lysyl oxidase subtypes. Examination of the TGFβ pathway showed that mice fed the WD supplemented with either olive oil or EPA had a significant (≥2.5-fold) increase in hepatic nuclear abundance of phospho-mothers against decapentaplegic homolog (Smad)3 when compared with mice fed the reference diet (RD); Smad3 is a key regulator of Col1A1 expression in stellate cells. In contrast, mice fed the WD supplemented with DHA had no increase in phospho-Smad3 when compared with mice fed the RD. Changes in hepatic phospho-Smad3 nuclear content correlated with proCol1A1 mRNA and protein abundance. Pretreatment of human LX2 stellate cells with DHA, but not other unsaturated fatty acids, blocked TGFβ1-mediated induction of Col1A1. In conclusion, DHA attenuates WD-induced fibrosis by targeting the TGFβ-Smad3-Col1A1 pathway in stellate cells. PMID:26315048

Water resources sensitivity to the isolated effects of land use, water demand and climate change under 2 degree global warming

NASA Astrophysics Data System (ADS)

Bisselink, Berny; Bernhard, Jeroen; de Roo, Ad

2017-04-01

One of the key impacts of global change are the future water resources. These water resources are influenced by changes in land use (LU), water demand (WD) and climate change. Recent developments in scenario modelling opened new opportunities for an integrated assessment. However, for identifying water resource management strategies it is helpful to focus on the isolated effects of possible changes in LU, WD and climate that may occur in the near future. In this work, we quantify the isolated contribution of LU, WD and climate to the integrated total water resources assuming a linear model behavior. An ensemble of five EURO-CORDEX RCP8.5 climate projections for the 31-year periods centered on the year of exceeding the global-mean temperature of 2 degree is used to drive the fully distributed hydrological model LISFLOOD for multiple river catchments in Europe. The JRC's Land Use Modelling Platform LUISA was used to obtain a detailed pan-European reference land use scenario until 2050. Water demand is estimated based on socio-economic (GDP, population estimates etc.), land use and climate projections as well. For each climate projection, four model runs have been performed including an integrated (LU, WD and climate) simulation and other three simulations to isolate the effect of LU, WD and climate. Changes relative to the baseline in terms of water resources indicators of the ensemble means of the 2 degree warming period and their associated uncertainties will reveal the integrated and isolated effect of LU, WD and climate change on water resources.

The end of the White Dwarf Cooling Sequence of NGC 6752

NASA Astrophysics Data System (ADS)

Bedin, Luigi

2017-08-01

We propose to study the last HST-accessible white dwarf (WD) cooling sequence (CS) for a nearby globular cluster (GC), the chemically complex, extreme blue horizontal branch cluster NGC 6752. Over 97% of stars end their lives as WDs, and the WD CS provides constraints not only on the age, but also potentially the star formation history of a GC. The CS of WDs also lies in the least-explored region of the color-magnitude diagram of old stellar populations. Recent deep imaging with HST has successfully reached the end of the WD CS in only three classical old GCs, M4, NGC 6397 and 47 Tuc, and reveals an unexpectedly complex, and double-peaked, WD CS in the metal rich old open cluster NGC 6791. One more investigation is in progress on the massive globular Omega Centauri, where over 14 sub-populations are known to exist.While almost every cluster is known to host multiple populations, every single cluster is unique. NGC 6752 is a bridge between the relatively simple globular clusters, and Omega Cen, the most complex globular cluster known. NGC 6752 has an extended blue horizontal branch, a collapsed core and 3 chemically distinct populations. It is our last chance to add diversity to our very limited sample of WD CS, so far containing only 3 globular clusters, one old open cluster, and the complex Omega Cen system. We need to undertake this investigation while HST is still operational, as there is no foreseeable opportunity in the post-HST era to have one extra WD CS in the homogeneus optical photometric system of HST.

High-fat, high-fructose, high-cholesterol feeding causes severe NASH and cecal microbiota dysbiosis in juvenile Ossabaw swine.

PubMed

Panasevich, M R; Meers, G M; Linden, M A; Booth, F W; Perfield, J W; Fritsche, K L; Wankhade, Umesh D; Chintapalli, Sree V; Shankar, K; Ibdah, J A; Rector, R S

2018-01-01

Pediatric obesity and nonalcoholic steatohepatitis (NASH) are on the rise in industrialized countries, yet our ability to mechanistically examine this relationship is limited by the lack of a suitable higher animal models. Here, we examined the effects of high-fat, high-fructose corn syrup, high-cholesterol Western-style diet (WD)-induced obesity on NASH and cecal microbiota dysbiosis in juvenile Ossabaw swine. Juvenile female Ossabaw swine (5 wk old) were fed WD (43.0% fat; 17.8% high-fructose corn syrup; 2% cholesterol) or low-fat diet (CON/lean; 10.5% fat) for 16 wk ( n = 6 each) or 36 wk ( n = 4 each). WD-fed pigs developed obesity, dyslipidemia, and systemic insulin resistance compared with CON pigs. In addition, obese WD-fed pigs developed severe NASH, with hepatic steatosis, hepatocyte ballooning, inflammatory cell infiltration, and fibrosis after 16 wk, with further exacerbation of histological inflammation and fibrosis after 36 wk of WD feeding. WD feeding also resulted in robust cecal microbiota changes including increased relative abundances of families and genera in Proteobacteria ( P < 0.05) (i.e., Enterobacteriaceae, Succinivibrionaceae, and Succinivibrio) and LPS-containing Desulfovibrionaceae and Desulfovibrio and a greater ( P < 0.05) predicted microbial metabolic function for LPS biosynthesis, LPS biosynthesis proteins, and peptidoglycan synthesis compared with CON-fed pigs. Overall, juvenile Ossabaw swine fed a high-fat, high-fructose, high-cholesterol diet develop obesity and severe microbiota dysbiosis with a proinflammatory signature and a NASH phenotype directly relevant to the pediatric/adolescent and young adult population.

Models for Predicting the Biomass of Cunninghamialanceolata Trees and Stands in Southeastern China

PubMed Central

Saeed, Sajjad

2017-01-01

Using existing equations to estimate the biomass of a single tree or a forest stand still involves large uncertainties. In this study, we developed individual-tree biomass models for Chinese Fir (Cunninghamia lanceolata.) stands in Fujian Province, southeast China, by using 74 previously established models that have been most commonly used to estimate tree biomass. We selected the best fit models and modified them. The results showed that the published model ln(B(Biomass)) = a + b * ln(D) + c * (ln(H))2 + d * (ln(H))3 + e * ln(WD) had the best fit for estimating the tree biomass of Chinese Fir stands. Furthermore, we observed that variables D(diameter at breast height), H (height), and WD(wood density)were significantly correlated with the total tree biomass estimation model. As a result, a natural logarithm structure gave the best estimates for the tree biomass structure. Finally, when a multi-step improvement on tree biomass model was performed, the tree biomass model with Tree volume(TV), WD and biomass wood density conversion factor (BECF),achieved the highest simulation accuracy, expressed as ln(TB) = −0.0703 + 0.9780 * ln(TV) + 0.0213 * ln(WD) + 1.0166 * ln(BECF). Therefore, when TV, WD and BECF were combined with tree biomass volume coefficient bi for Chinese Fir, the stand biomass (SB)model included both volume(SV) and coefficient bi variables of the stand as follows: bi = Exp(−0.0703+0.9780*ln(TV)+0.0213 * ln(WD)+1.0166*ln(BECF)). The stand biomass model is SB = SV/TV * bi. PMID:28095512

Models for Predicting the Biomass of Cunninghamialanceolata Trees and Stands in Southeastern China.

PubMed

Guangyi, Mei; Yujun, Sun; Saeed, Sajjad

2017-01-01

Using existing equations to estimate the biomass of a single tree or a forest stand still involves large uncertainties. In this study, we developed individual-tree biomass models for Chinese Fir (Cunninghamia lanceolata.) stands in Fujian Province, southeast China, by using 74 previously established models that have been most commonly used to estimate tree biomass. We selected the best fit models and modified them. The results showed that the published model ln(B(Biomass)) = a + b * ln(D) + c * (ln(H))2 + d * (ln(H))3 + e * ln(WD) had the best fit for estimating the tree biomass of Chinese Fir stands. Furthermore, we observed that variables D(diameter at breast height), H (height), and WD(wood density)were significantly correlated with the total tree biomass estimation model. As a result, a natural logarithm structure gave the best estimates for the tree biomass structure. Finally, when a multi-step improvement on tree biomass model was performed, the tree biomass model with Tree volume(TV), WD and biomass wood density conversion factor (BECF),achieved the highest simulation accuracy, expressed as ln(TB) = -0.0703 + 0.9780 * ln(TV) + 0.0213 * ln(WD) + 1.0166 * ln(BECF). Therefore, when TV, WD and BECF were combined with tree biomass volume coefficient bi for Chinese Fir, the stand biomass (SB)model included both volume(SV) and coefficient bi variables of the stand as follows: bi = Exp(-0.0703+0.9780*ln(TV)+0.0213 * ln(WD)+1.0166*ln(BECF)). The stand biomass model is SB = SV/TV * bi.

Docosahexaenoic acid blocks progression of western diet-induced nonalcoholic steatohepatitis in obese Ldlr-/- mice

PubMed Central

Lytle, Kelli A.; Wong, Carmen P.

2017-01-01

Background Nonalcoholic fatty liver disease (NAFLD) is a major public health concern in western societies. Nonalcoholic steatohepatitis (NASH), the progressive form of NAFLD, is characterized by hepatic steatosis, inflammation, oxidative stress and fibrosis. NASH is a risk factor for cirrhosis and hepatocellular carcinoma. NASH is predicted to be the leading cause of liver transplants by 2020. Despite this growing public health concern, there remain no Food and Drug Administration (FDA) approved NASH treatments. Using Ldlr -/- mice as a preclinical model of western diet (WD)-induced NASH, we previously established that dietary supplementation with docosahexaenoic acid (DHA, 22:6,ω3) attenuated WD-induced NASH in a prevention study. Herein, we evaluated the capacity of DHA supplementation of the WD and a low fat diet to fully reverse NASH in mice with pre-existing disease. Methods Ldlr -/- mice fed the WD for 22 wks developed metabolic syndrome (MetS) and a severe NASH phenotype, including obesity, dyslipidemia, hyperglycemia, hepatic steatosis, inflammation, fibrosis and low hepatic polyunsaturated fatty acid (PUFA) content. These mice were randomized to 5 groups: a baseline group (WDB, sacrificed at 22 wks) and 4 treatments: 1) WD + olive oil (WDO); 2) WD + DHA (WDD); 3) returned to chow + olive oil (WDChO); or 4) returned to chow + DHA (WDChD). The four treatment groups were maintained on their respective diets for 8 wks. An additional group was maintained on standard laboratory chow (Reference Diet, RD) for the 30-wk duration of the study. Results When compared to the WDB group, the WDO group displayed increased hepatic expression of genes linked to inflammation (Opn, Il1rn, Gdf15), hepatic fibrosis (collagen staining, Col1A1, Thbs2, Lox) reflecting disease progression. Mice in the WDD group, in contrast, had increased hepatic C20-22 ω3 PUFA and no evidence of NASH progression. MetS and NASH markers in the WDChO or WDChD groups were significantly attenuated and marginally different from the RD group, reflecting disease remission. Conclusion While these studies establish that DHA supplementation of the WD blocks WD-induced NASH progression, DHA alone does not promote full remission of diet-induced MetS or NASH. PMID:28422962

Evolution of genes and repeats in the Nimrod superfamily.

PubMed

Somogyi, Kálmán; Sipos, Botond; Pénzes, Zsolt; Kurucz, Eva; Zsámboki, János; Hultmark, Dan; Andó, István

2008-11-01

The recently identified Nimrod superfamily is characterized by the presence of a special type of EGF repeat, the NIM repeat, located right after a typical CCXGY/W amino acid motif. On the basis of structural features, nimrod genes can be divided into three types. The proteins encoded by Draper-type genes have an EMI domain at the N-terminal part and only one copy of the NIM motif, followed by a variable number of EGF-like repeats. The products of Nimrod B-type and Nimrod C-type genes (including the eater gene) have different kinds of N-terminal domains, and lack EGF-like repeats but contain a variable number of NIM repeats. Draper and Nimrod C-type (but not Nimrod B-type) proteins carry a transmembrane domain. Several members of the superfamily were claimed to function as receptors in phagocytosis and/or binding of bacteria, which indicates an important role in the cellular immunity and the elimination of apoptotic cells. In this paper, the evolution of the Nimrod superfamily is studied with various methods on the level of genes and repeats. A hypothesis is presented in which the NIM repeat, along with the EMI domain, emerged by structural reorganizations at the end of an EGF-like repeat chain, suggesting a mechanism for the formation of novel types of repeats. The analyses revealed diverse evolutionary patterns in the sequences containing multiple NIM repeats. Although in the Nimrod B and Nimrod C proteins show characteristics of independent evolution, many internal NIM repeats in Eater sequences seem to have undergone concerted evolution. An analysis of the nimrod genes has been performed using phylogenetic and other methods and an evolutionary scenario of the origin and diversification of the Nimrod superfamily is proposed. Our study presents an intriguing example how the evolution of multigene families may contribute to the complexity of the innate immune response.

Research on Fire-Resistant Diesel Fuel.

DTIC Science & Technology

1981-12-01

1[ >1 1? 1F RESEARCH ON FIRE-RESISTANT DIESEL FUEL INTERIM REPORT AFLRL No. 145 By W.D. Weatherford, Jr. G.E. Fodor M.D. Kanakia D.W. Naegeli B.R...GRANT NUMBER(S) W.D. Weatherford, Jr., G.E. Fodor, DAAK7O-80-C-OOO1 M.D. Kanakia, D.W. Naegeli , B.R. Wright (AFLRL) DAAK7O-82-C-OOO1 andF.W...Filters in Fuel Systems of U.S. Army Vehicles I:I , i , , , =- 111 REFERENCES 1. Weatherford, W.D., Jr. Fodor, G.E., Naegeli , D.W., Owens, E.C., Wright

Performance index: An expeditious tool to screen for improved drought resistance in the Lathyrus genus.

PubMed

Silvestre, Susana; Araújo, Susana de Sousa; Vaz Patto, Maria Carlota; Marques da Silva, Jorge

2014-07-01

Some species of the Lathyrus genus are among the most promising crops for marginal lands, with high resilience to drought, flood, and fungal diseases, combined with high yields and seed nutritional value. However, lack of knowledge on the mechanisms underlying its outstanding performance and methodologies to identify elite genotypes has hampered its proper use in breeding. Chlorophyll a fast fluorescence transient (JIP test), was used to evaluate water deficit (WD) resistance in Lathyrus genus. Our results reveal unaltered photochemical values for all studied genotypes showing resistance to mild WD. Under severe WD, two Lathyrus sativus genotypes showed remarkable resilience maintaining the photochemical efficiency, contrary to other genotypes studied. Performance index (PIABS) is the best parameter to screen genotypes with improved performance and grain production under WD. Moreover, we found that JIP indices are good indicators of genotypic grain production under WD. Quantum yield of electron transport (ϕEo) and efficiency with which trapped excitons can move electrons further than QA (ψ0) revealed as important traits related to improved photosynthetic performance and should be exploited in future Lathyrus germplasm improvements. The JIP test herein described showed to be an expeditious tool to screen and to identify elite genotypes with improved drought resistance.

Mass-accreting white dwarfs and type Ia supernovae

NASA Astrophysics Data System (ADS)

Wang, Bo

2018-05-01

Type Ia supernovae (SNe Ia) play a prominent role in understanding the evolution of the Universe. They are thought to be thermonuclear explosions of mass-accreting carbon-oxygen white dwarfs (CO WDs) in binaries, although the mass donors of the accreting WDs are still not well determined. In this article, I review recent studies on mass-accreting WDs, including H- and He-accreting WDs. I also review currently most studied progenitor models of SNe Ia, i.e., the single-degenerate model (including the WD+MS channel, the WD+RG channel and the WD+He star channel), the double-degenerate model (including the violent merger scenario) and the sub-Chandrasekhar mass model. Recent progress on these progenitor models is discussed, including the initial parameter space for producing SNe Ia, the binary evolutionary paths to SNe Ia, the progenitor candidates for SNe Ia, the possible surviving companion stars of SNe Ia, some observational constraints, etc. Some other potential progenitor models of SNe Ia are also summarized, including the hybrid CONe WD model, the core-degenerate model, the double WD collision model, the spin-up/spin-down model and the model of WDs near black holes. To date, it seems that two or more progenitor models are needed to explain the observed diversity among SNe Ia.

A Hot White Dwarf SDSS J134430.11+032423.1 with a Planetary Debris Disk

NASA Astrophysics Data System (ADS)

Li, Lifang; Zhang, Fenghui; Kong, Xiaoyang; Han, Quanwang; Li, Jiansha

2017-02-01

We discovered a debris disk around hot white dwarf (WD) SDSS J134430.11+032423.1 (SDSS J1344+0324). The effective temperature [{T}{eff} = 26,071(±163) K], surface gravity [{log}g=7.88(2)], and mass [M=0.58(1) {M}⊙ ] of this WD have been redetermined based on the analysis of its SDSS spectrum. We found that SDSS J1344+0324 is currently the hottest WD with a debris disk. Two spectra observed by SDSS at different times show that this object is similar to SDSS J1228+1040 with variable near-IR Ca II triplet emissions from a gaseous disk. The parameters of the debris disk are derived from the IR excess analysis of SDSS J1344+0324. We found that the disk is the coolest of all debris disks around WDs, and that the inner and outer radii are very close to the tide radius of the WD. Thus, the debris disk is very narrow (about 0.22 {R}⊙ ). This implies that it might be a newly formed disk resulting from the tidal disruption of a rocky planetary body that has just entered the tide volume of the WD. This might provide strong observational evidence for the formation of debris disks around WDs.

TIME-VARIABLE ALUMINUM ABSORPTION IN THE POLAR AR URSAE MAJORIS, AND AN UPDATED ESTIMATE FOR THE MASS OF THE WHITE DWARF

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

Bai, Yu; Justham, Stephen; Liu, JiFeng

2016-09-01

We present spectra of the extreme polar AR Ursae Majoris (AR UMa), which display a clear Al i absorption doublet, alongside spectra taken less than a year earlier in which that feature is not present. Re-examination of earlier SDSS spectra indicates that the Al i absorption doublet was also present ≈8 years before our first non-detection. We conclude that this absorbing material is unlikely to be on the surface of either the white dwarf (WD) or the donor star. We suggest that this Al i absorption feature arises in circumstellar material, perhaps produced by the evaporation of asteroids as theymore » approach the hot WD. The presence of any remaining reservoir of rocky material in AR UMa might help to constrain the prior evolution of this unusual binary system. We also apply spectral decomposition to find the stellar parameters of the M dwarf companion, and attempt to dynamically measure the mass of the WD in AR UMa by considering both the radial velocity curves of the H {sub β} emission line and the Na i absorption line. Thereby we infer a mass range for the WD in AR UMa of 0.91 M {sub ⊙} < M {sub WD} < 1.24 M {sub ⊙}.« less

Wilson disease - currently used anticopper therapy.

PubMed

Członkowska, Anna; Litwin, Tomasz

2017-01-01

Wilson disease (WD) is a genetic disorder of copper metabolism that can be treated successfully with pharmacologic treatment. Two groups of drugs are currently used: chelators (e.g., d-penicillamine and trientine), which increase urinary copper excretion, and zinc salts, which inhibit copper absorption in the digestive tract. The mechanisms of action lead to a negative copper balance, stopping pathologic accumulation of copper in the tissues and clearing affected organs of copper overload. Due to a lack of prospective clinical trials, the use of drugs depends mainly on center experience and the accessibility in different countries or regions. This chapter presents the different reports and recommendations regarding WD treatment. In addition to the different expert opinions on pharmacologic agents, there are a few axioms regarding WD treatment: treatment should start immediately after diagnosis, even in clinically presymptomatic cases; the patient should be treated for life, making compliance a key factor in treatment success; and the treatment should be monitored regularly via liver and hematologic tests, neurologic examination, and copper metabolism, modifying the treatment accordingly. Other drugs proposed for WD treatment (e.g., tetrathiomolybdate) are in clinical trials and lack current recommendations. Thus, only the currently available options for WD pharmacologic treatment are discussed. © 2017 Elsevier B.V. All rights reserved.

Finale of a Quartet: Hints on Supernova Formation

NASA Astrophysics Data System (ADS)

Fang, Xiao; Thompson, Todd A.; Hirata, Christopher M.

2018-01-01

The origin of Type Ia Supernovae (SNe) is not well understood. Two most popular hypotheses are the single-degenerate scenario, where one white dwarf (WD) accretes matter from its giant companion until the Chandrasekhar limit is reached, and the double-degenerate scenario, where two WDs merge and explode. We focus on the second scenario. It has long been realized that binary WD systems normally take extremely long time to merge via gravitational waves and it is still unclear whether WD mergers can fully account for the observed SN Ia rate. Recent effort has been devoted to the effects of introducing a distant tertiary to the binary system. The standard “Kozai-Lidov” mechanism can lead to high eccentricities of the binary WDs, which could lead to direct collisions or much efficient energy dissipation. Alternatively, we investigate the long-term evolution of the hierarchical quadruple systems, i.e. WD binary with a binary companion, which are basically unexplored, yet they should be numerous. We explore their interesting dynamics and find that the fraction of reaching high eccentricities is largely enhanced, which hints on a higher WD merger rate than predicted from triple systems with the same set of secular and non-secular effects considered. Considering the population of quadruple stellar systems, the quadruple scenario might contribute significantly to the overall rate of Ia SNe.

Evaluation of Kayser-Fleischer ring in Wilson disease by anterior segment optical coherence tomography.

PubMed

Sridhar, Mittanamalli S; Rangaraju, Advithi; Anbarasu, Kavitha; Reddy, Sharat Putta; Daga, Sachin; Jayalakshmi, Sita; Shaik, Bajibhi

2017-05-01

The purpose of the study is to present anterior segment optical coherence tomography (AS-OCT) as an alternative method of evaluating Kayser-Fleischer (KF) ring in Wilson disease (WD) not only by ophthalmologists but also by other clinicians dealing with WD. This was a retrospective case series of six WD patients with KF ring. Evaluation of KF ring was done by naked eye examination using torch light, slit lamp biomicroscopy (SL), and AS-OCT. SL examination was done using a narrow slit of the superior cornea. AS-OCT was done using the Optovue RTvue PremierTM device (Fremont, CA, USA). AS-OCT revealed KF ring as an intense hyperreflective band at the level of Descemet membrane (DM). Color scale of AS-OCT showed KF ring as greenish/greenish yellow/orange yellow/yellowish/red band. Validation of AS-OCT findings was done by second ophthalmologist, medical gastroenterologist, surgical gastroenterologist, and neurophysician. After seeing the first observation, they could identify the AS-OCT features in all pictures with ease. This is the first observation of KF ring in WD on AS-OCT. On AS-OCT, KF ring is visualized as intense hyperreflectivity at the level of DM in the peripheral cornea. Further, studies are needed to evaluate the usefulness of AS-OCT in WD management.

Time-variable Aluminum Absorption in the Polar AR Ursae Majoris, and an Updated Estimate for the Mass of the White Dwarf

NASA Astrophysics Data System (ADS)

Bai, Yu; Justham, Stephen; Liu, JiFeng; Guo, JinCheng; Gao, Qing; Gong, Hang

2016-09-01

We present spectra of the extreme polar AR Ursae Majoris (AR UMa), which display a clear Al I absorption doublet, alongside spectra taken less than a year earlier in which that feature is not present. Re-examination of earlier SDSS spectra indicates that the Al I absorption doublet was also present ≈8 years before our first non-detection. We conclude that this absorbing material is unlikely to be on the surface of either the white dwarf (WD) or the donor star. We suggest that this Al I absorption feature arises in circumstellar material, perhaps produced by the evaporation of asteroids as they approach the hot WD. The presence of any remaining reservoir of rocky material in AR UMa might help to constrain the prior evolution of this unusual binary system. We also apply spectral decomposition to find the stellar parameters of the M dwarf companion, and attempt to dynamically measure the mass of the WD in AR UMa by considering both the radial velocity curves of the H β emission line and the Na I absorption line. Thereby we infer a mass range for the WD in AR UMa of 0.91 M ⊙ < M WD < 1.24 M ⊙.

TGF-β1 is critical for Wallerian degeneration after rat sciatic nerve injury.

PubMed

Li, M; Zhang, P; Li, H; Zhu, Y; Cui, S; Yao, D

2015-01-22

Wallerian degeneration (WD) is a process of axonal degeneration distal to the injury site followed by a robust regenerative response. It involves degeneration and regeneration which can be directly induced by nerve injury and activated by transcription factors. Although WD has been studied extensively, the precise mechanisms of transcription factors regulating WD are still elusive. In this study, we reported the effect of transforming growth factor-β1 (TGF-β1) on WD after rat sciatic nerve injury. The data showed that TGF-β1 may express in injured rat sciatic nerve and cultured Schwann cells (SCs). Knock down of TGF-β1 expressions resulted in the reduction of SC proliferation and apoptosis, up regulation of cytokines and Smad2, 4. Enhanced expression of TGF-β1 could promote SC proliferation and apoptosis, down regulation of cytokines and Smad2, 4. Altered expressions of TGF-β1 may affect Smad and AKT but not c-Jun and extracellular regulated protein kinase (ERK) pathways. Our results revealed the role of TGF-β1 on WD and provided the basis for the molecular mechanisms of TGF-β1-regulated nerve degeneration and/or regeneration. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

Two novel WD40 domain–containing proteins, Ere1 and Ere2, function in the retromer-mediated endosomal recycling pathway

PubMed Central

Shi, Yufeng; Stefan, Christopher J.; Rue, Sarah M.; Teis, David; Emr, Scott D.

2011-01-01

Regulated secretion, nutrient uptake, and responses to extracellular signals depend on cell-surface proteins that are internalized and recycled back to the plasma membrane. However, the underlying mechanisms that govern membrane protein recycling to the cell surface are not fully known. Using a chemical-genetic screen in yeast, we show that the arginine transporter Can1 is recycled back to the cell surface via two independent pathways mediated by the sorting nexins Snx4/41/42 and the retromer complex, respectively. In addition, we identify two novel WD40-domain endosomal recycling proteins, Ere1 and Ere2, that function in the retromer pathway. Ere1 is required for Can1 recycling via the retromer-mediated pathway, but it is not required for the transport of other retromer cargoes, such as Vps10 and Ftr1. Biochemical studies reveal that Ere1 physically interacts with internalized Can1. Ere2 is present in a complex containing Ere1 on endosomes and functions as a regulator of Ere1. Taken together, our results suggest that Snx4/41/42 and the retromer comprise two independent pathways for the recycling of internalized cell-surface proteins. Moreover, a complex containing the two novel proteins Ere1 and Ere2 mediates cargo-specific recognition by the retromer pathway. PMID:21880895

Conservation of the Human Integrin-Type Beta-Propeller Domain in Bacteria

PubMed Central

Chouhan, Bhanupratap; Denesyuk, Alexander; Heino, Jyrki; Johnson, Mark S.; Denessiouk, Konstantin

2011-01-01

Integrins are heterodimeric cell-surface receptors with key functions in cell-cell and cell-matrix adhesion. Integrin α and β subunits are present throughout the metazoans, but it is unclear whether the subunits predate the origin of multicellular organisms. Several component domains have been detected in bacteria, one of which, a specific 7-bladed β-propeller domain, is a unique feature of the integrin α subunits. Here, we describe a structure-derived motif, which incorporates key features of each blade from the X-ray structures of human αIIbβ3 and αVβ3, includes elements of the FG-GAP/Cage and Ca2+-binding motifs, and is specific only for the metazoan integrin domains. Separately, we searched for the metazoan integrin type β-propeller domains among all available sequences from bacteria and unicellular eukaryotic organisms, which must incorporate seven repeats, corresponding to the seven blades of the β-propeller domain, and so that the newly found structure-derived motif would exist in every repeat. As the result, among 47 available genomes of unicellular eukaryotes we could not find a single instance of seven repeats with the motif. Several sequences contained three repeats, a predicted transmembrane segment, and a short cytoplasmic motif associated with some integrins, but otherwise differ from the metazoan integrin α subunits. Among the available bacterial sequences, we found five examples containing seven sequential metazoan integrin-specific motifs within the seven repeats. The motifs differ in having one Ca2+-binding site per repeat, whereas metazoan integrins have three or four sites. The bacterial sequences are more conserved in terms of motif conservation and loop length, suggesting that the structure is more regular and compact than those example structures from human integrins. Although the bacterial examples are not full-length integrins, the full-length metazoan-type 7-bladed β-propeller domains are present, and sometimes two tandem copies are found. PMID:22022374

Identification of interacting proteins of the TaFVE protein involved in spike development in bread wheat.

PubMed

Zheng, Yong-Sheng; Lu, Yu-Qing; Meng, Ying-Ying; Zhang, Rong-Zhi; Zhang, Han; Sun, Jia-Mei; Wang, Mu-Mu; Li, Li-Hui; Li, Ru-Yu

2017-05-01

WD-40 repeat-containing protein MSI4 (FVE)/MSI4 plays important roles in determining flowering time in Arabidopsis. However, its function is unexplored in wheat. In the present study, coimmunoprecipitation and nanoscale liquid chromatography coupled to MS/MS were used to identify FVE in wheat (TaFVE)-interacting or associated proteins. Altogether 89 differentially expressed proteins showed the same downregulated expression trends as TaFVE in wheat line 5660M. Among them, 62 proteins were further predicted to be involved in the interaction network of TaFVE and 11 proteins have been shown to be potential TaFVE interactors based on curated databases and experimentally determined in other species by the STRING. Both yeast two-hybrid assay and bimolecular fluorescence complementation assay showed that histone deacetylase 6 and histone deacetylase 15 directly interacted with TaFVE. Multiple chromatin-remodelling proteins and polycomb group proteins were also identified and predicted to interact with TaFVE. These results showed that TaFVE directly interacted with multiple proteins to form multiple complexes to regulate spike developmental process, e.g. histone deacetylate, chromatin-remodelling and polycomb repressive complex 2 complexes. In addition, multiple flower development regulation factors (e.g. flowering locus K homology domain, flowering time control protein FPA, FY, flowering time control protein FCA, APETALA 1) involved in floral transition were also identified in the present study. Taken together, these results further elucidate the regulatory functions of TaFVE and help reveal the genetic mechanisms underlying wheat spike differentiation. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

The nucleolar ubiquitin-specific protease USP36 deubiquitinates and stabilizes c-Myc

PubMed Central

Sun, Xiao-Xin; He, Xia; Yin, Li; Komada, Masayuki; Sears, Rosalie C.; Dai, Mu-Shui

2015-01-01

c-Myc protein stability and activity are tightly regulated by the ubiquitin-proteasome system. Aberrant stabilization of c-Myc contributes to many human cancers. c-Myc is ubiquitinated by SCFFbw7 (a SKP1-cullin-1-F-box complex that contains the F-box and WD repeat domain-containing 7, Fbw7, as the F-box protein) and several other ubiquitin ligases, whereas it is deubiquitinated and stabilized by ubiquitin-specific protease (USP) 28. The bulk of c-Myc degradation appears to occur in the nucleolus. However, whether c-Myc is regulated by deubiquitination in the nucleolus is not known. Here, we report that the nucleolar deubiquitinating enzyme USP36 is a novel c-Myc deubiquitinase. USP36 interacts with and deubiquitinates c-Myc in cells and in vitro, leading to the stabilization of c-Myc. This USP36 regulation of c-Myc occurs in the nucleolus. Interestingly, USP36 interacts with the nucleolar Fbw7γ but not the nucleoplasmic Fbw7α. However, it abolished c-Myc degradation mediated both by Fbw7γ and by Fbw7α. Consistently, knockdown of USP36 reduces the levels of c-Myc and suppresses cell proliferation. We further show that USP36 itself is a c-Myc target gene, suggesting that USP36 and c-Myc form a positive feedback regulatory loop. High expression levels of USP36 are found in a subset of human breast and lung cancers. Altogether, these results identified USP36 as a crucial and bono fide deubiquitinating enzyme controlling c-Myc’s nucleolar degradation pathway. PMID:25775507

Programmable DNA-binding proteins from Burkholderia provide a fresh perspective on the TALE-like repeat domain

PubMed Central

de Lange, Orlando; Wolf, Christina; Dietze, Jörn; Elsaesser, Janett; Morbitzer, Robert; Lahaye, Thomas

2014-01-01

The tandem repeats of transcription activator like effectors (TALEs) mediate sequence-specific DNA binding using a simple code. Naturally, TALEs are injected by Xanthomonas bacteria into plant cells to manipulate the host transcriptome. In the laboratory TALE DNA binding domains are reprogrammed and used to target a fused functional domain to a genomic locus of choice. Research into the natural diversity of TALE-like proteins may provide resources for the further improvement of current TALE technology. Here we describe TALE-like proteins from the endosymbiotic bacterium Burkholderia rhizoxinica, termed Bat proteins. Bat repeat domains mediate sequence-specific DNA binding with the same code as TALEs, despite less than 40% sequence identity. We show that Bat proteins can be adapted for use as transcription factors and nucleases and that sequence preferences can be reprogrammed. Unlike TALEs, the core repeats of each Bat protein are highly polymorphic. This feature allowed us to explore alternative strategies for the design of custom Bat repeat arrays, providing novel insights into the functional relevance of non-RVD residues. The Bat proteins offer fertile grounds for research into the creation of improved programmable DNA-binding proteins and comparative insights into TALE-like evolution. PMID:24792163

Western Diet and the Weakening of the Interoceptive Stimulus Control of Appetitive Behavior

PubMed Central

Sample, Camille H.; Jones, Sabrina; Hargrave, Sara L.; Jarrard, Leonard E.; Davidson, Terry L.

2017-01-01

In obesogenic environments food-related external cues are thought to overwhelm internal cues that normally regulate energy intake. We investigated how this shift from external to internal stimulus control might occur. Experiment 1 showed that rats could use stimuli arising from 0 and 4h food deprivation to predict sucrose delivery. Experiment 2 then examined (a) the ability of these deprivation cues to compete with external cues and (b) how consuming a Western-style diet (WD) affects that competition. Rats were trained to use both their deprivation cues and external cues as compound discriminative stimuli. Half of the rats were then placed on WD while the others remained on chow, and external cues were removed to assess learning about deprivation state cues. When tested with external cues removed, chow-fed rats continued to discriminate using only deprivation cues, while WD-fed rats did not. The WD-fed group performed similarly to control groups trained with a noncontingent relationship between deprivation cues and sucrose reinforcement. Previous studies provided evidence that discrimination based on interoceptive deprivation cues depends on the hippocampus and that WD intake could interfere with hippocampal functioning. A third experiment assessed the effects of neurotoxic hippocampal lesions on weight gain and on sensitivity to the appetite-suppressing effects of the satiety hormone cholecystokinin (CCK). Relative to controls, hippocampal-lesioned rats gained more weight and showed reduced sensitivity to a 1.0 ug but not 2.0 or 4.0 ug CCK doses. These findings suggest that WD intake reduces utilization of interoceptive energy state signals to regulate appetitive behavior via a mechanism that involves the hippocampus. PMID:27312269

Magnetic Susceptibility Changes in the Basal Ganglia and Brain Stem of Patients with Wilson's Disease: Evaluation with Quantitative Susceptibility Mapping.

PubMed

Doganay, Selim; Gumus, Kazim; Koc, Gonca; Bayram, Ayse Kacar; Dogan, Mehmet Sait; Arslan, Duran; Gumus, Hakan; Gorkem, Sureyya Burcu; Ciraci, Saliha; Serin, Halil Ibrahim; Coskun, Abdulhakim

2018-01-10

Wilson's disease (WD) is characterized with the accumulation of copper in the liver and brain. The objective of this study is to quantitatively measure the susceptibility changes of basal ganglia and brain stem of pediatric patients with neurological WD using quantitative susceptibility mapping (QSM) in comparison to healthy controls. Eleven patients with neurological WD (mean age 15 ± 3.3 years, range 10-22 years) and 14 agematched controls were prospectively recruited. Both groups were scanned on a 1.5 Tesla clinical scanner. In addition to T 1 - and T 2 -weighted MR images, a 3D multi-echo spoiled gradient echo (GRE) sequence was acquired and QSM images were derived offline. The quantitative measurement of susceptibility of corpus striatum, thalamus of each hemisphere, midbrain, and pons were assessed with the region of interest analysis on the QSM images. The susceptibility values for the patient and control groups were compared using twosample t-test. One patient with WD had T 1 shortening in the bilateral globus pallidus. Another one had hyperintensity in the bilateral putamen, caudate nuclei, and substantia nigra on T 2 -weighted images. The rest of the patients with WD and all subjects of the control group had no signal abnormalities on conventional MR images. The susceptibility measures of right side of globus pallidus, putamen, thalamus, midbrain, and entire pons were significantly different in patients compared to controls (P < 0.05). QSM method exhibits increased susceptibility differences of basal ganglia and brain stem in patients with WD that have neurologic impairment even if no signal alteration is detected on T 1 - and T 2 -weighted MR images.

Exposure to an obesogenic diet during adolescence leads to abnormal maturation of neural and behavioral substrates underpinning fear and anxiety.

PubMed

Vega-Torres, Julio David; Haddad, Elizabeth; Lee, Jeong Bin; Kalyan-Masih, Priya; Maldonado George, Wanda I; López Pérez, Leonardo; Piñero Vázquez, Darla M; Arroyo Torres, Yaría; Santiago Santana, José M; Obenaus, Andre; Figueroa, Johnny D

2018-05-01

Post-traumatic stress disorder (PTSD) and obesity are highly prevalent in adolescents. Emerging findings from our laboratory and others are consistent with the novel hypothesis that obese individuals may be predisposed to developing PTSD. Given that aberrant fear responses are pivotal in the pathogenesis of PTSD, the objective of this study was to determine the impact of an obesogenic Western-like high-fat diet (WD) on neural substrates associated with fear. Adolescent Lewis rats (n = 72) were fed with either the experimental WD (41.4% kcal from fat) or the control diet. The fear-potentiated startle paradigm was used to determine sustained and phasic fear responses. Diffusion tensor imaging metrics and T2 relaxation times were used to determine the structural integrity of the fear circuitry including the medial prefrontal cortex (mPFC) and the basolateral complex of the amygdala (BLA). The rats that consumed the WD exhibited attenuated fear learning and fear extinction. These behavioral impairments were associated with oversaturation of the fear circuitry and astrogliosis. The BLA T2 relaxation times were significantly decreased in the WD rats relative to the controls. We found elevated fractional anisotropy in the mPFC of the rats that consumed the WD. We show that consumption of a WD may lead to long-lasting damage to components of the fear circuitry. Our findings demonstrate that consumption of an obesogenic diet during adolescence has a profound impact in the maturation of the fear neurocircuitry. The implications of this research are significant as they identify potential biomarkers of risk for psychopathology in the growing obese population. Copyright © 2018 Elsevier Inc. All rights reserved.

Synchronization Timescale and Accretion Geometry in the Nearly-Synchronous Polar RX J1940.1-1025 (V1432 Aql)

NASA Astrophysics Data System (ADS)

Geckeler, R. D.; Staubert, R.

The magnetic Cataclysmic Variable RX J1940.1-1025 (V1432 Aql) belongs to the four-member subclass of polars (together with V1500 Cyg, BY Cam and RX J2115.7-5840) with a slight (<2 %) but significant non-synchronous rotation of the white dwarf with respect to the secondary. We present the results of our analysis of new CCD and X-ray data (RXTE) of the system. For the first time, we have detected a significant dP_spin/dt for the WD of the order of -10^{-8} s/s with a corresponding synchronization timescale tau_sync of 100 yrs, as expected from the dominant magnetic torque on the WD in this system. The application of our dipole accretion model allowed us to determine the parameter (R_t0'/R_wd)^{1/2}sinβ 3.6 thus constraining the accretion geometry, where R_t0 is the radius, at which the matter is captured by the magnetic field and beta is the colatitude of the magnetic axis. The 'dips' ( 700 s full width duration) in the optical and X-ray light curves, which follow the orbital period of the system, are most probably caused by the secondary, not by the accretion funnel. The RXTE X-ray data show, that a compact X-ray emitting source located near/on the surface of the WD is totally eclipsed by the secondary. It's position shows no significant variation with phase of the beat period. The center of light of the extended (a few WD diameter) optical emission shows a significant change of its position with beat phase with a half-amplitude of 100 s, corresponding to the diameter of the WD.

Behavioral and physiological changes during heat stress in Corriedale ewes exposed to water deprivation.

PubMed

Ghassemi Nejad, Jalil; Sung, Kyung-Il

2017-01-01

This study was conducted to investigate the behavioral and physiological changes of heat stressed Corriedale ewes exposed to water deprivation. Nine Corriedale ewes (average BW = 45 ± 3.7 kg) were individually fed diets based on maintenance requirements in metabolic crates. Ewes were assigned into three groups (9 sheep per treatment) according to a 3 × 3 Latin square design for 3 periods with 21-d duration for each period. The control (CON) group was given free access to water, 2 h water deprivation (2hWD), and 3 h water deprivation (3hWD) following feeding. No differences were found in fecal excretion frequency, standing frequency (number/d), and sitting frequency among the groups ( p  > 0.05). Measurements of standing duration (min/d) and urine excretion frequency (number/d) showed a significant decrease whereas sitting duration (min/d) showed a significant increase in the 2hWD and 3hWD groups when compared with the CON group ( p  < 0.05). Fecal score and heart rate (number/min) were not different among the groups ( p  > 0.05). However, respiratory rate (number/min) and panting score were found to be significantly higher in the 2hWD and 3hWD groups than in the CON group ( p  < 0.05). It is concluded that water deprivation following feeding intensifies physiological heat stress related indicators such as respiratory rate and panting score and changes behavioral parameters such as water intake and urine excretion frequency in heat stressed ewes. Daily adaptation to the extreme environmental conditions may occur actively in ewes.

