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1

Conservation and Rewiring of Functional Modules Revealed by an Epistasis Map in Fission Yeast  

PubMed Central

An epistasis map (E-MAP) was constructed in the fission yeast, Schizosaccharomyces pombe, by systematically measuring the phenotypes associated with pairs of mutations. This high-density, quantitative genetic interaction map focused on various aspects of chromosome function, including transcription regulation and DNA repair/replication. The E-MAP uncovered a previously unidentified component of the RNA interference (RNAi) machinery (rsh1) and linked the RNAi pathway to several other biological processes. Comparison of the S. pombe E-MAP to an analogous genetic map from the budding yeast revealed that, whereas negative interactions were conserved between genes involved in similar biological processes, positive interactions and overall genetic profiles between pairs of genes coding for physically associated proteins were even more conserved. Hence, conservation occurs at the level of the functional module (protein complex), but the genetic cross talk between modules can differ substantially.

Roguev, Assen; Bandyopadhyay, Sourav; Zofall, Martin; Zhang, Ke; Fischer, Tamas; Collins, Sean R.; Qu, Hongjing; Shales, Michael; Park, Han-Oh; Hayles, Jacqueline; Hoe, Kwang-Lae; Kim, Dong-Uk; Ideker, Trey; Grewal, Shiv I.; Weissman, Jonathan S.; Krogan, Nevan J.

2009-01-01

2

Validation of skeletal muscle cis-regulatory module predictions reveals nucleotide composition bias in functional enhancers.  

PubMed

We performed a genome-wide scan for muscle-specific cis-regulatory modules (CRMs) using three computational prediction programs. Based on the predictions, 339 candidate CRMs were tested in cell culture with NIH3T3 fibroblasts and C2C12 myoblasts for capacity to direct selective reporter gene expression to differentiated C2C12 myotubes. A subset of 19 CRMs validated as functional in the assay. The rate of predictive success reveals striking limitations of computational regulatory sequence analysis methods for CRM discovery. Motif-based methods performed no better than predictions based only on sequence conservation. Analysis of the properties of the functional sequences relative to inactive sequences identifies nucleotide sequence composition can be an important characteristic to incorporate in future methods for improved predictive specificity. Muscle-related TFBSs predicted within the functional sequences display greater sequence conservation than non-TFBS flanking regions. Comparison with recent MyoD and histone modification ChIP-Seq data supports the validity of the functional regions. PMID:22144875

Kwon, Andrew T; Chou, Alice Yi; Arenillas, David J; Wasserman, Wyeth W

2011-12-01

3

Gene-Disease Network Analysis Reveals Functional Modules in Mendelian, Complex and Environmental Diseases  

PubMed Central

Background Scientists have been trying to understand the molecular mechanisms of diseases to design preventive and therapeutic strategies for a long time. For some diseases, it has become evident that it is not enough to obtain a catalogue of the disease-related genes but to uncover how disruptions of molecular networks in the cell give rise to disease phenotypes. Moreover, with the unprecedented wealth of information available, even obtaining such catalogue is extremely difficult. Principal Findings We developed a comprehensive gene-disease association database by integrating associations from several sources that cover different biomedical aspects of diseases. In particular, we focus on the current knowledge of human genetic diseases including mendelian, complex and environmental diseases. To assess the concept of modularity of human diseases, we performed a systematic study of the emergent properties of human gene-disease networks by means of network topology and functional annotation analysis. The results indicate a highly shared genetic origin of human diseases and show that for most diseases, including mendelian, complex and environmental diseases, functional modules exist. Moreover, a core set of biological pathways is found to be associated with most human diseases. We obtained similar results when studying clusters of diseases, suggesting that related diseases might arise due to dysfunction of common biological processes in the cell. Conclusions For the first time, we include mendelian, complex and environmental diseases in an integrated gene-disease association database and show that the concept of modularity applies for all of them. We furthermore provide a functional analysis of disease-related modules providing important new biological insights, which might not be discovered when considering each of the gene-disease association repositories independently. Hence, we present a suitable framework for the study of how genetic and environmental factors, such as drugs, contribute to diseases. Availability The gene-disease networks used in this study and part of the analysis are available at http://ibi.imim.es/DisGeNET/DisGeNETweb.html#Download.