High-protein diet improves sensitivity to cholecystokinin and shifts the cecal microbiome without altering brain inflammation in diet-induced obesity in rats.

PubMed

Wang, Lixin; Jacobs, Jonathan P; Lagishetty, Venu; Yuan, Pu-Qing; Wu, Shuping V; Million, Mulugeta; Reeve, Joseph R; Pisegna, Joseph R; Taché, Yvette

2017-10-01

High-protein diet (HPD) curtails obesity and/or fat mass, but it is unknown whether it reverses neuroinflammation or alters glucose levels, CCK sensitivity, and gut microbiome in rats fed a Western diet (WD)-induced obesity (DIO). Male rats fed a WD (high fat and sugar) for 12 wk were switched to a HPD for 6 wk. Body composition, food intake, meal pattern, sensitivity to intraperitoneal CCK-8S, blood glucose, brain signaling, and cecal microbiota were assessed. When compared with a normal diet, WD increased body weight (9.3%) and fat mass (73.4%). CCK-8S (1.8 or 5.2 nmol/kg) did not alter food intake and meal pattern in DIO rats. Switching to a HPD for 6 wk reduced fat mass (15.7%) with a nonsignificantly reduced body weight gain, normalized blood glucose, and decreased feeding after CCK-8S. DIO rats on the WD or switched to a HPD showed comparable microbial diversity. However, in HPD versus WD rats, there was enrichment of 114 operational taxonomic units (OTUs) and depletion of 188 OTUs. Of those, Akkermansia muciniphila (enriched on a HPD), an unclassified Clostridiales, a member of the RF39 order, and a Phascolarctobacterium were significantly associated with fat mass. The WD increased cytokine expression in the hypothalamus and dorsal medulla that was unchanged by switching to HPD. These data indicate that HPD reduces body fat and restores glucose homeostasis and CCK sensitivity, while not modifying brain inflammation. In addition, expansion of cecal Akkermansia muciniphila correlated to fat mass loss may represent a potential peripheral mechanism of HPD beneficial effects.

Western diet enhances intestinal tumorigenesis in Min/+ mice, associating with mucosal metabolic and inflammatory stress and loss of Apc heterozygosity.

PubMed

Niku, Mikael; Pajari, Anne-Maria; Sarantaus, Laura; Päivärinta, Essi; Storvik, Markus; Heiman-Lindh, Anu; Suokas, Santeri; Nyström, Minna; Mutanen, Marja

2017-01-01

Western-type diet (WD) is a risk factor for colorectal cancer, but the underlying mechanisms are poorly understood. We investigated the interaction of WD and heterozygous mutation in the Apc gene on adenoma formation and metabolic and immunological changes in the histologically normal intestinal mucosa of Apc Min/+ (Min/+) mice. The diet used was high in saturated fat and low in calcium, vitamin D, fiber and folate. The number of adenomas was twofold higher in the WD mice compared to controls, but adenoma size, proliferation or apoptosis did not differ. The ratio of the Min to wild-type allele was higher in the WD mice, indicating accelerated loss of Apc heterozygosity (LOH). Densities of intraepithelial CD3ε + T lymphocytes and of mucosal FoxP3 + regulatory T cells were higher in the WD mice, implying inflammatory changes. Western blot analyses from the mucosa of the WD mice showed suppressed activation of the ERK and AKT pathways and a tendency for reduced activation of the mTOR pathway as measured in phosphoS6/S6 levels. The expression of pyruvate dehydrogenase kinase 4 was up-regulated in both mRNA and protein levels. Gene expression analyses showed changes in oxidation/reduction, fatty acid and monosaccharide metabolic pathways, tissue organization, cell fate and regulation of apoptosis. Together, our results suggest that the high-risk Western diet primes the intestine to tumorigenesis through synergistic effects in energy metabolism, inflammation and oxidative stress, which culminate in the acceleration of LOH of the Apc gene. Copyright © 2016 Elsevier Inc. All rights reserved.

Low-mass Pre-He White Dwarf Stars in Kepler Eclipsing Binaries with Multi-periodic Pulsations

NASA Astrophysics Data System (ADS)

Zhang, X. B.; Fu, J. N.; Liu, N.; Luo, C. Q.; Ren, A. B.

2017-12-01

We report the discovery of two thermally bloated low-mass pre-He white dwarfs (WDs) in two eclipsing binaries, KIC 10989032 and KIC 8087799. Based on the Kepler long-cadence photometry, we determined comprehensive photometric solutions of the two binary systems. The light curve analysis reveals that KIC 10989032 is a partially eclipsed detached binary system containing a probable low-mass WD with the temperature of about 10,300 K. Having a WD with the temperature of about 13,300, KKIC 8087799 is typical of an EL CVn system. By utilizing radial velocity measurements available for the A-type primary star of KIC 10989032, the mass and radius of the WD component are determined to be 0.24+/- 0.02 {M}⊙ and 0.50+/- 0.01 {R}⊙ , respectively. The values of mass and radius of the WD in KIC 8087799 are estimated as 0.16 ± 0.02 M ⊙ and 0.21 ± 0.01 R ⊙, respectively, according to the effective temperature and mean density of the A-type star derived from the photometric solution. We therefore introduce KIC 10989032 and KIC 8087799 as the eleventh and twelfth dA+WD eclipsing binaries in the Kepler field. Moreover, both binaries display marked multi-periodic pulsations superimposed on binary effects. A preliminary frequency analysis is applied to the light residuals when subtracting the synthetic eclipsing light curves from the observations, revealing that the light pulsations of the two systems are both due to the δ Sct-type primaries. We hence classify KIC 10989032 and KIC 8087799 as two WD+δ Sct binaries.

Single Amino Acid Repeats in the Proteome World: Structural, Functional, and Evolutionary Insights

PubMed Central

Kumar, Amitha Sampath; Sowpati, Divya Tej; Mishra, Rakesh K.

2016-01-01

Microsatellites or simple sequence repeats (SSR) are abundant, highly diverse stretches of short DNA repeats present in all genomes. Tandem mono/tri/hexanucleotide repeats in the coding regions contribute to single amino acids repeats (SAARs) in the proteome. While SSRs in the coding region always result in amino acid repeats, a majority of SAARs arise due to a combination of various codons representing the same amino acid and not as a consequence of SSR events. Certain amino acids are abundant in repeat regions indicating a positive selection pressure behind the accumulation of SAARs. By analysing 22 proteomes including the human proteome, we explored the functional and structural relationship of amino acid repeats in an evolutionary context. Only ~15% of repeats are present in any known functional domain, while ~74% of repeats are present in the disordered regions, suggesting that SAARs add to the functionality of proteins by providing flexibility, stability and act as linker elements between domains. Comparison of SAAR containing proteins across species reveals that while shorter repeats are conserved among orthologs, proteins with longer repeats, >15 amino acids, are unique to the respective organism. Lysine repeats are well conserved among orthologs with respect to their length and number of occurrences in a protein. Other amino acids such as glutamic acid, proline, serine and alanine repeats are generally conserved among the orthologs with varying repeat lengths. These findings suggest that SAARs have accumulated in the proteome under positive selection pressure and that they provide flexibility for optimal folding of functional/structural domains of proteins. The insights gained from our observations can help in effective designing and engineering of proteins with novel features. PMID:27893794

Structure of a Novel O-Linked N-Acetyl-d-glucosamine (O-GlcNAc) Transferase, GtfA, Reveals Insights into the Glycosylation of Pneumococcal Serine-rich Repeat Adhesins*

PubMed Central

Shi, Wei-Wei; Jiang, Yong-Liang; Zhu, Fan; Yang, Yi-Hu; Shao, Qiu-Yan; Yang, Hong-Bo; Ren, Yan-Min; Wu, Hui; Chen, Yuxing; Zhou, Cong-Zhao

2014-01-01

Protein glycosylation catalyzed by the O-GlcNAc transferase (OGT) plays a critical role in various biological processes. In Streptococcus pneumoniae, the core enzyme GtfA and co-activator GtfB form an OGT complex to glycosylate the serine-rich repeat (SRR) of adhesin PsrP (pneumococcal serine-rich repeat protein), which is involved in the infection and pathogenesis. Here we report the 2.0 Å crystal structure of GtfA, revealing a β-meander add-on domain beyond the catalytic domain. It represents a novel add-on domain, which is distinct from the all-α-tetratricopeptide repeats in the only two structure-known OGTs. Structural analyses combined with binding assays indicate that this add-on domain contributes to forming an active GtfA-GtfB complex and recognizing the acceptor protein. In addition, the in vitro glycosylation system enables us to map the O-linkages to the serine residues within the first SRR of PsrP. These findings suggest that fusion with an add-on domain might be a universal mechanism for diverse OGTs that recognize varying acceptor proteins/peptides. PMID:24936067

WDR62 Regulates Early Neural and Glial Progenitor Specification of Human Pluripotent Stem Cells

PubMed Central

Alshawaf, Abdullah J.; Antonic, Ana; Skafidas, Efstratios

2017-01-01

Mutations in WD40-repeat protein 62 (WDR62) are commonly associated with primary microcephaly and other developmental cortical malformations. We used human pluripotent stem cells (hPSC) to examine WDR62 function during human neural differentiation and model early stages of human corticogenesis. Neurospheres lacking WDR62 expression showed decreased expression of intermediate progenitor marker, TBR2, and also glial marker, S100β. In contrast, inhibition of c-Jun N-terminal kinase (JNK) signalling during hPSC neural differentiation induced upregulation of WDR62 with a corresponding increase in neural and glial progenitor markers, PAX6 and EAAT1, respectively. These findings may signify a role of WDR62 in specifying intermediate neural and glial progenitors during human pluripotent stem cell differentiation. PMID:28690640

IRF4 haploinsufficiency in a family with Whipple’s disease

PubMed Central

Guérin, Antoine; Kerner, Gaspard; Marr, Nico; Markle, Janet G; Fenollar, Florence; Wong, Natalie; Boughorbel, Sabri; Avery, Danielle T; Ma, Cindy S; Bougarn, Salim; Bouaziz, Matthieu; Béziat, Vivien; Della Mina, Erika; Oleaga-Quintas, Carmen; Lazarov, Tomi; Worley, Lisa; Nguyen, Tina; Patin, Etienne; Deswarte, Caroline; Martinez-Barricarte, Rubén; Boucherit, Soraya; Ayral, Xavier; Edouard, Sophie; Boisson-Dupuis, Stéphanie; Rattina, Vimel; Bigio, Benedetta; Vogt, Guillaume; Geissmann, Frédéric; Quintana-Murci, Lluis; Chaussabel, Damien; Tangye, Stuart G; Raoult, Didier; Abel, Laurent; Bustamante, Jacinta

2018-01-01

Most humans are exposed to Tropheryma whipplei (Tw). Whipple’s disease (WD) strikes only a small minority of individuals infected with Tw (<0.01%), whereas asymptomatic chronic carriage is more common (<25%). We studied a multiplex kindred, containing four WD patients and five healthy Tw chronic carriers. We hypothesized that WD displays autosomal dominant (AD) inheritance, with age-dependent incomplete penetrance. We identified a single very rare non-synonymous mutation in the four patients: the private R98W variant of IRF4, a transcription factor involved in immunity. The five Tw carriers were younger, and also heterozygous for R98W. We found that R98W was loss-of-function, modified the transcriptome of heterozygous leukocytes following Tw stimulation, and was not dominant-negative. We also found that only six of the other 153 known non-synonymous IRF4 variants were loss-of-function. Finally, we found that IRF4 had evolved under purifying selection. AD IRF4 deficiency can underlie WD by haploinsufficiency, with age-dependent incomplete penetrance. PMID:29537367

Scaling relationships for nonadiabatic energy relaxation times in warm dense matter: toward understanding the equation of state.

PubMed

Pradhan, Ekadashi; Magyar, Rudolph J; Akimov, Alexey V

2016-11-30

Understanding the dynamics of electron-ion energy transfer in warm dense (WD) matter is important to the measurement of equation of state (EOS) properties and for understanding the energy balance in dynamic simulations. In this work, we present a comprehensive investigation of nonadiabatic electron relaxation and thermal excitation dynamics in aluminum under high pressure and temperature. Using quantum-classical trajectory surface hopping approaches, we examine the role of nonadiabatic couplings and electronic decoherence in electron-nuclear energy transfer in WD aluminum. The computed timescales range from 400 fs to 4.0 ps and are consistent with existing experimental studies. We have derived general scaling relationships between macroscopic parameters of WD systems such as temperature or mass density and the timescales of energy redistribution between quantum and classical degrees of freedom. The scaling laws are supported by computational results. We show that electronic decoherence plays essential role and can change the functional dependencies qualitatively. The established scaling relationships can be of use in modelling of WD matter.

Young Blue Straggler Stars in the Galactic Field

NASA Astrophysics Data System (ADS)

Ekanayake, Gemunu; Wilhelm, Ronald

2018-06-01

In this study we present an analysis of a sample of field blue straggler (BS) stars that show high ultra violet emission in their spectral energy distributions (SED): indication of a hot white dwarf (WD) companion to BS. Using photometry available in the Sloan Digital Sky Survey (SDSS) and Galaxy Evolution Explorer (GALEX ) surveys we identified 80 stars with UV excess. To determine the parameter distributions (mass, temperature and age) of the WD companions, we developed a fitting routine that could fit binary model SEDs to the observed SED. Results from this fit indicate the need for a hot WD companion to provide the excess UV flux. The WD mass distribution peaks at ˜0.4 M⊙, suggesting the primary formation channel of field BSs is case B mass transfer, i.e. when the donor star is in red giant phase of its evolution. Based on stellar evolutionary models, we estimate the lower limit of the binary mass transfer efficiency to be β ˜ 0.5.

WFC3 Micro-arcsecond astrometry of the possible SNIa progenitor BPM 71214

NASA Astrophysics Data System (ADS)

Debes, John

2012-10-01

We propose to use the newly commissioned scanning mode on WFC3 to obtain astrometric measurements of the ~0.008 AU WD/M dwarf binary BPM 71214. This system is a fascinating mystery for post-common envelope binary evolution and may be a SN1a progenitor. COS spectra of the WD in the system shows that it is rapidly rotating with a vsin i of 200 km/s, implying that it has already accreted significant mass from its companion, but mass transfer has since stopped. The COS spectra imply a near Chandrasekar mass for the WD, while optical spectroscopy suggests a mass of 0.8 M_Sun. We propose to take four orbits of WFC3 observations in scanning mode to obtain astrometric measurements of this system at a per-measurement precision of ~30~micro-arcseconds. Such measurements will definitively constrain the mass of the WD and fully solve for both masses in the binary.

White dwarf stars and the age of the Galactic disk

NASA Technical Reports Server (NTRS)

Wood, M. A.

1990-01-01

The history of the Galaxy is written in its oldest stars, the white dwarf (WD) stars. Significant limits can be placed on both the Galactic age and star formation history. A wide range of input WD model sequences is used to derive the current limits to the age estimates suggested by fitting to the observed falloff in the WD luminosity function. The results suggest that the star formation rate over the history of the Galaxy has been relatively constant, and that the disk age lies in the range 6-12 billion years, depending upon the assumed structure of WD stars, and in particular on the core composition and surface helium layer mass. Using plausible mixed C/O core input models, the estimates for the disk age range from 8-10.5 Gyr, i.e.,sustantially younger than most age estimates for the halo globular clusters. After speculating on the significance of the results, expected observational and theoretical refinements which will further enhance the reliability of the method are discussed.

Water deficit effects on tomato quality depend on fruit developmental stage and genotype.

PubMed

Ripoll, Julie; Urban, Laurent; Brunel, Béatrice; Bertin, Nadia

2016-01-15

Many studies have advocated that water deficit (WD) may exert beneficial effects on fruit quality. However, the fruit response to WD at specific developmental stages was seldom investigated, although different mechanisms could be involved at each stage and lead to different effects on final fruit quality. In the present study, a moderate WD (-60% of water supply compared to control) was applied during each of the three major phases of fruit development, namely cell division (CD), cell expansion (CE) and maturation (MT). Two cocktail tomato (Solanum lycopersicum L.) genotypes were studied, one producing poor quality fruits (LA1420), and the other one producing tasty fruits (PlovdivXXIVa named Plovdiv). Contrasted responses were observed between the two genotypes. For both of them, fruit fresh mass and size were not significantly reduced by WD, whatever the developmental phase affected. Osmotic regulations were likely involved in the CD treatment for LA1420 fruits, which accumulated more sugars (both on a dry and fresh matter basis) and less acids (on a dry matter basis). In the CE treatment, other adaptive strategies involving sugar metabolism and sub-cellular compartmentation were suggested. In contrast, the composition of Plovdiv fruits changed only under the MT treatment, with less sugars, acids and carotenoids compared to control fruits (both on a dry and fresh matter basis). Total ascorbic acid (AsA) was not significantly influenced by treatments in both genotypes. On their whole, results suggest that, depending on genotypes, fruits are sweeter and less acidic under WD, but that the nutritive value related to vitamin and carotenoid contents may be lessened. The sensitivity of each developmental phase highly depends on the genotype. All phases were sensitive to WD for LA1420, but only the ripening phase for Plovdiv. Interestingly, major changes in fruit composition were observed in LA1420 which presents poor fruit quality under control conditions. This suggests the onset of fast adaptive response to WD at the fruit level in this genotype. Copyright © 2015 Elsevier GmbH. All rights reserved.

A Large Complement of the Predicted Arabidopsis ARM Repeat Proteins Are Members of the U-Box E3 Ubiquitin Ligase Family1[w

PubMed Central

Mudgil, Yashwanti; Shiu, Shin-Han; Stone, Sophia L.; Salt, Jennifer N.; Goring, Daphne R.

2004-01-01

The Arabidopsis genome was searched to identify predicted proteins containing armadillo (ARM) repeats, a motif known to mediate protein-protein interactions in a number of different animal proteins. Using domain database predictions and models generated in this study, 108 Arabidopsis proteins were identified that contained a minimum of two ARM repeats with the majority of proteins containing four to eight ARM repeats. Clustering analysis showed that the 108 predicted Arabidopsis ARM repeat proteins could be divided into multiple groups with wide differences in their domain compositions and organizations. Interestingly, 41 of the 108 Arabidopsis ARM repeat proteins contained a U-box, a motif present in a family of E3 ligases, and these proteins represented the largest class of Arabidopsis ARM repeat proteins. In 14 of these U-box/ARM repeat proteins, there was also a novel conserved domain identified in the N-terminal region. Based on the phylogenetic tree, representative U-box/ARM repeat proteins were selected for further study. RNA-blot analyses revealed that these U-box/ARM proteins are expressed in a variety of tissues in Arabidopsis. In addition, the selected U-box/ARM proteins were found to be functional E3 ubiquitin ligases. Thus, these U-box/ARM proteins represent a new family of E3 ligases in Arabidopsis. PMID:14657406

A large complement of the predicted Arabidopsis ARM repeat proteins are members of the U-box E3 ubiquitin ligase family.

PubMed

Mudgil, Yashwanti; Shiu, Shin-Han; Stone, Sophia L; Salt, Jennifer N; Goring, Daphne R

2004-01-01

The Arabidopsis genome was searched to identify predicted proteins containing armadillo (ARM) repeats, a motif known to mediate protein-protein interactions in a number of different animal proteins. Using domain database predictions and models generated in this study, 108 Arabidopsis proteins were identified that contained a minimum of two ARM repeats with the majority of proteins containing four to eight ARM repeats. Clustering analysis showed that the 108 predicted Arabidopsis ARM repeat proteins could be divided into multiple groups with wide differences in their domain compositions and organizations. Interestingly, 41 of the 108 Arabidopsis ARM repeat proteins contained a U-box, a motif present in a family of E3 ligases, and these proteins represented the largest class of Arabidopsis ARM repeat proteins. In 14 of these U-box/ARM repeat proteins, there was also a novel conserved domain identified in the N-terminal region. Based on the phylogenetic tree, representative U-box/ARM repeat proteins were selected for further study. RNA-blot analyses revealed that these U-box/ARM proteins are expressed in a variety of tissues in Arabidopsis. In addition, the selected U-box/ARM proteins were found to be functional E3 ubiquitin ligases. Thus, these U-box/ARM proteins represent a new family of E3 ligases in Arabidopsis.

On dual and three space problems for the compact approximation property

NASA Astrophysics Data System (ADS)

Choi, Changsun; Kim, Ju Myung

2006-11-01

We introduce the properties W*D and BW*D for the dual space of a Banach space. And then solve the dual problem for the compact approximation property (CAP): if X* has the CAP and the W*D, then X has the CAP. Also, we solve the three space problem for the CAP: for example, if M is a closed subspace of a Banach space such that M[perpendicular] is complemented in X* and X* has the W*D, then X has the CAP whenever X/M has the CAP and M has the bounded CAP. Corresponding problems for the bounded compact approximation property are also addressed.

ST proteins, a new family of plant tandem repeat proteins with a DUF2775 domain mainly found in Fabaceae and Asteraceae.

PubMed

Albornos, Lucía; Martín, Ignacio; Iglesias, Rebeca; Jiménez, Teresa; Labrador, Emilia; Dopico, Berta

2012-11-07

Many proteins with tandem repeats in their sequence have been described and classified according to the length of the repeats: I) Repeats of short oligopeptides (from 2 to 20 amino acids), including structural cell wall proteins and arabinogalactan proteins. II) Repeats that range in length from 20 to 40 residues, including proteins with a well-established three-dimensional structure often involved in mediating protein-protein interactions. (III) Longer repeats in the order of 100 amino acids that constitute structurally and functionally independent units. Here we analyse ShooT specific (ST) proteins, a family of proteins with tandem repeats of unknown function that were first found in Leguminosae, and their possible similarities to other proteins with tandem repeats. ST protein sequences were only found in dicotyledonous plants, limited to several plant families, mainly the Fabaceae and the Asteraceae. ST mRNAs accumulate mainly in the roots and under biotic interactions. Most ST proteins have one or several Domain(s) of Unknown Function 2775 (DUF2775). All deduced ST proteins have a signal peptide, indicating that these proteins enter the secretory pathway, and the mature proteins have tandem repeat oligopeptides that share a hexapeptide (E/D)FEPRP followed by 4 partially conserved amino acids, which could determine a putative N-glycosylation signal, and a fully conserved tyrosine. In a phylogenetic tree, the sequences clade according to taxonomic group. A possible involvement in symbiosis and abiotic stress as well as in plant cell elongation is suggested, although different STs could play different roles in plant development. We describe a new family of proteins called ST whose presence is limited to the plant kingdom, specifically to a few families of dicotyledonous plants. They present 20 to 40 amino acid tandem repeat sequences with different characteristics (signal peptide, DUF2775 domain, conservative repeat regions) from the described group of 20 to 40 amino acid tandem repeat proteins and also from known cell wall proteins with repeat sequences. Several putative roles in plant physiology can be inferred from the characteristics found.

ST proteins, a new family of plant tandem repeat proteins with a DUF2775 domain mainly found in Fabaceae and Asteraceae

PubMed Central

2012-01-01

Background Many proteins with tandem repeats in their sequence have been described and classified according to the length of the repeats: I) Repeats of short oligopeptides (from 2 to 20 amino acids), including structural cell wall proteins and arabinogalactan proteins. II) Repeats that range in length from 20 to 40 residues, including proteins with a well-established three-dimensional structure often involved in mediating protein-protein interactions. (III) Longer repeats in the order of 100 amino acids that constitute structurally and functionally independent units. Here we analyse ShooT specific (ST) proteins, a family of proteins with tandem repeats of unknown function that were first found in Leguminosae, and their possible similarities to other proteins with tandem repeats. Results ST protein sequences were only found in dicotyledonous plants, limited to several plant families, mainly the Fabaceae and the Asteraceae. ST mRNAs accumulate mainly in the roots and under biotic interactions. Most ST proteins have one or several Domain(s) of Unknown Function 2775 (DUF2775). All deduced ST proteins have a signal peptide, indicating that these proteins enter the secretory pathway, and the mature proteins have tandem repeat oligopeptides that share a hexapeptide (E/D)FEPRP followed by 4 partially conserved amino acids, which could determine a putative N-glycosylation signal, and a fully conserved tyrosine. In a phylogenetic tree, the sequences clade according to taxonomic group. A possible involvement in symbiosis and abiotic stress as well as in plant cell elongation is suggested, although different STs could play different roles in plant development. Conclusions We describe a new family of proteins called ST whose presence is limited to the plant kingdom, specifically to a few families of dicotyledonous plants. They present 20 to 40 amino acid tandem repeat sequences with different characteristics (signal peptide, DUF2775 domain, conservative repeat regions) from the described group of 20 to 40 amino acid tandem repeat proteins and also from known cell wall proteins with repeat sequences. Several putative roles in plant physiology can be inferred from the characteristics found. PMID:23134664

Herbal adaptogens combined with protein fractions from bovine colostrum and hen egg yolk reduce liver TNF-α expression and protein carbonylation in Western diet feeding in rats.

PubMed

Mobley, C Brooks; Toedebusch, Ryan G; Lockwood, Christopher M; Heese, Alexander J; Zhu, Conan; Krieger, Anna E; Cruthirds, Clayton L; Hofheins, John C; Company, Joseph M; Wiedmeyer, Charles E; Kim, Dae Y; Booth, Frank W; Roberts, Michael D

2014-01-01

We examined if a purported anti-inflammatory supplement (AF) abrogated Western-diet (WD)-induced liver pathology in rats. AF contained: 1) protein concentrates from bovine colostrum and avian egg yolk; 2) herbal adaptogens and antioxidants; and 3) acetyl-L-carnitine. Nine month-old male Brown Norway rats were allowed ad libitum access to WD for 41-43 days and randomly assigned to WD + AF feeding twice daily for the last 31-33 days (n = 8), or WD and water-placebo feeding twice daily for the last 31-33 days (n = 8). Rats fed a low-fat/low-sucrose diet (CTL, n = 6) for 41-43 days and administered a water-placebo twice daily for the last 31-33 days were also studied. Twenty-four hours following the last gavage-feed, liver samples were analyzed for: a) select mRNAs (via RT-PCR) as well as genome-wide mRNA expression patterns (via RNA-seq); b) lipid deposition; and, c) protein carbonyl and total antioxidant capacity (TAC). Serum was also examined for TAC, 8-isoprostane and clinical chemistry markers. WD + AF rats experienced a reduction in liver Tnf-α mRNA (-2.8-fold, p < 0.01). Serum and liver TAC was lower in WD + AF versus WD and CTL rats (p < 0.05), likely due to exogenous antioxidant ingredients provided through AF as evidenced by a tendency for mitochondrial SOD2 mRNA to increase in WD + AF versus CTL rats (p = 0.07). Liver fat deposition nor liver protein carbonyl content differed between WD + AF versus WD rats, although liver protein carbonyls tended to be lower in WD + AF versus CTL rats (p = 0.08). RNA-seq revealed that 19 liver mRNAs differed between WD + AF versus WD when both groups were compared with CTL rats (+/- 1.5-fold, p < 0.01). Bioinformatics suggest that AF prevented WD-induced alterations in select genes related to the transport and metabolism of carbohydrates in favor of select genes related to lipid transport and metabolism. Finally, serum clinical safety markers and liver pathology (via lesion counting) suggests that chronic consumption of AF was well tolerated. AF supplementation elicits select metabolic, anti-inflammatory, and anti-oxidant properties which was in spite of WD feeding and persisted up to 24 hours after receiving a final dose.

Energy of charged states in the acetanilide crystal: Trapping of charge-transfer states at vacancies as a possible mechanism for optical damage

NASA Astrophysics Data System (ADS)

Tsiaousis, D.; Munn, R. W.

2004-04-01

Calculations for the acetanilide crystal yield the effective polarizability (16.6 Å3), local electric field tensor, effective dipole moment (5.41 D), and dipole-dipole energy (-12.8 kJ/mol). Fourier-transform techniques are used to calculate the polarization energy P for a single charge in the perfect crystal (-1.16 eV); the charge-dipole energy WD is zero if the crystal carries no bulk dipole moment. Polarization energies for charge-transfer (CT) pairs combine with the Coulomb energy EC to give the screened Coulomb energy Escr; screening is nearly isotropic, with Escr≈EC/2.7. For CT pairs WD reduces to a term δWD arising from the interaction of the charge on each ion with the change in dipole moment on the other ion relative to the neutral molecule. The dipole moments calculated by density-functional theory methods with the B3LYP functional at the 6-311++G** level are 3.62 D for the neutral molecule, changing to 7.13 D and 4.38 D for the anion and cation, relative to the center of mass. Because of the large change in the anion, δWD reaches -0.9 eV and modifies the sequence of CT energies markedly from that of Escr, giving the lowest two CT pairs at -1.98 eV and -1.41 eV. The changes in P and WD near a vacancy are calculated; WD changes for the individual charges because the vacancy removes a dipole moment and modifies the crystal dielectric response, but δWD and EC do not change. A vacancy yields a positive change ΔP that scatters a charge or CT pair, but the change ΔWD can be negative and large enough to outweigh ΔP, yielding traps with depths that can exceed 150 meV for single charges and for CT pairs. Divacancies yield traps with depths nearly equal to the sum of those produced by the separate vacancies and so they can exceed 300 meV. These results are consistent with a mechanism of optical damage in which vacancies trap optically generated CT pairs that recombine and release energy; this can disrupt the lattice around the vacancy, thereby favoring trapping and recombination of CT pairs generated by subsequent photon absorption, leading to further lattice disruption. Revisions to previous calculations on trapping of CT pairs in anthracene are reported.

Herbal adaptogens combined with protein fractions from bovine colostrum and hen egg yolk reduce liver TNF-α expression and protein carbonylation in Western diet feeding in rats

PubMed Central

2014-01-01

Background We examined if a purported anti-inflammatory supplement (AF) abrogated Western-diet (WD)-induced liver pathology in rats. AF contained: 1) protein concentrates from bovine colostrum and avian egg yolk; 2) herbal adaptogens and antioxidants; and 3) acetyl-L-carnitine. Methods Nine month-old male Brown Norway rats were allowed ad libitum access to WD for 41–43 days and randomly assigned to WD + AF feeding twice daily for the last 31–33 days (n = 8), or WD and water-placebo feeding twice daily for the last 31–33 days (n = 8). Rats fed a low-fat/low-sucrose diet (CTL, n = 6) for 41–43 days and administered a water-placebo twice daily for the last 31–33 days were also studied. Twenty-four hours following the last gavage-feed, liver samples were analyzed for: a) select mRNAs (via RT-PCR) as well as genome-wide mRNA expression patterns (via RNA-seq); b) lipid deposition; and, c) protein carbonyl and total antioxidant capacity (TAC). Serum was also examined for TAC, 8-isoprostane and clinical chemistry markers. Results WD + AF rats experienced a reduction in liver Tnf-α mRNA (-2.8-fold, p < 0.01). Serum and liver TAC was lower in WD + AF versus WD and CTL rats (p < 0.05), likely due to exogenous antioxidant ingredients provided through AF as evidenced by a tendency for mitochondrial SOD2 mRNA to increase in WD + AF versus CTL rats (p = 0.07). Liver fat deposition nor liver protein carbonyl content differed between WD + AF versus WD rats, although liver protein carbonyls tended to be lower in WD + AF versus CTL rats (p = 0.08). RNA-seq revealed that 19 liver mRNAs differed between WD + AF versus WD when both groups were compared with CTL rats (+/- 1.5-fold, p < 0.01). Bioinformatics suggest that AF prevented WD-induced alterations in select genes related to the transport and metabolism of carbohydrates in favor of select genes related to lipid transport and metabolism. Finally, serum clinical safety markers and liver pathology (via lesion counting) suggests that chronic consumption of AF was well tolerated. Conclusions AF supplementation elicits select metabolic, anti-inflammatory, and anti-oxidant properties which was in spite of WD feeding and persisted up to 24 hours after receiving a final dose. PMID:24822076

Interactions between the S-domain receptor kinases and AtPUB-ARM E3 ubiquitin ligases suggest a conserved signaling pathway in Arabidopsis.

PubMed

Samuel, Marcus A; Mudgil, Yashwanti; Salt, Jennifer N; Delmas, Frédéric; Ramachandran, Shaliny; Chilelli, Andrea; Goring, Daphne R

2008-08-01

The Arabidopsis (Arabidopsis thaliana) genome encompasses multiple receptor kinase families with highly variable extracellular domains. Despite their large numbers, the various ligands and the downstream interacting partners for these kinases have been deciphered only for a few members. One such member, the S-receptor kinase, is known to mediate the self-incompatibility (SI) response in Brassica. S-receptor kinase has been shown to interact and phosphorylate a U-box/ARM-repeat-containing E3 ligase, ARC1, which, in turn, acts as a positive regulator of the SI response. In an effort to identify conserved signaling pathways in Arabidopsis, we performed yeast two-hybrid analyses of various S-domain receptor kinase family members with representative Arabidopsis plant U-box/ARM-repeat (AtPUB-ARM) E3 ligases. The kinase domains from S-domain receptor kinases were found to interact with ARM-repeat domains from AtPUB-ARM proteins. These kinase domains, along with M-locus protein kinase, a positive regulator of SI response, were also able to phosphorylate the ARM-repeat domains in in vitro phosphorylation assays. Subcellular localization patterns were investigated using transient expression assays in tobacco (Nicotiana tabacum) BY-2 cells and changes were detected in the presence of interacting kinases. Finally, potential links to the involvement of these interacting modules to the hormone abscisic acid (ABA) were investigated. Interestingly, AtPUB9 displayed redistribution to the plasma membrane of BY-2 cells when either treated with ABA or coexpressed with the active kinase domain of ARK1. As well, T-DNA insertion mutants for ARK1 and AtPUB9 lines were altered in their ABA sensitivity during germination and acted at or upstream of ABI3, indicating potential involvement of these proteins in ABA responses.

ARE ULTRA-LONG GAMMA-RAY BURSTS CAUSED BY BLUE SUPERGIANT COLLAPSARS, NEWBORN MAGNETARS, OR WHITE DWARF TIDAL DISRUPTION EVENTS?

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

Ioka, Kunihito; Hotokezaka, Kenta; Piran, Tsvi, E-mail: kunihito.ioka@yukawa.kyoto-u.ac.jp

Ultra-long gamma-ray bursts (ulGRBs) are a new population of GRBs with extreme durations of ∼10{sup 4} s. Leading candidates for their origin are blue supergiant collapsars, magnetars, and white dwarf tidal disruption events (WD-TDEs) caused by massive black holes (BHs). Recent observations of supernova-like (SN-like) bumps associated with ulGRBs challenged both the WD-TDE and the blue supergiant models because of the detection of SNe and the absence of hydrogen lines, respectively. We propose that WD-TDEs can accommodate the observed SN-like bumps if the fallback WD matter releases energy into the unbound WD ejecta. The observed ejecta energy, luminosity, and velocitymore » are explained by the gravitational energy, Eddington luminosity, and escape velocity of the formed accretion disk, respectively. We also show that the observed X-rays can ionize the ejecta, eliminating lines. The SN-like light curves (SN 2011kl) for the ulGRB 111209A are consistent with all three models, although a magnetar model is unnatural because the spin-down time required to power the SN-like bump is a hundred times longer than the GRB. Our results imply that TDEs are a possible energy source for SN-like events in general and for ulGRBs in particular.« less

Hydrogen and helium shell burning during white dwarf accretion

NASA Astrophysics Data System (ADS)

Cui, Xiao; Meng, Xiang-Cun; Han, Zhan-Wen

2018-05-01

Type Ia supernovae (SNe Ia) are believed to be thermonuclear explosions of carbon oxygen (CO) white dwarfs (WDs) with masses close to the Chandrasekhar mass limit. How a CO WD accretes matter and grows in mass to this limit is not well understood, hindering our understanding of SN Ia explosions and the reliability of using SNe Ia as a cosmological distance indicator. In this work, we employed the stellar evolution code MESA to simulate the accretion process of hydrogen-rich material onto a 1.0 M ⊙ CO WD at a high rate (over the Eddington limit) of 4.3 × 10‑7 M ⊙ yr‑1. The simulation demonstrates the characteristics of the double shell burning on top of the WD, with a hydrogen shell burning on top of a helium burning shell. The results show that helium shell burning is not steady (i.e. it flashes). Flashes from the helium shell are weaker than those in the case of accretion of helium-rich material onto a CO WD. The carbon to oxygen mass ratio resulting from the helium shell burning is higher than what was previously thought. Interestingly, the CO WD growing due to accretion has an outer part containing a small fraction of helium in addition to carbon and oxygen. The flashes become weaker and weaker as the accretion continues.

Wolffian duct derivative anomalies: technical considerations when encountered during robot-assisted radical prostatectomy.

PubMed

Acharya, Sujeet S; Gundeti, Mohan S; Zagaja, Gregory P; Shalhav, Arieh L; Zorn, Kevin C

2009-04-01

Although malformations of the genitourinary tract are typically identified during childhood, they can remain silent until incidental detection in evaluation and treatment of other pathologies during adulthood. The advent of the minimally invasive era in urologic surgery has given rise to unique challenges in the surgical management of anomalies of the genitourinary tract. This article reviews the embryology of anomalies of Wolffian duct (WD) derivatives with specific attention to the seminal vesicles, vas deferens, ureter, and kidneys. This is followed by a discussion of the history of the laparoscopic approach to WD derivative anomalies. Finally, we present two cases to describe technical considerations when managing these anomalies when encountered during robotic-assisted radical prostatectomy. The University of Chicago Robotic Laparoscopic Radical Prostatectomy (RLRP) database was reviewed for cases where anomalies of WD derivatives were encountered. We describe how modifications in technique allowed for completion of the procedure without difficulty. None Of the 1230 RLRP procedures performed at our institution by three surgeons, only two cases (0.16%) have been noted to have a WD anomaly. These cases were able to be completed without difficulty by making simple modifications in technique. Although uncommon, it is important for the urologist to be familiar with the origin and surgical management of WD anomalies, particularly when detected incidentally during surgery. Simple modifications in technique allow for completion of RLRP without difficulty.

Changes in cardiac contractility during graded exercise are greater in subjects with smaller body mass index, and greater in men than women: analyses using wave intensity and force-frequency relations.

PubMed

Tanaka, Midori; Sugawara, Motoaki; Niki, Kiyomi; Ogasawara, Yasuo

2018-06-15

Estimation of the contractility of the left ventricle during exercise is an important part of the rehabilitation protocol. It is known that cardiac contractility increases with an increase in heart rate. This phenomenon is called the force-frequency relation (FFR). Using wave intensity, we aimed to evaluate FFR noninvasively during graded exercise. We enrolled 83 healthy subjects. Using ultrasonic diagnostic equipment, we measured wave intensity (WD), which was defined in terms of blood velocity and arterial diameter, in the carotid artery and heart rate (HR) before and during bicycle ergometer exercise. FFRs were constructed by plotting the maximum value of WD (WD 1 ) against HR. We analyzed the variation among FFR responses of individual subjects. WD 1 increased linearly with an increase in HR during exercise. The average slope of the FFR was 1.0 ± 0.5 m/s 3  bpm. The slope of FFR decreased with an increase in body mass index (BMI). The slopes of FFRs were steeper in men than women, although there were no differences in BMI between men and women. The FFR was obtained noninvasively by carotid arterial wave intensity (WD 1 ) and graded exercise. The slope of the FFR decreased with an increase in BMI, and was steeper in men than women.

Discovery of a Detached, Eclipsing 40 Minute Period Double White Dwarf Binary and a Friend: Implications for He+CO White Dwarf Mergers

NASA Astrophysics Data System (ADS)

Brown, Warren R.; Kilic, Mukremin; Kosakowski, Alekzander; Gianninas, A.

2017-09-01

We report the discovery of two detached double white dwarf (WD) binaries, SDSS J082239.546+304857.19 and SDSS J104336.275+055149.90, with orbital periods of 40 and 46 minutes, respectively. The 40 minute system is eclipsing; it is composed of a 0.30 M ⊙ and a 0.52 M ⊙ WD. The 46 minute system is a likely LISA verification binary. The short 20 ± 2 Myr and ˜34 Myr gravitational-wave merger times of the two binaries imply that many more such systems have formed and merged over the age of the Milky Way. We update the estimated Milky Way He+CO WD binary merger rate and affirm our previously published result: He+CO WD binaries merge at a rate at least 40 times greater than the formation rate of stable mass-transfer AM CVn binaries, and so the majority must have unstable mass-transfer. The implication is that spin-orbit coupling in He+CO WD mergers is weak, or perhaps nova-like outbursts drive He+CO WDs into merger, as proposed by Shen. Based on observations obtained at the MMT Observatory, a joint facility of the Smithsonian Institution and the University of Arizona, and on observations obtained with the Apache Point Observatory 3.5 m telescope, which is owned and operated by the Astrophysical Research Consortium.

Development of disease-resistant marker-free tomato by R/RS site-specific recombination.

PubMed

Khan, Raham Sher; Nakamura, Ikuo; Mii, Masahiro

2011-06-01

The selection marker genes, imparting antibiotic or herbicide resistance, in the final transgenics have been criticized by the public and considered a hindrance in their commercialization. Multi-auto-transformation (MAT) vector system has been one of the strategies to produce marker-free transgenic plants without using selective chemicals and plant growth regulators (PGRs). In the study reported here, isopentenyltransferase (ipt) gene was used as a selection marker and wasabi defensin (WD) gene, isolated from Wasabia japonica as a target gene. WD was cloned from the binary vector, pEKH-WD to an ipt-type MAT vector, pMAT21 by gateway cloning and transferred to Agrobacterium tumefaciens strain EHA105. Infected cotyledons of tomato cv. Reiyo were cultured on PGR- and antibiotic-free MS medium. Adventitious shoots were developed by the explants infected with the pMAT21/wasabi defensin. The same PGR- and antibiotic-free MS medium was used in subcultures of the adventitious shoot lines (ASLs) to produce ipt and normal shoots. Approximately, 6 months after infection morphologically normal shoots were produced. Molecular analyses of the developed shoots confirmed the integration of gene of interest (WD) and excision of the selection marker (ipt). Expression of WD was confirmed by Northern blot and Western blot analyses. The marker-free transgenic plants exhibited enhanced resistance against Botrytis cinerea (gray mold), Alternaria solani (early blight), Fusarium oxysporum (Fusarium wilt) and Erysiphe lycopersici (powdery mildew).

Physiology and transcriptomics of water-deficit stress responses in wheat cultivars TAM 111 and TAM 112.

PubMed

Reddy, Srirama Krishna; Liu, Shuyu; Rudd, Jackie C; Xue, Qingwu; Payton, Paxton; Finlayson, Scott A; Mahan, James; Akhunova, Alina; Holalu, Srinidhi V; Lu, Nanyan

2014-09-01

Hard red winter wheat crops on the U.S. Southern Great Plains often experience moderate to severe drought stress, especially during the grain filling stage, resulting in significant yield losses. Cultivars TAM 111 and TAM 112 are widely cultivated in the region, share parentage and showed superior but distinct adaption mechanisms under water-deficit (WD) conditions. Nevertheless, the physiological and molecular basis of their adaptation remains unknown. A greenhouse study was conducted to understand the differences in the physiological and transcriptomic responses of TAM 111 and TAM 112 to WD stress. Whole-plant data indicated that TAM 112 used more water, produced more biomass and grain yield under WD compared to TAM 111. Leaf-level data at the grain filling stage indicated that TAM 112 had elevated abscisic acid (ABA) content and reduced stomatal conductance and photosynthesis as compared to TAM 111. Sustained WD during the grain filling stage also resulted in greater flag leaf transcriptome changes in TAM 112 than TAM 111. Transcripts associated with photosynthesis, carbohydrate metabolism, phytohormone metabolism, and other dehydration responses were uniquely regulated between cultivars. These results suggested a differential role for ABA in regulating physiological and transcriptomic changes associated with WD stress and potential involvement in the superior adaptation and yield of TAM 112. Copyright © 2014 Elsevier GmbH. All rights reserved.

Periodic optical variability and debris accretion in white dwarfs: a test for a causal connection*

NASA Astrophysics Data System (ADS)

Hallakoun, Na'ama; Maoz, Dan; Agol, Eric; Brown, Warren R.; Dufour, Patrick; Farihi, Jay; Gänsicke, Boris T.; Kilic, Mukremin; Kosakowski, Alekzander; Loeb, Abraham; Mazeh, Tsevi; Mullally, Fergal

2018-05-01

Recent Kepler photometry has revealed that about half of white dwarfs (WDs) have periodic, low-level (˜10-4 - 10-3), optical variations. Hubble Space Telescope (HST) ultraviolet spectroscopy has shown that up to about one half of WDs are actively accreting rocky planetary debris, as evidenced by the presence of photospheric metal absorption lines. We have obtained HST ultraviolet spectra of seven WDs that have been monitored for periodic variations, to test the hypothesis that these two phenomena are causally connected, i.e. that the optical periodic modulation is caused by WD rotation coupled with an inhomogeneous surface distribution of accreted metals. We detect photospheric metals in four out of the seven WDs. However, we find no significant correspondence between the existence of optical periodic variability and the detection of photospheric ultraviolet absorption lines. Thus, the null hypothesis stands, that the two phenomena are not directly related. Some other source of WD surface inhomogeneity, perhaps related to magnetic field strength, combined with the WD rotation, or alternatively effects due to close binary companions, may be behind the observed optical modulation. We report the marginal detection of molecular hydrogen in WD J1949+4734, only the fourth known WD with detected H2 lines. We also re-classify J1926+4219 as a carbon-rich He-sdO subdwarf.

Consumption of the Soluble Dietary Fibre Complex PolyGlycopleX® Reduces Glycaemia and Increases Satiety of a Standard Meal Postprandially

PubMed Central

Solah, Vicky A.; O’Mara-Wallace, Babette; Meng, Xingqiong; Gahler, Roland J.; Kerr, Deborah A.; James, Anthony P.; Fenton, Haelee K.; Johnson, Stuart K.; Wood, Simon

2016-01-01

The effect of consumption of PolyGlycopleX® (PGX®) was compared to wheat dextrin (WD) in combination with a standard meal, on postprandial satiety and glycaemia in a double-blind, randomised crossover trial, of 14 healthy subjects trained as a satiety panel. At each of six two-hour satiety sessions, subjects consumed one of three different test meals on two separate occasions. The test meals were: a standard meal plus 5 g PGX; a standard meal plus 4.5 g of PGX as softgels; and a standard meal plus 5 g of WD. Subjects recorded fullness using a labelled magnitude scale at 0, 15, 30, 45, 60, 90, and 120 min and the total area under the curve (AUC), mean fullness vs. time was calculated. The meals with PGX (in granular and softgel form) gave higher satiety (AUC) (477 ± 121 and 454 ± 242 cm·min), than the meal with WD (215 ± 261 cm·min) (p < 0.001). Subjects had blood glucose levels measured after the meals with PGX (granules) and WD. Glucose response (AUC) was significantly lower (p < 0.001) after the PGX meal than for the WD meal.  The high viscosity reported for PGX is a likely mechanism behind the significant satiety and blood glucose modulating effects observed in this study. PMID:27164135

Characterization and evolution of the mitochondrial DNA control region in hornbills (Bucerotiformes).

PubMed

Delport, Wayne; Ferguson, J Willem H; Bloomer, Paulette

2002-06-01

We determined the mitochondrial DNA control region sequences of six Bucerotiformes. Hornbills have the typical avian gene order and their control region is similar to other avian control regions in that it is partitioned into three domains: two variable domains that flank a central conserved domain. Two characteristics of the hornbill control region sequence differ from that of other birds. First, domain I is AT rich as opposed to AC rich, and second, the control region is approximately 500 bp longer than that of other birds. Both these deviations from typical avian control region sequence are explainable on the basis of repeat motifs in domain I of the hornbill control region. The repeat motifs probably originated from a duplication of CSB-1 as has been determined in chicken, quail, and snowgoose. Furthermore, the hornbill repeat motifs probably arose before the divergence of hornbills from each other but after the divergence of hornbills from other avian taxa. The mitochondrial control region of hornbills is suitable for both phylogenetic and population studies, with domains I and II probably more suited to population and phylogenetic analyses, respectively.

Working towards Skills: Perspectives on Workforce Development in SMEs. Research Report.

ERIC Educational Resources Information Center

Hughes, Maria; Keddie, Vince; Webb, Peter; Corney, Mark

Research into workforce development (WD) considered the relationship between corporate assessments of workers' development needs and WD strategies; how learning at work takes place; and what learning methods are used and their effectiveness. Focus was on practice in small and medium-sized enterprises (SMEs). Methodology included a literature…

Poly-dipeptides encoded by the C9orf72 repeats bind nucleoli, impede RNA biogenesis, and kill cells.

PubMed

Kwon, Ilmin; Xiang, Siheng; Kato, Masato; Wu, Leeju; Theodoropoulos, Pano; Wang, Tao; Kim, Jiwoong; Yun, Jonghyun; Xie, Yang; McKnight, Steven L

2014-09-05

Many RNA regulatory proteins controlling pre-messenger RNA splicing contain serine:arginine (SR) repeats. Here, we found that these SR domains bound hydrogel droplets composed of fibrous polymers of the low-complexity domain of heterogeneous ribonucleoprotein A2 (hnRNPA2). Hydrogel binding was reversed upon phosphorylation of the SR domain by CDC2-like kinases 1 and 2 (CLK1/2). Mutated variants of the SR domains changing serine to glycine (SR-to-GR variants) also bound to hnRNPA2 hydrogels but were not affected by CLK1/2. When expressed in mammalian cells, these variants bound nucleoli. The translation products of the sense and antisense transcripts of the expansion repeats associated with the C9orf72 gene altered in neurodegenerative disease encode GRn and PRn repeat polypeptides. Both peptides bound to hnRNPA2 hydrogels independent of CLK1/2 activity. When applied to cultured cells, both peptides entered cells, migrated to the nucleus, bound nucleoli, and poisoned RNA biogenesis, which caused cell death. Copyright © 2014, American Association for the Advancement of Science.

Sorting Out Effects of Active Stream Restoration: Channel Morphology, Channel Change Processes and Potential Controls

NASA Astrophysics Data System (ADS)

McDowell, P. F.

2017-12-01

In many active restoration projects, instream structures or modifications are designed to produce specific change in channel form, such as reduced W:D or increased pool depth, yet there is little monitoring to evaluate effectiveness. Active restoration often takes place within a context of other land management changes that can have an effect on channel form. Thus, the effects of active restoration are difficult to separate from the effects of other management actions. We measured morphologic response to restoration designs on sections of the Middle Fork John Day River, a gravel-cobble bed river under a cattle grazing regime in the Blue Mountain of Oregon. Since 2000, restoration actions have included elimination of cattle grazing in the riparian zone (passive restoration), riparian planting of woody vegetation, instream log structures for fish habitat and pool maintenance, and elimination of a major flow diversion. We listed the hypothetical effects of each of these management changes, showing overlap among effects of active and passive restoration. Repeat cross-section and longitudinal profile surveys over eight years, and repeat aerial imagery, documented changes in channel width, depth and bed morphology, and processes of change (bank erosion or aggradation, point bar erosion or aggradation, bed incision or aggradation), in two restored reaches and two adjacent control (unrestored) reaches. Morphologic changes were modest. Bankfull cross-section area, width, and W:D all decreased slightly in both restored reaches. Control reaches were unchanged or increased slightly. Processes of change were markedly different among the four reaches, with different reaches dominated by different processes. One restored reach was dominated by slight bed aggradation, increased pool depth and deep pools/km, while the other restored reach was dominated by bank erosion, bar aggradation and slight bed incision, along with increased deep pools/km. The longitudinal profile showed significant re-arrangement of bed morphology. The spatial context of processes and controls allows some separation of the effectiveness of different management actions. Active restoration directly increased pool depth, but passive restoration apparently had more impact on aggradation/degradation and width.

Programmable DNA-binding proteins from Burkholderia provide a fresh perspective on the TALE-like repeat domain.

PubMed

de Lange, Orlando; Wolf, Christina; Dietze, Jörn; Elsaesser, Janett; Morbitzer, Robert; Lahaye, Thomas

2014-06-01

The tandem repeats of transcription activator like effectors (TALEs) mediate sequence-specific DNA binding using a simple code. Naturally, TALEs are injected by Xanthomonas bacteria into plant cells to manipulate the host transcriptome. In the laboratory TALE DNA binding domains are reprogrammed and used to target a fused functional domain to a genomic locus of choice. Research into the natural diversity of TALE-like proteins may provide resources for the further improvement of current TALE technology. Here we describe TALE-like proteins from the endosymbiotic bacterium Burkholderia rhizoxinica, termed Bat proteins. Bat repeat domains mediate sequence-specific DNA binding with the same code as TALEs, despite less than 40% sequence identity. We show that Bat proteins can be adapted for use as transcription factors and nucleases and that sequence preferences can be reprogrammed. Unlike TALEs, the core repeats of each Bat protein are highly polymorphic. This feature allowed us to explore alternative strategies for the design of custom Bat repeat arrays, providing novel insights into the functional relevance of non-RVD residues. The Bat proteins offer fertile grounds for research into the creation of improved programmable DNA-binding proteins and comparative insights into TALE-like evolution. © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.

Solution properties of the archaeal CRISPR DNA repeat-binding homeodomain protein Cbp2

PubMed Central

Kenchappa, Chandra S.; Heidarsson, Pétur O.; Kragelund, Birthe B.; Garrett, Roger A.; Poulsen, Flemming M.

2013-01-01

Clustered regularly interspaced short palindromic repeats (CRISPR) form the basis of diverse adaptive immune systems directed primarily against invading genetic elements of archaea and bacteria. Cbp1 of the crenarchaeal thermoacidophilic order Sulfolobales, carrying three imperfect repeats, binds specifically to CRISPR DNA repeats and has been implicated in facilitating production of long transcripts from CRISPR loci. Here, a second related class of CRISPR DNA repeat-binding protein, denoted Cbp2, is characterized that contains two imperfect repeats and is found amongst members of the crenarchaeal thermoneutrophilic order Desulfurococcales. DNA repeat-binding properties of the Hyperthermus butylicus protein Cbp2Hb were characterized and its three-dimensional structure was determined by NMR spectroscopy. The two repeats generate helix-turn-helix structures separated by a basic linker that is implicated in facilitating high affinity DNA binding of Cbp2 by tethering the two domains. Structural studies on mutant proteins provide support for Cys7 and Cys28 enhancing high thermal stability of Cbp2Hb through disulphide bridge formation. Consistent with their proposed CRISPR transcriptional regulatory role, Cbp2Hb and, by inference, other Cbp1 and Cbp2 proteins are closely related in structure to homeodomain proteins with linked helix-turn-helix (HTH) domains, in particular the paired domain Pax and Myb family proteins that are involved in eukaryal transcriptional regulation. PMID:23325851

De novo identification of highly diverged protein repeats by probabilistic consistency.

PubMed

Biegert, A; Söding, J

2008-03-15

An estimated 25% of all eukaryotic proteins contain repeats, which underlines the importance of duplication for evolving new protein functions. Internal repeats often correspond to structural or functional units in proteins. Methods capable of identifying diverged repeated segments or domains at the sequence level can therefore assist in predicting domain structures, inferring hypotheses about function and mechanism, and investigating the evolution of proteins from smaller fragments. We present HHrepID, a method for the de novo identification of repeats in protein sequences. It is able to detect the sequence signature of structural repeats in many proteins that have not yet been known to possess internal sequence symmetry, such as outer membrane beta-barrels. HHrepID uses HMM-HMM comparison to exploit evolutionary information in the form of multiple sequence alignments of homologs. In contrast to a previous method, the new method (1) generates a multiple alignment of repeats; (2) utilizes the transitive nature of homology through a novel merging procedure with fully probabilistic treatment of alignments; (3) improves alignment quality through an algorithm that maximizes the expected accuracy; (4) is able to identify different kinds of repeats within complex architectures by a probabilistic domain boundary detection method and (5) improves sensitivity through a new approach to assess statistical significance. Server: http://toolkit.tuebingen.mpg.de/hhrepid; Executables: ftp://ftp.tuebingen.mpg.de/pub/protevo/HHrepID

The Structure of Neurexin 1[alpha] Reveals Features Promoting a Role as Synaptic Organizer

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

Chen, Fang; Venugopal, Vandavasi; Murray, Beverly

{alpha}-Neurexins are essential synaptic adhesion molecules implicated in autism spectrum disorder and schizophrenia. The {alpha}-neurexin extracellular domain consists of six LNS domains interspersed by three EGF-like repeats and interacts with many different proteins in the synaptic cleft. To understand how {alpha}-neurexins might function as synaptic organizers, we solved the structure of the neurexin 1{alpha} extracellular domain (n1{alpha}) to 2.65 {angstrom}. The L-shaped molecule can be divided into a flexible repeat I (LNS1-EGF-A-LNS2), a rigid horseshoe-shaped repeat II (LNS3-EGF-B-LNS4) with structural similarity to so-called reelin repeats, and an extended repeat III (LNS5-EGF-B-LNS6) with controlled flexibility. A 2.95 {angstrom} structure of n1{alpha}more » carrying splice insert SS3 in LNS4 reveals that SS3 protrudes as a loop and does not alter the rigid arrangement of repeat II. The global architecture imposed by conserved structural features enables {alpha}-neurexins to recruit and organize proteins in distinct and variable ways, influenced by splicing, thereby promoting synaptic function.« less

Ligand-Binding Properties and Conformational Dynamics of Autolysin Repeat Domains in Staphylococcal Cell Wall Recognition

PubMed Central

Zoll, Sebastian; Schlag, Martin; Shkumatov, Alexander V.; Rautenberg, Maren; Svergun, Dmitri I.; Götz, Friedrich

2012-01-01

The bifunctional major autolysin Atl plays a key role in staphylococcal cell separation. Processing of Atl yields catalytically active amidase (AM) and glucosaminidase (GL) domains that are each fused to repeating units. The two repeats of AM (R1 and R2) target the enzyme to the septum, where it cleaves murein between dividing cells. We have determined the crystal structure of R2, which reveals that each repeat folds into two half-open β-barrel subunits. We further demonstrate that lipoteichoic acid serves as a receptor for the repeats and that this interaction depends on conserved surfaces in each subunit. Small-angle X-ray scattering of the mature amidase reveals the presence of flexible linkers separating the AM, R1, and R2 units. Different levels of flexibility for each linker provide mechanistic insights into the conformational dynamics of the full-length protein and the roles of its components in cell wall association and catalysis. Our analysis supports a model in which the repeats direct the catalytic AM domain to the septum, where it can optimally perform the final step of cell division. PMID:22609916

Late onset Wilson's disease: therapeutic implications.

PubMed

Członkowska, Anna; Rodo, Maria; Gromadzka, Grazyna

2008-04-30

The clinical symptoms of Wilson's disease (WD) usually develop between 3 and 40 years of age and include signs of liver and/or neurologic and psychiatric disease. We report on an 84-year-old woman with WD. Despite the absence of treatment, the only symptom she presented with, until the age of 74 years, was Kayser-Fleisher rings. At the age of 74, she developed slightly abnormal liver function. This case raises the following issues: (a) Should WD be considered in all patients of all ages who manifest signs related to the disease? (b) Are ATP7B mutations fully penetrant? (c) Should all patients diagnosed presymptomatically receive anticopper therapy? (c) 2008 Movement Disorder Society.

ExtLaw_H18: Extinction law code

NASA Astrophysics Data System (ADS)

Hosek, Matthew W., Jr.; Lu, Jessica R.; Anderson, Jay; Do, Tuan; Schlafly, Edward F.; Ghez, Andrea M.; Clarkson, William I.; Morris, Mark R.; Albers, Saundra M.

2018-03-01

ExtLaw_H18 generates the extinction law between 0.8 - 2.2 microns. The law is derived using the Westerlund 1 (Wd1) main sequence (A_Ks 0.6 mag) and Arches cluster field Red Clump at the Galactic Center (A_Ks 2.7 mag). To derive the law a Wd1 cluster age of 5 Myr is assumed, though changing the cluster age between 4 Myr - 7 Myr has no effect on the law. This extinction law can be applied to highly reddened stellar populations that have similar foreground material as Wd1 and the Arches RC, namely dust from the spiral arms of the Milky Way in the Galactic Plane.

The heptad repeats region is essential for AcMNPV P10 filament formation and not the proline-rich or the C-terminus basic regions.

PubMed

Dong, Chunsheng; Deng, Fei; Li, Dan; Wang, Hualin; Hu, Zhihong

2007-09-01

Baculovirus P10 protein is a small conserved protein and is expressed as bundles of filaments in the host cell during the late phase of virus infection. So far the published results on the domain responsible for filament structural formation have been contradictory. Electron microscopy revealed that the C-terminus basic region was involved in filament structural formation in the Autographa californica multiple nucleocapsid nucleopolyhedrovirus (AcMNPV) [van Oers, M.M., Flipsen, J.T., Reusken, C.B., Sliwinsky, E.L., Vlak, J.M., 1993. Functional domains of the p10 protein of Autographa californica nuclear polyhedorsis virus. J. Gen. Virol. 74, 563-574.]. While in the Helicoverpa armigera nucleopolyhedrovirus (HearNPV), the heptad repeats region but not the C-terminus domain was proven to be responsible for filament formation [Dong, C., Li, D., Long, G., Deng, F., Wang, H., Hu, Z., 2005. Identification of functional domains required for HearNPV P10 filament formation. Virology 338, 112-120.]. In this manuscript, fluorescence confocal microscopy was applied to study AcMNPV P10 filament formation. A set of plasmids containing different P10 structural domains fused with a fluorescent protein were constructed and transfected into Sf-9 cells. The data indicated that the heptad repeats region, but not the proline-rich region or the C-terminus basic region, is essential for AcMNPV P10 filament formation. Co-transfection of P10s tagged with different fluorescent revealed that P10s with defective heptad repeats region could not interact with intact heptad repeats region or even full-length P10s to form filament structure. Within the heptad repeats region, deletion of the three amino acids spacing of AcMNPV P10 appeared to have no significant impact on the formation of filament structures, but the content of the heptad repeats region appeared to play a role in the morphology of the filaments.

Crystal structure of the second fibronectin type III (FN3) domain from human collagen α1 type XX.

PubMed

Zhao, Jingfeng; Ren, Jixia; Wang, Nan; Cheng, Zhong; Yang, Runmei; Lin, Gen; Guo, Yi; Cai, Dayong; Xie, Yong; Zhao, Xiaohong

2017-12-01

Collagen α1 type XX, which contains fibronectin type III (FN3) repeats involving six FN3 domains (referred to as the FN#1-FN#6 domains), is an unusual member of the fibril-associated collagens with interrupted triple helices (FACIT) subfamily of collagens. The results of standard protein BLAST suggest that the FN3 repeats might contribute to collagen α1 type XX acting as a cytokine receptor. To date, solution NMR structures of the FN#3, FN#4 and FN#6 domains have been determined. To obtain further structural evidence to understand the relationship between the structure and function of the FN3 repeats from collagen α1 type XX, the crystal structure of the FN#2 domain from human collagen α1 type XX (residues Pro386-Pro466; referred to as FN2-HCXX) was solved at 2.5 Å resolution. The crystal structure of FN2-HCXX shows an immunoglobulin-like fold containing a β-sandwich structure, which is formed by a three-stranded β-sheet (β1, β2 and β5) packed onto a four-stranded β-sheet (β3, β4, β6 and β7). Two consensus domains, tencon and fibcon, are structural analogues of FN2-HCXX. Fn8, an FN3 domain from human oncofoetal fibronectin, is the closest structural analogue of FN2-HCXX derived from a naturally occurring sequence. Based solely on the structural similarity of FN2-HCXX to other FN3 domains, the detailed functions of FN2-HCXX and the FN3 repeats in collagen α1 type XX cannot be identified.

Versatile communication strategies among tandem WW domain repeats

PubMed Central

Dodson, Emma Joy; Fishbain-Yoskovitz, Vered; Rotem-Bamberger, Shahar

2015-01-01

Interactions mediated by short linear motifs in proteins play major roles in regulation of cellular homeostasis since their transient nature allows for easy modulation. We are still far from a full understanding and appreciation of the complex regulation patterns that can be, and are, achieved by this type of interaction. The fact that many linear-motif-binding domains occur in tandem repeats in proteins indicates that their mutual communication is used extensively to obtain complex integration of information toward regulatory decisions. This review is an attempt to overview, and classify, different ways by which two and more tandem repeats cooperate in binding to their targets, in the well-characterized family of WW domains and their corresponding polyproline ligands. PMID:25710931

Elevated copper impairs hepatic nuclear receptor function in Wilson's disease

USDA-ARS?s Scientific Manuscript database

Wilson's disease (WD) is an autosomal recessive disorder that results in accumulation of copper in the liver as a consequence of mutations in the gene encoding the copper-transporting P-type ATPase (ATP7B). WD is a chronic liver disorder, and individuals with the disease present with a variety of co...

VizieR Online Data Catalog: WD+dMs from the SUPERBLINK proper motion survey (Skinner+, 2017)

NASA Astrophysics Data System (ADS)

Skinner, J. N.; Morgan, D. P.; West, A. A.; Lepine, S.; Thorstensen, J. R.

2018-06-01

To select for nearby WD+dMs, we used the SUPERBLINK proper motion survey (Lepine et al. 2002, J/AJ/124/1190; Lepine & Shara 2005, Cat. I/298), an ongoing all-sky survey that identifies and characterizes stars with proper motions μ>40 mas/yr. For this study, we used the 2011 July version of SUPERBLINK, which listed 2270481 stars, and was estimated to be >90% complete to V=19.0. We selected WD+dMs based on a combination of V magnitudes derived from the DSS plates (see Lepine & Shara 2005, Cat. I/298), near-UV magnitudes from GALEX, and Ks magnitudes from 2MASS. Using the UV-optical-IR color selection outlined in Skinner et al. (2014AJ....148..115S), we selected targets for spectroscopic follow-up (see bottom panel of Figure 1). We acquired optical spectroscopy of 178 newly identified WD+dM candidates, with the Boller and Chivens CCD spectrograph (CCDS), using both the Hiltner 2.4 m and McGraw-Hill 1.3 m telescopes located at the MDM Observatory. (3 data files).

Research on surface modification of nano-zirconia

NASA Astrophysics Data System (ADS)

Chen, Wen; Zhang, Cun-Lin; Yang, Xiao-Yi

2005-02-01

The mechanisms about the aggregation and dispersibility of nano-zirconia were analyzed in detail. And nano-zirconia powders which were surface-modified with silane coupling reagent WD70 were prepared in order to disperse homogeneously in ethanol in this investigation. The grain size and grain phase of nano-zirconia were obtained by XRD. Research and characterization on the structure and surface characteristic of surface-modified nano-zirconia were achieved by XPS, TG-DSC, TEM and FT-IR. The results given by FT-IR and XPS showed WD70 was jointed on the surface of nano-zirconia through both physical adsorption and chemical binding after the de-methanol reaction between the methoxyl groups of WD70 and the hydroxy groups on the surface of nano-zirconia. And the corresponding model of surface-modified nano-zirconia was given. The images provided by TEM presented intuitionistic effect of surface modification on the dispersibility of nano-zirconia in ethanol. And TG-DSC analysis ascertained the amount of WD70 that was jointed on the surface of nano-zirconia and the amount was about 6.21 percent.

H3K9me2/3 Binding of the MBT Domain Protein LIN-61 Is Essential for Caenorhabditis elegans Vulva Development

PubMed Central

Koester-Eiserfunke, Nora; Fischle, Wolfgang

2011-01-01

MBT domain proteins are involved in developmental processes and tumorigenesis. In vitro binding and mutagenesis studies have shown that individual MBT domains within clustered MBT repeat regions bind mono- and dimethylated histone lysine residues with little to no sequence specificity but discriminate against the tri- and unmethylated states. However, the exact function of promiscuous histone methyl-lysine binding in the biology of MBT domain proteins has not been elucidated. Here, we show that the Caenorhabditis elegans four MBT domain protein LIN-61, in contrast to other MBT repeat factors, specifically interacts with histone H3 when methylated on lysine 9, displaying a strong preference for di- and trimethylated states (H3K9me2/3). Although the fourth MBT repeat is implicated in this interaction, H3K9me2/3 binding minimally requires MBT repeats two to four. Further, mutagenesis of residues conserved with other methyl-lysine binding MBT regions in the fourth MBT repeat does not abolish interaction, implicating a distinct binding mode. In vivo, H3K9me2/3 interaction of LIN-61 is required for C. elegans vulva development within the synMuvB pathway. Mutant LIN-61 proteins deficient in H3K9me2/3 binding fail to rescue lin-61 synMuvB function. Also, previously identified point mutant synMuvB alleles are deficient in H3K9me2/3 interaction although these target residues that are outside of the fourth MBT repeat. Interestingly, lin-61 genetically interacts with two other synMuvB genes, hpl-2, an HP1 homologous H3K9me2/3 binding factor, and met-2, a SETDB1 homologous H3K9 methyl transferase (H3K9MT), in determining C. elegans vulva development and fertility. Besides identifying the first sequence specific and di-/trimethylation binding MBT domain protein, our studies imply complex multi-domain regulation of ligand interaction of MBT domains. Our results also introduce a mechanistic link between LIN-61 function and biology, and they establish interplay of the H3K9me2/3 binding proteins, LIN-61 and HPL-2, as well as the H3K9MT MET-2 in distinct developmental pathways. PMID:21437264

Inter-relationships among Diet, Obesity and Hippocampal-dependent Cognitive Function

PubMed Central

Davidson, Terry L.; Hargrave, Sara L.; Swithers, Susan E.; Sample, Camille H.; Fu, Xue; Kinzig, Kimberly P.; Zheng, Wei

2013-01-01

Intake of a Western diet (WD), which is high in saturated fat and sugar, is associated with deficits in hippocampal-dependent learning and memory processes as well as with markers of hippocampal pathology. In the present study, rats were trained to asymptote on hippocampal-dependent serial feature negative (FN) and hippocampal-independent simple discrimination problems. Performance was then assessed following 7 days on ad libitum chow and after 10, 24, 40, 60, and 90 days of maintenance on WD, on ketogenic (KETO) diet which is high in saturated fat and low in sugar and other carbohydrates, or continued maintenance on chow (CHOW). Confirming and extending previous findings, diet-induced obese (DIO) rats fed WD showed impaired FN performance, increased BBB permeability, and increased fasting blood glucose levels compared to CHOW controls and to diet resistant (DR) rats that did not become obese when maintained on WD. For rats fed the KETO diet, FN performance and BBB integrity was more closely associated with level of circulating ketone bodies than with obesity phenotype (DR or DIO) with higher levels of ketones appearing to provide a protective effect. The evidence also indicated that FN deficits preceded and predicted increased body weight and adiposity. This research (a) further substantiates previous findings of WD-induced deficits in hippocampal-dependent feature negative discriminations, (b) suggests that ketones may be protective against diet-induced cognitive impairment, and (c) provides evidence that diet-induced cognitive impairment precedes weight gain and obesity. PMID:23999121

A high-sugar and high-fat diet impairs cardiac systolic and diastolic function in mice.

PubMed

Carbone, Salvatore; Mauro, Adolfo G; Mezzaroma, Eleonora; Kraskauskas, Donatas; Marchetti, Carlo; Buzzetti, Raffaella; Van Tassell, Benjamin W; Abbate, Antonio; Toldo, Stefano

2015-11-01

Heart failure (HF) is a clinical syndrome characterized by dyspnea, fatigue, exercise intolerance and cardiac dysfunction. Unhealthy diet has been associated with increased risk of obesity and heart disease, but whether it directly affects cardiac function, and promotes the development and progression of HF is unknown. We fed 8-week old male or female CD-1 mice with a standard diet (SD) or a diet rich in saturated fat and sugar, resembling a "Western" diet (WD). Cardiac systolic and diastolic function was measured at baseline and 4 and 8 weeks by Doppler echocardiography, and left ventricular (LV) end-diastolic pressure (EDP) by cardiac catheterization prior to sacrifice. An additional group of mice received WD for 4 weeks followed by SD (wash-out) for 8 weeks. WD-fed mice experienced a significant decreased in LV ejection fraction (LVEF), reflecting impaired systolic function, and a significant increase in isovolumetric relaxation time (IRT), myocardial performance index (MPI), and LVEDP, showing impaired diastolic function, without any sex-related differences. Switching to a SD after 4 weeks of WD partially reversed the cardiac systolic and diastolic dysfunction. A diet rich in saturated fat and sugars (WD) impairs cardiac systolic and diastolic function in the mouse. Further studies are required to define the mechanism through which diet affects cardiac function, and whether dietary interventions can be used in patients with, or at risk for, HF. Published by Elsevier Ireland Ltd.

Synergistic anti-tumor effects of melatonin and PUFAs from walnuts in a murine mammary adenocarcinoma model.

PubMed

Garcia, Carolina P; Lamarque, Alicia L; Comba, Andrea; Berra, María A; Silva, Renata A; Labuckas, Diana O; Das, Undurti N; Eynard, Aldo R; Pasqualini, Maria E

2015-04-01

The aim of this study was to determine the effects of some polyunsaturated fatty acids plus phytomelatonin from walnuts in the development of mammary gland adenocarcinoma. BALB/c mice were fed a semisynthetic diet supplemented with either 6% walnut oil and 8% walnut flour containing phytomelatonin (walnut diet: WD); or 6% corn oil plus commercial melatonin (melatonin diet: MD), or the control group (CD), which received only 6% of corn oil. Membrane fatty acids of tumor cells (TCs) were analyzed by gas liquid chromatography, cyclooxygenase (COX) and lipoxygenase (LOX) derivatives, and plasma melatonin by high-performance liquid chromatography; apoptosis and tumor-infiltrating lymphocytes by flow cytometry. TCs from the MD and WD mice showed significant decreases in linoleic acid compared with the CD group (P < 0.05). Significantly lower levels of LOX-[13(S)-HODE] were found in TCs from the MD and WD group than in CD (P < 0.0001). COX-[12(S)-HHT] was lower and 12 LOX-[12(S)-HETE] was higher in TCs from the MD group than form the WD and CD arms (P < 0.05). Plasma melatonin, apoptosis, tumor infiltration, and survival time were significantly lower in CD mice than in MD and WD mice (P < 0.05). This study shows that melatonin, along with polyunsaturated fatty acids, exerts a selective inhibition of some COX and LOX activities and has a synergistic anti-tumor effect on a mammary gland adenocarcinoma model. Published by Elsevier Inc.

Bovine milk oligosaccharides decrease gut permeability and improve inflammation and microbial dysbiosis in diet-induced obese mice

PubMed Central

Boudry, Gaëlle; Hamilton, M. Kristina; Chichlowski, Maciej; Wickramasinghe, Saumya; Barile, Daniela; Kalanetra, Karen M.; Mills, David A.; Raybould, Helen E.

2017-01-01

Obesity is characterized by altered gut homeostasis, including dysbiosis and increased gut permeability closely linked to the development of metabolic disorders. Milk oligosaccharides are complex sugars that selectively enhance the growth of specific beneficial bacteria in the gastrointestinal tract and could be used as prebiotics. The aim of the study was to demonstrate the effects of bovine milk oligosaccharides (BMO) and Bifidobacterium longum ssp. infantis (B. infantis) on restoring diet-induced obesity intestinal microbiota and barrier function defects in mice. Male C57/BL6 mice were fed a Western diet (WD, 40% fat/kcal) or normal chow (C, 14% fat/kcal) for 7 wk. During the final 2 wk of the study, the diet of a subgroup of WD-fed mice was supplemented with BMO (7% wt/wt). Weekly gavage of B. infantis was performed in all mice starting at wk 3, yet B. infantis could not be detected in any luminal contents when mice were killed. Supplementation of the WD with BMO normalized the cecal and colonic microbiota with increased abundance of Lactobacillus compared with both WD and C mice and restoration of Allobaculum and Ruminococcus levels to that of C mice. The BMO supplementation reduced WD-induced increase in paracellular and transcellular flux in the large intestine as well as mRNA levels of the inflammatory marker tumor necrosis factor α. In conclusion, BMO are promising prebiotics to modulate gut microbiota and intestinal barrier function for enhanced health. PMID:28131576

The Mass Distribution of Companions to Low-mass White Dwarfs

NASA Astrophysics Data System (ADS)

Andrews, Jeff J.; Price-Whelan, Adrian M.; Agüeros, Marcel A.

2014-12-01

Measuring the masses of companions to single-line spectroscopic binary stars is (in general) not possible because of the unknown orbital plane inclination. Even when the mass of the visible star can be measured, only a lower limit can be placed on the mass of the unseen companion. However, since these inclination angles should be isotropically distributed, for a large enough, unbiased sample, the companion mass distribution can be deconvolved from the distribution of observables. In this work, we construct a hierarchical probabilistic model to infer properties of unseen companion stars given observations of the orbital period and projected radial velocity of the primary star. We apply this model to three mock samples of low-mass white dwarfs (LMWDs; M <~ 0.45 M ⊙) and a sample of post-common-envelope binaries. We use a mixture of two Gaussians to model the WD and neutron star (NS) companion mass distributions. Our model successfully recovers the initial parameters of these test data sets. We then apply our model to 55 WDs in the extremely low-mass (ELM) WD Survey. Our maximum a posteriori model for the WD companion population has a mean mass μWD = 0.74 M ⊙, with a standard deviation σWD = 0.24 M ⊙. Our model constrains the NS companion fraction f NS to be <16% at 68% confidence. We make samples from the posterior distribution publicly available so that future observational efforts may compute the NS probability for newly discovered LMWDs.

Factors influencing work disability in psoriatic arthritis: first results from a large UK multicentre study.

PubMed

Tillett, William; Shaddick, Gavin; Askari, Ayman; Cooper, Annie; Creamer, Paul; Clunie, Gavin; Helliwell, Philip S; Kay, Lesley; Korendowych, Eleanor; Lane, Suzanne; Packham, Jonathan; Shaban, Ragai; Williamson, Lyn; McHugh, Neil

2015-01-01

The aim of this study was to determine the extent to which structural damage, clinical disease activity, demographic and social factors are associated with work disability (WD) in PsA. Four hundred patients fulfilling CASPAR (Classification Criteria for Psoriatic Arthritis) criteria for PsA were recruited from 23 hospitals across the UK. Demographic, socio-economic, work, clinical and radiographic data were collected. WD was assessed with the Work Productivity and Activity Impairment Specific Health Problem (WPAI-SHP) questionnaire reporting WD as a percentage of absenteeism (work time missed), presenteeism (impairment at work/reduced effectiveness) and work productivity loss (overall work impairment/absenteeism plus presenteeism). Logistic and linear regressions were conducted to investigate associations with WD. Two hundred and thirty-six participants of any age were in work. Absenteeism, presenteeism and productivity loss rates were 14% (s.d. 29.0), 39% (s.d. 27.2) and 46% (s.d. 30.4), respectively. Ninety-two (26%) participants of working age were unemployed. Greater age, disease duration of 2-5 years and worse physical function were associated with unemployment. Patients reported that employer awareness and helpfulness exerted a strongly positive influence on remaining in employment. Higher levels of global and joint-specific disease activity and worse physical function were associated with greater levels of presenteeism and productivity loss among those who remained in work. Reduced effectiveness at work was associated with measures of disease activity, whereas unemployment, considered the endpoint of WD, was associated with employer factors, age and disease duration. A longitudinal study is under way to determine whether treatment to reduce disease activity ameliorates WD in the real-world setting. © The Author 2014. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Calcium and 1,25-dihydroxyvitamin D3 modulate genes of immune and inflammatory pathways in the human colon: a human crossover trial.

PubMed

Protiva, Petr; Pendyala, Swaroop; Nelson, Celeste; Augenlicht, Leonard H; Lipkin, Martin; Holt, Peter R

2016-05-01

A high dietary calcium intake with adequate vitamin D status has been linked to lower colorectal cancer risk, but the mechanisms of these effects are poorly understood. The objective of this study was to elucidate the effects of a Western-style diet (WD) and supplemental calcium and/or 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] on the colorectal mucosa. We conducted 2 crossover trials to define molecular pathways in the human colorectum altered by 1) a 4-wk WD supplemented with and without 2 g calcium carbonate/d and 2) a 4-wk WD supplemented with 1,25(OH)2D3 (0.5 μg/d) with or without 2 g calcium carbonate/d. The primary study endpoint was genome-wide gene expression in biopsy specimens of the rectosigmoid colonic mucosa. Serum and urinary calcium concentrations were also measured. Changes in urinary calcium accurately reflected calcium consumption. The WD induced modest upregulation of genes involved in inflammatory pathways, including interferon signaling, and calcium supplementation reversed these toward baseline. In contrast, supplementation of the WD with 1,25(OH)2D3 induced striking upregulation of genes involved in inflammation, immune response, extracellular matrix, and cell adhesion. Calcium supplementation largely abrogated these changes. Supplementing 1,25(OH)2D3 to a WD markedly upregulated genes in immune response and inflammation pathways, which were largely reversed by calcium supplementation. This study provides clinical trial evidence of global gene expression changes occurring in the human colorectum in response to calcium and 1,25(OH)2D3 intervention. One action of 1,25(OH)2D3 is to upregulate adaptive immunity. Calcium appears to modulate this effect, pointing to its biological interaction in the mucosa. This trial was registered at clinicaltrials.gov as NCT00298545 Trial protocol is available at http://clinicalstudies.rucares.org (protocol numbers PHO475 and PHO554). © 2016 American Society for Nutrition.

Is Western Diet-Induced Nonalcoholic Steatohepatitis in Ldlr-/- Mice Reversible?

PubMed Central

Lytle, Kelli A.; Jump, Donald B.

2016-01-01

Background Nonalcoholic fatty liver disease (NAFLD) is a major public health burden in western societies. The progressive form of NAFLD, nonalcoholic steatohepatitis (NASH), is characterized by hepatosteatosis, inflammation, oxidative stress, and hepatic damage that can progress to fibrosis and cirrhosis; risk factors for hepatocellular carcinoma. Given the scope of NASH, validating treatment protocols (i.e., low fat diets and weight loss) is imperative. Methods We evaluated the efficacy of two diets, a non-purified chow (NP) and purified (low-fat low-cholesterol, LFLC) diet to reverse western diet (WD)-induced NASH and fibrosis in Ldlr-/- mice. Results Mice fed WD for 22–24 weeks developed robust hepatosteatosis with mild fibrosis, while mice maintained on the WD an additional 7–8 weeks developed NASH with moderate fibrosis. Returning WD-fed mice to the NP or LFLC diets significantly reduced body weight and plasma markers of metabolic syndrome (dyslipidemia, hyperglycemia) and hepatic gene expression markers of inflammation (Mcp1), oxidative stress (Nox2), fibrosis (Col1A, LoxL2, Timp1) and collagen crosslinking (hydroxyproline). Time course analyses established that plasma triglycerides and hepatic Col1A1 mRNA were rapidly reduced following the switch from the WD to the LFLC diet. However, hepatic triglyceride content and fibrosis did not return to normal levels 8 weeks after the change to the LFLC diet. Time course studies further revealed a strong association (r2 ≥ 0.52) between plasma markers of inflammation (TLR2 activators) and hepatic fibrosis markers (Col1A, Timp1, LoxL2). Inflammation and fibrosis markers were inversely associated (r2 ≥ 0.32) with diet-induced changes in hepatic ω3 and ω6 polyunsaturated fatty acids (PUFA) content. Conclusion These studies establish a temporal link between plasma markers of inflammation and hepatic PUFA and fibrosis. Low-fat low-cholesterol diets promote reversal of many, but not all, features associated with WD-induced NASH and fibrosis in Ldlr-/- mice. PMID:26761430

Mycorrhizal-Mediated Lower Proline Accumulation in Poncirus trifoliata under Water Deficit Derives from the Integration of Inhibition of Proline Synthesis with Increase of Proline Degradation

PubMed Central

Zou, Ying-Ning; Wu, Qiang-Sheng; Huang, Yong-Ming; Ni, Qiu-Dan; He, Xin-Hua

2013-01-01

Proline accumulation was often correlated with drought tolerance of plants infected by arbuscular mycorrhizal fungi (AMF), whereas lower proline in some AM plants including citrus was also found under drought stress and the relevant mechanisms have not been fully elaborated. In this study proline accumulation and activity of key enzymes relative to proline biosynthesis (▵1-pyrroline-5-carboxylate synthetase, P5CS; ornithine-δ-aminotransferase, OAT) and degradation (proline dehydrogenase, ProDH) were determined in trifoliate orange (Poncirus trifoliata, a widely used citrus rootstock) inoculated with or without Funneliformis mosseae and under well-watered (WW) or water deficit (WD). AMF colonization significantly increased plant height, stem diameter, leaf number, root volume, biomass production of both leaves and roots and leaf relative water content, irrespectively of water status. Water deficit induced more tissue proline accumulation, in company with an increase of P5CS activity, but a decrease of OAT and ProDH activity, no matter whether under AM or no-AM. Compared with no-AM treatment, AM treatment resulted in lower proline concentration and content in leaf, root, and total plant under both WW and WD. The AMF colonization significantly decreased the activity of both P5CS and OAT in leaf, root, and total plant under WW and WD, except for an insignificant difference of root OAT under WD. The AMF inoculation also generally increased tissue ProDH activity under WW and WD. Plant proline content significantly positively correlated with plant P5CS activity, negatively with plant ProDH activity, but not with plant OAT activity. These results suggest that AM plants may suffer less from WD, thereby inducing lower proline accumulation, which derives from the integration of an inhibition of proline synthesis with an enhancement of proline degradation. PMID:24260421

Constraints to hydraulic acclimation under reduced light in two contrasting Phaseolus vulgaris cultivars.

PubMed

Matzner, Steven L; Rettedal, David D; Harmon, Derek A; Beukelman, MacKenzie R

2014-08-01

Two cultivars of Phaseolus vulgaris L. were grown under three light levels to determine if hydraulic acclimation to light occurs in herbaceous annuals and whether intraspecific trade-offs constrain hydraulic traits. Acclimation occurred in response to reduced light and included decreased stomatal density (SD) and increased specific leaf area (SLA). Reduced light resulted in lower wood density (WD); decreased cavitation resistance, measured as the xylem pressure causing a 50 % reduction in stem conductivity (P50); and increased hydraulic capacity, measured as average leaf mass specific transpiration (E(LM)). Significant or marginally significant trade-offs between P50 and WD, WD and E(LM), and E(LM) and P50 reflected variation due to both genotype and environmental effects. A trade-off between WD and P50 within one cultivar indicated that morphological adjustment was constrained. Coordinated changes in WD, P50, and E(LM) within each cultivar in response to light were consistent with trade-offs constraining plasticity. A water-use efficiency (WUE, measured as δ(13)C) versus hydraulic capacity (E(LM)) trade-off was observed within each cultivar, further indicating that hydraulic trade-offs can constrain acclimation. Larger plants had lower hydraulic capacity (E(LM)) but greater cavitation resistance, WD, and WUE. Distinct hydraulic strategies were observed with the cultivar adapted to irrigated conditions having higher stomatal conductance and stem flow rates. The cultivar adapted to rain-fed conditions had higher leaf area and greater cavitation resistance. Hydraulic trade-offs were observed within the herbaceous P. vulgaris resulting from both genotype and environmental effects. Trade-offs within a cultivar reflected constraints to hydraulic acclimation in response to changing light. © The Author 2014. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Second Primary Malignancies in Patients with Well-differentiated/Dedifferentiated Liposarcoma.

PubMed

Jung, Eric; Fiore, Marco; Gronchi, Alessandro; Grignol, Valerie; Pollock, Raphael E; Chong, Susan S; Chopra, Shefali; Hamilton, Ann S; Tseng, William W

2018-06-01

Well-differentiated/dedifferentiated (WD/DD) liposarcoma is a rare malignancy of putative adipocyte origin. To our knowledge, there have only been isolated case reports describing second primary cancer in patients with this disease. We report on a combined case series of such patients and explore the frequency of this occurrence using a national cancer database. Demographics and clinicopathological data were collected from patients with WD/DD liposarcoma who were found to have a concurrent or subsequent second primary cancer, at one of three sarcoma referral centers from 2014-2016. The Surveillance, Epidemiology and End Results (SEER) database was also queried to identify adult patients diagnosed with WD/DD liposarcoma between 1973-2012. Observed/expected (O/E) ratios of second primary malignancies among these cases were calculated by comparison to the age-adjusted cancer incidence in the general population using SEER*stat software. In total, 26 out of 312 consecutive patients (8.3%) with WD/DD liposarcoma at our centers had a second primary cancer identified within 2 years of liposarcoma diagnosis. In the SEER database, among 1,845 patients with WD/DD liposarcoma, 75 (4.1%) had a second cancer within 2 years after liposarcoma diagnosis (O/E ratio=1.81, 99% confidence interval(CI)=1.33-2.40). Patients less than 50 years old at the time of liposarcoma diagnosis had a higher O/E ratio for second primary malignancy compared to older patients. A total of 269 patients (14.6%) developed a second cancer (O/E=1.33, 99% CI=1.15-1.54). In some patients with WD/DD liposarcoma, there appears to be an increased risk of having a second primary cancer. Further validation and investigation is needed, as this finding may have implications (e.g. closer screening) for patients with this disease. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Investigating the influence of standard staining procedures on the copper distribution and concentration in Wilson's disease liver samples by laser ablation-inductively coupled plasma-mass spectrometry.

PubMed

Hachmöller, Oliver; Aichler, Michaela; Schwamborn, Kristina; Lutz, Lisa; Werner, Martin; Sperling, Michael; Walch, Axel; Karst, Uwe

2017-12-01

The influence of rhodanine and haematoxylin and eosin (HE) staining on the copper distribution and concentration in liver needle biopsy samples originating from patients with Wilson's disease (WD), a rare autosomal recessive inherited disorder of the copper metabolism, is investigated. In contemporary diagnostic of WD, rhodanine staining is used for histopathology, since rhodanine and copper are forming a red to orange-red complex, which can be recognized in the liver tissue using a microscope. In this paper, a laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) method is applied for the analysis of eight different WD liver samples. Apart from a spatially resolved elemental detection as qualitative information, this LA-ICP-MS method offers also quantitative information by external calibration with matrix-matched gelatine standards. The sample set of this work included an unstained and a rhodanine stained section of each WD liver sample. While unstained sections of WD liver samples showed very distinct structures of the copper distribution with high copper concentrations, rhodanine stained sections revealed a blurred copper distribution with significant decreased concentrations in a range from 20 to more than 90%. This implies a copper removal from the liver tissue by complexation during the rhodanine staining. In contrast to this, a further HE stained sample of one WD liver sample did not show a significant decrease in the copper concentration and influence on the copper distribution in comparison to the unstained section. Therefore, HE staining can be combined with the analysis by means of LA-ICP-MS in two successive steps from one thin section of a biopsy specimen. This allows further information to be gained on the elemental distribution by LA-ICP-MS additional to results obtained by histological staining. Copyright © 2017 Elsevier GmbH. All rights reserved.

DISCOVERY OF PULSATIONS, INCLUDING POSSIBLE PRESSURE MODES, IN TWO NEW EXTREMELY LOW MASS, He-CORE WHITE DWARFS

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

Hermes, J. J.; Montgomery, M. H.; Winget, D. E.

2013-03-10

We report the discovery of the second and third pulsating extremely low mass (ELM) white dwarfs (WDs), SDSS J111215.82+111745.0 (hereafter J1112) and SDSS J151826.68+065813.2 (hereafter J1518). Both have masses < 0.25 M{sub Sun} and effective temperatures below 10, 000 K, establishing these putatively He-core WDs as a cooler class of pulsating hydrogen-atmosphere WDs (DAVs, or ZZ Ceti stars). The short-period pulsations evidenced in the light curve of J1112 may also represent the first observation of acoustic (p-mode) pulsations in any WD, which provide an exciting opportunity to probe this WD in a complimentary way compared to the long-period g-modes thatmore » are also present. J1112 is a T{sub eff} =9590 {+-} 140 K and log g =6.36 {+-} 0.06 WD. The star displays sinusoidal variability at five distinct periodicities between 1792 and 2855 s. In this star, we also see short-period variability, strongest at 134.3 s, well short of the expected g-modes for such a low-mass WD. The other new pulsating WD, J1518, is a T{sub eff} =9900 {+-} 140 K and log g =6.80 {+-} 0.05 WD. The light curve of J1518 is highly non-sinusoidal, with at least seven significant periods between 1335 and 3848 s. Consistent with the expectation that ELM WDs must be formed in binaries, these two new pulsating He-core WDs, in addition to the prototype SDSS J184037.78+642312.3, have close companions. However, the observed variability is inconsistent with tidally induced pulsations and is so far best explained by the same hydrogen partial-ionization driving mechanism at work in classic C/O-core ZZ Ceti stars.« less

The separation distribution and merger rate of double white dwarfs: improved constraints

NASA Astrophysics Data System (ADS)

Maoz, Dan; Hallakoun, Na'ama; Badenes, Carles

2018-05-01

We obtain new and precise information on the double white dwarf (DWD) population and on its gravitational-wave-driven merger rate by combining the constraints on the DWD population from two previous studies on radial velocity variation. One of the studies is based on a sample of white dwarfs (WDs) from the Sloan Digital Sky Survey (SDSS, which with its low spectral resolution probes systems at separations a < 0.05 au) and the other is based on the ESO-VLT Supernova-Ia Progenitor surveY (SPY, which with its high spectral resolution is sensitive to a < 4 au). From a joint likelihood analysis, the DWD fraction among WDs is fbin = 0.095 ± 0.020 (1σ, random) +0.010 (systematic) in the separation range ≲4 au. The index of a power-law distribution of initial WD separations (at the start of solely gravitational-wave-driven binary evolution), N(a)da ∝ aαda, is α = -1.30 ± 0.15 (1σ) +0.05 (systematic). The Galactic WD merger rate per WD is Rmerge = (9.7 ± 1.1) × 10-12 yr-1. Integrated over the Galaxy lifetime, this implies that 8.5-11 per cent of all WDs ever formed have merged with another WD. If most DWD mergers end as more-massive WDs, then some 10 per cent of WDs are DWD-merger products, consistent with the observed fraction of WDs in a `high-mass bump' in the WD mass function. The DWD merger rate is 4.5-7 times the Milky Way's specific Type Ia supernova (SN Ia) rate. If most SN Ia explosions stem from the mergers of some DWDs (say, those with massive-enough binary components) then ˜15 per cent of all WD mergers must lead to a SN Ia.

The Continuing Search for Variability Among Cool White Dwarfs

NASA Astrophysics Data System (ADS)

Schaefer, J. J.; Oswalt, T. D.; Johnston, K. B.; Rudkin, M.; Heinz, T.

2002-12-01

The Continuing Search for Variability Among Cool White Dwarfs Justin J. Schaefer University of Wyoming Department of Physics and Astronomy P.O. Box 3905 Laramie, Wyoming 82071 USA (schaefju@uwyo.edu) Terry D. Oswalt, Kyle Johnston, Merissa Rudkin, Tamalyn Heinz Florida Institute of Technology and the SARA Observatory Department of Physics & Space Sciences 150 West University Boulevard Melbourne, Florida 32901 USA (oswalt@luyten.astro.fit.edu, kyjohnst@fit.edu, mrudkin@astro.fit.edu, theinz@fit.edu) ABSTRACT We present BVRI photometry of eleven binaries with white dwarf (WD) components. The observations were obtained at the SARA 0.9-meter telescope on Kitt Peak during the summer of 2002. Standard system (B-V), (V-R) and (R-I) color indices of four white dwarfs were determined. This data will be used to estimate the WD cooling ages in wide WD+dM binaries, as part of our ongoing research program to determine the chromospheric activity-age relation for M dwarf stars. Time-series differential photometry was also collected for eight cool white dwarfs as part of a program to explore the variability in the low luminosity, low temperature regime of the WD cooling track. We failed to detect any variability greater than ~0.04 magnitudes in these stars. Several nights of differential photometry data were collected on the DAO WD + K dwarf short-period variable HS1136+6646. From the light variations we determined a likely orbital period of 0.825 +/-0.009 days. Strong evidence is presented for two other possible periods within this light curve, possibly indicative of rotational modulation by the WD component. We gratefully acknowledge support from the National Science Foundation, which funds the SARA Research Experiences for Undergraduates program via grant AST-0097616 to Florida Tech. One of us (TDO) also acknowledges partial support for this work from NASA (subcontract Y701296) and the NSF (AST 0206115).

White Dwarf Mergers On Adaptive Meshes. I. Methodology And Code Verification

DOE PAGES

Katz, Max P.; Zingale, Michael; Calder, Alan C.; ...

2016-03-02

The Type Ia supernova (SN Ia) progenitor problem is one of the most perplexing and exciting problems in astrophysics, requiring detailed numerical modeling to complement observations of these explosions. One possible progenitor that has merited recent theoretical attention is the white dwarf (WD) merger scenario, which has the potential to naturally explain many of the observed characteristics of SNe Ia. To date there have been relatively few self-consistent simulations of merging WD systems using mesh-based hydrodynamics. This is the first study in a series describing simulations of these systems using a hydrodynamics code with adaptive mesh refinement. In this papermore » we describe our numerical methodology and discuss our implementation in the compressible hydrodynamics code CASTRO, which solves the Euler equations, and the Poisson equation for self-gravity, and couples the gravitational and rotation forces to the hydrodynamics. Standard techniques for coupling gravitation and rotation forces to the hydrodynamics do not adequately conserve the total energy of the system for our problem, but recent advances in the literature allow progress and we discuss our implementation here. We present a set of test problems demonstrating the extent to which our software sufficiently models a system where large amounts of mass are advected on the computational domain over long timescales. Finally, future papers in this series will describe our treatment of the initial conditions of these systems and will examine the early phases of the merger to determine its viability for triggering a thermonuclear detonation.« less

[CCT chaperonins and their cochaperons].

PubMed

Bregier, Cezary; Kupikowska, Barbara; Fabczak, Hanna; Fabczak, Stanisław

2008-01-01

Chaperonins are large oligomers consisting of two superimposed rings, each enclosing a cavity used for the folding of other proteins. They have been divided into two groups. Chaperonins of type I were identified in mitochondria and chloroplasts (Hsp60) or bacterial cytosol (GroEL) as well. Chaperonins type II were found in Archea and the eukaryotic cell cytosol (CCT). Protein folding occurs in the chaperonin after its conformational changes induced upon ATP binding. Mechanism of the protein folding, although still poorly defined, clearly differs from the one established for GroEL. Although CCT with prefoldin seems to be mainly involved in the folding of actin and tubulin, other substrates engaged in various cellular processes are beginning to be characterized, including proteins possessing WD40-repeats. Moreover, several lines of evidence suggest that beside prefoldin, CCT may work in concert with phosducin-like proteins (PhLPs).

Giant Primeval Magnetic Dipoles

NASA Astrophysics Data System (ADS)

Thompson, Christopher

2017-07-01

Macroscopic magnetic dipoles are considered cosmic dark matter. Permanent magnetism in relativistic field structures can involve some form of superconductivity, one example being current-carrying string loops (“springs”) with vanishing net tension. We derive the cross-section for free classical dipoles to collide, finding it depends weakly on orientation when mutual precession is rapid. The collision rate of “spring” loops with tension { T }˜ {10}-8{c}4/G in galactic halos approaches the measured rate of fast radio bursts (FRBs) if the loops compose most of the dark matter. A large superconducting dipole (LSD) with mass ˜1020 g and size ˜1 mm will form a ˜100 km magnetosphere moving through interstellar plasma. Although hydromagnetic drag is generally weak, it is strong enough to capture some LSDs into long-lived rings orbiting supermassive black holes (SMBHs) that form by the direct collapse of massive gas clouds. Repeated collisions near young SMBHs could dominate the global collision rate, thereby broadening the dipole mass spectrum. Colliding LSDs produce tiny, hot electromagnetic explosions. The accompanying paper shows that these explosions couple effectively to propagating low-frequency electromagnetic modes, with output peaking at 0.01-1 THz. We describe several constraints on, and predictions of, LSDs as cosmic dark matter. The shock formed by an infalling LSD triggers self-sustained thermonuclear burning in a C/O (ONeMg) white dwarf (WD) of mass ≳1 M ⊙ (1.3 M ⊙). The spark is generally located off the center of the WD. The rate of LSD-induced explosions matches the observed rate of Type Ia supernovae.

New nearby white dwarfs from Gaia DR1 TGAS and UCAC5/URAT

NASA Astrophysics Data System (ADS)

Scholz, R.-D.; Meusinger, H.; Jahreiß, H.

2018-05-01

Aims: Using an accurate Tycho-Gaia Astrometric Solution (TGAS) 25 pc sample that is nearly complete for GK stars and selecting common proper motion (CPM) candidates from the 5th United States Naval Observatory CCD Astrograph Catalog (UCAC5), we search for new white dwarf (WD) companions around nearby stars with relatively small proper motions. Methods: To investigate known CPM systems in TGAS and to select CPM candidates in TGAS+UCAC5, we took into account the expected effect of orbital motion on the proper motion and proper motion catalogue errors. Colour-magnitude diagrams (CMDs) MJ /J - Ks and MG /G - J were used to verify CPM candidates from UCAC5. Assuming their common distance with a given TGAS star, we searched for candidates that occupied similar regions in the CMDs as the few known nearby WDs (four in TGAS) and WD companions (three in TGAS+UCAC5). The CPM candidates with colours and absolute magnitudes corresponding neither to the main sequence nor to the WD sequence were considered as doubtful or subdwarf candidates. Results: With a minimum proper motion of 60 mas yr-1, we selected three WD companion candidates; two of which are also confirmed by their significant parallaxes measured in URAT data, whereas the third may also be a chance alignment of a distant halo star with a nearby TGAS star that has an angular separation of about 465 arcsec. One additional nearby WD candidate was found from its URAT parallax and GJKs photometry. With HD 166435 B orbiting a well-known G1 star at ≈24.6 pc with a projected physical separation of ≈700 AU, we discovered one of the hottest WDs, classified by us as DA2.0 ± 0.2, in the solar neighbourhood. We also found TYC 3980-1081-1 B, a strong cool WD companion candidate around a recently identified new solar neighbour with a TGAS parallax corresponding to a distance of ≈8.3 pc and our photometric classification as ≈M2 dwarf. This raises the question of whether previous assumptions on the completeness of the WD sample to a distance of 13 pc were correct. Partly based on observations with the 2.2 m telescope of the German-Spanish Astronomical Centre at Calar Alto, Spain

Model-Assisted Estimation of the Genetic Variability in Physiological Parameters Related to Tomato Fruit Growth under Contrasted Water Conditions

PubMed Central

Constantinescu, Dario; Memmah, Mohamed-Mahmoud; Vercambre, Gilles; Génard, Michel; Baldazzi, Valentina; Causse, Mathilde; Albert, Elise; Brunel, Béatrice; Valsesia, Pierre; Bertin, Nadia

2016-01-01

Drought stress is a major abiotic stress threatening plant and crop productivity. In case of fleshy fruits, understanding mechanisms governing water and carbon accumulations and identifying genes, QTLs and phenotypes, that will enable trade-offs between fruit growth and quality under Water Deficit (WD) condition is a crucial challenge for breeders and growers. In the present work, 117 recombinant inbred lines of a population of Solanum lycopersicum were phenotyped under control and WD conditions. Plant water status, fruit growth and composition were measured and data were used to calibrate a process-based model describing water and carbon fluxes in a growing fruit as a function of plant and environment. Eight genotype-dependent model parameters were estimated using a multiobjective evolutionary algorithm in order to minimize the prediction errors of fruit dry and fresh mass throughout fruit development. WD increased the fruit dry matter content (up to 85%) and decreased its fresh weight (up to 60%), big fruit size genotypes being the most sensitive. The mean normalized root mean squared errors of the predictions ranged between 16–18% in the population. Variability in model genotypic parameters allowed us to explore diverse genetic strategies in response to WD. An interesting group of genotypes could be discriminated in which (i) the low loss of fresh mass under WD was associated with high active uptake of sugars and low value of the maximum cell wall extensibility, and (ii) the high dry matter content in control treatment (C) was associated with a slow decrease of mass flow. Using 501 SNP markers genotyped across the genome, a QTL analysis of model parameters allowed to detect three main QTLs related to xylem and phloem conductivities, on chromosomes 2, 4, and 8. The model was then applied to design ideotypes with high dry matter content in C condition and low fresh mass loss in WD condition. The ideotypes outperformed the RILs especially for large and medium fruit-size genotypes, by combining high pedicel conductance and high active uptake of sugars. Interestingly, five small fruit-size RILs were close to the selected ideotypes, and likely bear interesting traits and alleles for adaptation to WD. PMID:28018381

THE EFFECTS OF CLOSE COMPANIONS (AND ROTATION) ON THE MAGNETIC ACTIVITY OF M DWARFS

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

Morgan, Dylan P.; West, Andrew A.; Dhital, Saurav

2012-10-01

We present a study of close white dwarf and M dwarf (WD+dM) binary systems and examine the effect that a close companion has on the magnetic field generation in M dwarfs. We use a base sample of 1602 white dwarf main-sequence binaries from Rebassa-Mansergas et al. to develop a set of color cuts in GALEX, SDSS, UKIDSS, and 2MASS color space. Then using the SDSS Data Release 8 spectroscopic database, we construct a sample of 1756 WD+dM high-quality pairs from our color cuts and previous catalogs. We separate the individual WD and dM from each spectrum using an iterative techniquemore » that compares the WD and dM components to best-fit templates. Using the absolute height above the Galactic plane as a proxy for age, and the H{alpha} emission line as an indicator for magnetic activity, we investigate the age-activity relation for our sample for spectral types {<=} M7. Our results show that early-type M dwarfs ({<=}M4) in close binary systems are more likely to be active and have longer activity lifetimes compared to their field counterparts. However, at a spectral type of M5 (just past the onset of full convection in M dwarfs), the activity fraction and lifetimes of WD+dM binary systems become more comparable to that of the field M dwarfs. One of the implications of having a close binary companion is presumed to be increased stellar rotation through disk disruption, tidal effects, or angular momentum exchange. Thus, we interpret the similarity in activity behavior between late-type dMs in WD+dM pairs and late-type field dMs to be due to a decrease in sensitivity in close binary companions (or stellar rotation), which has implications for the nature of magnetic activity in fully convective stars. Using the WD components of the pairs, we find WD cooling ages to use as an additional constraint on the age-activity relation for our sample. We find that, on average, active early-type dMs tend to be younger and that active late-type dMs span a much broader age regime making them indistinguishable from the inactive late-type population. We also show that magnetic strength, as measured by H{alpha}, is comparable between paired and field M dwarfs until a spectral type of M6/M7 where M dwarf activity for stars with close companions becomes much stronger. In addition, we present 37 very close candidate pairs with fast-moving orbits that display radial velocity changes over hour timescales.« less

The Effects of Close Companions (and Rotation) on the Magnetic Activity of M Dwarfs

NASA Astrophysics Data System (ADS)

Morgan, Dylan P.; West, Andrew A.; Garcés, Ane; Catalán, Silvia; Dhital, Saurav; Fuchs, Miriam; Silvestri, Nicole M.

2012-10-01

We present a study of close white dwarf and M dwarf (WD+dM) binary systems and examine the effect that a close companion has on the magnetic field generation in M dwarfs. We use a base sample of 1602 white dwarf main-sequence binaries from Rebassa-Mansergas et al. to develop a set of color cuts in GALEX, SDSS, UKIDSS, and 2MASS color space. Then using the SDSS Data Release 8 spectroscopic database, we construct a sample of 1756 WD+dM high-quality pairs from our color cuts and previous catalogs. We separate the individual WD and dM from each spectrum using an iterative technique that compares the WD and dM components to best-fit templates. Using the absolute height above the Galactic plane as a proxy for age, and the Hα emission line as an indicator for magnetic activity, we investigate the age-activity relation for our sample for spectral types <= M7. Our results show that early-type M dwarfs (<=M4) in close binary systems are more likely to be active and have longer activity lifetimes compared to their field counterparts. However, at a spectral type of M5 (just past the onset of full convection in M dwarfs), the activity fraction and lifetimes of WD+dM binary systems become more comparable to that of the field M dwarfs. One of the implications of having a close binary companion is presumed to be increased stellar rotation through disk disruption, tidal effects, or angular momentum exchange. Thus, we interpret the similarity in activity behavior between late-type dMs in WD+dM pairs and late-type field dMs to be due to a decrease in sensitivity in close binary companions (or stellar rotation), which has implications for the nature of magnetic activity in fully convective stars. Using the WD components of the pairs, we find WD cooling ages to use as an additional constraint on the age-activity relation for our sample. We find that, on average, active early-type dMs tend to be younger and that active late-type dMs span a much broader age regime making them indistinguishable from the inactive late-type population. We also show that magnetic strength, as measured by Hα, is comparable between paired and field M dwarfs until a spectral type of M6/M7 where M dwarf activity for stars with close companions becomes much stronger. In addition, we present 37 very close candidate pairs with fast-moving orbits that display radial velocity changes over hour timescales.

Sequence analyses reveal that a TPR-DP module, surrounded by recombinable flanking introns, could be at the origin of eukaryotic Hop and Hip TPR-DP domains and prokaryotic GerD proteins.

PubMed

Hernández Torres, Jorge; Papandreou, Nikolaos; Chomilier, Jacques

2009-05-01

The co-chaperone Hop [heat shock protein (HSP) organising protein] is known to bind both Hsp70 and Hsp90. Hop comprises three repeats of a tetratricopeptide repeat (TPR) domain, each consisting of three TPR motifs. The first and last TPR domains are followed by a domain containing several dipeptide (DP) repeats called the DP domain. These analyses suggest that the hop genes result from successive recombination events of an ancestral TPR-DP module. From a hydrophobic cluster analysis of homologous Hop protein sequences derived from gene families, we can postulate that shifts in the open reading frames are at the origin of the present sequences. Moreover, these shifts can be related to the presence or absence of biological function. We propose to extend the family of Hop co-chaperons into the kingdom of bacteria, as several structurally related genes have been identified by hydrophobic cluster analysis. We also provide evidence of common structural characteristics between hop and hip genes, suggesting a shared precursor of ancestral TPR-DP domains.

Classification of proteins with shared motifs and internal repeats in the ECOD database

PubMed Central

Kinch, Lisa N.; Liao, Yuxing

2016-01-01

Abstract Proteins and their domains evolve by a set of events commonly including the duplication and divergence of small motifs. The presence of short repetitive regions in domains has generally constituted a difficult case for structural domain classifications and their hierarchies. We developed the Evolutionary Classification Of protein Domains (ECOD) in part to implement a new schema for the classification of these types of proteins. Here we document the ways in which ECOD classifies proteins with small internal repeats, widespread functional motifs, and assemblies of small domain‐like fragments in its evolutionary schema. We illustrate the ways in which the structural genomics project impacted the classification and characterization of new structural domains and sequence families over the decade. PMID:26833690

The Tyrosine Sulfate Domain of Fibromodulin Binds Collagen and Enhances Fibril Formation.

PubMed

Tillgren, Viveka; Mörgelin, Matthias; Önnerfjord, Patrik; Kalamajski, Sebastian; Aspberg, Anders

2016-11-04

Small leucine-rich proteoglycans interact with other extracellular matrix proteins and are important regulators of matrix assembly. Fibromodulin has a key role in connective tissues, binding collagen through two identified binding sites in its leucine-rich repeat domain and regulating collagen fibril formation in vitro and in vivo Some nine tyrosine residues in the fibromodulin N-terminal domain are O-sulfated, a posttranslational modification often involved in protein interactions. The N-terminal domain mimics heparin, binding proteins with clustered basic amino acid residues. Because heparin affects collagen fibril formation, we investigated whether tyrosine sulfate is involved in fibromodulin interactions with collagen. Using full-length fibromodulin and its N-terminal tyrosine-sulfated domain purified from tissue, as well as recombinant fibromodulin fragments, we found that the N-terminal domain binds collagen. The tyrosine-sulfated domain and the leucine-rich repeat domain both bound to three specific sites along the collagen type I molecule, at the N terminus and at 100 and 220 nm from the N terminus. The N-terminal domain shortened the collagen fibril formation lag phase and tyrosine sulfation was required for this effect. The isolated leucine-rich repeat domain inhibited the fibril formation rate, and full-length fibromodulin showed a combination of these effects. The fibrils formed in the presence of fibromodulin or its fragments showed more organized structure. Fibromodulin and its tyrosine sulfate domain remained bound on the formed fiber. Taken together, this suggests a novel, regulatory function for tyrosine sulfation in collagen interaction and control of fibril formation. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

A β-solenoid model of the Pmel17 repeat domain: insights to the formation of functional amyloid fibrils

NASA Astrophysics Data System (ADS)

Louros, Nikolaos N.; Baltoumas, Fotis A.; Hamodrakas, Stavros J.; Iconomidou, Vassiliki A.

2016-02-01

Pmel17 is a multidomain protein involved in biosynthesis of melanin. This process is facilitated by the formation of Pmel17 amyloid fibrils that serve as a scaffold, important for pigment deposition in melanosomes. A specific luminal domain of human Pmel17, containing 10 tandem imperfect repeats, designated as repeat domain (RPT), forms amyloid fibrils in a pH-controlled mechanism in vitro and has been proposed to be essential for the formation of the fibrillar matrix. Currently, no three-dimensional structure has been resolved for the RPT domain of Pmel17. Here, we examine the structure of the RPT domain by performing sequence threading. The resulting model was subjected to energy minimization and validated through extensive molecular dynamics simulations. Structural analysis indicated that the RPT model exhibits several distinct properties of β-solenoid structures, which have been proposed to be polymerizing components of amyloid fibrils. The derived model is stabilized by an extensive network of hydrogen bonds generated by stacking of highly conserved polar residues of the RPT domain. Furthermore, the key role of invariant glutamate residues is proposed, supporting a pH-dependent mechanism for RPT domain assembly. Conclusively, our work attempts to provide structural insights into the RPT domain structure and to elucidate its contribution to Pmel17 amyloid fibril formation.

rigor mortis encodes a novel nuclear receptor interacting protein required for ecdysone signaling during Drosophila larval development.

PubMed

Gates, Julie; Lam, Geanette; Ortiz, José A; Losson, Régine; Thummel, Carl S

2004-01-01

Pulses of the steroid hormone ecdysone trigger the major developmental transitions in Drosophila, including molting and puparium formation. The ecdysone signal is transduced by the EcR/USP nuclear receptor heterodimer that binds to specific response elements in the genome and directly regulates target gene transcription. We describe a novel nuclear receptor interacting protein encoded by rigor mortis (rig) that is required for ecdysone responses during larval development. rig mutants display defects in molting, delayed larval development, larval lethality, duplicated mouth parts, and defects in puparium formation--phenotypes that resemble those seen in EcR, usp, E75A and betaFTZ-F1 mutants. Although the expression of these nuclear receptor genes is essentially normal in rig mutant larvae, the ecdysone-triggered switch in E74 isoform expression is defective. rig encodes a protein with multiple WD-40 repeats and an LXXLL motif, sequences that act as specific protein-protein interaction domains. Consistent with the presence of these elements and the lethal phenotypes of rig mutants, Rig protein interacts with several Drosophila nuclear receptors in GST pull-down experiments, including EcR, USP, DHR3, SVP and betaFTZ-F1. The ligand binding domain of betaFTZ-F1 is sufficient for this interaction, which can occur in an AF-2-independent manner. Antibody stains reveal that Rig protein is present in the brain and imaginal discs of second and third instar larvae, where it is restricted to the cytoplasm. In larval salivary gland and midgut cells, however, Rig shuttles between the cytoplasm and nucleus in a spatially and temporally regulated manner, at times that correlate with the major lethal phase of rig mutants and major switches in ecdysone-regulated gene expression. Taken together, these data indicate that rig exerts essential functions during larval development through gene-specific effects on ecdysone-regulated transcription, most likely as a cofactor for one or more nuclear receptors. Furthermore, the dynamic intracellular redistribution of Rig protein suggests that it may act to refine spatial and temporal responses to ecdysone during development.

Evaluating the Effects of Restraint Systems on 4WD Testing Methodologies: A Collaborative Effort between the NVFEL and ANL

EPA Science Inventory

Testing vehicles for emissions and fuel economy has traditionally been conducted with a single-axle chassis dynamometer. The 2006 SAE All Wheel Drive Symposium cited four wheel drive (4WD) and all wheel drive (AWD) sales as climbing from 20% toward 30% of a motor vehicle mar...

A MODEL OF WHITE DWARF PULSAR AR SCORPII

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

Geng, Jin-Jun; Huang, Yong-Feng; Zhang, Bing, E-mail: gengjinjun@gmail.com, E-mail: hyf@nju.edu.cn, E-mail: zhang@physics.unlv.edu

2016-11-01

A 3.56 hr white dwarf (WD)–M dwarf (MD) close binary system, AR Scorpii, was recently reported to show pulsating emission in radio, IR, optical, and UV, with a 1.97 minute period, which suggests the existence of a WD with a rotation period of 1.95 minutes. We propose a model to explain the temporal and spectral characteristics of the system. The WD is a nearly perpendicular rotator, with both open field line beams sweeping the MD stellar wind periodically. A bow shock propagating into the stellar wind accelerates electrons in the wind. Synchrotron radiation of these shocked electrons can naturally accountmore » for the broadband (from radio to X-rays) spectral energy distribution of the system.« less

Evolution of Protein Domain Repeats in Metazoa

PubMed Central

Schüler, Andreas; Bornberg-Bauer, Erich

2016-01-01

Repeats are ubiquitous elements of proteins and they play important roles for cellular function and during evolution. Repeats are, however, also notoriously difficult to capture computationally and large scale studies so far had difficulties in linking genetic causes, structural properties and evolutionary trajectories of protein repeats. Here we apply recently developed methods for repeat detection and analysis to a large dataset comprising over hundred metazoan genomes. We find that repeats in larger protein families experience generally very few insertions or deletions (indels) of repeat units but there is also a significant fraction of noteworthy volatile outliers with very high indel rates. Analysis of structural data indicates that repeats with an open structure and independently folding units are more volatile and more likely to be intrinsically disordered. Such disordered repeats are also significantly enriched in sites with a high functional potential such as linear motifs. Furthermore, the most volatile repeats have a high sequence similarity between their units. Since many volatile repeats also show signs of recombination, we conclude they are often shaped by concerted evolution. Intriguingly, many of these conserved yet volatile repeats are involved in host-pathogen interactions where they might foster fast but subtle adaptation in biological arms races. Key Words: protein evolution, domain rearrangements, protein repeats, concerted evolution. PMID:27671125

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

Zhou, Chuanyi; Shen, Liangfang, E-mail: lfshen2008@163.com; Mao, Lei

MicroRNAs (miRNAs) are involved in the cervical carcinogenesis and progression. In this study, we investigated the role of miR-92a in progression and invasion of cervical cancer. MiR-92a was significantly upregulated in cervical cancer tissues and cell lines. Overexpression of miR-92a led to remarkably enhanced proliferation by promoting cell cycle transition from G1 to S phase and significantly enhanced invasion of cervical cancer cells, while its knockdown significantly reversed these cellular events. Bioinformatics analysis suggested F-box and WD repeat domain-containing 7 (FBXW7) as a novel target of miR-92a, and miR-92a suppressed the expression level of FBXW7 mRNA by direct binding tomore » its 3′-untranslated region (3′UTR). Expression of miR-92a was negatively correlated with FBXW7 in cervical cancer tissues. Furthermore, Silencing of FBXW7 counteracted the effects of miR-92a suppression, while its overexpression reversed oncogenic effects of miR-92a. Together, these findings indicate that miR-92a acts as an onco-miRNA and may contribute to the progression and invasion of cervical cancer, suggesting miR-92a as a potential novel diagnostic and therapeutic target of cervical cancer. - Highlights: • miR-92a is elevated in cervical cancer tissues and cell lines. • miR-92a promotes cervical cancer cell proliferation, cell cycle transition from G1 to S phase and invasion. • FBXW7 is a direct target of miR-92a. • FBXW7 counteracts the oncogenic effects of miR-92a on cervical cancer cells.« less

A Role of hIPI3 in DNA Replication Licensing in Human Cells.

PubMed

Huang, Yining; Amin, Aftab; Qin, Yan; Wang, Ziyi; Jiang, Huadong; Liang, Lu; Shi, Linjing; Liang, Chun

2016-01-01

The yeast Ipi3p is required for DNA replication and cell viability in Sacharomyces cerevisiae. It is an essential component of the Rix1 complex (Rix1p/Ipi2p-Ipi1p-Ipi3p) that is required for the processing of 35S pre-rRNA in pre-60S ribosomal particles and for the initiation of DNA replication. The human IPI3 homolog is WDR18 (WD repeat domain 18), which shares significant homology with yIpi3p. Here we report that knockdown of hIPI3 resulted in substantial defects in the chromatin association of the MCM complex, DNA replication, cell cycle progression and cell proliferation. Importantly, hIPI3 silencing did not result in a reduction of the protein level of hCDC6, hMCM7, or the ectopically expressed GFP protein, indicating that protein synthesis was not defective in the same time frame of the DNA replication and cell cycle defects. Furthermore, the mRNA and protein levels of hIPI3 fluctuate in the cell cycle, with the highest levels from M phase to early G1 phase, similar to other pre-replicative (pre-RC) proteins. Moreover, hIPI3 interacts with other replication-initiation proteins, co-localizes with hMCM7 in the nucleus, and is important for the nuclear localization of hMCM7. We also found that hIPI3 preferentially binds to the origins of DNA replication including those at the c-Myc, Lamin-B2 and β-Globin loci. These results indicate that hIPI3 is involved in human DNA replication licensing independent of its role in ribosome biogenesis.

FBW7 (F-box and WD Repeat Domain-Containing 7) Negatively Regulates Glucose Metabolism by Targeting the c-Myc/TXNIP (Thioredoxin-Binding Protein) Axis in Pancreatic Cancer.

PubMed

Ji, Shunrong; Qin, Yi; Liang, Chen; Huang, Run; Shi, Si; Liu, Jiang; Jin, Kaizhou; Liang, Dingkong; Xu, Wenyan; Zhang, Bo; Liu, Liang; Liu, Chen; Xu, Jin; Ni, Quanxing; Chiao, Paul J; Li, Min; Yu, Xianjun

2016-08-01

FBW7 functions as a tumor suppressor by targeting oncoproteins for destruction. We previously reported that the oncogenic mutation of KRAS inhibits the tumor suppressor FBW7 via the Ras-Raf-MEK-ERK pathway, which facilitates the proliferation and survival of pancreatic cancer cells. However, the underlying mechanism by which FBW7 suppresses pancreatic cancer remains unexplored. Here, we sought to elucidate the function of FBW7 in pancreatic cancer glucose metabolism and malignancy. Combining maximum standardized uptake value (SUVmax), which was obtained preoperatively via a PET/CT scan, with immunohistochemistry staining, we analyzed the correlation between SUVmax and FBW7 expression in pancreatic cancer tissues. The impact of FBW7 on glucose metabolism was further validated in vitro and in vivo Finally, gene expression profiling was performed to identify core signaling pathways. The expression level of FBW7 was negatively associated with SUVmax in pancreatic cancer patients. FBW7 significantly suppressed glucose metabolism in pancreatic cancer cells in vitro Using a xenograft model, MicroPET/CT imaging results indicated that FBW7 substantially decreased 18F-fluorodeoxyglucose ((18)F-FDG) uptake in xenograft tumors. Gene expression profiling data revealed that TXNIP, a negative regulator of metabolic transformation, was a downstream target of FBW7. Mechanistically, we demonstrated that TXNIP was a c-Myc target gene and that FBW7 regulated TXNIP expression in a c-Myc-dependent manner. Our results thus reveal that FBW7 serves as a negative regulator of glucose metabolism through regulation of the c-Myc/TXNIP axis in pancreatic cancer. Clin Cancer Res; 22(15); 3950-60. ©2016 AACR. ©2016 American Association for Cancer Research.

GLI pathogenesis-related 1 functions as a tumor-suppressor in lung cancer.

PubMed

Sheng, Xiumei; Bowen, Nathan; Wang, Zhengxin

2016-03-18

GLI pathogenesis-related 1 (GLIPR1) was originally identified in glioblastomas and its expression was also found to be down-regulated in prostate cancer. Functional studies revealed both growth suppression and proapoptotic activities for GLIPR1 in multiple cancer cell lines. GLIPR1's role in lung cancer has not been investigated. Protein arginine methyltransferase 5 (PRMT5) is a protein arginine methyltransferase and forms a stoichiometric complex with the WD repeat domain 77 (WDR77) protein. Both PRMT5 and WDR77 are essential for growth of lung epithelial and cancer cells. But additional gene products that interact genetically or biochemichally with PRMT5 and WDR77 in the control of lung cancer cell growth are not characterized. DNA microarray and immunostaining were used to detect GLIPR1 expression during lung development and lung tumorigenesis. GLIPR1 expression was also analyzed in the TCGA lung cancer cohort. The consequence of GLIPR1 on growth of lung cancer cells in the tissue culture and lung tumor xenografts in the nude mice was observed. We found that GLIPR1 expression is negatively associated with PRMT5/WDR77. GLIPR1 is absent in growing epithelial cells at the early stages of mouse lung development and highly expressed in the adult lung. Expression of GLIPR1 was down-regulated during lung tumorigenesis and its expression suppressed growth of lung cancer cells in the tissue culture and lung tumor xenografts in mice. GLIPR1 regulates lung cancer growth through the V-Erb-B avian erythroblastic leukemia viral oncogene homolog 3 (ErbB3). This study reveals a novel pathway that PRMT5/WDR77 regulates GLIPR1 expression to control lung cancer cell growth and GLIPR1 as a potential therapeutic agent for lung cancer.

Analysis of cellulose synthase genes from domesticated apple identifies collinear genes WDR53 and CesA8A: partial co-expression, bicistronic mRNA, and alternative splicing of CESA8A

PubMed Central

Guerriero, Gea; Spadiut, Oliver; Kerschbamer, Christine; Giorno, Filomena; Baric, Sanja; Ezcurra, Inés

2016-01-01

Cellulose synthase (CesA) genes constitute a complex multigene family with six major phylogenetic clades in angiosperms. The recently sequenced genome of domestic apple, Malus×domestica, was mined for CesA genes, by blasting full-length cellulose synthase protein (CESA) sequences annotated in the apple genome against protein databases from the plant models Arabidopsis thaliana and Populus trichocarpa. Thirteen genes belonging to the six angiosperm CesA clades and coding for proteins with conserved residues typical of processive glycosyltransferases from family 2 were detected. Based on their phylogenetic relationship to Arabidopsis CESAs, as well as expression patterns, a nomenclature is proposed to facilitate further studies. Examination of their genomic organization revealed that MdCesA8-A is closely linked and co-oriented with WDR53, a gene coding for a WD40 repeat protein. The WDR53 and CesA8 genes display conserved collinearity in dicots and are partially co-expressed in the apple xylem. Interestingly, the presence of a bicistronic WDR53–CesA8A transcript was detected in phytoplasma-infected phloem tissues of apple. The bicistronic transcript contains a spliced intergenic sequence that is predicted to fold into hairpin structures typical of internal ribosome entry sites, suggesting its potential cap-independent translation. Surprisingly, the CesA8A cistron is alternatively spliced and lacks the zinc-binding domain. The possible roles of WDR53 and the alternatively spliced CESA8 variant during cellulose biosynthesis in M.×domestica are discussed. PMID:23048131

FBW7 is associated with prognosis, inhibits malignancies and enhances temozolomide sensitivity in glioblastoma cells.

PubMed

Lin, Jing; Ji, Aihui; Qiu, Guanzhong; Feng, Huaizhi; Li, Jian; Li, Shuo; Zou, Yongxiang; Cui, Yong; Song, Chaoli; He, Hua; Lu, Yicheng

2018-04-01

F-box and WD repeat domain-containing 7 (FBW7) is a SCF-type E3 ubiquitin ligase targeting a multitude of oncoproteins for degradation. Acting as one of the most important tumor suppressors, it is frequently inactivated in various tumors. In this study we aimed to evaluate the relationship of FBW7 with glioma pathology and prognosis, and examine its effect in glioma malignancies and temozolomide (TMZ)-based therapy. Clinical tissues and TCGA database analysis revealed that FBW7 expression was correlated inversely with glioma histology and positively with patient survival time. Lentivirus transfection-induced FBW7 overexpression significantly suppressed proliferation, invasion and migration of U251 and U373 cells, whereas knockdown of FBW7 by targeted shRNA promoted proliferation, invasion and migration of glioma cells. Most importantly, the expression level of FBW7 was found to affect the 50% inhibitory concentration (IC50) of U251 and the TMZ-resistant variant. Combining TMZ with FBW7 overexpression notably increased the cytotoxicity compared to TMZ treatment alone, which was conversely attenuated by FBW7 knockdown. Moreover, flow cytometry (FC) analysis showed overexpression of FBW7, TMZ or the combination-increased proportion of G2/M arrest and the apoptotic rate, whereas FBW7 inhibition reduced G2/M arrest and apoptosis in U251 cells. Finally, mechanistic study found that FBW7 overexpression downregulated Aurora B, Mcl1 and Notch1 levels in a time-dependent pattern and this expressional suppression was independent of TMZ. These findings collectively demonstrate the critical role of FBW7 as a prognostic factor and a potential target to overcome chemoresistance of glioblastoma. © 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Variant in the RFWD3 gene associated with PATN1, a modifier of leopard complex spotting.

PubMed

Holl, H M; Brooks, S A; Archer, S; Brown, K; Malvick, J; Penedo, M C T; Bellone, R R

2016-02-01

Leopard complex spotting (LP), the result of an incompletely dominant mutation in TRPM1, produces a collection of unique depigmentation patterns in the horse. Although the LP mutation allows for expression of the various patterns, other loci are responsible for modification of the extent of white. Pedigree analysis of families segregating for high levels of patterning indicated a single dominant gene, named Pattern-1 (PATN1), as a major modifier of LP. Linkage analysis in two half-sibling families segregating for PATN1 identified a 15-Mb region on ECA3p that warranted further investigation. Whole transcriptome sequencing of skin samples from horses with and without the PATN1 allele was performed to identify genic SNPs for fine mapping. Two Sequenom assays were utilized to genotype 192 individuals from five LP-carrying breeds. The initial panel highlighted a 1.6-Mb region without a clear candidate gene. In the second round of fine mapping, SNP ECA3:23 658 447T>G in the 3'-UTR of RING finger and WD repeat domain 3 (RFWD3) reached a significance level of P = 1.063 × 10(-39). Sequencing of RFWD3 did not identify any coding polymorphisms specific to PATN1 horses. Genotyping of the RFWD3 3'-UTR SNP in 54 additional LP animals and 327 horses from nine breeds not segregating for LP further supported the association (P = 4.17 × 10(-115)). This variant is a strong candidate for PATN1 and may be particularly useful for LP breeders to select for high levels of white patterning. © 2015 Stichting International Foundation for Animal Genetics.

Reprogramming Antagonizes the Oncogenicity of HOXA13-Long Noncoding RNA HOTTIP Axis in Gastric Cancer Cells.

PubMed

Wu, Deng-Chyang; Wang, Sophie S W; Liu, Chung-Jung; Wuputra, Kenly; Kato, Kohsuke; Lee, Yen-Liang; Lin, Ying-Chu; Tsai, Ming-Ho; Ku, Chia-Chen; Lin, Wen-Hsin; Wang, Shin-Wei; Kishikawa, Shotaro; Noguchi, Michiya; Wu, Chu-Chieh; Chen, Yi-Ting; Chai, Chee-Yin; Lin, Chen-Lung Steve; Kuo, Kung-Kai; Yang, Ya-Han; Miyoshi, Hiroyuki; Nakamura, Yukio; Saito, Shigeo; Nagata, Kyosuke; Lin, Chang-Shen; Yokoyama, Kazunari K

2017-10-01

Reprogramming of cancer cells into induced pluripotent stem cells (iPSCs) is a compelling idea for inhibiting oncogenesis, especially through modulation of homeobox proteins in this reprogramming process. We examined the role of various long noncoding RNAs (lncRNAs)-homeobox protein HOXA13 axis on the switching of the oncogenic function of bone morphogenetic protein 7 (BMP7), which is significantly lost in the gastric cancer cell derived iPS-like cells (iPSLCs). BMP7 promoter activation occurred through the corecruitment of HOXA13, mixed-lineage leukemia 1 lysine N-methyltransferase, WD repeat-containing protein 5, and lncRNA HoxA transcript at the distal tip (HOTTIP) to commit the epigenetic changes to the trimethylation of lysine 4 on histone H3 in cancer cells. By contrast, HOXA13 inhibited BMP7 expression in iPSLCs via the corecruitment of HOXA13, enhancer of zeste homolog 2, Jumonji and AT rich interactive domain 2, and lncRNA HoxA transcript antisense RNA (HOTAIR) to various cis-element of the BMP7 promoter. Knockdown experiments demonstrated that HOTTIP contributed positively, but HOTAIR regulated negatively to HOXA13-mediated BMP7 expression in cancer cells and iPSLCs, respectively. These findings indicate that the recruitment of HOXA13-HOTTIP and HOXA13-HOTAIR to different sites in the BMP7 promoter is crucial for the oncogenic fate of human gastric cells. Reprogramming with octamer-binding protein 4 and Jun dimerization protein 2 can inhibit tumorigenesis by switching off BMP7. Stem Cells 2017;35:2115-2128. © 2017 The Authors Stem Cells published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.

FBXW7 expression affects the response to chemoradiotherapy and overall survival among patients with oral squamous cell carcinoma: A single-center retrospective study.

PubMed

Arita, Hidetaka; Nagata, Masashi; Yoshida, Ryoji; Matsuoka, Yuichiro; Hirosue, Akiyuki; Kawahara, Kenta; Sakata, Junki; Nakashima, Hikaru; Kojima, Taku; Toya, Ryo; Murakami, Ryuji; Hiraki, Akimitsu; Shinohara, Masanori; Nakayama, Hideki

2017-10-01

FBXW7 (F-box and WD repeat domain containing-7) is a tumor suppressor protein that regulates the degradation of various oncoproteins in several malignancies. However, limited information is available regarding FBXW7 expression in oral squamous cell carcinoma. Therefore, this study aimed to determine the clinical significance of FBXW7 expression in oral squamous cell carcinoma. The FBXW7 expression patterns in oral squamous cell carcinoma and adjacent normal tissues from 15 patients who underwent radical resection were evaluated using quantitative real-time polymerase chain reaction and immunohistochemical staining. In addition, immunohistochemistry was performed using paraffin-embedded sections from biopsy specimens obtained from 110 patients with oral squamous cell carcinoma who underwent surgery after 5 fluorouracil-based chemoradiotherapy. The associations of FBXW7 expression with various clinicopathological features and prognosis were evaluated in these patients. As a results, in the 15 matched samples, the FBXW7 expression was significantly decreased in the oral squamous cell carcinoma tissues compared to that in the adjacent normal tissues. In the clinicopathological analysis, compared to high protein expression, low FBXW7 expression was found to significantly associate with a poor histological response to preoperative chemoradiotherapy. Kaplan-Meier curve analysis revealed that low FBXW7 expression was significantly associated with a poor prognosis, and FBXW7 expression was found to be an independent predictor of overall survival in the multivariate analysis. Our results suggest that FBXW7 may function as a tumor suppressor protein in oral squamous cell carcinoma. In addition, FBXW7 could be a potential biomarker for predicting not only the clinical response to chemoradiotherapy but also overall survival in patients with oral squamous cell carcinoma.

Crystal structure of tandem type III fibronectin domains from Drosophila neuroglian at 2.0 A.

PubMed

Huber, A H; Wang, Y M; Bieber, A J; Bjorkman, P J

1994-04-01

We report the crystal structure of two adjacent fibronectin type III repeats from the Drosophila neural cell adhesion molecule neuroglian. Each domain consists of two antiparallel beta sheets and is folded topologically identically to single fibronectin type III domains from the extracellular matrix proteins tenascin and fibronectin. beta bulges and left-handed polyproline II helices disrupt the regular beta sheet structure of both neuroglian domains. The hydrophobic interdomain interface includes a metal-binding site, presumably involved in stabilizing the relative orientation between domains and predicted by sequence comparision to be present in the vertebrate homolog molecule L1. The neuroglian domains are related by a near perfect 2-fold screw axis along the longest molecular dimension. Using this relationship, a model for arrays of tandem fibronectin type III repeats in neuroglian and other molecules is proposed.

Interactions between the S-Domain Receptor Kinases and AtPUB-ARM E3 Ubiquitin Ligases Suggest a Conserved Signaling Pathway in Arabidopsis1[W][OA

PubMed Central

Samuel, Marcus A.; Mudgil, Yashwanti; Salt, Jennifer N.; Delmas, Frédéric; Ramachandran, Shaliny; Chilelli, Andrea; Goring, Daphne R.

2008-01-01

The Arabidopsis (Arabidopsis thaliana) genome encompasses multiple receptor kinase families with highly variable extracellular domains. Despite their large numbers, the various ligands and the downstream interacting partners for these kinases have been deciphered only for a few members. One such member, the S-receptor kinase, is known to mediate the self-incompatibility (SI) response in Brassica. S-receptor kinase has been shown to interact and phosphorylate a U-box/ARM-repeat-containing E3 ligase, ARC1, which, in turn, acts as a positive regulator of the SI response. In an effort to identify conserved signaling pathways in Arabidopsis, we performed yeast two-hybrid analyses of various S-domain receptor kinase family members with representative Arabidopsis plant U-box/ARM-repeat (AtPUB-ARM) E3 ligases. The kinase domains from S-domain receptor kinases were found to interact with ARM-repeat domains from AtPUB-ARM proteins. These kinase domains, along with M-locus protein kinase, a positive regulator of SI response, were also able to phosphorylate the ARM-repeat domains in in vitro phosphorylation assays. Subcellular localization patterns were investigated using transient expression assays in tobacco (Nicotiana tabacum) BY-2 cells and changes were detected in the presence of interacting kinases. Finally, potential links to the involvement of these interacting modules to the hormone abscisic acid (ABA) were investigated. Interestingly, AtPUB9 displayed redistribution to the plasma membrane of BY-2 cells when either treated with ABA or coexpressed with the active kinase domain of ARK1. As well, T-DNA insertion mutants for ARK1 and AtPUB9 lines were altered in their ABA sensitivity during germination and acted at or upstream of ABI3, indicating potential involvement of these proteins in ABA responses. PMID:18552232

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

Wang, Yuli; Zhang, Pengju; Wang, Yunshan

The ErbB3 receptor–binding protein EBP1 encodes two alternatively spliced isoforms P48 and P42. While there is evidence of differential roles for these isoforms in tumorigenesis, little is known about their underlying mechanisms. In this paper, we demonstrate that EBP1 isoforms interact with the SCF-type ubiquitin ligase FBXW7 in distinct ways to exert opposing roles in tumorigenesis. EBP1 P48 bound to the WD domain of FBXW7 as an oncogenic substrate of FBXW7. EBP1 P48 binding sequestered FBXW7α to the cytosol, modulating its role in protein degradation and attenuating its tumor suppressor function. In contrast, EBP1 P42 bound to both the F-boxmore » domain of FBXW7 as well as FBXW7 substrates. This adapter function of EBP1 P42 stabilized the interaction of FBXW7 with its substrates and promoted FBXW7-mediated degradation of oncogenic targets, enhancing its overall tumor-suppressing function. Finally and overall, our results establish distinct physical and functional interactions between FBXW7 and EBP1 isoforms, which yield their mechanistically unique isoform-specific functions of EBP1 in cancer.« less

Identification and Characterization of Functionally Critical, Conserved Motifs in the Internal Repeats and N-terminal Domain of Yeast Translation Initiation Factor 4B (yeIF4B)*

PubMed Central

Zhou, Fujun; Walker, Sarah E.; Mitchell, Sarah F.; Lorsch, Jon R.; Hinnebusch, Alan G.

2014-01-01

eIF4B has been implicated in attachment of the 43 S preinitiation complex (PIC) to mRNAs and scanning to the start codon. We recently determined that the internal seven repeats (of ∼26 amino acids each) of Saccharomyces cerevisiae eIF4B (yeIF4B) compose the region most critically required to enhance mRNA recruitment by 43 S PICs in vitro and stimulate general translation initiation in yeast. Moreover, although the N-terminal domain (NTD) of yeIF4B contributes to these activities, the RNA recognition motif is dispensable. We have now determined that only two of the seven internal repeats are sufficient for wild-type (WT) yeIF4B function in vivo when all other domains are intact. However, three or more repeats are needed in the absence of the NTD or when the functions of eIF4F components are compromised. We corroborated these observations in the reconstituted system by demonstrating that yeIF4B variants with only one or two repeats display substantial activity in promoting mRNA recruitment by the PIC, whereas additional repeats are required at lower levels of eIF4A or when the NTD is missing. These findings indicate functional overlap among the 7-repeats and NTD domains of yeIF4B and eIF4A in mRNA recruitment. Interestingly, only three highly conserved positions in the 26-amino acid repeat are essential for function in vitro and in vivo. Finally, we identified conserved motifs in the NTD and demonstrate functional overlap of two such motifs. These results provide a comprehensive description of the critical sequence elements in yeIF4B that support eIF4F function in mRNA recruitment by the PIC. PMID:24285537

Direct mapping of symbolic DNA sequence into frequency domain in global repeat map algorithm

PubMed Central

Glunčić, Matko; Paar, Vladimir

2013-01-01

The main feature of global repeat map (GRM) algorithm (www.hazu.hr/grm/software/win/grm2012.exe) is its ability to identify a broad variety of repeats of unbounded length that can be arbitrarily distant in sequences as large as human chromosomes. The efficacy is due to the use of complete set of a K-string ensemble which enables a new method of direct mapping of symbolic DNA sequence into frequency domain, with straightforward identification of repeats as peaks in GRM diagram. In this way, we obtain very fast, efficient and highly automatized repeat finding tool. The method is robust to substitutions and insertions/deletions, as well as to various complexities of the sequence pattern. We present several case studies of GRM use, in order to illustrate its capabilities: identification of α-satellite tandem repeats and higher order repeats (HORs), identification of Alu dispersed repeats and of Alu tandems, identification of Period 3 pattern in exons, implementation of ‘magnifying glass’ effect, identification of complex HOR pattern, identification of inter-tandem transitional dispersed repeat sequences and identification of long segmental duplications. GRM algorithm is convenient for use, in particular, in cases of large repeat units, of highly mutated and/or complex repeats, and of global repeat maps for large genomic sequences (chromosomes and genomes). PMID:22977183

Activity and Kinematics of White Dwarf-M Dwarf Binaries from the SUPERBLINK Proper Motion Survey

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

Skinner, Julie N.; Morgan, Dylan P.; West, Andrew A.

We present an activity and kinematic analysis of high proper motion white dwarf-M dwarf binaries (WD+dMs) found in the SUPERBLINK survey, 178 of which are new identifications. To identify WD+dMs, we developed a UV–optical–IR color criterion and conducted a spectroscopic survey to confirm each candidate binary. For the newly identified systems, we fit the two components using model white dwarf spectra and M dwarf template spectra to determine physical parameters. We use H α chromospheric emission to examine the magnetic activity of the M dwarf in each system, and investigate how its activity is affected by the presence of amore » white dwarf companion. We find that the fraction of WD+dM binaries with active M dwarfs is significantly higher than their single M dwarf counterparts at early and mid-spectral types. We corroborate previous studies that find high activity fractions at both close and intermediate separations. At more distant separations, the binary fraction appears to approach the activity fraction for single M dwarfs. Using derived radial velocities and the proper motions, we calculate 3D space velocities for the WD+dMs in SUPERBLINK. For the entire SUPERBLINK WD+dMs, we find a large vertical velocity dispersion, indicating a dynamically hotter population compared to high proper motion samples of single M dwarfs. We compare the kinematics for systems with active M dwarfs and those with inactive M dwarfs, and find signatures of asymmetric drift in the inactive sample, indicating that they are drawn from an older population.« less

A Western diet induced NAFLD in LDLR(-/)(-) mice is associated with reduced hepatic glutathione synthesis.

PubMed

Li, Ling; Zhang, Guo-Fang; Lee, Kwangwon; Lopez, Rocio; Previs, Stephen F; Willard, Belinda; McCullough, Arthur; Kasumov, Takhar

2016-07-01

Oxidative stress plays a key role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Glutathione is the major anti-oxidant involved in cellular oxidative defense, however there are currently no simple non-invasive methods for assessing hepatic glutathione metabolism in patients with NAFLD. As a primary source of plasma glutathione, liver plays an important role in interorgan glutathione homeostasis. In this study, we have tested the hypothesis that measurements of plasma glutathione turnover could be used to assess the hepatic glutathione metabolism in LDLR(-/)(-) mice, a mouse model of diet-induced NAFLD. Mice were fed a standard low fat diet (LFD) or a high fat diet containing cholesterol (a Western type diet (WD)). The kinetics of hepatic and plasma glutathione were quantified using the (2)H2O metabolic labeling approach. Our results show that a WD leads to reduced fractional synthesis rates (FSR) of hepatic (25%/h in LFD vs. 18%/h in WD, P<0.05) and plasma glutathione (43%/h in LFD vs. 21%/h in WD, P<0.05), without any significant effect on their absolute production rates (PRs). WD-induced concordant changes in both hepatic and plasma glutathione turnover suggest that the plasma glutathione turnover measurements could be used to assess hepatic glutathione metabolism. The safety, simplicity, and low cost of the (2)H2O-based glutathione turnover approach suggest that this method has the potential for non-invasive probing of hepatic glutathione metabolism in patients with NAFLD and other diseases. Copyright © 2016 Elsevier Inc. All rights reserved.

A Western diet induced NAFLD in LDLR−/− mice is associated with reduced hepatic glutathione synthesis

PubMed Central

Li, Ling; Zhang, Guo-Fang; Lee, Kwangwon; Lopez, Rocio; Previs, Stephen F.; Willard, Belinda; McCullough, Arthur; Kasumov, Takhar

2017-01-01

Oxidative stress plays a key role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Glutathione is the major anti-oxidant involved in cellular oxidative defense, however there are currently no simple non-invasive methods for assessing hepatic glutathione metabolism in patients with NAFLD. As a primary source of plasma glutathione, liver plays an important role in interorgan glutathione homeostasis. In this study, we have tested the hypothesis that measurements of plasma glutathione turnover could be used to assess the hepatic glutathione metabolism in LDLR−/− mice, a mouse model of diet-induced NAFLD. Mice were fed a standard low fat diet (LFD) or a high fat diet containing cholesterol (a Western type diet (WD)). The kinetics of hepatic and plasma glutathione were quantified using the 2H2O metabolic labeling approach. Our results show that a WD leads to reduced fractional synthesis rates (FSR) of hepatic (25%/h in LFD vs. 18%/h in WD, P < 0.05) and plasma glutathione (43%/h in LFD vs. 21%/h in WD, P <0.05), without any significant effect on their absolute production rates (PRs). WD-induced concordant changes in both hepatic and plasma glutathione turnover suggest that the plasma glutathione turnover measurements could be used to assess hepatic glutathione metabolism. The safety, simplicity, and low cost of the 2H2O-based glutathione turnover approach suggest that this method has the potential for non-invasive probing of hepatic glutathione metabolism in patients with NAFLD and other diseases. PMID:27036364

Estrogen Receptor α Participates to the Beneficial Effect of Red Wine Polyphenols in a Mouse Model of Obesity-Related Disorders

PubMed Central

Leonetti, Daniela; Soleti, Raffaella; Clere, Nicolas; Vergori, Luisa; Jacques, Caroline; Duluc, Lucie; Dourguia, Catherine; Martínez, Maria C.; Andriantsitohaina, Ramaroson

2017-01-01

Red wine polyphenol extracts (polyphenols) ameliorate cardiovascular and metabolic disorders associated with obesity. Previously, we demonstrated that the alpha isoform of estrogen receptor (ERα) triggers the vascular protection of polyphenols. Here, we investigated the contribution of ERα on the effects of polyphenols on cardiovascular and metabolic alterations associated with obesity. We used ovariectomized wild type or ERα-deficient mice receiving standard (SD) or western (WD) diets, or SD and WD containing polyphenols (SD+polyphenols and WD+polyphenols, respectively) over a 12-week period. Body weight was measured during treatment. Echocardiography examination was performed before sacrifice. Blood and tissues were sampled for biochemical and functional analysis with respect to nitric oxide (NO•) and oxidative stress. Vascular reactivity and liver mitochondrial complexes were analyzed. In WD-fed mice, polyphenols reduced adiposity, plasma triglycerides and oxidative stress in aorta, heart, adipose and liver tissues and enhanced NO• production in aorta and liver. ERα deletion prevented or reduced the beneficial effects of polyphenols, especially visceral adiposity, aortic and liver oxidative stresses and NO• bioavailability. ERα deletion, however, had no effect on polyphenol’s ability to decrease the fat accumulation and oxidative stress of subcutaneous adipose tissue. Also, ERα deletion did not modify the decrease of ROS levels induced by polyphenols treatment in the visceral adipose tissue and heart from WD-fed mice. Dietary supplementation of polyphenols remarkably attenuates features of metabolic syndrome; these effects are partially mediated by ERα-dependent mechanisms. This study demonstrates the therapeutic potential of this extract in metabolic and cardiovascular alterations linked to excessive energy intake. PMID:28119607

Mass retention efficiencies of He accretion onto carbon-oxygen white dwarfs and type Ia supernovae

NASA Astrophysics Data System (ADS)

Wu, C.; Wang, B.; Liu, D.; Han, Z.

2017-07-01

Context. Type Ia supernovae (SNe Ia) play a crucial role in studying cosmology and galactic chemical evolution. They are thought to be thermonuclear explosions of carbon-oxygen white dwarfs (CO WDs) when their masses reach the Chandrasekar mass limit in binaries. Previous studies have suggested that He novae may be progenitor candidates of SNe Ia. However, the mass retention efficiencies during He nova outbursts are still uncertain. Aims: In this article, we aim to study the mass retention efficiencies of He nova outbursts and to investigate whether SNe Ia can be produced through He nova outbursts. Methods: Using the stellar evolution code Modules for Experiments in Stellar Astrophysics, we simulated a series of multicycle He-layer flashes, in which the initial WD masses range from 0.7 to 1.35 M⊙ with various accretion rates. Results: We obtained the mass retention efficiencies of He nova outbursts for various initial WD masses, which can be used in the binary population synthesis studies. In our simulations, He nova outbursts can increase the mass of the WD to the Chandrasekar mass limit and the explosive carbon burning can be triggered in the center of the WD; this suggests that He nova outbursts can produce SNe Ia. Meanwhile, the mass retention efficiencies in the present work are lower than those of previous studies, which leads to a lower birthrates of SNe Ia through the WD + He star channel. Furthermore, we obtained the elemental abundances distribution at the moment of explosive carbon burning, which can be used as the initial input parameters in studying explosion models of SNe Ia.

Wilson Disease: Epigenetic effects of choline supplementation on phenotype and clinical course in a mouse model.

PubMed

Medici, Valentina; Kieffer, Dorothy A; Shibata, Noreene M; Chima, Harpreet; Kim, Kyoungmi; Canovas, Angela; Medrano, Juan F; Islas-Trejo, Alma D; Kharbanda, Kusum K; Olson, Kristin; Su, Ruijun J; Islam, Mohammad S; Syed, Raisa; Keen, Carl L; Miller, Amy Y; Rutledge, John C; Halsted, Charles H; LaSalle, Janine M

2016-11-01

Wilson disease (WD), a genetic disorder affecting copper transport, is characterized by hepatic and neurological manifestations with variable and often unpredictable presentation. Global DNA methylation in liver was previously modified by dietary choline in tx-j mice, a spontaneous mutant model of WD. We therefore hypothesized that the WD phenotype and hepatic gene expression of tx-j offspring could be modified by maternal methyl supplementation during pregnancy. In an initial experiment, female tx-j mice or wild type mice were fed control or choline-supplemented diets 2 weeks prior to mating through embryonic day 17. Transcriptomic analysis (RNA-seq) on embryonic livers revealed tx-j-specific differences in genes related to oxidative phosphorylation, mitochondrial dysfunction, and the neurological disorders Huntington's disease and Alzheimer disease. Maternal choline supplementation restored the transcript levels of a subset of genes to wild type levels. In a separate experiment, a group of tx-j offspring continued to receive choline-supplemented or control diets, with or without the copper chelator penicillamine (PCA) for 12 weeks until 24 weeks of age. Combined choline supplementation and PCA treatment of 24-week-old tx-j mice was associated with increased liver transcript levels of methionine metabolism and oxidative phosphorylation-related genes. Sex differences in gene expression within each treatment group were also observed. These results demonstrate that the transcriptional changes in oxidative phosphorylation and methionine metabolism genes in WD that originate during fetal life are, in part, prevented by prenatal maternal choline supplementation, a finding with potential relevance to preventive treatments of WD.

Inter-relationships among diet, obesity and hippocampal-dependent cognitive function.

PubMed

Davidson, T L; Hargrave, S L; Swithers, S E; Sample, C H; Fu, X; Kinzig, K P; Zheng, W

2013-12-03

Intake of a Western diet (WD), which is high in saturated fat and sugar, is associated with deficits in hippocampal-dependent learning and memory processes as well as with markers of hippocampal pathology. In the present study, rats were trained to asymptote on hippocampal-dependent serial feature negative (FN) and hippocampal-independent simple discrimination problems. Performance was then assessed following 7 days on ad libitum chow and after 10, 24, 40, 60, and 90 days of maintenance on WD, on ketogenic (KETO) diet, which is high in saturated fat and low in sugar and other carbohydrates, or continued maintenance on chow (CHOW). Confirming and extending previous findings, diet-induced obese (DIO) rats fed WD showed impaired FN performance, increased blood-brain barrier (BBB) permeability, and increased fasting blood glucose levels compared to CHOW controls and to diet-resistant (DR) rats that did not become obese when maintained on WD. For rats fed the KETO diet, FN performance and BBB integrity were more closely associated with level of circulating ketone bodies than with obesity phenotype (DR or DIO), with higher levels of ketones appearing to provide a protective effect. The evidence also indicated that FN deficits preceded and predicted increased body weight and adiposity. This research (a) further substantiates previous findings of WD-induced deficits in hippocampal-dependent FN discriminations, (b) suggests that ketones may be protective against diet-induced cognitive impairment, and (c) provides evidence that diet-induced cognitive impairment precedes weight gain and obesity. Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.

Potential for Dietary ω-3 Fatty Acids to Prevent Nonalcoholic Fatty Liver Disease and Reduce the Risk of Primary Liver Cancer123

PubMed Central

Jump, Donald B; Depner, Christopher M; Tripathy, Sasmita; Lytle, Kelli A

2015-01-01

Nonalcoholic fatty liver disease (NAFLD) has increased in parallel with central obesity, and its prevalence is anticipated to increase as the obesity epidemic remains unabated. NAFLD is now the most common cause of chronic liver disease in developed countries and is defined as excessive lipid accumulation in the liver, that is, hepatosteatosis. NAFLD ranges in severity from benign fatty liver to nonalcoholic steatohepatitis (NASH), and NASH is characterized by hepatic injury, inflammation, oxidative stress, and fibrosis. NASH can progress to cirrhosis, and cirrhosis is a risk factor for primary hepatocellular carcinoma (HCC). The prevention of NASH will lower the risk of cirrhosis and NASH-associated HCC. Our studies have focused on NASH prevention. We developed a model of NASH by using mice with the LDL cholesterol receptor gene ablated fed the Western diet (WD). The WD induces a NASH phenotype in these mice that is similar to that seen in humans and includes robust induction of hepatic steatosis, inflammation, oxidative stress, and fibrosis. With the use of transcriptomic, lipidomic, and metabolomic approaches, we examined the capacity of 2 dietary ω-3 (n–3) polyunsaturated fatty acids, eicosapentaenoic acid (20:5ω-3; EPA) and docosahexaenoic acid (22:6ω-3; DHA), to prevent WD-induced NASH. Dietary DHA was superior to EPA at attenuating WD-induced changes in plasma lipids and hepatic injury and at reversing WD effects on hepatic metabolism, oxidative stress, and fibrosis. The outcome of these studies suggests that DHA may be useful in preventing NASH and reducing the risk of HCC. PMID:26567194

Effects of zero point vibration on the reaction dynamics of water dimer cations following ionization.

PubMed

Tachikawa, Hiroto

2017-06-30

Reactions of water dimer cation (H2O)2+ following ionization have been investigated by means of a direct ab initio molecular dynamics method. In particular, the effects of zero point vibration and zero point energy (ZPE) on the reaction mechanism were considered in this work. Trajectories were run on two electronic potential energy surfaces (PESs) of (H2O)2+: ground state ( 2 A″-like state) and the first excited state ( 2 A'-like state). All trajectories on the ground-state PES lead to the proton-transferred product: H 2 O + (Wd)-H 2 O(Wa) → OH(Wd)-H 3 O + (Wa), where Wd and Wa refer to the proton donor and acceptor water molecules, respectively. Time of proton transfer (PT) varied widely from 15 to 40 fs (average time of PT = 30.9 fs). The trajectories on the excited-state PES gave two products: an intermediate complex with a face-to-face structure (H 2 O-OH 2 ) + and a PT product. However, the proton was transferred to the opposite direction, and the reverse PT was found on the excited-state PES: H 2 O(Wd)-H 2 O + (Wa) → H 3 O + (Wd)-OH(Wa). This difference occurred because the ionizing water molecule in the dimer switched between the ground and excited states. The reaction mechanism of (H2O)2+ and the effects of ZPE are discussed on the basis of the results. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Vulnerability Imposed by Diet and Brain Trauma for Anxiety-Like Phenotype: Implications for Post-Traumatic Stress Disorders

PubMed Central

Tyagi, Ethika; Agrawal, Rahul; Zhuang, Yumei; Abad, Catalina; Waschek, James A.; Gomez-Pinilla, Fernando

2013-01-01

Mild traumatic brain injury (mTBI, cerebral concussion) is a risk factor for the development of psychiatric illness such as posttraumatic stress disorder (PTSD). We sought to evaluate how omega-3 fatty acids during brain maturation can influence challenges incurred during adulthood (transitioning to unhealthy diet and mTBI) and predispose the brain to a PTSD-like pathobiology. Rats exposed to diets enriched or deficient in omega-3 fatty acids (n-3) during their brain maturation period, were transitioned to a western diet (WD) when becoming adult and then subjected to mTBI. TBI resulted in an increase in anxiety-like behavior and its molecular counterpart NPY1R, a hallmark of PTSD, but these effects were more pronounced in the animals exposed to n-3 deficient diet and switched to WD. The n-3 deficiency followed by WD disrupted BDNF signaling and the activation of elements of BDNF signaling pathway (TrkB, CaMKII, Akt and CREB) in frontal cortex. TBI worsened these effects and more prominently in combination with the n-3 deficiency condition. Moreover, the n-3 deficiency primed the immune system to the challenges imposed by the WD and brain trauma as evidenced by results showing that the WD or mTBI affected brain IL1β levels and peripheral Th17 and Treg subsets only in animals previously conditioned to the n-3 deficient diet. These results provide novel evidence for the capacity of maladaptive dietary habits to lower the threshold for neurological disorders in response to challenges. PMID:23483949

Vulnerability imposed by diet and brain trauma for anxiety-like phenotype: implications for post-traumatic stress disorders.

PubMed

Tyagi, Ethika; Agrawal, Rahul; Zhuang, Yumei; Abad, Catalina; Waschek, James A; Gomez-Pinilla, Fernando

2013-01-01

Mild traumatic brain injury (mTBI, cerebral concussion) is a risk factor for the development of psychiatric illness such as posttraumatic stress disorder (PTSD). We sought to evaluate how omega-3 fatty acids during brain maturation can influence challenges incurred during adulthood (transitioning to unhealthy diet and mTBI) and predispose the brain to a PTSD-like pathobiology. Rats exposed to diets enriched or deficient in omega-3 fatty acids (n-3) during their brain maturation period, were transitioned to a western diet (WD) when becoming adult and then subjected to mTBI. TBI resulted in an increase in anxiety-like behavior and its molecular counterpart NPY1R, a hallmark of PTSD, but these effects were more pronounced in the animals exposed to n-3 deficient diet and switched to WD. The n-3 deficiency followed by WD disrupted BDNF signaling and the activation of elements of BDNF signaling pathway (TrkB, CaMKII, Akt and CREB) in frontal cortex. TBI worsened these effects and more prominently in combination with the n-3 deficiency condition. Moreover, the n-3 deficiency primed the immune system to the challenges imposed by the WD and brain trauma as evidenced by results showing that the WD or mTBI affected brain IL1β levels and peripheral Th17 and Treg subsets only in animals previously conditioned to the n-3 deficient diet. These results provide novel evidence for the capacity of maladaptive dietary habits to lower the threshold for neurological disorders in response to challenges.

Wilson Disease: Epigenetic effects of choline supplementation on phenotype and clinical course in a mouse model

PubMed Central

Medici, Valentina; Kieffer, Dorothy A.; Shibata, Noreene M.; Chima, Harpreet; Kim, Kyoungmi; Canovas, Angela; Medrano, Juan F.; Islas-Trejo, Alma D.; Kharbanda, Kusum K.; Olson, Kristin; Su, Ruijun J.; Islam, Mohammad S.; Syed, Raisa; Keen, Carl L.; Miller, Amy Y.; Rutledge, John C.; Halsted, Charles H.; LaSalle, Janine M.

2016-01-01

ABSTRACT Wilson disease (WD), a genetic disorder affecting copper transport, is characterized by hepatic and neurological manifestations with variable and often unpredictable presentation. Global DNA methylation in liver was previously modified by dietary choline in tx-j mice, a spontaneous mutant model of WD. We therefore hypothesized that the WD phenotype and hepatic gene expression of tx-j offspring could be modified by maternal methyl supplementation during pregnancy. In an initial experiment, female tx-j mice or wild type mice were fed control or choline-supplemented diets 2 weeks prior to mating through embryonic day 17. Transcriptomic analysis (RNA-seq) on embryonic livers revealed tx-j-specific differences in genes related to oxidative phosphorylation, mitochondrial dysfunction, and the neurological disorders Huntington's disease and Alzheimer disease. Maternal choline supplementation restored the transcript levels of a subset of genes to wild type levels. In a separate experiment, a group of tx-j offspring continued to receive choline-supplemented or control diets, with or without the copper chelator penicillamine (PCA) for 12 weeks until 24 weeks of age. Combined choline supplementation and PCA treatment of 24-week-old tx-j mice was associated with increased liver transcript levels of methionine metabolism and oxidative phosphorylation-related genes. Sex differences in gene expression within each treatment group were also observed. These results demonstrate that the transcriptional changes in oxidative phosphorylation and methionine metabolism genes in WD that originate during fetal life are, in part, prevented by prenatal maternal choline supplementation, a finding with potential relevance to preventive treatments of WD. PMID:27611852

Deposition of steeply infalling debris around white dwarf stars

NASA Astrophysics Data System (ADS)

Brown, John C.; Veras, Dimitri; Gänsicke, Boris T.

2017-06-01

High-metallicity pollution is common in white dwarf (WD) stars hosting remnant planetary systems. However, they rarely have detectable debris accretion discs, possibly because much of the influx is fast steeply infalling debris in star-grazing orbits, producing a more tenuous signature than a slowly accreting disc. Processes governing such deposition between the Roche radius and photosphere have so far received little attention and we model them here analytically by extending recent work on sun-grazing comets to WD systems. We find that the evolution of cm-to-km size (a0) infallers most strongly depends on two combinations of parameters, which effectively measure sublimation rate and binding strength. We then provide an algorithm to determine the fate of infallers for any WD, and apply the algorithm to four limiting combinations of hot versus cool (young/old) WDs with snowy (weak, volatile) versus rocky (strong, refractory) infallers. We find: (I) Total sublimation above the photosphere befalls all small infallers across the entire WD temperature (TWD) range, the threshold size rising with TWD and 100× larger for rock than snow. (II) All very large objects fragment tidally regardless of TWD: for rock, a0 ≽ 105 cm; for snow, a0 ≽ 103-3 × 104 cm across all WD cooling ages. (III) A considerable range of a0 avoids fragmentation and total sublimation, yielding impacts or grazes with cold WDs. This range rapidly narrows with increasing TWD, especially for snowy bodies. Finally, we briefly discuss how the various forms of deposited debris may finally reach the photosphere surface itself.

Effects of long-term individual and combined water and temperature stress on the growth of rice, wheat and maize: relationship with morphological and physiological acclimation.

PubMed

Perdomo, Juan Alejandro; Conesa, Miquel À; Medrano, Hipólito; Ribas-Carbó, Miquel; Galmés, Jeroni

2015-10-01

This study evaluates the long-term individual and combined effects of high temperature (HT) and water deficit (WD) stress on plant growth, leaf gas-exchange and water use efficiency in cultivars of the three most important crops worldwide, rice, wheat and maize. Total plant biomass (B t ) accumulation decreased under all treatments, being the combined HT-WD treatment the most detrimental in all three species. Although decreases in B t correlated with adjustments in biomass allocation patterns (i.e. the leaf area ratio), most of the variation observed in B t was explained by changes in leaf gas exchange parameters. Thus, integrated values of leaf carbon balance obtained from daily course measurements of photosynthesis and respiration were better predictors of plant growth than the instantaneous measurements of leaf gas exchange. Leaf water use efficiency, assessed both by gas exchange and carbon isotope measurements, was negatively correlated with B t under WD, but not under the combined WD and HT treatment. A comparative analysis of the negative effects of single and combined stresses on the main parameters showed an additive component for WD and HT in rice and maize, in contrast to wheat. Overall, the results of the specific cultivars included in the study suggest that the species native climate plays a role shaping the species acclimation potential to the applied stresses. In this regard, wheat, originated in a cold climate, was the most affected species, which foretells a higher affectation of this crop due to climate change. © 2014 Scandinavian Plant Physiology Society.

Introduction & Overview to Symposium 240: Binary Stars as Critical Tools and Tests in Contemporary Astrophysics

DTIC Science & Technology

2006-01-01

neutron stars and black holes properties of condensed matter Post CE Binaries V471 Tau (K2 V + wd) Symbiotic Binaries (M III + wd) X-ray Binaries CH...low-mass stars the respect they deserve, since these stars may be the dominant contributor to baryonic mass in the Universe. Ben Lane discussed recent

76 FR 41513 - Proclaiming Certain Lands, Bowlin North Property, as an Addition to the Pueblo of Laguna...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-07-14

... Assistant Secretary-- Indian Affairs proclaimed approximately 99.5623 acres, more or less, to be added to..., New Mexico Professional Surveyor Number 11597. Said parcels contain 99.5623 acres, more or less. Said... I'' contains 1,387,489.99 sq. ft. (31.8524 Ac.) more or less. PARCEL II: (WD: Bk. 9816, Pg. 8285, WD...

A dearth of small particles in the transiting material around the white dwarf WD 1145+017

NASA Astrophysics Data System (ADS)

Xu, S.; Rappaport, S.; van Lieshout, R.; Vanderburg, A.; Gary, B.; Hallakoun, N.; Ivanov, V. D.; Wyatt, M. C.; DeVore, J.; Bayliss, D.; Bento, J.; Bieryla, A.; Cameron, A.; Cann, J. M.; Croll, B.; Collins, K. A.; Dalba, P. A.; Debes, J.; Doyle, D.; Dufour, P.; Ely, J.; Espinoza, N.; Joner, M. D.; Jura, M.; Kaye, T.; McClain, J. L.; Muirhead, P.; Palle, E.; Panka, P. A.; Provencal, J.; Randall, S.; Rodriguez, J. E.; Scarborough, J.; Sefako, R.; Shporer, A.; Strickland, W.; Zhou, G.; Zuckerman, B.

2018-03-01

White dwarf WD 1145+017 is orbited by several clouds of dust, possibly emanating from actively disintegrating bodies. These dust clouds reveal themselves through deep, broad, and evolving transits in the star's light curve. Here, we report two epochs of multiwavelength photometric observations of WD 1145+017, including several filters in the optical, Ks and 4.5 μm bands in 2016 and 2017. The observed transit depths are different at these wavelengths. However, after correcting for excess dust emission at Ks and 4.5 μm, we find the transit depths for the white dwarf itself are the same at all wavelengths, at least to within the observational uncertainties of ˜5-10 per cent. From this surprising result, and under the assumption of low optical depth dust clouds, we conclude that there is a deficit of small particles (with radii s ≲ 1.5 μm) in the transiting material. We propose a model wherein only large particles can survive the high equilibrium temperature environment corresponding to 4.5 h orbital periods around WD 1145+017, while small particles sublimate rapidly. In addition, we evaluate dust models that are permitted by our measurements of infrared emission.

Wolman disease associated with hemophagocytic lymphohistiocytosis: attempts for an explanation.

PubMed

Taurisano, Roberta; Maiorana, Arianna; De Benedetti, Fabrizio; Dionisi-Vici, Carlo; Boldrini, Renata; Deodato, Federica

2014-10-01

The lysosomal acid lipase (LAL) is the enzyme responsible of the hydrolysis of cholesteryl esters and triglycerides within endo-lysosomes. Loss of enzyme activity leads to accumulation of cholesteryl esters and triglycerides in the lysosome of most tissues. The complete deficiency of LAL is responsible of Wolman disease (WD), a severe systemic disease manifesting in the first days of life with vomiting, diarrhea, failure to thrive, hepatosplenomegaly, jaundice, anemia, and thrombocytopenia. Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition which may be genetically determined or secondary to infections, malignancies, immune deficiencies, and rheumatologic disorders. So far, some inborn errors of metabolism have been associated with HLH (e.g., lysinuric protein intolerance, Gaucher's disease), and it has been anecdotally described in three WD patients, without any specific pathogenetic hypothesis. Here, we report on a WD patient, showing clear clinical, biochemical, and histological features indicative of HLH. We discuss the pathophysiological role of cholesteryl ester-induced inflammasome activation in macrophages, leading to a secondary HLH. This case indicates that WD can cause secondary HLH and suggests that a careful metabolic workup should be performed when facing to a pediatric patient with HLH.

Bilateral Ocular Myositis Associated with Whipple's Disease

PubMed Central

Parkash, Vivak; Mudhar, Hardeep Singh; Wagner, Bart E.; Raoult, Didier; Batty, Ruth; Lepidi, Hubert; Burke, John; Collini, Paul; de Silva, Thushan

2017-01-01

Purpose To describe the clinical features of a Caucasian female patient with a history of treated gastrointestinal Whipple's disease (WD) who developed new-onset diplopia, with a description of the histopathological features of the extraocular muscle biopsies. Methods A previously fit 38-year-old Caucasian female presented with acute-onset diplopia after being on a sustained medication regime for biopsy-proven gastrointestinal WD. A magnetic resonance imaging scan of her orbits with gadolinium revealed diffuse enhancement of the bellies of the extraocular muscles bilaterally, particularly the medial rectus, superior rectus, and superior oblique muscles, consistent with an infiltrative myositis. She underwent unilateral extraocular muscle biopsies. Results The extraocular muscle biopsies contained macrophages between the muscle fibres. These contained periodic acid-Schiff-positive cytoplasmic granules. Immunohistochemistry with an antibody raised to Tropheryma whipplei showed positive staining of the same macrophages. Transmission electron microscopy confirmed the presence of effete T. whipplei cell membranes in lysosomes. Conclusion This case describes bilateral WD-associated extraocular muscle myositis. The exact mechanism for this unusual presentation is unclear, but both a WD-associated immune reconstitution inflammatory syndrome and treatment failure are possibilities, with a good response observed to antibiotic therapy and adjunctive corticosteroids. PMID:28275598

Retransformation of marker-free potato for enhanced resistance against fungal pathogens by pyramiding chitinase and wasabi defensin genes.

PubMed

Khan, Raham Sher; Darwish, Nader Ahmed; Khattak, Bushra; Ntui, Valentine Otang; Kong, Kynet; Shimomae, Kazuki; Nakamura, Ikuo; Mii, Masahiro

2014-09-01

Multi-auto-transformation vector system has been one of the strategies to produce marker-free transgenic plants without using selective chemicals and plant growth regulators and thus facilitating transgene stacking. In the study reported here, retransformation was carried out in marker-free transgenic potato CV. May Queen containing ChiC gene (isolated from Streptomyces griseus strain HUT 6037) with wasabi defensin (WD) gene (isolated from Wasabia japonica) to pyramid the two disease resistant genes. Molecular analyses of the developed shoots confirmed the existence of both the genes of interest (ChiC and WD) in transgenic plants. Co-expression of the genes was confirmed by RT-PCR, northern blot, and western blot analyses. Disease resistance assay of in vitro plants showed that the transgenic lines co-expressing both the ChiC and WD genes had higher resistance against the fungal pathogens, Fusarium oxysporum (Fusarium wilt) and Alternaria solani (early blight) compared to the non-transformed control and the transgenic lines expressing either of the ChiC or WD genes. The disease resistance potential of the transgenic plants could be increased by transgene stacking or multiple transformations.

Thermonuclear Explosions from Hybrid C/O/Ne White Dwarf Progenitors Ignited Centrally After Interior Mixing

NASA Astrophysics Data System (ADS)

Augustine, Carlyn

2018-01-01

Type Ia Supernovae are thermonuclear explosions of white dwarf (WD) stars. Past studies predict the existence of "hybrid" white dwarfs, made of a C/O/Ne core with a O/Ne shell, and that these are viable progenitors for supernovae. More recent work found that the C/O core is mixed with the surrounding O/Ne while the WD cools. Inspired by this scenario, we performed simulations of thermonuclear supernovae in the single degenerate paradigm from these hybrid progenitors. Our investigation began by constructing a hybrid white dwarf model with the one-dimensional stellar evolution code MESA. The model was allowed to go through unstable interior mixing ignite carbon burning centrally. The MESA model was then mapped to a two-dimensional initial condition and an explosion simulated from that with FLASH. For comparison, a similar simulation of an explosion was performed from a traditional C/O progenitor WD. Comparing the yields produced by explosion simulations allows us to determine which model produces more 56Ni, and therefore brighter events, and how explosions from these models differ from explosions from previous models without the mixing during the WD cooling.

WD60/FAP163 is a dynein intermediate chain required for retrograde intraflagellar transport in cilia

PubMed Central

Patel-King, Ramila S.; Gilberti, Renée M.; Hom, Erik F. Y.; King, Stephen M.

2013-01-01

Retrograde intraflagellar transport (IFT) is required for assembly of cilia. We identify a Chlamydomonas flagellar protein (flagellar-associated protein 163 [FAP163]) as being closely related to the D1bIC(FAP133) intermediate chain (IC) of the dynein that powers this movement. Biochemical analysis revealed that FAP163 is present in the flagellar matrix and is actively trafficked by IFT. Furthermore, FAP163 copurified with D1bIC(FAP133) and the LC8 dynein light chain, indicating that it is an integral component of the retrograde IFT dynein. To assess the functional role of FAP163, we generated an RNA interference knockdown of the orthologous protein (WD60) in planaria. The Smed-wd60(RNAi) animals had a severe ciliary assembly defect that dramatically compromised whole-organism motility. Most cilia were present as short stubs that had accumulated large quantities of IFT particle–like material between the doublet microtubules and the membrane. The few remaining approximately full-length cilia had a chaotic beat with a frequency reduced from 24 to ∼10 Hz. Thus WD60/FAP163 is a dynein IC that is absolutely required for retrograde IFT and ciliary assembly. PMID:23864713

partial E

NASA Astrophysics Data System (ADS)

Roller, Goetz

2017-04-01

Nuclear planetology [1] is a new research field, tightly constrained by a coupled 187Re-232Th-238U systematics [2-6], which by means of nuclear astrophysics aims also at understanding the thermal evolution of Earth-like planets after Mercury-like contraction and Fermi-pressure controlled gravitational collapse events towards the end of their cooling period. In nuclear planetology, Earth-like planets are regarded as old (redshift z >15), down-cooled and differentiated black dwarfs (Fe-C BLD's), so-called interlopers from the Galactic bulge [7], which are subjected to endoergic 56Fe(γ,α)52Cr (etc.) reactions (photodisintegration), (γ,n) or (γ,p) and fusion reactions like 12C(α,γ)16O. It is remarkable that, beside of its surface temperature Teff of its outer core surface, the Earth shows also striking similarity in volume V (radius rEarth ≈6.370 km) with an old white dwarf star (WD; rWD ≈6.300 km) like WD0346+246. This major boundary condition for nuclear planetology can be described in terms of V Earth = V WD = V const=4•π•r3/3 (rWD ≈ rEarth). However, in addition to the fact that Earth is habitable, the most obvious difference between a WD and the Earth is their density ρ (ρ=m/V; m mass, V volume): while a WD may contain 1MO(MO= solar mass) per V const, the mass of the Earth is only a tiny fraction of this, ≈3•10-6 MO per V const. Therefore, it is crucial to understand ∂ρ, or why mEarth«mWD for V const. Here I argue that the application of principles constrained by the theory of relativity [8] may offer a possible answer to this question: it is generally accepted that mass is directly related to energy, E=m•c2 (E energy; m mass; c velocity of light) or m=E/c2. From m˜E we derive that any mass change can be described in terms of energy change [8]. Instead of ρ=m/V we may thus write ρ=E/c2•V, and because of the special scenario V Earth = V WD = V const discussed here, the denominator of this equation becomes a constant term C=c2•Vconst =9.73•1037m5s-2. From this it follows, that ρ=E/C, or ρ•C=E. Therefore, we arrive at ρ ˜E for the WD/FeC-BLD case or, considering the evolution of the system over time t: ∂ρ/∂t˜∂E/∂t.Hence, concerning time integrated planetary evolution it may be concluded that any density change ∂ρ of an old stellar remnant towards a ≈3•10-6 MO habitable Earth-like planet is a measure for the system's energy change ∂E. In the light of nuclear planetology this result has to be considered to understand the formation and evolution of crusts and mantles on planets and moons. [1] Roller (2015), Abstract T34B-0407, AGU Spring Meeting 2015. [2] Roller (2015), Goldschmidt Conf. Abstr. 25, 2672. [3] Roller (2016), Goldschmidt Conf. Abstr. 26, 2642. [4] Roller (2016), JPS Conf. Proc., Nuclei in the Cosmos (NIC XIV), Niigata, Japan, subm. (NICXIV-001); NICXIV Abstr. #1570244284. [5] Roller (2016), JPS Conf. Proc., Nuclei in the Cosmos (NIC XIV), Niigata, Japan, subm. (NICXIV-002); NICXIV Abstr. #1570244285). [6] Roller (2016), JPS Conf. Proc., Nuclei in the Cosmos (NIC XIV), Niigata, Japan, subm. (NICXIV-003); NICXIV Abstr. #1570244281. [7] Howes et al. (2015), Nature 527, 484-487. [8] Einstein (1905), Annalen d. Physik, 18, 639-641.

Formal Language Design in the Context of Domain Engineering

DTIC Science & Technology

2000-03-28

73 Related Work 75 5.1 Feature oriented domain analysis ( FODA ) 75 5.2 Organizational domain modeling (ODM) 76 5.3 Domain-Specific Software...However there are only a few that are well defined and used repeatedly in practice. These include: Feature oriented domain analysis ( FODA ), Organizational...Feature oriented domain analysis ( FODA ) Feature oriented domain analysis ( FODA ) is a domain analysis method being researched and applied by the SEI

Identification and characterization of tandem repeats in exon III of dopamine receptor D4 (DRD4) genes from different mammalian species.

PubMed

Larsen, Svend Arild; Mogensen, Line; Dietz, Rune; Baagøe, Hans Jørgen; Andersen, Mogens; Werge, Thomas; Rasmussen, Henrik Berg

2005-12-01

In this study we have identified and characterized dopamine receptor D4 (DRD4) exon III tandem repeats in 33 public available nucleotide sequences from different mammalian species. We found that the tandem repeat in canids could be described in a novel and simple way, namely, as a structure composed of 15- and 12- bp modules. Tandem repeats composed of 18-bp modules were found in sequences from the horse, zebra, onager, and donkey, Asiatic bear, polar bear, common raccoon, dolphin, harbor porpoise, and domestic cat. Several of these sequences have been analyzed previously without a tandem repeat being found. In the domestic cow and gray seal we identified tandem repeats composed of 36-bp modules, each consisting of two closely related 18-bp basic units. A tandem repeat consisting of 9-bp modules was identified in sequences from mink and ferret. In the European otter we detected an 18-bp tandem repeat, while a tandem repeat consisting of 27-bp modules was identified in a sequence from European badger. Both these tandem repeats were composed of 9-bp basic units, which were closely related with the 9-bp repeat modules identified in the mink and ferret. Tandem repeats could not be identified in sequences from rodents. All tandem repeats possessed a high GC content with a strong bias for C. On phylogenetic analysis of the tandem repeats evolutionary related species were clustered into the same groups. The degree of conservation of the tandem repeats varied significantly between species. The deduced amino acid sequences of most of the tandem repeats exhibited a high propensity for disorder. This was also the case with an amino acid sequence of the human DRD4 exon III tandem repeat, which was included in the study for comparative purposes. We identified proline-containing motifs for SH3 and WW domain binding proteins, potential phosphorylation sites, PDZ domain binding motifs, and FHA domain binding motifs in the amino acid sequences of the tandem repeats. The numbers of potential functional sites varied pronouncedly between species. Our observations provide a platform for future studies of the architecture and evolution of the DRD4 exon III tandem repeat, and they suggest that differences in the structure of this tandem repeat contribute to specialization and generation of diversity in receptor function.

Space, agency, and withdrawal: birth control choices of women in Turkey.

PubMed

Sirkeci, Ibrahim; Cindoglu, Dilek

2012-01-01

Withdrawal (WD) is not a reliable method for preventing unwanted pregnancies, yet it is still a very popular form of birth control in many societies, including Turkey. We look at the relationship between women's agency and physical space in relation to birth control choices of women in Turkey. Agency in our context refers to a woman's ability to resist domination and subordination to the patriarchal beliefs valuing her reproductivity over her pleasure. Our analysis of the Turkish Demographic Health Survey (TDHS) suggests that (a) the available space in the household for possible private encounters between husband and wife, and (b) the women's capacity to insert her agency into her life choices are closely correlated with WD choices. Women with better social and physical resources prefer WD less.

Undulating tongue in Wilson's disease

PubMed Central

Nagappa, M; Sinha, S; Saini, JS; Bindu, PS; Taly, AB

2014-01-01

We report an unusual occurrence of involuntary movement involving the tongue in a patient with confirmed Wilson's disease (WD). She manifested with slow, hypophonic speech and dysphagia of 4 months duration, associated with pseudobulbar affect, apathy, drooling and dystonia of upper extremities of 1 month duration. Our patient had an uncommon tongue movement which was arrhythmic. There was no feature to suggest tremor, chorea or dystonia. It might be described as athetoid as there was a writhing quality, but of lesser amplitude. Thus, the phenomenology was uncommon in clinical practice and the surface of the tongue was seen to “ripple” like a liquid surface agitated by an object or breeze. Isolated lingual dyskinesias are rare in WD. It is important to evaluate them for WD, a potentially treatable disorder. PMID:25024581

Discovery of optical flickering from the symbiotic star EF Aquilae

NASA Astrophysics Data System (ADS)

Zamanov, R. K.; Boeva, S.; Nikolov, Y. M.; Petrov, B.; Bachev, R.; Latev, G. Y.; Popov, V. A.; Stoyanov, K. A.; Bode, M. F.; Martí, J.; Tomov, T.; Antonova, A.

2017-07-01

We report optical CCD photometry of the recently identified symbiotic star EF Aql. Our observations in Johnson V and B bands clearly show the presence of stochastic light variations with an amplitude of about 0.2 mag on a time scale of minutes. The observations point toward a white dwarf (WD) as the hot component in the system. It is the 11-th object among more than 200 symbiotic stars known with detected optical flickering. Estimates of the mass accretion rate onto the WD and the mass loss rate in the wind of the Mira secondary star lead to the conclusion that less than 1 per cent of the wind is captured by the WD. Eight further candidates for the detection of flickering in similar systems are suggested.

Immunization with Bacillus Spores Expressing Toxin A Peptide Repeats Protects against Infection with Clostridium difficile Strains Producing Toxins A and B ▿ †

PubMed Central

Permpoonpattana, Patima; Hong, Huynh A.; Phetcharaburanin, Jutarop; Huang, Jen-Min; Cook, Jenny; Fairweather, Neil F.; Cutting, Simon M.

2011-01-01

Clostridium difficile is a leading cause of nosocomial infection in the developed world. Two toxins, A and B, produced by most strains of C. difficile are implicated as virulence factors, yet only recently has the requirement of these for infection been investigated by genetic manipulation. Current vaccine strategies are focused mostly on parenteral delivery of toxoids. In this work, we have used bacterial spores (Bacillus subtilis) as a delivery vehicle to evaluate the carboxy-terminal repeat domains of toxins A and B as protective antigens. Our findings are important and show that oral immunization of the repeat domain of toxin A is sufficient to confer protection in a hamster model of infection designed to closely mimic the human course of infection. Importantly, neutralizing antibodies to the toxin A repeat domain were shown to be cross-reactive with the analogous domain of toxin B and, being of high avidity, provided protection against challenge with a C. difficile strain producing toxins A and B (A+B+). Thus, although many strains produce both toxins, antibodies to only toxin A can mediate protection. Animals vaccinated with recombinant spores were fully able to survive reinfection, a property that is particularly important for a disease with which patients are prone to relapse. We show that mucosal immunization, not parenteral delivery, is required to generate secretory IgA and that production of these neutralizing polymeric antibodies correlates with protection. This work demonstrates that an effective vaccine against C. difficile can be designed around two attributes, mucosal delivery and the repeat domain of toxin A. PMID:21482682

Western diet induces colonic nitrergic myenteric neuropathy and dysmotility in mice via saturated fatty acid- and lipopolysaccharide-induced TLR4 signalling.

PubMed

Reichardt, François; Chassaing, Benoit; Nezami, Behtash Ghazi; Li, Ge; Tabatabavakili, Sahar; Mwangi, Simon; Uppal, Karan; Liang, Bill; Vijay-Kumar, Matam; Jones, Dean; Gewirtz, Andrew T; Srinivasan, Shanthi

2017-03-01

A high-fat diet (60% kcal from fat) is associated with motility disorders inducing constipation and loss of nitrergic myenteric neurons in the proximal colon. Gut microbiota dysbiosis, which occurs in response to HFD, contributes to endotoxaemia. High levels of lipopolysaccharide lead to apoptosis in cultured myenteric neurons that express Toll-like receptor 4 (TLR4). Consumption of a Western diet (WD) (35% kcal from fat) for 6 weeks leads to gut microbiota dysbiosis associated with altered bacterial metabolites and increased levels of plasma free fatty acids. These disorders precede the nitrergic myenteric cell loss observed in the proximal colon. Mice lacking TLR4 did not exhibit WD-induced myenteric cell loss and dysmotility. Lipopolysaccharide-induced in vitro enteric neurodegeneration requires the presence of palmitate and may be a result of enhanced NO production. The present study highlights the critical role of plasma saturated free fatty acids that are abundant in the WD with respect to driving enteric neuropathy and colonic dysmotility. The consumption of a high-fat diet (HFD) is associated with myenteric neurodegeneration, which in turn is associated with delayed colonic transit and constipation. We examined the hypothesis that an inherent increase in plasma free fatty acids (FFA) in the HFD together with an HFD-induced alteration in gut microbiota contributes to the pathophysiology of these disorders. C57BL/6 mice were fed a Western diet (WD) (35% kcal from fat enriched in palmitate) or a purified regular diet (16.9% kcal from fat) for 3, 6, 9 and 12 weeks. Gut microbiota dysbiosis was investigated by fecal lipopolysaccharide (LPS) measurement and metabolomics (linear trap quadrupole-Fourier transform mass spectrometer) analysis. Plasma FFA and LPS levels were assessed, in addition to colonic and ileal nitrergic myenteric neuron quantifications and motility. Compared to regular diet-fed control mice, WD-fed mice gained significantly more weight without blood glucose alteration. Dysbiosis was exhibited after 6 weeks of feeding, as reflected by increased fecal LPS and bacterial metabolites and concomitant higher plasma FFA. The numbers of nitrergic myenteric neurons were reduced in the proximal colon after 9 and 12 weeks of WD and this was also associated with delayed colonic transit. WD-fed Toll-like receptor 4 (TLR4) -/- mice did not exhibit myenteric cell loss or dysmotility. Finally, LPS (0.5-2 ng·ml -1 ) and palmitate (20 and 30 μm) acted synergistically to induce neuronal cell death in vitro, which was prevented by the nitric oxide synthase inhibitor NG-nitro-l-arginine methyl ester. In conclusion, WD-feeding results in increased levels of FFA and microbiota that, even in absence of hyperglycaemia or overt endotoxaemia, synergistically induce TLR4-mediated neurodegeneration and dysmotility. © 2016 The Authors. The Journal of Physiology © 2016 The Physiological Society.

Value of dual contrast liver MRI at 3.0 T in differentiating well-differentiated hepatocellular carcinomas from dysplastic nodules: preliminary results of multivariate analysis.

PubMed

Yoon, Min A; Kim, Se Hyung; Park, Hee Sun; Lee, Dong Ho; Lee, Jae Young; Han, Joon Koo; Choi, Byung Ihn

2009-10-01

To assess the diagnostic value of dual contrast magnetic resonance imaging (DC-MRI) in the differentiation of well-differentiated hepatocellular carcinomas (WD-HCCs) from dysplastic nodules (DNs) and to determine the significant MRI predictors using univariate and multivariate analyses. Thirty-two WD-HCCs and 33 DNs in 28 patients who underwent liver transplantation with available histopathology as a gold standard were enrolled in this study. All patients underwent DC-MRI using superparamagnetic iron oxide (SPIO) and gadolinium (Gd) agents on a 3 T MRI unit. For all patients, precontrast T1- and T2-weighted (T2W) images as well as post-SPIO T2- and T2*W images were obtained. Then, for dynamic MRI, arterial (AP), portal, and equilibrium images were also obtained. Two radiologists reviewed the MR images for analyzing signal intensity on the all MR sequences in consensus. On AP images, the degree of enhancement was subjectively categorized into 4 groups: no, minimal, moderate, and strong enhancement. For quantitative analysis, relative arterial enhancement ratio was calculated by averaging 3 regions of interest values of each nodule on pre-Gd T1W and AP images. Each variable was initially evaluated using univariate analyses to assess statistically significant MRI findings differentiating HCCs and DNs, then with multivariate logistic regression analysis to find the most predictable MRI findings. Twenty WD-HCCs showed iso- or high SI on precontrast T2W images, whereas 23 DNs showed low SI (P = 0.003). Most DNs showed low SI on post-SPIO T2W (30/33) and T2*W (25/33) images, whereas HCCs tended to show heterogeneous high or high SI (16/32 and 19/32) (P < 0.012). On post-SPIO and pre-Gd T1W GRE images, 28 WD-HCCs showed iso- or high SI, whereas 24 DNs showed low SI (P < 0.001). On AP images, 20 HCCs revealed more than minimal degree of enhancement, whereas 32 DNs did not show any enhancement (P < 0.001). Mean relative arterial enhancement ratio of HCCs (39.4%) was also significantly larger than that of DNs (15.6%) (P = 0.001). On portal images, WD-HCCs tended to show iso- or high SI (n = 21), whereas DNs showed low SI (n = 29) (P < 0.001). Multivariate analysis revealed that a subjective degree of enhancement on AP images and SI on post-SPIO and pre-Gd T1W GRE images were the 2 variables that independently differentiated WD-HCCs from DNs. The use of DC-MRI is helpful in the differentiation of WD HCCs and DNs. More specifically, a subjective degree of enhancement on AP images and SI on post-SPIO and pre-Gd T1W GRE images are the 2 variables that independently differentiate WD-HCCs from DNs.

A conserved gene family encodes transmembrane proteins with fibronectin, immunoglobulin and leucine-rich repeat domains (FIGLER)

PubMed Central

Munfus, Delicia L; Haga, Christopher L; Burrows, Peter D; Cooper, Max D

2007-01-01

Background In mouse the cytokine interleukin-7 (IL-7) is required for generation of B lymphocytes, but human IL-7 does not appear to have this function. A bioinformatics approach was therefore used to identify IL-7 receptor related genes in the hope of identifying the elusive human cytokine. Results Our database search identified a family of nine gene candidates, which we have provisionally named fibronectin immunoglobulin leucine-rich repeat (FIGLER). The FIGLER 1–9 genes are predicted to encode type I transmembrane glycoproteins with 6–12 leucine-rich repeats (LRR), a C2 type Ig domain, a fibronectin type III domain, a hydrophobic transmembrane domain, and a cytoplasmic domain containing one to four tyrosine residues. Members of this multichromosomal gene family possess 20–47% overall amino acid identity and are differentially expressed in cell lines and primary hematopoietic lineage cells. Genes for FIGLER homologs were identified in macaque, orangutan, chimpanzee, mouse, rat, dog, chicken, toad, and puffer fish databases. The non-human FIGLER homologs share 38–99% overall amino acid identity with their human counterpart. Conclusion The extracellular domain structure and absence of recognizable cytoplasmic signaling motifs in members of the highly conserved FIGLER gene family suggest a trophic or cell adhesion function for these molecules. PMID:17854505

Sequence analyses reveal that a TPR–DP module, surrounded by recombinable flanking introns, could be at the origin of eukaryotic Hop and Hip TPR–DP domains and prokaryotic GerD proteins

PubMed Central

Papandreou, Nikolaos; Chomilier, Jacques

2008-01-01

The co-chaperone Hop [heat shock protein (HSP) organising protein] is known to bind both Hsp70 and Hsp90. Hop comprises three repeats of a tetratricopeptide repeat (TPR) domain, each consisting of three TPR motifs. The first and last TPR domains are followed by a domain containing several dipeptide (DP) repeats called the DP domain. These analyses suggest that the hop genes result from successive recombination events of an ancestral TPR–DP module. From a hydrophobic cluster analysis of homologous Hop protein sequences derived from gene families, we can postulate that shifts in the open reading frames are at the origin of the present sequences. Moreover, these shifts can be related to the presence or absence of biological function. We propose to extend the family of Hop co-chaperons into the kingdom of bacteria, as several structurally related genes have been identified by hydrophobic cluster analysis. We also provide evidence of common structural characteristics between hop and hip genes, suggesting a shared precursor of ancestral TPR–DP domains. Electronic supplementary material The online version of this article (doi:10.1007/s12192-008-0083-8) contains supplementary material, which is available to authorized users. PMID:18987995

Comparison of the carboxy-terminal DP-repeat region in the co-chaperones Hop and Hip

PubMed Central

Nelson, Gregory M.; Huffman, Holly; Smith, David F.

2003-01-01

Functional steroid receptor complexes are assembled and maintained by an ordered pathway of interactions involving multiple components of the cellular chaperone machinery. Two of these components, Hop and Hip, serve as co-chaperones to the major heat shock proteins (Hsps), Hsp70 and Hsp90, and participate in intermediate stages of receptor assembly. In an effort to better understand the functions of Hop and Hip in the assembly process, we focused on a region of similarity located near the C-terminus of each co-chaperone. Contained within this region is a repeated sequence motif we have termed the DP repeat. Earlier mutagenesis studies implicated the DP repeat of either Hop or Hip in Hsp70 binding and in normal assembly of the co-chaperones with progesterone receptor (PR) complexes. We report here that the DP repeat lies within a protease-resistant domain that extends to or is near the C-terminus of both co-chaperones. Point mutations in the DP repeats render the C-terminal regions hypersensitive to proteolysis. In addition, a Hop DP mutant displays altered proteolytic digestion patterns, which suggest that the DP-repeat region influences the folding of other Hop domains. Although the respective DP regions of Hop and Hip share sequence and structural similarities, they are not functionally interchangeable. Moreover, a double-point mutation within the second DP-repeat unit of Hop that converts this to the sequence found in Hip disrupts Hop function; however, the corresponding mutation in Hip does not alter its function. We conclude that the DP repeats are important structural elements within a C-terminal domain, which is important for Hop and Hip function. PMID:14627198

Comparison of the carboxy-terminal DP-repeat region in the co-chaperones Hop and Hip.

PubMed

Nelson, Gregory M; Huffman, Holly; Smith, David F

2003-01-01

Functional steroid receptor complexes are assembled and maintained by an ordered pathway of interactions involving multiple components of the cellular chaperone machinery. Two of these components, Hop and Hip, serve as co-chaperones to the major heat shock proteins (Hsps), Hsp70 and Hsp90, and participate in intermediate stages of receptor assembly. In an effort to better understand the functions of Hop and Hip in the assembly process, we focused on a region of similarity located near the C-terminus of each co-chaperone. Contained within this region is a repeated sequence motif we have termed the DP repeat. Earlier mutagenesis studies implicated the DP repeat of either Hop or Hip in Hsp70 binding and in normal assembly of the co-chaperones with progesterone receptor (PR) complexes. We report here that the DP repeat lies within a protease-resistant domain that extends to or is near the C-terminus of both co-chaperones. Point mutations in the DP repeats render the C-terminal regions hypersensitive to proteolysis. In addition, a Hop DP mutant displays altered proteolytic digestion patterns, which suggest that the DP-repeat region influences the folding of other Hop domains. Although the respective DP regions of Hop and Hip share sequence and structural similarities, they are not functionally interchangeable. Moreover, a double-point mutation within the second DP-repeat unit of Hop that converts this to the sequence found in Hip disrupts Hop function; however, the corresponding mutation in Hip does not alter its function. We conclude that the DP repeats are important structural elements within a C-terminal domain, which is important for Hop and Hip function.

Noise in DORIS station position time series provided by IGN-JPL, INASAN and CNES-CLS Analysis Centres for the ITRF2014 realization

NASA Astrophysics Data System (ADS)

Khelifa, Sofiane

2016-12-01

The purpose of this paper is to compare the noise characteristics in DORIS station positions between the three solutions derived by IGN-JPL (named as IGN), INASAN (named as INA) and CNES-CLS (named as LCA) Analysis Centres for ITRF2014 contribution, and to evaluate the improvements of these reprocessed solutions in terms of noise level with the previous ITRF2008 solutions. To the weekly STCD (STation Coordinate Difference) residual position time series of 23 stations referred to ITRF2008 and expressed in the local frame (North, East and Up), we calculated the Allan variance to identify their noise type, and applied the wavelet transform to assess their annual and semi-annual signals, and their noise level. The results reveal that the three solutions are dominated by white noise in all three components. The noise level is the lowest in the LCA solution; the average noise level in respectively, North, East and Vertical components is around 5.9 mm, 9.3 mm and 6.6 mm for LCA, 9 mm, 11.6 mm and 9 mm for IGN, and 8.7 mm, 11.6 mm and 9.1 mm for INA. The results also show that the tropical (±23.5°) stations are more distorted than mid-latitude and high latitude stations. In terms of noise level, the reprocessed LCA solution (lca14wd40) and its previous solution (lca11wd02) converge to similar results, while the reprocessed IGN (ign14wd15) and INA (ina14wd08) solutions show improvements with respect to their previous solutions (ign11wd01) and (ina12wd01) respectively, especially in the East component. Furthermore, the possible origin of the estimated annual signal was also investigated by comparing it with hydrology and atmospheric loading displacements. The annual Vertical component for the three solutions is more correlated with the GLDAS/Noah hydrology model with an average correlation of about 0.35, and shows a strong correlation of about 0.76 with ECMWF-IB and ECMWF-MOG2D atmospheric models for the station Krasnoyarsk (KRBB) in Siberia.

Calcium and 1,25-dihydroxyvitamin D3 modulate genes of immune and inflammatory pathways in the human colon: a human crossover trial123

PubMed Central

Protiva, Petr; Pendyala, Swaroop; Nelson, Celeste; Augenlicht, Leonard H; Lipkin, Martin; Holt, Peter R

2016-01-01

Background: A high dietary calcium intake with adequate vitamin D status has been linked to lower colorectal cancer risk, but the mechanisms of these effects are poorly understood. Objective: The objective of this study was to elucidate the effects of a Western-style diet (WD) and supplemental calcium and/or 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] on the colorectal mucosa. Design: We conducted 2 crossover trials to define molecular pathways in the human colorectum altered by 1) a 4-wk WD supplemented with and without 2 g calcium carbonate/d and 2) a 4-wk WD supplemented with 1,25(OH)2D3 (0.5 μg/d) with or without 2 g calcium carbonate/d. The primary study endpoint was genome-wide gene expression in biopsy specimens of the rectosigmoid colonic mucosa. Serum and urinary calcium concentrations were also measured. Results: Changes in urinary calcium accurately reflected calcium consumption. The WD induced modest upregulation of genes involved in inflammatory pathways, including interferon signaling, and calcium supplementation reversed these toward baseline. In contrast, supplementation of the WD with 1,25(OH)2D3 induced striking upregulation of genes involved in inflammation, immune response, extracellular matrix, and cell adhesion. Calcium supplementation largely abrogated these changes. Conclusions: Supplementing 1,25(OH)2D3 to a WD markedly upregulated genes in immune response and inflammation pathways, which were largely reversed by calcium supplementation. This study provides clinical trial evidence of global gene expression changes occurring in the human colorectum in response to calcium and 1,25(OH)2D3 intervention. One action of 1,25(OH)2D3 is to upregulate adaptive immunity. Calcium appears to modulate this effect, pointing to its biological interaction in the mucosa. This trial was registered at clinicaltrials.gov as NCT00298545. Trial protocol is available at http://clinicalstudies.rucares.org (protocol numbers PHO475 and PHO554). PMID:27009752

HST/COS Far-ultraviolet Spectroscopic Analysis of U Geminorum Following a Wide Outburst

NASA Astrophysics Data System (ADS)

Godon, Patrick; Shara, Michael M.; Sion, Edward M.; Zurek, David

2017-12-01

We used the Cosmic Origins Spectrograph (COS) on the Hubble Space Telescope (HST) to obtain a series of four far-ultraviolet (FUV; 915-2148 Å) spectroscopic observations of the prototypical dwarf nova U Geminorum during its cooling following a two-week outburst. Our FUV spectral analysis of the data indicates that the white dwarf (WD) cools from a temperature of ˜41,500 K, 15 days after the peak of the outburst, to ˜36,250 K, 56 days after the peak of the outburst, assuming a massive WD (log(g) = 8.8) and a distance of 100.4 ± 3.7 pc. These results are self-consistent with a ˜1.1 M ⊙ WD with a 5000 ± 200 km radius. The spectra show absorption lines of H I, He II, C II III IV, N III IV, O VI, S IV, Si II III IV, Al III, Ar III, and Fe II, but no emission features. We find suprasolar abundances of nitrogen, confirming the anomalous high N/C ratio. The FUV light curve reveals a ±5% modulation with the orbital phase, showing dips near phases 0.25 and ˜0.75, where the spectra exhibit an increase in the depth of some absorption lines and in particular strong absorption lines from Si II, Al III, and Ar III. The phase dependence we observe is consistent with material overflowing the disk rim at the hot spot, reaching a maximum elevation near phase 0.75, falling back at smaller radii near phase 0.5 where it bounces off the disk surface, and again rising above the disk near phase ˜0.25. There is a large scatter in the absorption lines’ velocities, especially for the silicon lines, while the carbon lines seem to match more closely the orbital velocity of the WD. This indicates that many absorption lines are affected by—or form in—the overflowing stream material veiling the WD, making the analysis of the WD spectra more difficult. Based on observations made with the NASA/ESA Hubble Space Telescope, obtained at the Space Telescope Science Institute, which is operated by AURA, Inc., under NASA contract NAS 5-26555.

MicroRNAs regulate the main events in rice drought stress response by manipulating the water supply to shoots.

PubMed

Fard, Ehsan Mohseni; Bakhshi, Behnam; Farsi, Mohammad; Kakhki, Amin Mirshamsi; Nikpay, Nava; Ebrahimi, Mohammad Ali; Mardi, Mohsen; Salekdeh, Ghasem Hosseini

2017-10-24

MicroRNAs (miRNAs) are small endogenous regulatory RNAs that are involved in a variety of biological processes related to proliferation, development, and response to biotic and abiotic stresses. miRNA profiles of rice (Oryza sativa L. cv. IR64.) leaves in a partial root zone drying (PRD) system were analysed using a high-throughput sequencing approach to identify miRNAs associated with drought signalling. The treatments performed in this study were as follows: well-watered ("wet" roots, WW), wherein both halves of the pot were watered daily; drought ("dry" roots, DD), wherein water was withheld from both halves of the pot; and well-watered/drought ("wet" and "dry" roots, WD), wherein one half of each pot was watered daily, the same as in WW, and water was withheld from the other part, the same as in DD. High-throughput sequencing enabled us to detect novel miRNAs and study the differential expression of known miRNAs. A total of 209 novel miRNAs were detected in this study. Differential miRNA profiling of the DD, WD and WW conditions showed differential expression of 159 miRNAs, among which 83, 44 and 32 miRNAs showed differential expression under both DD and WD conditions. The detection of putative targets of the differentially expressed miRNAs and investigation of their functions showed that most of these genes encode transcription factors involved in growth and development, leaf morphology, regulation of hormonal homeostasis, and stress response. The most important differences between the DD and WD conditions involved regulation of the levels of hormones such as auxin, cytokinin, abscisic acid, and jasmonic acid and also regulation of phosphor homeostasis. Overall, differentially expressed miRNAs under WD conditions were found to differ from those under DD conditions, with such differences playing a role in adaptation and inducing the normal condition. The mechanisms involved in regulating hormonal homeostasis and involved in energy production and consumption were found to be the most important regulatory pathways distinguishing the DD and WD conditions.

The Role of Mammalian Target of Rapamycin (mTOR) in Insulin Signaling.

PubMed

Yoon, Mee-Sup

2017-10-27

The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that controls a wide spectrum of cellular processes, including cell growth, differentiation, and metabolism. mTOR forms two distinct multiprotein complexes known as mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2), which are characterized by the presence of raptor and rictor, respectively. mTOR controls insulin signaling by regulating several downstream components such as growth factor receptor-bound protein 10 (Grb10), insulin receptor substrate (IRS-1), F-box/WD repeat-containing protein 8 (Fbw8), and insulin like growth factor 1 receptor/insulin receptor (IGF-IR/IR). In addition, mTORC1 and mTORC2 regulate each other through a feedback loop to control cell growth. This review outlines the current understanding of mTOR regulation in insulin signaling in the context of whole body metabolism.

Basal body stability and ciliogenesis requires the conserved component Poc1

PubMed Central

Osborn, Daniel P.S.; Giddings, Thomas H.; Beales, Philip L.; Winey, Mark

2009-01-01

Centrioles are the foundation for centrosome and cilia formation. The biogenesis of centrioles is initiated by an assembly mechanism that first synthesizes the ninefold symmetrical cartwheel and subsequently leads to a stable cylindrical microtubule scaffold that is capable of withstanding microtubule-based forces generated by centrosomes and cilia. We report that the conserved WD40 repeat domain–containing cartwheel protein Poc1 is required for the structural maintenance of centrioles in Tetrahymena thermophila. Furthermore, human Poc1B is required for primary ciliogenesis, and in zebrafish, DrPoc1B knockdown causes ciliary defects and morphological phenotypes consistent with human ciliopathies. T. thermophila Poc1 exhibits a protein incorporation profile commonly associated with structural centriole components in which the majority of Poc1 is stably incorporated during new centriole assembly. A second dynamic population assembles throughout the cell cycle. Our experiments identify novel roles for Poc1 in centriole stability and ciliogenesis. PMID:20008567

Control of apoptosis by Drosophila DCAF12.

PubMed

Hwangbo, Dae-Sung; Biteau, Benoit; Rath, Sneha; Kim, Jihyun; Jasper, Heinrich

2016-05-01

Regulated Apoptosis (Programmed Cell Death, PCD) maintains tissue homeostasis in adults, and ensures proper growth and morphogenesis of tissues during development of metazoans. Accordingly, defects in cellular processes triggering or executing apoptotic programs have been implicated in a variety of degenerative and neoplastic diseases. Here, we report the identification of DCAF12, an evolutionary conserved member of the WD40-motif repeat family of proteins, as a new regulator of apoptosis in Drosophila. We find that DCAF12 is required for Diap1 cleavage in response to pro-apoptotic signals, and is thus necessary and sufficient for RHG (Reaper, Hid, and Grim)-mediated apoptosis. Loss of DCAF12 perturbs the elimination of supernumerary or proliferation-impaired cells during development, and enhances tumor growth induced by loss of neoplastic tumor suppressors, highlighting the wide requirement for DCAF12 in PCD. Copyright © 2016 Elsevier Inc. All rights reserved.

[The mechanism of root hair development and molecular regulation in plants].

PubMed

Wang, Yue-Ping; Li, Ying-Hui; Guan, Rong-Xia; Liu, Zhang-Xiong; Chen, Xiong-Ting; Chang, Ru-Zhen; Qiu, Li-Juan

2007-04-01

The formation of the root epidermis in Arabidopsis thaliana provides a simple model to study mechanisms underlying patterning in plants. Root hair increases the root surface area and effectively increases the root diameter, so root hair is thought to aid plants in nutrient uptake, anchorage and microbe interactions. The determination of root hair development has two types, lateral inhibition with feedback and position-dependent pattern of cell differentiation. The initiation and development of root hair in Arabidopsis provide a simple and efficacious model for the study of cell fate determination in plants. Molecular genetic studies identify a suite of putative transcription factors which regulate the epidermal cell pattern. The homeodomain protein GLABRA2 (GL2), R2R3 MYB-type transcription factor WEREWOLF (WER) and WD-repeat protein TRANSPARENTT TESTA GLABRA (TTG) are required for specification of non-hair cell type. The CAPRICE (CPC) and TRYPTICHON (TRY) are involved in specifying the hair cell fate.

Evaluation of time domain and spectral domain optical coherence tomography in the measurement of diabetic macular edema.

PubMed

Forooghian, Farzin; Cukras, Catherine; Meyerle, Catherine B; Chew, Emily Y; Wong, Wai T

2008-10-01

To evaluate macular thickness and volume measurements and their intrasession repeatability in two optical coherence tomography (OCT) systems: the Stratus OCT, a time domain system, and the Cirrus HD-OCT, a spectral domain system (both by Carl Zeiss Meditec, Inc., Dublin, CA), in the context of diabetic macular edema (DME). Thirty-three eyes of 33 diabetic patients with clinically significant macular edema (CSME) were scanned in a single session by a single operator on both OCT systems. Macular thickness measurements of nine standard macular subfields and total macular volume were obtained and analyzed. Bland-Altman plots were constructed to assess agreement in macular measurements. Intraclass correlation coefficients (ICCs), coefficients of repeatability (CR(W)), and coefficients of variation (CV(W)) were used to assess intrasession repeatability. Macular thickness in nine retinal subfields and macular volume were significantly higher in the Cirrus HD-OCT system compared with the Stratus OCT system. Subfield thickness and total volume measurements, respectively, were 30 to 55 microm and 3.2 mm(3) greater for the Cirrus HD-OCT system compared with the Stratus OCT system. Both Stratus OCT and Cirrus HD-OCT systems demonstrated high intrasession repeatability, with overlapping ranges for CR(W), CV(W), and ICC. Repeatability measures (CR(W) and CV(W)) differed significantly between systems in only one of nine subfields (outer temporal subfield). Absolute measures of macular thickness and volume in patients with DME differed significantly in magnitude between the Stratus OCT and Cirrus HD-OCT systems. However, both OCT systems demonstrated high intrasessional repeatability. Although the two systems may not be used interchangeably, they appear equally reliable in generating macular measurements for clinical practice and research.

Synergistic enhancement of cellulase pairs linked by consensus ankyrin repeats: Determination of the roles of spacing, orientation, and enzyme identity.

PubMed

Cunha, Eva S; Hatem, Christine L; Barrick, Doug

2016-08-01

Biomass deconstruction to small simple sugars is a potential approach to biofuels production; however, the highly recalcitrant nature of biomass limits the economic viability of this approach. Thus, research on efficient biomass degradation is necessary to achieve large-scale production of biofuels. Enhancement of cellulolytic activity by increasing synergism between cellulase enzymes holds promise in achieving high-yield biofuels production. Here we have inserted cellulase pairs from extremophiles into hyperstable α-helical consensus ankyrin repeat domain scaffolds. Such chimeric constructs allowed us to optimize arrays of enzyme pairs against a variety of cellulolytic substrates. We found that endocellulolytic domains CelA (CA) and Cel12A (C12A) act synergistically in the context of ankyrin repeats, with both three and four repeat spacing. The extent of synergy differs for different substrates. Also, having C12A N-terminal to CA provides greater synergy than the reverse construct, especially against filter paper. In contrast, we do not see synergy for these enzymes in tandem with CelK (CK) catalytic domain, a larger exocellulase, demonstrating the importance of enzyme identity in synergistic enhancement. Furthermore, we found endocellulases CelD and CA with three repeat spacing to act synergistically against filter paper. Importantly, connecting CA and C12A with a disordered linker of similar contour length shows no synergistic enhancement, indicating that synergism results from connecting these domains with folded ankyrin repeats. These results show that ankyrin arrays can be used to vary spacing and orientation between enzymes, helping to design and optimize artificial cellulosomes, providing a novel architecture for synergistic enhancement of enzymatic cellulose degradation. Proteins 2016; 84:1043-1054. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Synergistic enhancement of cellulase pairs linked by consensus ankyrin repeats: determination of the roles of spacing, orientation and enzyme identity

PubMed Central

Cunha, Eva S.; Hatem, Christine L.; Barrick, Doug

2017-01-01

Biomass deconstruction to small simple sugars is a potential approach to biofuels production, however the highly recalcitrant nature of biomass limits the economic viability of this approach. Thus, research on efficient biomass degradation is necessary to achieve large-scale production of biofuels. Enhancement of cellulolytic activity by increasing synergism between cellulase enzymes holds promise in achieving high-yield biofuels production. Here we have inserted cellulase pairs from extremophiles into hyper-stable α-helical consensus ankyrin repeat domain scaffolds. Such chimeric constructs allowed us to optimize arrays of enzyme pairs against a variety of cellulolytic substrates. We found that endocellulolytic domains CelA (CA) and Cel12A (C12A) act synergistically in the context of ankyrin repeats, with both three and four repeat spacing. The extent of synergy differs for different substrates. Also, having C12A N-terminal to CA provides greater synergy than the reverse construct, especially against filter paper. In contrast, we do not see synergy for these enzymes in tandem with CelK (CK) catalytic domain, a larger exocellulase, demonstrating the importance of enzyme identity in synergistic enhancement. Furthermore, we found endocellulases CelD and CA with three repeat spacing to act synergistically against filter paper. Importantly, connecting CA and C12A with a disordered linker of similar contour length, shows no synergistic enhancement, indicating that synergism results from connecting these domains with folded ankyrin repeats. These results show that ankyrin arrays can be used to vary spacing and orientation between enzymes, helping to design and optimize artificial cellulosomes, providing a novel architecture for synergistic enhancement of enzymatic cellulose degradation. PMID:27071357

The cryo-electron microscopy structure of huntingtin

NASA Astrophysics Data System (ADS)

Guo, Qiang; Bin Huang; Cheng, Jingdong; Seefelder, Manuel; Engler, Tatjana; Pfeifer, Günter; Oeckl, Patrick; Otto, Markus; Moser, Franziska; Maurer, Melanie; Pautsch, Alexander; Baumeister, Wolfgang; Fernández-Busnadiego, Rubén; Kochanek, Stefan

2018-03-01

Huntingtin (HTT) is a large (348 kDa) protein that is essential for embryonic development and is involved in diverse cellular activities such as vesicular transport, endocytosis, autophagy and the regulation of transcription. Although an integrative understanding of the biological functions of HTT is lacking, the large number of identified HTT interactors suggests that it serves as a protein-protein interaction hub. Furthermore, Huntington’s disease is caused by a mutation in the HTT gene, resulting in a pathogenic expansion of a polyglutamine repeat at the amino terminus of HTT. However, only limited structural information regarding HTT is currently available. Here we use cryo-electron microscopy to determine the structure of full-length human HTT in a complex with HTT-associated protein 40 (HAP40; encoded by three F8A genes in humans) to an overall resolution of 4 Å. HTT is largely α-helical and consists of three major domains. The amino- and carboxy-terminal domains contain multiple HEAT (huntingtin, elongation factor 3, protein phosphatase 2A and lipid kinase TOR) repeats arranged in a solenoid fashion. These domains are connected by a smaller bridge domain containing different types of tandem repeats. HAP40 is also largely α-helical and has a tetratricopeptide repeat-like organization. HAP40 binds in a cleft and contacts the three HTT domains by hydrophobic and electrostatic interactions, thereby stabilizing the conformation of HTT. These data rationalize previous biochemical results and pave the way for improved understanding of the diverse cellular functions of HTT.

[Withholding and withdrawing treatment in patients admitted in an Internal Medicine ward].

PubMed

García Caballero, R; Herreros, B; Real de Asúa, D; Alonso, R; Barrera, M M; Castilla, V

2016-01-01

Many of the patients admitted to a general medical ward have a compromised quality of life, or short life expectancy, so they are potential candidates for withhold/withdraw (WH/WD) treatment. The first objectif was to describe which measures were WH/WD among patients who died during their admission in a general medical ward from a tertiary hospital in Madrid. Secondly, to define the clinical characteristics of this population. A cross-sectional descriptive study during 6 months from 2011 and 2012 of all the patients dead while their admission in the Internal Medicine Department. 2007 patients were admitted, 211 died (10.5%). 121 (57%) were female, with 85±9 years of mean age. 103 (48.8%) came from a residential facility and 105 fulfilled terminality criteria (49.8%). One decision to WH/WD treatment was made in 182 patients (86.3%, CI 95%: 81.4-91.1), two in 99 cases (46.9%, CI 95%: 39.9-53.9) and 3 or more in 31 subjects (14.7%, CI 95%: 9.6-19.7). The most frequent decisions involved do-not-resuscitate orders (154, 73.0%), rejection of «aggressive treatment measures» (80, 38.0%), use of antibiotics (19, 9.0%), admission in ICU (18, 8.5%), and/or surgical treatment (11, 5.2%). WH/WD treatment is very frequent among patients who died in a general medical ward. The most frequent involved do-not-resuscitate orders and rejection of «aggressive treatment measures». WH/WD decisions are adopted in an elderly population, with extensive comorbidity and an elevated prevalence of advanced dementia and/or terminal disease. Copyright © 2015 SECA. Published by Elsevier Espana. All rights reserved.

Loss of the Liver X Receptors Disrupts the Balance of Hematopoietic Populations, With Detrimental Effects on Endothelial Progenitor Cells.

PubMed

Rasheed, Adil; Tsai, Ricky; Cummins, Carolyn L

2018-05-08

The liver X receptors (LXRs; α/β) are nuclear receptors known to regulate cholesterol homeostasis and the production of select hematopoietic populations. The objective of this study was to determine the importance of LXRs and a high-fat high-cholesterol diet on global hematopoiesis, with special emphasis on endothelial progenitor cells (EPCs), a vasoreparative cell type that is derived from bone marrow hematopoietic stem cells. Wild-type and LXR double-knockout ( Lxr αβ -/- ) mice were fed a Western diet (WD) to increase plasma cholesterol levels. In WD-fed Lxr αβ -/- mice, flow cytometry and complete blood cell counts revealed that hematopoietic stem cells, a myeloid progenitor, and mature circulating myeloid cells were increased; EPC numbers were significantly decreased. Hematopoietic stem cells from WD-fed Lxr αβ -/- mice showed increased cholesterol content, along with increased myeloid colony formation compared with chow-fed mice. In contrast, EPCs from WD-fed Lxr αβ -/- mice also demonstrated increased cellular cholesterol content that was associated with greater expression of the endothelial lineage markers Cd144 and Vegfr2 , suggesting accelerated differentiation of the EPCs. Treatment of human umbilical vein endothelial cells with conditioned medium collected from these EPCs increased THP-1 monocyte adhesion. Increased monocyte adhesion to conditioned medium-treated endothelial cells was recapitulated with conditioned medium from Lxr αβ -/- EPCs treated with cholesterol ex vivo, suggesting cholesterol is the main component of the WD inducing EPC dysfunction. LXRs are crucial for maintaining the balance of hematopoietic cells in a hypercholesterolemic environment and for mitigating the negative effects of cholesterol on EPC differentiation/secretome changes that promote monocyte-endothelial adhesion. © 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

Negative Pressure Wound Therapy with Surgical Gloves to Repair Soft Tissue Defects in Hands.

PubMed

Fujitani, Teruaki; Zenke, Yukichi; Shinone, Michitaka; Menuki, Kunitaka; Fukumoto, Keizo; Sakai, Akinori

2015-09-01

The efficacy of negative pressure wound therapy (NPWT) in the treatment of skin defect wounds has been established, but it is difficult to apply to hand surgery because of the easy occurrence of air leaks. We report two cases of performing NPWT with surgical gloves. Case1: A 37-year-old male was injured on his right dorsal hand from a punch. He presented to our hospital three days after the injury because of swelling and pain. The wound was infected and contused, so wound lavage and debridement (W&D) were performed under local anesthesia. The infected condition didn't improve after antimicrobial infusion, so W&D were performed again 8 days after the first visit. Then W&D were performed every day, and the infection subsided 15 days after the first visit. NPWT was initiated for the purpose of managing exudate and the wound condition, and healthy granulation tissue formed gradually. Finally, transpositional flap and full-thickness skin graft were performed on day 29. Case2: A 43-year-old male accidentally sustained a high pressure injection of oil into his dorsal hand. He presented to our hospital the next day, and W&D were performed. W&D were performed again two days after the first visit, and artificial dermis was applied over a part of the wound that was impossible to close. A decision was made to apply NPWT and a surgical glove for the purpose of reducing swelling and managing wound exudate. The swelling decreased and granulation tissue formed gradually, then nine days after the first visit a sural nerve graft was applied to bridge the defective area, and a full thickness skin graft was applied. We achieved good wound closure and hand function recovery after using NPWT and a surgical glove.

The effects of equal caloric high fat and western diet on metabolic syndrome, oxidative stress and vascular endothelial function in mice.

PubMed

Heinonen, I; Rinne, P; Ruohonen, S T; Ruohonen, S; Ahotupa, M; Savontaus, E

2014-07-01

Nutrition contributes to increased adiposity, but it remains to be determined whether high fat rather than Western diet exacerbates the development of obesity and other characteristics of metabolic syndrome and vascular function. We studied the effects of high fat (45% kcal) diet (HFD) and equal caloric Western diet (WD) high in fat, sucrose and cholesterol for 8 weeks in male C57B1/6N mice. Mice fed with HFD and WD showed substantially higher body adiposity (body fat %) compared with control mice receiving low fat (10%) diet (LFD). However, total body weight was higher only in HFD mice compared with other groups. The amount of liver triglycerides, cholesterol and oxidative damage was higher in WD mice compared with mice on LFD. There were no significant differences in fasting blood glucose or serum insulin, serum or muscle triglycerides, glucose tolerance or systolic blood pressure between the groups, but serum free fatty acids were increased in HFD mice compared with LFD. Increased levels of tissue and serum diene conjugation as a marker of oxidative stress were evident especially in WD mice. The endothelium-dependent relaxations were significantly impaired in the small mesenteric arteries of HFD mice, but not in the aorta. Maximal relaxations correlated negatively with body adiposity in WD but not in HFD mice. The major finding in the present study is that without changing body weight, Western diet induces marked whole-body oxidative stress and elevates body adiposity, which associates with the endothelial function of resistance arteries. © 2014 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.

mPGES-1-derived PGE2 mediates dehydration natriuresis

PubMed Central

Jia, Zhanjun; Liu, Gang; Sun, Ying; Kakizoe, Yutaka; Guan, Guangju; Zhang, Aihua; Zhou, Shu-Feng

2013-01-01

PGE2 is a natriuretic factor whose production is elevated after water deprivation (WD) but its role in dehydration natriuresis is not well-defined. The goal of the present study was to investigate the role of microsomal prostaglandin E synthase-1 (mPGES-1) in dehydration natriuresis. After 24-h WD, wild-type (WT) mice exhibited a significant increase in 24-h urinary Na+ excretion accompanied with normal plasma Na+ concentration and osmolality. In contrast, WD-induced elevation of urinary Na+ excretion was completely abolished in mPGES-1 knockout (KO) mice in parallel with increased plasma Na+ concentration and a trend increase in plasma osmolality. WD induced a 1.8-fold increase in urinary PGE2 output and a 1.6-fold increase in PGE2 content in the renal medulla of WT mice, both of which were completely abolished by mPGES-1 deletion. Similar patterns of changes were observed for urinary nitrate/nitrite and cGMP. The natriuresis in dehydrated WT mice was associated with a significant downregulation of renal medullary epithelial Na channel-α mRNA and protein, contrasting to unaltered expressions in dehydrated KO mice. By quantitative RT-PCR, WD increased the endothelial nitric oxide synthase (eNOS), inducible NOS, and neuronal NOS expressions in the renal medulla of WT mice by 3.9-, 1.48-, and 2.6-fold, respectively, all of which were significantly blocked in mPGES-1 KO mice. The regulation of eNOS expression was further confirmed by immunoblotting. Taken together, our results suggest that mPGES-1-derived PGE2 contributes to dehydration natriuresis likely via NO/cGMP. PMID:23171554

Leaf δ15N as a physiological indicator of the responsiveness of N2-fixing alfalfa plants to elevated [CO2], temperature and low water availability

PubMed Central

Ariz, Idoia; Cruz, Cristina; Neves, Tomé; Irigoyen, Juan J.; Garcia-Olaverri, Carmen; Nogués, Salvador; Aparicio-Tejo, Pedro M.; Aranjuelo, Iker

2015-01-01

The natural 15N/14N isotope composition (δ15N) of a tissue is a consequence of its N source and N physiological mechanisms in response to the environment. It could potentially be used as a tracer of N metabolism in plants under changing environmental conditions, where primary N metabolism may be complex, and losses and gains of N fluctuate over time. In order to test the utility of δ15N as an indicator of plant N status in N2-fixing plants grown under various environmental conditions, alfalfa (Medicago sativa L.) plants were subjected to distinct conditions of [CO2] (400 vs. 700 μmol mol−1), temperature (ambient vs. ambient +4°C) and water availability (fully watered vs. water deficiency—WD). As expected, increased [CO2] and temperature stimulated photosynthetic rates and plant growth, whereas these parameters were negatively affected by WD. The determination of δ15N in leaves, stems, roots, and nodules showed that leaves were the most representative organs of the plant response to increased [CO2] and WD. Depletion of heavier N isotopes in plants grown under higher [CO2] and WD conditions reflected decreased transpiration rates, but could also be related to a higher N demand in leaves, as suggested by the decreased leaf N and total soluble protein (TSP) contents detected at 700 μmol mol−1 [CO2] and WD conditions. In summary, leaf δ15N provides relevant information integrating parameters which condition plant responsiveness (e.g., photosynthesis, TSP, N demand, and water transpiration) to environmental conditions. PMID:26322051

Docosahexaenoic Acid Attenuates Hepatic Inflammation, Oxidative Stress, and Fibrosis without Decreasing Hepatosteatosis in a Ldlr−/− Mouse Model of Western Diet-Induced Nonalcoholic Steatohepatitis123

PubMed Central

Depner, Christopher M.; Philbrick, Kenneth A.; Jump, Donald B.

2013-01-01

The incidence of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) has increased in parallel with the incidence of obesity. While both NAFLD and NASH are characterized by hepatosteatosis, NASH is characterized by hepatic damage, inflammation, oxidative stress, and fibrosis. We previously reported that feeding Ldlr−/− mice a high-fat, high-cholesterol diet containing menhaden oil attenuated several markers of NASH, including hepatosteatosis, inflammation, and fibrosis. Herein, we test the hypothesis that DHA [22:6 (n-3)] is more effective than EPA [20:5 (n-3)] at preventing Western diet (WD)-induced NASH in Ldlr−/− mice. Mice were fed the WD supplemented with either olive oil (OO), EPA, DHA, or EPA + DHA for 16 wk. WD + OO feeding induced a severe NASH phenotype, characterized by robust hepatosteatosis, inflammation, oxidative stress, and fibrosis. Whereas none of the C20–22 (n-3) fatty acid treatments prevented WD-induced hepatosteatosis, all 3 (n-3) PUFA-containing diets significantly attenuated WD-induced inflammation, fibrosis, and hepatic damage. The capacity of dietary DHA to suppress hepatic markers of inflammation (Clec4F, F4/80, Trl4, Trl9, CD14, Myd88), fibrosis (Procol1α1, Tgfβ1), and oxidative stress (NADPH oxidase subunits Nox2, p22phox, p40phox, p47phox, p67phox) was significantly greater than dietary EPA. The effects of DHA on these markers paralleled DHA-mediated suppression of hepatic Fads1 mRNA abundance and hepatic arachidonic acid content. Because DHA suppression of NASH markers does not require a reduction in hepatosteatosis, dietary DHA may be useful in combating NASH in obese humans. PMID:23303872

Impact of dietary fat on the development of non-alcoholic fatty liver disease in Ldlr−/− mice

PubMed Central

Jump, Donald B.; Depner, Christopher M.; Tripathy, Sasmita; Lytle, Kelli A.

2015-01-01

The prevalence of non-alcoholic fatty liver disease (NAFLD) has increased in parallel with central obesity and is now the most common chronic liver disease in developed countries. NAFLD is defined as excessive accumulation of lipid in the liver, i.e. hepatosteatosis. The severity of NAFLD ranges from simple fatty liver (steatosis) to non-alcoholic steatohepatitis (NASH). Simple steatosis is relatively benign until it progresses to NASH, which is characterised by hepatic injury, inflammation, oxidative stress and fibrosis. Hepatic fibrosis is a risk factor for cirrhosis and primary hepatocellular carcinoma. Our studies have focused on the impact of diet on the onset and progression of NASH. We developed a mouse model of NASH by feeding Ldlr−/− mice a western diet (WD), a diet moderately high in saturated and trans-fat, sucrose and cholesterol. The WD induced a NASH phenotype in Ldlr−/− mice that recapitulates many of the clinical features of human NASH. We also assessed the capacity of the dietary n-3 PUFA, i.e. EPA (20 : 5,n-3) and DHA (22 : 6,n-3), to prevent WD-induced NASH in Ldlr−/− mice. Histologic, transcriptomic, lipidomic and metabolomic analyses established that DHA was equal or superior to EPA at attenuating WD-induced dyslipidemia and hepatic injury, inflammation, oxidative stress and fibrosis. Dietary n-3 PUFA, however, had no significant effect on WD-induced changes in body weight, body fat or blood glucose. These studies provide a molecular and metabolic basis for understanding the strengths and weaknesses of using dietary n-3 PUFA to prevent NASH in human subjects. PMID:26282529

Work-related measures of physical and behavioral health function: Test-retest reliability.

PubMed

Marino, Molly Elizabeth; Meterko, Mark; Marfeo, Elizabeth E; McDonough, Christine M; Jette, Alan M; Ni, Pengsheng; Bogusz, Kara; Rasch, Elizabeth K; Brandt, Diane E; Chan, Leighton

2015-10-01

The Work Disability Functional Assessment Battery (WD-FAB), developed for potential use by the US Social Security Administration to assess work-related function, currently consists of five multi-item scales assessing physical function and four multi-item scales assessing behavioral health function; the WD-FAB scales are administered as Computerized Adaptive Tests (CATs). The goal of this study was to evaluate the test-retest reliability of the WD-FAB Physical Function and Behavioral Health CATs. We administered the WD-FAB scales twice, 7-10 days apart, to a sample of 376 working age adults and 316 adults with work-disability. Intraclass correlation coefficients were calculated to measure the consistency of the scores between the two administrations. Standard error of measurement (SEM) and minimal detectable change (MDC90) were also calculated to measure the scales precision and sensitivity. For the Physical Function CAT scales, the ICCs ranged from 0.76 to 0.89 in the working age adult sample, and 0.77-0.86 in the sample of adults with work-disability. ICCs for the Behavioral Health CAT scales ranged from 0.66 to 0.70 in the working age adult sample, and 0.77-0.80 in the adults with work-disability. The SEM ranged from 3.25 to 4.55 for the Physical Function scales and 5.27-6.97 for the Behavioral Health function scales. For all scales in both samples, the MDC90 ranged from 7.58 to 16.27. Both the Physical Function and Behavioral Health CATs of the WD-FAB demonstrated good test-retest reliability in adults with work-disability and general adult samples, a critical requirement for assessing work related functioning in disability applicants and in other contexts. Copyright © 2015 Elsevier Inc. All rights reserved.

THE NUCLEUS OF THE PLANETARY NEBULA EGB 6 AS A POST-MIRA BINARY

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

Bond, Howard E.; Ciardullo, Robin; Esplin, Taran L.

EGB 6 is a faint, large, ancient planetary nebula (PN). Its central star, a hot DAOZ white dwarf (WD), is a prototype of a rare class of PN nuclei associated with dense, compact emission-line knots. The central star also shows excess fluxes in both the near-infrared (NIR) and mid-infrared (MIR). In a 2013 paper, we used Hubble Space Telescope ( HST ) images to show that the compact nebula is a point-like source, located 0.″16 (∼118 AU) from the WD. We attributed the NIR excess to an M dwarf companion star, which appeared to coincide with the dense emission knot.more » We now present new ground-based NIR spectroscopy, showing that the companion is actually a much cooler source with a continuous spectrum, apparently a dust-enshrouded low-luminosity star. New HST images confirm common proper motion of the emission knot and red source with the WD. The I -band, NIR, and MIR fluxes are variable, possibly on timescales as short as days. We can fit the spectral energy distribution (SED) with four blackbodies (the WD, a ∼1850 K NIR component, and MIR dust at 385 and 175 K). Alternatively, we show that the NIR/MIR SED is very similar to that of Class 0/I young stellar objects. We suggest a scenario in which the EGB 6 nucleus is descended from a wide binary similar to the Mira system, in which a portion of the wind from an AGB star was captured into an accretion disk around a companion star; a remnant of this disk has survived to the present time and is surrounded by gas photoionized by UV radiation from the WD.« less

Work-related measures of Physical and Behavioral Health Function: Test-Retest Reliability

PubMed Central

Marino, Molly Elizabeth; Meterko, Mark; Marfeo, Elizabeth E.; McDonough, Christine M.; Jette, Alan M.; Ni, Pengsheng; Bogusz, Kara; Rasch, Elizabeth K.; Brandt, Diane E.; Chan, Leighton

2015-01-01

Background The Work Disability Functional Assessment Battery (WD-FAB), developed for potential use by the US Social Security Administration to assess work-related function, currently consists of five multi-item scales assessing physical function and four multi-item scales assessing behavioral health function; the WD-FAB scales are administered as Computerized Adaptive Tests (CATs). Objective The goal of this study was to evaluate the test-retest reliability of the WD-FAB Physical Function and Behavioral Health CATs. Methods We administered the WD-FAB scales twice, 7–10 days apart, to a sample of 376 working age adults and 316 adults with work-disability. Intraclass correlation coefficients were calculated to measure the consistency of the scores between the two administrations. Standard error of measurement (SEM) and minimal detectable change (MDC90) were also calculated to measure the scales precision and sensitivity. Results For the Physical Function CAT scales, the ICCs ranged from 0.76–0.89 in the working age adult sample, and 0.77–0.86 in the sample of adults with work-disability. ICCs for the Behavioral Health CAT scales ranged from 0.66–0.70 in the working age adult sample, and 0.77–0.80 in the adults with work-disability. The SEM ranged from 3.25–4.55 for the Physical Function scales and 5.27–6.97 for the Behavioral Health function scales. For all scales in both samples, the MDC90 ranged from 7.58–16.27. Conclusion Both the Physical Function and Behavioral Health CATs of the WD-FAB demonstrated good test-retest reliability in adults with work-disability and general adult samples, a critical requirement for assessing work related functioning in disability applicants and in other contexts. PMID:25991419

Usefulness of a Dual Macro- and Micro-Energy-Dispersive X-Ray Fluorescence Spectrometer to Develop Quantitative Methodologies for Historic Mortar and Related Materials Characterization.

PubMed

García-Florentino, Cristina; Maguregui, Maite; Romera-Fernández, Miriam; Queralt, Ignasi; Margui, Eva; Madariaga, Juan Manuel

2018-05-01

Wavelength dispersive X-ray fluorescence (WD-XRF) spectrometry has been widely used for elemental quantification of mortars and cements. In this kind of instrument, samples are usually prepared as pellets or fused beads and the whole volume of sample is measured at once. In this work, the usefulness of a dual energy dispersive X-ray fluorescence spectrometer (ED-XRF), working at two lateral resolutions (1 mm and 25 μm) for macro and microanalysis respectively, to develop quantitative methods for the elemental characterization of mortars and concretes is demonstrated. A crucial step before developing any quantitative method with this kind of spectrometers is to verify the homogeneity of the standards at these two lateral resolutions. This new ED-XRF quantitative method also demonstrated the importance of matrix effects in the accuracy of the results being necessary to use Certified Reference Materials as standards. The results obtained with the ED-XRF quantitative method were compared with the ones obtained with two WD-XRF quantitative methods employing two different sample preparation strategies (pellets and fused beads). The selected ED-XRF and both WD-XRF quantitative methods were applied to the analysis of real mortars. The accuracy of the ED-XRF results turn out to be similar to the one achieved by WD-XRF, except for the lightest elements (Na and Mg). The results described in this work proved that μ-ED-XRF spectrometers can be used not only for acquiring high resolution elemental map distributions, but also to perform accurate quantitative studies avoiding the use of more sophisticated WD-XRF systems or the acid extraction/alkaline fusion required as destructive pretreatment in Inductively coupled plasma mass spectrometry based procedures.

EVOLUTION OF CATACLYSMIC VARIABLES AND RELATED BINARIES CONTAINING A WHITE DWARF

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

Kalomeni, B.; Rappaport, S.; Molnar, M.

We present a binary evolution study of cataclysmic variables (CVs) and related systems with white dwarf (WD) accretors, including for example, AM CVn systems, classical novae, supersoft X-ray sources (SXSs), and systems with giant donor stars. Our approach intentionally avoids the complications associated with population synthesis algorithms, thereby allowing us to present the first truly comprehensive exploration of all of the subsequent binary evolution pathways that zero-age CVs might follow (assuming fully non-conservative, Roche-lobe overflow onto an accreting WD) using the sophisticated binary stellar evolution code MESA. The grid consists of 56,000 initial models, including 14 WD accretor masses, 43more » donor-star masses (0.1–4.7 M {sub ⊙}), and 100 orbital periods. We explore evolution tracks in the orbital period and donor-mass ( P {sub orb}– M {sub don}) plane in terms of evolution dwell times, masses of the WD accretor, accretion rate, and chemical composition of the center and surface of the donor star. We report on the differences among the standard CV tracks, those with giant donor stars, and ultrashort period systems. We show where in parameter space one can expect to find SXSs, present a diagnostic to distinguish among different evolutionary paths to forming AM CVn binaries, quantify how the minimum orbital period in CVs depends on the chemical composition of the donor star, and update the P {sub orb}( M {sub wd}) relation for binaries containing WDs whose progenitors lost their envelopes via stable Roche-lobe overflow. Finally, we indicate where in the P {sub orb}– M {sub don} the accretion disks will tend to be stable against the thermal-viscous instability, and where gravitational radiation signatures may be found with LISA.« less

A single-degenerate channel for the progenitors of Type Ia supernovae with different metallicities

NASA Astrophysics Data System (ADS)

Meng, X.; Chen, X.; Han, Z.

2009-06-01

A single-degenerate channel for the progenitors of Type Ia supernovae (SNe Ia) is currently accepted, in which a carbon-oxygen white dwarf (CO WD) accretes hydrogen-rich material from its companion, increases its mass to the Chandrasekhar mass limit and then explodes as a SN Ia. Incorporating the prescription of Hachisu et al. for the accretion efficiency into Eggleton's stellar evolution code, and assuming that the prescription is valid for all metallicities, we performed binary stellar evolution calculations for more than 25000 close WD binaries with metallicities Z = 0.06, 0.05, 0.04, 0.03, 0.02, 0.01, 0.004, 0.001, 0.0003 and 0.0001. For our calculations, the companions are assumed to be unevolved or slightly evolved stars (WD + MS). As a result, the initial parameter spaces for SNe Ia at various Z are presented in the orbital period-secondary mass (logPi, Mi2) plane. Our study shows that both the initial mass of the secondary and the initial orbital period increase with metallicity. Thus, the minimum mass of the CO WD for SNe Ia decreases with metallicity Z. The difference in the minimum mass may be as large as 0.24Msolar for different Z. Adopting the results above, we studied the birth rate of SNe Ia for various Z via a binary population synthesis approach. If a single starburst is assumed, SNe Ia occur systemically earlier and the peak value of the birth rate is larger for a high Z. The Galactic birth rate from the WD + MS channel is lower than (but comparable to) that inferred from observations. Our study indicates that supernovae like SN2002ic will not occur in extremely low-metallicity environments, if the delayed dynamical-instability model is appropriate.

Contribution of Va24Vb11 natural killer T cells in Wilsonian hepatitis.

PubMed

Kinebuchi, M; Matsuura, A; Ohya, K; Abo, W; Kitazawa, J

2005-01-01

Wilson disease (WD) is an autosomal recessive disorder of copper transport, resulting in copper accumulation and toxicity to the liver and brain. There is no evidence that the WD patient's immune system attacks copper accumulated hepatocytes. Here we describe that the frequency and absolute number of Valpha24+Vbeta11+ natural killer T (NKT) cells were significantly increased in 3 cases of WD, whereas those of CD3+CD161+ NKT cells were within the normal range. Patients no. 1 and 2 had a presymptomatic form of WD. Their tissue specimens showed pathological changes of mild degeneration of hepatocytes with a few infiltrating mononuclear cells and a low degree of fatty change. Patient no. 3 displayed fulminant hepatitis with Coombs-negative haemolytic anaemia. The tissue specimens of patient no. 3 showed macronodular cirrhosis with thick fibrosis, inflammatory infiltrates and spotty necrosis. Human Valpha24+Vbeta11+ NKT cells are almost equal to CD1d-restricted NKT cells. Therefore we investigated CD1d-restricted NKT cells in the LEC rat as an animal model of WD. In LEC rats before hepatitis onset, the number and phenotype of liver NKT cells were normal. At about 4 months of age all LEC rats developed acute hepatitis accompanied by acute jaundice, and CD161high NKT cells developed in their livers. CD161highalphabetaTCRbright NKT cells developed in some of them. Their hepatitis was severe. CD161highalphabetaTCRbright NKT cells expressed an invariant rat Valpha14-Jalpha281 chain, which is CD1d-restricted. Furthermore, liver lymphocytes in the acute jaundiced LEC rats with CD161highalphabetaTCRbright NKT cells had significant and CD1d-specific cytotoxic activity.

Activity and Kinematics of White Dwarf-M Dwarf Binaries from the SUPERBLINK Proper Motion Survey

NASA Astrophysics Data System (ADS)

Skinner, Julie N.; Morgan, Dylan P.; West, Andrew A.; Lépine, Sébastien; Thorstensen, John R.

2017-09-01

We present an activity and kinematic analysis of high proper motion white dwarf-M dwarf binaries (WD+dMs) found in the SUPERBLINK survey, 178 of which are new identifications. To identify WD+dMs, we developed a UV-optical-IR color criterion and conducted a spectroscopic survey to confirm each candidate binary. For the newly identified systems, we fit the two components using model white dwarf spectra and M dwarf template spectra to determine physical parameters. We use Hα chromospheric emission to examine the magnetic activity of the M dwarf in each system, and investigate how its activity is affected by the presence of a white dwarf companion. We find that the fraction of WD+dM binaries with active M dwarfs is significantly higher than their single M dwarf counterparts at early and mid-spectral types. We corroborate previous studies that find high activity fractions at both close and intermediate separations. At more distant separations, the binary fraction appears to approach the activity fraction for single M dwarfs. Using derived radial velocities and the proper motions, we calculate 3D space velocities for the WD+dMs in SUPERBLINK. For the entire SUPERBLINK WD+dMs, we find a large vertical velocity dispersion, indicating a dynamically hotter population compared to high proper motion samples of single M dwarfs. We compare the kinematics for systems with active M dwarfs and those with inactive M dwarfs, and find signatures of asymmetric drift in the inactive sample, indicating that they are drawn from an older population. Based on observations obtained at the MDM Observatory operated by Dartmouth College, Columbia University, The Ohio State University, and the University of Michigan.

Evolution of Cataclysmic Variables and Related Binaries Containing a White Dwarf

NASA Astrophysics Data System (ADS)

Kalomeni, B.; Nelson, L.; Rappaport, S.; Molnar, M.; Quintin, J.; Yakut, K.

2016-12-01

We present a binary evolution study of cataclysmic variables (CVs) and related systems with white dwarf (WD) accretors, including for example, AM CVn systems, classical novae, supersoft X-ray sources (SXSs), and systems with giant donor stars. Our approach intentionally avoids the complications associated with population synthesis algorithms, thereby allowing us to present the first truly comprehensive exploration of all of the subsequent binary evolution pathways that zero-age CVs might follow (assuming fully non-conservative, Roche-lobe overflow onto an accreting WD) using the sophisticated binary stellar evolution code MESA. The grid consists of 56,000 initial models, including 14 WD accretor masses, 43 donor-star masses (0.1-4.7 M ⊙), and 100 orbital periods. We explore evolution tracks in the orbital period and donor-mass (P orb-M don) plane in terms of evolution dwell times, masses of the WD accretor, accretion rate, and chemical composition of the center and surface of the donor star. We report on the differences among the standard CV tracks, those with giant donor stars, and ultrashort period systems. We show where in parameter space one can expect to find SXSs, present a diagnostic to distinguish among different evolutionary paths to forming AM CVn binaries, quantify how the minimum orbital period in CVs depends on the chemical composition of the donor star, and update the P orb(M wd) relation for binaries containing WDs whose progenitors lost their envelopes via stable Roche-lobe overflow. Finally, we indicate where in the P orb-M don the accretion disks will tend to be stable against the thermal-viscous instability, and where gravitational radiation signatures may be found with LISA.

Bleeding score in type 1 von Willebrand disease patients using the condensed MCMDM-1 vWD validated questionnaire.

PubMed

Pathare, A; Al Hajri, F; Al Omrani, S; Al Obaidani, N; Al Balushi, B; Al Falahi, K

2018-05-13

Assessment of the severity of bleeding symptom has led to the evolution of bleeding assessment tools which are now validated. To administer the condensed molecular and clinical markers for the diagnosis and management of type 1 von Willebrand disease VWD (MCMDM-1 vWD) questionnaire to the Omani type 1 vWD patients and correlate it with the laboratory parameters. Patients and controls were personally interviewed and the condensed MCMDM-1 vWD questionnaire administered by a single investigator. Bleeding score (BS) was calculated, based on the presence or absence of the bleeding symptoms according to a standard validated questionnaire in both the patients and the controls. The median age of the patient cohort was 27 (range, 7-49) years with 60.87% of females. The median time to administer condensed MCMDM-1 BS questionnaire was 11 minutes (interquartile range-IQR;7,16). Overall, bleeding from the oral cavity was the most predominant symptom (63%). The median BS was 5 (IQR;1,8) although individual scores ranged between 0 and 29. However, there was no statistically significant difference in BS between genders (males: median 4; IQR 1,6 and females: median 5, IQR 1,10) (P > .05, Kruskal-Wallis test) The Spearman's correlation value of BS was weak with FVIII:C levels and von Willebrand Ristocetin co-factor activity; very weak with von Willebrand Antigen level, and moderate with vonWillebrand Collagen Binding activity being -0.29, -0.28, -0.14 and -0.43, respectively. The BS reflects the severity of bleeding among the vWD patients. Although the BS was abnormal, it did not correlate significantly with the surrogate laboratory parameters [P > .05]. © 2018 John Wiley & Sons Ltd.

WD 1145+017: optical activity during 2016-2017 and limits on the X-ray flux

NASA Astrophysics Data System (ADS)

Rappaport, S.; Gary, B. L.; Vanderburg, A.; Xu, S.; Pooley, D.; Mukai, K.

2018-02-01

WD 1145+017 was observed from 2016 November through 2017 June for the purpose of further characterizing the transit behaviour of the dusty debris clouds orbiting this white dwarf. The optical observations were carried out with a small ground-based telescope run by an amateur astronomer, and covered 53 different nights over the 8-month interval. We have found that the optical activity has increased to the highest level observed since its discovery with Kepler K2, with approximately 17 per cent of the optical flux extinguished per orbit. The source exhibits some transits with depths of up to 55 per cent and durations as long as 2 h. The dominant period of the orbiting dust clouds during 2016-2017 is 4.49126 h. We present `waterfall' images for the entire 2016-2017 and 2015-2016 observing seasons. In addition, the white dwarf was observed with the Chandra X-ray Observatory for 10-ks on each of four different occasions, separated by about a month each. The upper limit on the average X-ray flux from WD 1145+017 is ≃ 5 × 10-15 erg cm-2 s-1 (unabsorbed over the range 0.1-100 keV), which translates to an upper limit on the X-ray luminosity, Lx, of ≃ 2 × 1028 erg s-1. If L_x ˜eq G M_wd \\dot{M}_acc/R_wd, where Mwd and Rwd are the mass and radius of the white dwarf, and \\dot{M}_acc is the accretion rate, then \\dot{M}_acc ≲ 2 × 10^{11} g s-1. This is just consistent with the value of \\dot{M} that is inferred from the level of dust activity.

Leaf δ(15)N as a physiological indicator of the responsiveness of N2-fixing alfalfa plants to elevated [CO2], temperature and low water availability.

PubMed

Ariz, Idoia; Cruz, Cristina; Neves, Tomé; Irigoyen, Juan J; Garcia-Olaverri, Carmen; Nogués, Salvador; Aparicio-Tejo, Pedro M; Aranjuelo, Iker

2015-01-01

The natural (15)N/(14)N isotope composition (δ(15)N) of a tissue is a consequence of its N source and N physiological mechanisms in response to the environment. It could potentially be used as a tracer of N metabolism in plants under changing environmental conditions, where primary N metabolism may be complex, and losses and gains of N fluctuate over time. In order to test the utility of δ(15)N as an indicator of plant N status in N2-fixing plants grown under various environmental conditions, alfalfa (Medicago sativa L.) plants were subjected to distinct conditions of [CO2] (400 vs. 700 μmol mol(-1)), temperature (ambient vs. ambient +4°C) and water availability (fully watered vs. water deficiency-WD). As expected, increased [CO2] and temperature stimulated photosynthetic rates and plant growth, whereas these parameters were negatively affected by WD. The determination of δ(15)N in leaves, stems, roots, and nodules showed that leaves were the most representative organs of the plant response to increased [CO2] and WD. Depletion of heavier N isotopes in plants grown under higher [CO2] and WD conditions reflected decreased transpiration rates, but could also be related to a higher N demand in leaves, as suggested by the decreased leaf N and total soluble protein (TSP) contents detected at 700 μmol mol(-1) [CO2] and WD conditions. In summary, leaf δ(15)N provides relevant information integrating parameters which condition plant responsiveness (e.g., photosynthesis, TSP, N demand, and water transpiration) to environmental conditions.

HST Observations of Astrophysically Important Visual Binaries

NASA Astrophysics Data System (ADS)

Bond, Howard

2013-10-01

We propose to continue our long-term program of astrometry of close visual binaries, with the primary goal of determining purely dynamical masses for 3 important main-sequence stars and 9 white dwarfs {WDs}. A secondary aim is to set limits on third bodies in the systems down to planetary mass. Three of our targets are naked-eye stars with much fainter companions that are extremely difficult to image from the ground. Our other 2 targets are double WDs, whose small separations and faintness likewise make them difficult to measure using ground-based techniques. Observations have been completed for a 3rd double WD.The bright stars, to be imaged with WFC3, are: {1} Procyon {P = 40.83 yr}, containing a bright F star and a much fainter WD companion. With the continued monitoring proposed here, we will obtain masses to an accuracy of better than 1%, providing a testbed for theories of both Sun-like stars and WDs. {2} Sirius {P = 50.14 yr}, an A-type star also having a faint WD companion, Sirius B, the nearest and brightest of all WDs. {3} Mu Cas {P = 21.08 yr}, a nearby metal-deficient G dwarf for which accurate masses will lead to the stars' helium contents, with cosmological implications. The faint double WDs, to be observed with FGS, are: {1} G 107-70 {P = 18.84 yr}, and {2} WD 1818+126 {P = 12.19 yr}. Our astrometry of these systems will add 4 accurate masses to the handful of WD masses that are directly known from dynamical measurements. The FGS measurements will also provide precise parallaxes for the systems, a necessary ingredient in the mass determinations.

HST Observations of Astrophysically Important Visual Binaries

NASA Astrophysics Data System (ADS)

Bond, Howard

2015-10-01

We propose to continue our long-term program of astrometry of close visual binaries, with the primary goal of determining purely dynamical masses for 3 important main-sequence stars and 9 white dwarfs (WDs). A secondary aim is to set limits on third bodies in the systems down to planetary mass. Three of our targets are naked-eye stars with much fainter companions that are extremely difficult to image from the ground. Our other 2 targets are double WDs, whose small separations and faintness likewise make them difficult to measure using ground-based techniques. Observations have been completed for a 3rd double WD.The bright stars, to be imaged with WFC3, are: (1) Procyon (P = 40.83 yr), containing a bright F star and a much fainter WD companion. With the continued monitoring proposed here, we will obtain masses to an accuracy of better than 1%, providing a testbed for theories of both Sun-like stars and WDs. (2) Sirius (P = 50.14 yr), an A-type star also having a faint WD companion, Sirius B, the nearest and brightest of all WDs. (3) Mu Cas (P = 21.08 yr), a nearby metal-deficient G dwarf for which accurate masses will lead to the stars' helium contents, with cosmological implications. The faint double WDs, to be observed with FGS, are: (1) G 107-70 (P = 18.84 yr), and (2) WD 1818+126 (P = 12.19 yr). Our astrometry of these systems will add 4 accurate masses to the handful of WD masses that are directly known from dynamical measurements. The FGS measurements will also provide precise parallaxes for the systems, a necessary ingredient in the mass determinations.

HST Observations of Astrophysically Important Visual Binaries

NASA Astrophysics Data System (ADS)

Bond, Howard

2014-10-01

We propose to continue our long-term program of astrometry of close visual binaries, with the primary goal of determining purely dynamical masses for 3 important main-sequence stars and 9 white dwarfs (WDs). A secondary aim is to set limits on third bodies in the systems down to planetary mass. Three of our targets are naked-eye stars with much fainter companions that are extremely difficult to image from the ground. Our other 2 targets are double WDs, whose small separations and faintness likewise make them difficult to measure using ground-based techniques. Observations have been completed for a 3rd double WD.The bright stars, to be imaged with WFC3, are: (1) Procyon (P = 40.83 yr), containing a bright F star and a much fainter WD companion. With the continued monitoring proposed here, we will obtain masses to an accuracy of better than 1%, providing a testbed for theories of both Sun-like stars and WDs. (2) Sirius (P = 50.14 yr), an A-type star also having a faint WD companion, Sirius B, the nearest and brightest of all WDs. (3) Mu Cas (P = 21.08 yr), a nearby metal-deficient G dwarf for which accurate masses will lead to the stars' helium contents, with cosmological implications. The faint double WDs, to be observed with FGS, are: (1) G 107-70 (P = 18.84 yr), and (2) WD 1818+126 (P = 12.19 yr). Our astrometry of these systems will add 4 accurate masses to the handful of WD masses that are directly known from dynamical measurements. The FGS measurements will also provide precise parallaxes for the systems, a necessary ingredient in the mass determinations.

151-km single-end phase-sensitive optical time-domain reflectometer assisted by optical repeater

NASA Astrophysics Data System (ADS)

Song, Muping; Zhu, Weiji; Xia, Qiaolan; Yin, Cong; Lu, Yan; Wu, Ying; Zhuang, Shouwang

2018-02-01

A phase-sensitive optical time-domain reflectometry (ϕOTDR) system that can detect intrusion over 150 km is presented. The ϕOTDR system uses nonbalanced optical repeaters to extend the sensing distance. The repeater consists of two erbium-doped optical fiber amplifiers (EDFAs) and one Raman amplifier (RA). One EDFA power amplifier amplifies the forward-transmitting pulse, and one EDFA preamplifier is used for the backscattering signal, respectively. The RA helps keeping the power along the fiber stable. The optical repeater is installed at the connection of two adjacent fibers to compensate the power decline due to fiber loss. It is easy to install the repeater midway among the fiber links in the system for longer-distance sensing since there is no need of modifying the original sensing system. The theoretical analysis of the repeater is given to describe its effect on the distributed sensing. In experiments, several ϕOTDR traces show a good agreement with theoretical results. Using the optical repeater, 35-Hz vibration at 151 km is successfully measured with signal-to-noise ratio of 8 dB without extra signal processing.

Inhalative pre-treatment of donor lungs using the aerosolized prostacyclin analog iloprost ameliorates reperfusion injury.

PubMed

Wittwer, Thorsten; Franke, Ulrich F W; Ochs, Matthias; Sandhaus, Tim; Schuette, Alex; Richter, Stefan; Dreyer, Niels; Knudsen, Lars; Müller, Thomas; Schubert, Harald; Richter, Joachim; Wahlers, Thorsten

2005-10-01

Lung transplantation is effective for end-stage pulmonary disease, but its successful application is still limited by organ shortage and sub-optimal preservation techniques. Therefore, optimal allograft protection is essential to reduce organ dysfunction, especially in the early post-operative period. Intravenous prostanoids are routinely used to ameliorate reperfusion injury. However, the latest evidence suggests similar efficacy using inhaled prostacyclin. Thus, we evaluated the impact of donor pre-treatment using the prostacyclin analog, iloprost, on post-ischemic function of Perfadex-protected allografts. In Group 1, 5 pig lungs were preserved with Perfadex (PER group) solution and stored for 27 hours. In Group 2, 100 microg of iloprost was aerosolized over 30 minutes using a novel mobile ultrasonic nebulizer (Optineb) before identical organ harvest (PER-ILO group). After left lung transplantation and contralateral lung exclusion, hemodynamic variables, Po2/Fio2 and dynamic compliance were monitored for 6 hours and compared with sham-operated controls. Pulmonary edema was determined stereologically and by wet-to-dry (W/D) weight ratio. Statistical assessment included analysis of variance (ANOVA) with repeated measures. Dynamic compliance and pulmonary vascular resistance (PVR) were superior in iloprost-treated compared with untreated organs (p < 0.05), whereas oxygenation was comparable between groups. W/D ratio revealed a significantly smaller amount of lung water in PER-ILO organs (p = 0.048), whereas stereologic data showed a trend toward less intra-alveolar edema. Endobronchial application of iloprost in donor lungs before Perfadex preservation decreases post-ischemic edema and significantly improves lung compliance and vascular resistance. This innovative approach is easily applicable in the clinical setting and offers a new strategy for improvement of pulmonary allograft preservation.

Effects of early-life exposure to Western diet and wheel access on metabolic syndrome profiles in mice bred for high voluntary exercise.

PubMed

Meek, T H; Eisenmann, J C; Keeney, B K; Hannon, R M; Dlugosz, E M; Garland, T

2014-03-01

Experimental studies manipulating diet and exercise have shown varying effects on metabolic syndrome components in both humans and rodents. To examine the potential interactive effects of diet, exercise and genetic background, we studied mice from four replicate lines bred (52 generations) for high voluntary wheel running (HR lines) and four unselected control lines (C). At weaning, animals were housed for 60 days with or without wheels and fed either a standard chow or Western diet (WD, 42% kcal from fat). Four serial (three juvenile and one adult) blood samples were taken to measure fasting total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), triglycerides and glucose. Western diet was obesogenic for all mice, even after accounting for the amount of wheel running and kilojoules consumed. Western diet significantly raised glucose as well as TC and HDL-C concentrations. At the level of individual variation (repeatability), there was a modest correlation (r = 0.3-0.5) of blood lipids over time, which was reduced with wheel access and/or WD. Neither genetic selection history nor wheel access had a statistically significant effect on blood lipids. However, HR and C mice had divergent ontogenetic trajectories for body mass and caloric intake. HR mice also had lower adiposity, an effect that was dependent on wheel access. The environmental factors of diet and wheel access had pronounced effects on body mass, food consumption and fasting glucose concentrations, interacting with each other and/or with genetic strain. These data underscore the importance (and often unpredictable nature) of genotype-by-environment and environment-by-environment interactions when studying body weight regulation. © 2013 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

Testing Common Envelopes on Double White Dwarf Binaries

NASA Astrophysics Data System (ADS)

Nandez, Jose L. A.; Ivanova, Natalia; Lombardi, James C., Jr.

2015-06-01

The formation of a double white dwarf binary likely involves a common envelope (CE) event between a red giant and a white dwarf (WD) during the most recent episode of Roche lobe overflow mass transfer. We study the role of recombination energy with hydrodynamic simulations of such stellar interactions. We find that the recombination energy helps to expel the common envelope entirely, while if recombination energy is not taken into account, a significant fraction of the common envelope remains bound. We apply our numerical methods to constrain the progenitor system for WD 1101+364 - a double WD binary that has well-measured mass ratio of q=0.87±0.03 and an orbital period of 0.145 days. Our best-fit progenitor for the pre-common envelope donor is a 1.5 ⊙ red giant.

Crystallization of carbon-oxygen mixtures in white dwarf stars.

PubMed

Horowitz, C J; Schneider, A S; Berry, D K

2010-06-11

We determine the phase diagram for dense carbon-oxygen mixtures in white dwarf (WD) star interiors using molecular dynamics simulations involving liquid and solid phases. Our phase diagram agrees well with predictions from Ogata et al. and from Medin and Cumming and gives lower melting temperatures than Segretain et al. Observations of WD crystallization in the globular cluster NGC 6397 by Winget et al. suggest that the melting temperature of WD cores is close to that for pure carbon. If this is true, our phase diagram implies that the central oxygen abundance in these stars is less than about 60%. This constraint, along with assumptions about convection in stellar evolution models, limits the effective S factor for the 12C(α,γ)16O reaction to S(300)≤170  keV b.

Acid sphingomyelinase deficiency in Western diet-fed mice protects against adipocyte hypertrophy and diet-induced liver steatosis.

PubMed

Sydor, Svenja; Sowa, Jan-Peter; Megger, Dominik A; Schlattjan, Martin; Jafoui, Sami; Wingerter, Lena; Carpinteiro, Alexander; Baba, Hideo A; Bechmann, Lars P; Sitek, Barbara; Gerken, Guido; Gulbins, Erich; Canbay, Ali

2017-05-01

Alterations in sphingolipid and ceramide metabolism have been associated with various diseases, including nonalcoholic fatty liver disease (NAFLD). Acid sphingomyelinase (ASM) converts the membrane lipid sphingomyelin to ceramide, thereby affecting membrane composition and domain formation. We investigated the ways in which the Asm knockout (Smpd1 -/- ) genotype affects diet-induced NAFLD. Smpd1 -/- mice and wild type controls were fed either a standard or Western diet (WD) for 6 weeks. Liver and adipose tissue morphology and mRNA expression were assessed. Quantitative proteome analysis of liver tissue was performed. Expression of selected genes was quantified in adipose and liver tissue of obese NAFLD patients. Although Smpd1 -/- mice exhibited basal steatosis with normal chow, no aggravation of NAFLD-type injury was observed with a Western diet. This protective effect was associated with the absence of adipocyte hypertrophy and the increased expression of genes associated with brown adipocyte differentiation. In white adipose tissue from obese patients with NAFLD, no expression of these genes was detectable. To further elucidate which pathways in liver tissue may be affected by Smpd1 -/- , we performed an unbiased proteome analysis. Protein expression in WD-fed Smpd1 -/- mice indicated a reduction in Rictor (mTORC2) activity; this reduction was confirmed by diminished Akt phosphorylation and altered mRNA expression of Rictor target genes. These findings indicate that the protective effect of Asm deficiency on diet-induced steatosis is conferred by alterations in adipocyte morphology and lipid metabolism and by reductions in Rictor activation.

Expression, purification and preliminary biochemical and structural characterization of the leucine rich repeat namesake domain of leucine rich repeat kinase 2.

PubMed

Vancraenenbroeck, Renée; Lobbestael, Evy; Weeks, Stephen D; Strelkov, Sergei V; Baekelandt, Veerle; Taymans, Jean-Marc; De Maeyer, Marc

2012-03-01

Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial Parkinson's disease. Much research effort has been directed towards the catalytic core region of LRRK2 composed of GTPase (ROC, Ras of complex proteins) and kinase domains and a connecting COR (C-terminus of ROC) domain. In contrast, the precise functions of the protein-protein interaction domains, such as the leucine-rich repeat (LRR) domain, are not known. In the present study, we modeled the LRRK2 LRR domain (LRR(LRRK2)) using a template assembly approach, revealing the presence of 14 LRRs. Next, we focused on the expression and purification of LRR(LRRK2) in Escherichia coli. Buffer optimization revealed that the protein requires the presence of a zwitterionic detergent, namely Empigen BB, during solubilization and the subsequent purification and characterization steps. This indicates that the detergent captures the hydrophobic surface patches of LRR(LRRK2) thereby suppressing its aggregation. Circular dichroism (CD) spectroscopy measured 18% α-helices and 21% β-sheets, consistent with predictions from the homology model. Size exclusion chromatography (SEC) and dynamic light scattering measurements showed the presence of a single species, with a Stokes radius corresponding to the model dimensions of a protein monomer. Furthermore, no obvious LRR(LRRK2) multimerization was detected via cross-linking studies. Finally, the LRR(LRRK2) clinical mutations did not influence LRR(LRRK2) secondary, tertiary or quaternary structure as determined via SEC and CD spectroscopy. We therefore conclude that these mutations are likely to affect putative LRR(LRRK2) inter- and intramolecular interactions. Copyright © 2011 Elsevier B.V. All rights reserved.

Crystal Structures of the Tetratricopeptide Repeat Domains of Kinesin Light Chains: Insight into Cargo Recognition Mechanisms

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

Zhu, Haizhong; Lee, Han Youl; Tong, Yufeng

Kinesin-1 transports various cargos along the axon by interacting with the cargos through its light chain subunit. Kinesin light chains (KLC) utilize its tetratricopeptide repeat (TPR) domain to interact with over 10 different cargos. Despite a high sequence identity between their TPR domains (87%), KLC1 and KLC2 isoforms exhibit differential binding properties towards some cargos. We determined the structures of human KLC1 and KLC2 tetratricopeptide repeat (TPR) domains using X-ray crystallography and investigated the different mechanisms by which KLCs interact with their cargos. Using isothermal titration calorimetry, we attributed the specific interaction between KLC1 and JNK-interacting protein 1 (JIP1) cargomore » to residue N343 in the fourth TRP repeat. Structurally, the N343 residue is adjacent to other asparagines and lysines, creating a positively charged polar patch within the groove of the TPR domain. Whereas, KLC2 with the corresponding residue S328 did not interact with JIP1. Based on these finding, we propose that N343 of KLC1 can form 'a carboxylate clamp' with its neighboring asparagine to interact with JIP1, similar to that of HSP70/HSP90 organizing protein-1's (HOP1) interaction with heat shock proteins. For the binding of cargos shared by KLC1 and KLC2, we propose a different site located within the groove but not involving N343. We further propose a third binding site on KLC1 which involves a stretch of polar residues along the inter-TPR loops that may form a network of hydrogen bonds to JIP3 and JIP4. Together, these results provide structural insights into possible mechanisms of interaction between KLC TPR domains and various cargo proteins.« less

Disruption rates for one vulnerable soil in Organ Pipe Cactus National Monument, Arizona, USA

USGS Publications Warehouse

Webb, Robert H.; Esque, Todd C.; Nussear, Kenneth E.; Sturm, Mark

2013-01-01

Rates of soil disruption from hikers and vehicle traffic are poorly known, particularly for arid landscapes. We conducted an experiment in Organ Pipe Cactus National Monument (ORPI) in western Arizona, USA, on an air-dry very fine sandy loam that is considered to be vulnerable to disruption. We created variable-pass tracks using hikers, an all-terrain vehicle (ATV), and a four-wheel drive vehicle (4WD) and measured changes in cross-track topography, penetration depth, and bulk density. Hikers (one pass = 5 hikers) increased bulk density and altered penetration depth but caused minimal surface disruption up to 100 passes; a minimum of 10 passes were required to overcome surface strength of this dry soil. Both ATV and 4WD traffic significantly disrupted the soil with one pass, creating deep ruts with increasing passes that rendered the 4WD trail impassable after 20 passes. Despite considerable soil loosening (dilation), bulk density increased in the vehicle trails, and lateral displacement created berms of loosened soil. This soil type, when dry, can sustain up to 10 passes of hikers but only one vehicle pass before significant soil disruption occurs; greater disruption is expected when soils are wet. Bulk density increased logarithmically with applied pressure from hikers, ATV, and 4WD.

Sympathetic network drive during water deprivation does not increase respiratory or cardiac rhythmic sympathetic nerve activity.

PubMed

Holbein, Walter W; Toney, Glenn M

2013-06-15

Effects of water deprivation on rhythmic bursting of sympathetic nerve activity (SNA) were investigated in anesthetized, bilaterally vagotomized, euhydrated (control) and 48-h water-deprived (WD) rats (n = 8/group). Control and WD rats had similar baseline values of mean arterial pressure, heart rate, end-tidal CO2, and central respiratory drive. Although integrated splanchnic SNA (sSNA) was greater in WD rats than controls (P < 0.01), analysis of respiratory rhythmic bursting of sSNA revealed that inspiratory rhythmic burst amplitude was actually smaller (P < 0.005) in WD rats (+68 ± 6%) than controls (+208 ± 20%), and amplitudes of the early expiratory (postinspiratory) trough and late expiratory burst of sSNA were not different between groups. Further analysis revealed that water deprivation had no effect on either the amplitude or periodicity of the cardiac rhythmic oscillation of sSNA. Collectively, these data indicate that the increase of sSNA produced by water deprivation is not attributable to either increased respiratory or cardiac rhythmic burst discharge. Thus the sympathetic network response to acute water deprivation appears to differ from that of chronic sympathoexcitation in neurogenic forms of arterial hypertension, where increased respiratory rhythmic bursting of SNA and baroreflex adaptations have been reported.

Inner Edges of Compact Debris Disks around Metal-rich White Dwarfs

NASA Astrophysics Data System (ADS)

Rafikov, Roman R.; Garmilla, José A.

2012-12-01

A number of metal-rich white dwarfs (WDs) are known to host compact, dense particle disks, which are thought to be responsible for metal pollution of these stars. In many such systems, the inner radii of disks inferred from their spectra are so close to the WD that particles directly exposed to starlight must be heated above 1500 K and are expected to be unstable against sublimation. To reconcile this expectation with observations, we explore particle sublimation in H-poor debris disks around WDs. We show that because of the high metal vapor pressure the characteristic sublimation temperature in these disks is 300-400 K higher than in their protoplanetary analogs, allowing particles to survive at higher temperatures. We then look at the structure of the inner edges of debris disks and show that they should generically feature superheated inner rims directly exposed to starlight with temperatures reaching 2500-3500 K. Particles migrating through the rim toward the WD (and rapidly sublimating) shield the disk behind them from strong stellar heating, making the survival of solids possible close to the WD. Our model agrees well with observations of WD+disk systems provided that disk particles are composed of Si-rich material such as olivine, and have sizes in the range ~0.03-30 cm.

MID-INFRARED SPECTROSCOPIC OBSERVATIONS OF THE DUST-FORMING CLASSICAL NOVA V2676 OPH

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

Kawakita, Hideyo; Arai, Akira; Shinnaka, Yoshiharu

2017-02-01

The dust-forming nova V2676 Oph is unique in that it was the first nova to provide evidence of C{sub 2} and CN molecules during its near-maximum phase and evidence of CO molecules during its early decline phase. Observations of this nova have revealed the slow evolution of its lightcurves and have also shown low isotopic ratios of carbon ({sup 12}C/{sup 13}C) and nitrogen ({sup 14}N/{sup 15}N) in its envelope. These behaviors indicate that the white dwarf (WD) star hosting V2676 Oph is a CO-rich WD rather than an ONe-rich WD (typically larger in mass than the former). We performed mid-infraredmore » spectroscopic and photometric observations of V2676 Oph in 2013 and 2014 (respectively 452 and 782 days after its discovery). No significant [Ne ii] emission at 12.8 μ m was detected at either epoch. These provided evidence for a CO-rich WD star hosting V2676 Oph. Both carbon-rich and oxygen-rich grains were detected in addition to an unidentified infrared feature at 11.4 μ m originating from polycyclic aromatic hydrocarbon molecules or hydrogenated amorphous carbon grains in the envelope of V2676 Oph.« less

Quality-Related Monitoring and Grading of Granulated Products by Weibull-Distribution Modeling of Visual Images with Semi-Supervised Learning.

PubMed

Liu, Jinping; Tang, Zhaohui; Xu, Pengfei; Liu, Wenzhong; Zhang, Jin; Zhu, Jianyong

2016-06-29

The topic of online product quality inspection (OPQI) with smart visual sensors is attracting increasing interest in both the academic and industrial communities on account of the natural connection between the visual appearance of products with their underlying qualities. Visual images captured from granulated products (GPs), e.g., cereal products, fabric textiles, are comprised of a large number of independent particles or stochastically stacking locally homogeneous fragments, whose analysis and understanding remains challenging. A method of image statistical modeling-based OPQI for GP quality grading and monitoring by a Weibull distribution(WD) model with a semi-supervised learning classifier is presented. WD-model parameters (WD-MPs) of GP images' spatial structures, obtained with omnidirectional Gaussian derivative filtering (OGDF), which were demonstrated theoretically to obey a specific WD model of integral form, were extracted as the visual features. Then, a co-training-style semi-supervised classifier algorithm, named COSC-Boosting, was exploited for semi-supervised GP quality grading, by integrating two independent classifiers with complementary nature in the face of scarce labeled samples. Effectiveness of the proposed OPQI method was verified and compared in the field of automated rice quality grading with commonly-used methods and showed superior performance, which lays a foundation for the quality control of GP on assembly lines.

Analysis of heterogeneous gallstones using laser-induced breakdown spectroscopy (LIBS) and wavelength dispersive X-ray fluorescence (WD-XRF).

PubMed

Jaswal, Brij Bir S; Kumar, Vinay; Sharma, Jitendra; Rai, Pradeep K; Gondal, Mohammed A; Gondal, Bilal; Singh, Vivek K

2016-04-01

Laser-induced breakdown spectroscopy (LIBS) is an emerging analytical technique with numerous advantages such as rapidity, multi-elemental analysis, no specific sample preparation requirements, non-destructiveness, and versatility. It has been proven to be a robust elemental analysis tool attracting interest because of being applied to a wide range of materials including biomaterials. In this paper, we have performed spectroscopic studies on gallstones which are heterogeneous in nature using LIBS and wavelength dispersive X-ray fluorescence (WD-XRF) techniques. It has been observed that the presence and relative concentrations of trace elements in different kind of gallstones (cholesterol and pigment gallstones) can easily be determined using LIBS technique. From the experiments carried out on gallstones for trace elemental mapping and detection, it was found that LIBS is a robust tool for such biomedical applications. The stone samples studied in the present paper were classified using the Fourier transform infrared (FTIR) spectroscopy. WD-XRF spectroscopy has been applied for the qualitative and quantitative analysis of major and trace elements present in the gallstone which was compared with the LIBS data. The results obtained in the present paper show interesting prospects for LIBS and WD-XRF to study cholelithiasis better.

Convection Destroys the Core/Mantle Structure in Hybrid C/O/Ne White Dwarfs

NASA Astrophysics Data System (ADS)

Brooks, Jared; Schwab, Josiah; Bildsten, Lars; Quataert, Eliot; Paxton, Bill

2017-01-01

A hybrid C/O/Ne white dwarf (WD)—an unburned C/O core surrounded by an O/Ne/Na mantle—can be formed if the carbon flame is quenched in a super-AGB star or white dwarf merger remnant. We show that this segregated hybrid structure becomes unstable to rapid mixing within 2000 years of the onset of WD cooling. Carbon burning includes a weak reaction that removes electrons, resulting in a lower electron-to-baryon ratio ({Y}{{e}}) in the regions processed by carbon burning compared to the unburned C/O core, making the O/Ne mantle denser than the C/O core as the WD cools. This is unstable to efficient mixing. We use the results of {\\mathtt{MESA}} models with different size C/O cores to quantify the rate at which the cores mix with the mantle as they cool. In all cases, we find that the WDs undergo significant core/mantle mixing on timescales shorter than the time available to grow the WD to the Chandrasekhar mass (MCh) by accretion. As a result, hybrid WDs that reach MCh due to later accretion will have lower central carbon fractions than assumed thus far. We briefly discuss the implications of these results for the possibility of SNe Ia from hybrid WDs.

The Massive CO White Dwarf in the Symbiotic Recurrent Nova RS Ophiuchi

NASA Astrophysics Data System (ADS)

Mikołajewska, Joanna; Shara, Michael M.

2017-10-01

If accreting white dwarfs (WDs) in binary systems are to produce type Ia supernovae (SNe Ia), they must grow to nearly the Chandrasekhar mass and ignite carbon burning. Proving conclusively that a WD has grown substantially since its birth is a challenging task. Slow accretion of hydrogen inevitably leads to the erosion, rather than the growth of WDs. Rapid hydrogen accretion does lead to growth of a helium layer, due to both decreased degeneracy and the inhibition of mixing of the accreted hydrogen with the underlying WD. However, until recently, simulations of helium-accreting WDs all claimed to show the explosive ejection of a helium envelope once it exceeded ˜ {10}-1 {M}⊙ . Because CO WDs cannot be born with masses in excess of ˜ 1.1 {M}⊙ , any such object in excess of ˜ 1.2 {M}⊙ must have grown substantially. We demonstrate that the WD in the symbiotic nova RS Oph is in the mass range 1.2-1.4 M ⊙. We compare UV spectra of RS Oph with those of novae with ONe WDs and with novae erupting on CO WDs. The RS Oph WD is clearly made of CO, demonstrating that it has grown substantially since birth. It is a prime candidate to eventually produce an SN Ia.

V3885 Sagittarius: A Comparison With a Range of Standard Model Accretion Disks

NASA Technical Reports Server (NTRS)

Linnell, Albert P.; Godon, Patrick; Hubeny, Ivan; Sion, Edward M; Szkody, Paula; Barrett, Paul E.

2009-01-01

A chi-squared analysis of standard model accretion disk synthetic spectrum fits to combined Far Ultraviolet Spectroscopic Explorer and Space Telescope Imaging Spectrograph spectra of V3885 Sagittarius, on an absolute flux basis, selects a model that accurately represents the observed spectral energy distribution. Calculation of the synthetic spectrum requires the following system parameters. The cataclysmic variable secondary star period-mass relation calibrated by Knigge in 2006 and 2007 sets the secondary component mass. A mean white dwarf (WD) mass from the same study, which is consistent with an observationally determined mass ratio, sets the adopted WD mass of 0.7M(solar mass), and the WD radius follows from standard theoretical models. The adopted inclination, i = 65 deg, is a literature consensus, and is subsequently supported by chi-squared analysis. The mass transfer rate is the remaining parameter to set the accretion disk T(sub eff) profile, and the Hipparcos parallax constrains that parameter to mas transfer = (5.0 +/- 2.0) x 10(exp -9) M(solar mass)/yr by a comparison with observed spectra. The fit to the observed spectra adopts the contribution of a 57,000 +/- 5000 K WD. The model thus provides realistic constraints on mass transfer and T(sub eff) for a large mass transfer system above the period gap.

VizieR Online Data Catalog: Solar neighborhood. XXXIX. Nearby white dwarfs (Subasavage+, 2017)

NASA Astrophysics Data System (ADS)

Subasavage, J. P.; Jao, W.-C.; Henry, T. J.; Harris, H. C.; Dahn, C. C.; Bergeron, P.; Dufour, P.; Dunlap, B. H.; Barlow, B. N.; Ianna, P. A.; Lepine, S.; Margheim, S. J.

2017-10-01

Standardized photometric observations were carried out at three separate telescopes. The Small & Moderate Aperture Research Telescope System (SMARTS) 0.9m telescope at Cerro Tololo Inter-American Observatory (CTIO) was used during Cerro Tololo Inter-American Observatory Parallax Investigation (CTIOPI) observing runs when conditions were photometric. A Tektronics 2K*2K detector was used in region-of-interest mode centered on the central quarter of the full CCD producing a Field Of View (FOV) of 6.8'*6.8'. The SMARTS 1.0m telescope at CTIO was used with the Y4KCam 4K*4K imager, producing a 19.7'*19.7' FOV. Finally, the Ritchey 40-in telescope at USNO Flagstaff Station (NOFS) was used with a Tektronics 2K*2K detector with a 20.0'*20.0' FOV. Near-infrared JHKs photometry was collected for WD0851-246, at the CTIO 4.0 m Blanco telescope using the NEWFIRM during an engineering night on 2011.27 UT. National Optical Astronomy Observatory (NOAO) Extremely Wide-field Infrared Image (NEWFIRM) is a 4K*4K InSb mosaic that provides a 28'*28' FOV on the Blanco telescope. Additional photometry values were extracted from the Sloan Digital Sky Survey (SDSS) DR12 (Alam et al. 2015, Cat. V/147), 2MASS, and the United Kingdom Infra-Red Telescope (UKIRT) Infrared Sky Survey (UKIDSS) DR9 Large Area Survey (LAS; see Lawrence et al. 2012, Cat. II/319), when available. Two White Dwarfs (WDs) presented here (WD1743-545 and WD2057-493) are newly discovered nearby WDs identified during a spectroscopic survey of WD candidates in the southern hemisphere (J. Subasavage et al. 2017, in preparation) taken from the SUPERBLINK catalog (Lepine & Shara 2015ASPC..493..455S). A third WD included here (WD2307-691) was previously unclassified, yet is a common proper-motion companion to a Hipparcos star within 25pc (HIP114416). A fourth WD (WD2028-171) was suspected to be a WD by the authors based on a trawl of the New Luyten Two Tenths (NLTT) catalog (Luyten 1979, Cat. I/98). Finally, a fifth WD (WD1241-798) was first spectroscopically identified as a WD by Subasavage et al. (2008AJ....136..899S; Paper XX) but with an ambiguous spectral type of DC/DQ. The SOuthern Astrophysical Research (SOAR) 4m telescope with the Goodman spectrograph was used for spectroscopic follow up as part of a larger spectroscopic campaign to identify nearby WDs to be released in a future publication. Observations were taken with a 600 lines-per-mm VPH grating with a 1.0'' slit width to provide 2.1Å resolution in wavelength range of 3600Å-6200Å. Trigonometric parallax data acquisition and reduction techniques for the CTIOPI program are discussed fully in Jao et al. (2005AJ....129.1954J). In brief, the instrument setup and basic data calibrations are identical to those used for photometric observations (i.e., the SMARTS 0.9m telescope coupled with the central quarter of a Tektronics 2K*2K detector). A parallax target's reference field is determined upon first observation. We use one of the Johnson-Kron-Cousins VRI filters, selected to optimize the signal on the PI star and reference stars (the parallax filter), as well as to keep exposure times greater than ~30s and less than ~600s, when possible. Because of a damaged Tek 2 V filter (referred to as oV) that occurred in early 2005, the CTIOPI program used a comparable V filter (referred to as nV) from 2005 to mid-2009. The astrometry is affected by this change because the passbands were slightly different. It was determined empirically that trigonometric parallax determinations are sound if at least ~1-2 years of data are available both before and after the filter switch. However, subtle signals from a perturbing companion would not be reliable. In 2009, it was determined that the crack near the corner of the filter did not impact the FOV of the CTIOPI data, as only the central quarter of the CCD is used. Thus, a switch back to the original V (oV) was completed in mid-2009. U. S. Naval Observatory Flagstaff Station (NOFS) astrometric data have been collected with the Kaj Strand 61-in Astrometric Reflector using three separate CCDs over the multiple decades that NOFS has measured stellar parallaxes. Initially, a Texas Instruments (TI) 800*800 (TI800) CCD, followed by a Tektronics 2048*2048 (Tek2K) CCD, and most recently an EEV (English Electric Valve, now e2v) 2048*4096 (EEV24) CCD were used. The latter two cameras are still in operation at NOFS for astrometric work and were used for all but two of the NOFS parallaxes presented here. The TI800 CCD was used to measure the parallaxes for WD0213+396 and WD1313-198. A total of four filters were used for astrometric work. ST-R (also known as STWIDER) is centered near 700nm with a FWHM of 250nm. A2-1 is an optically flat interference filter centered near 698nm with a FWHM of 172nm. I-2 is an optically flat interference filter centered near 810nm with a FWHM of 191nm. Z-2 is an optically flat 3mm thick piece of Schott RG830 glass that produces a relatively sharp blue-edge cutoff near 830nm and for which the red edge is defined by the CCD sensitivity. More details on the filters can be found in C. Dahn et al. (2017, in preparation). (8 data files).

The 8th and 9th tandem spectrin-like repeats of utrophin cooperatively form a functional unit to interact with polarity-regulating kinase PAR-1b.

PubMed

Yamashita, Kazunari; Suzuki, Atsushi; Satoh, Yoshinori; Ide, Mariko; Amano, Yoshiko; Masuda-Hirata, Maki; Hayashi, Yukiko K; Hamada, Keisuke; Ogata, Kazuhiro; Ohno, Shigeo

2010-01-01

Utrophin is a widely expressed paralogue of dystrophin, the protein responsible for Duchenne muscular dystrophy. Utrophin is a large spectrin-like protein whose C-terminal domain mediates anchorage to a laminin receptor, dystroglycan (DG). The rod domain, composed of 22 spectrin-like repeats, connects the N-terminal actin-binding domain and the C-terminal DG binding domain, and thus mediates molecular linkage between intracellular F-actin and extracellular basement membrane. Previously, we demonstrated that a cell polarity-regulating kinase, PAR-1b, interacts with the utrophin-DG complex, and positively regulates the interaction between utrophin and DG. In this study, we demonstrate that the 8th and 9th spectrin-like repeats (R8 and R9) of utrophin cooperatively form a PAR-1b-interacting domain, and that Ser1258 within R9 is specifically phosphorylated by PAR-1b. Substitution of Ser1258 to alanine reduces the interaction between utrophin and DG, suggesting that the Ser1258 phosphorylation contributes to the stabilization of the utrophin-DG complex. Interestingly, PAR-1b also binds and phosphorylates R8-9 of dystrophin, and colocalizes with dystrophin at the skeletal muscle membrane. These results reveal a novel function of the rod domain of utrophin beyond that of a passive structural linker connecting the N- and C-terminal domain. Copyright 2009 Elsevier Inc. All rights reserved.

Notch intracellular domain deficiency in nuclear localization activity retains the ability to enhance neural stem cell character and block neurogenesis in mammalian brain development.

PubMed

Jang, Jiwon; Byun, Sung-Hyun; Han, Dasol; Lee, Junsub; Kim, Juwan; Lee, Nayeon; Kim, Inhee; Park, Soojeong; Ha, Soobong; Kwon, Mookwang; Ahn, Jyhyun; Chung, Woo-Jae; Kweon, Dae-Hyuk; Cho, Jae Youl; Kim, Sunyoung; Yoon, Keejung

2014-12-01

Notch has a broad range of regulatory functions in many developmental processes, including hematopoiesis, neurogenesis, and angiogenesis. Notch has several key functional regions such as the RBP-Jκ/CBF1 association module (RAM) domain, nuclear localization signals (NLS), and ankyrin (ANK) repeats. However, previous reports assessing the level of importance of these domains in the Notch signaling pathway are controversial. In this study, we have assessed the level of contribution of each Notch domain to the regulation of mammalian neural stem cells in vivo as well as in vitro. Reporter assays and real-time polymerase chain reactions show that the ANK repeats and RAM domain are indispensable to the transactivation of Notch target genes, whereas a nuclear export signal (NES)-fused Notch intracellular domain (NICD) mutant defective in nuclear localization exerts a level of activity comparable to unmodified NICD. Transactivational ability appears to be tightly coupled to Notch functions during brain development. Unlike ANK repeats and RAM domain deletion mutants, NES-NICD recapitulates NICD features such as promotion of astrogenesis at the expense of neurogenesis in vitro and enhancement of neural stem cell character in vivo. Our data support the previous observation that intranuclear localization is not essential to the oncogenesis of Notch1 in certain types of cells and imply the importance of the noncanonical Notch signaling pathway in the regulation of mammalian neural stem cells.