Bauer-Mehren, Anna; Bundschus, Markus; Rautschka, Michael; Mayer, Miguel A.; Sanz, Ferran; Furlong, Laura I.

2011-01-01

4

Conservation and Rewiring of Functional Modules Revealed by an Epistasis Map in Fission Yeast  

Microsoft Academic Search

An epistasis map (E-MAP) was constructed in the fission yeast, Schizosaccharomyces pombe, by systematically measuring the phenotypes associated with pairs of mutations. This high-density, quantitative genetic interaction map focused on various aspects of chromosome function, including transcription regulation and DNA repair\\/replication. The E-MAP uncovered a previously unidentified component of the RNA interference (RNAi) machinery (rsh1) and linked the RNAi pathway

Assen Roguev; Sourav Bandyopadhyay; Martin Zofall; Ke Zhang; Tamas Fischer; Sean R. Collins; Hongjing Qu; Michael Shales; Han-Oh Park; Jacqueline Hayles; Kwang-Lae Hoe; Dong-Uk Kim; Trey Ideker; Shiv I. Grewal; Jonathan S. Weissman; Nevan J. Krogan

2008-01-01

5

Network analysis of genomic alteration profiles reveals co-altered functional modules and driver genes for glioblastoma.  

PubMed

The heterogeneity of genetic alterations in human cancer genomes presents a major challenge to advancing our understanding of cancer mechanisms and identifying cancer driver genes. To tackle this heterogeneity problem, many approaches have been proposed to investigate genetic alterations and predict driver genes at the individual pathway level. However, most of these approaches ignore the correlation of alteration events between pathways and miss many genes with rare alterations collectively contributing to carcinogenesis. Here, we devise a network-based approach to capture the cooperative functional modules hidden in genome-wide somatic mutation and copy number alteration profiles of glioblastoma (GBM) from The Cancer Genome Atlas (TCGA), where a module is a set of altered genes with dense interactions in the protein interaction network. We identify 7 pairs of significantly co-altered modules that involve the main pathways known to be altered in GBM (TP53, RB and RTK signaling pathways) and highlight the striking co-occurring alterations among these GBM pathways. By taking into account the non-random correlation of gene alterations, the property of co-alteration could distinguish oncogenic modules that contain driver genes involved in the progression of GBM. The collaboration among cancer pathways suggests that the redundant models and aggravating models could shed new light on the potential mechanisms during carcinogenesis and provide new indications for the design of cancer therapeutic strategies. PMID:23344900

Gu, Yunyan; Wang, Hongwei; Qin, Yao; Zhang, Yujing; Zhao, Wenyuan; Qi, Lishuang; Zhang, Yuannv; Wang, Chenguang; Guo, Zheng

2013-01-23

6

Spectral modulation masking patterns reveal tuning to spectral envelope frequency.  

PubMed

Auditory processing appears to include a series of domain-specific filtering operations that include tuning in the audio-frequency domain, followed by tuning in the temporal modulation domain, and perhaps tuning in the spectral modulation domain. To explore the possibility of tuning in the spectral modulation domain, a masking experiment was designed to measure masking patterns in the spectral modulation domain. Spectral modulation transfer functions (SMTFs) were measured for modulation frequencies from 0.25 to 14 cycles/octave superimposed on noise carriers either one octave (800-1600 Hz, 6400-12,800 Hz) or six octaves wide (200-12,800 Hz). The resulting SMTFs showed maximum sensitivity to modulation between 1 and 3 cycles/octave with reduced sensitivity above and below this region. Masked spectral modulation detection thresholds were measured for masker modulation frequencies of 1, 3, and 5 cycles/octave with a fixed modulation depth of 15 dB. The masking patterns obtained for each masker frequency and carrier band revealed tuning (maximum masking) near the masker frequency, which is consistent with the theory that spectral envelope perception is governed by a series of spectral modulation channels tuned to different spectral modulation frequencies. PMID:17672648

Saoji, Aniket A; Eddins, David A

2007-08-01

7

In silico screening reveals structurally diverse, nanomolar inhibitors of NQO2 that are functionally active in cells and can modulate NF?B signalling  

PubMed Central

The NCI chemical database has been screened using in silico docking to identify novel nanomolar inhibitors of NRH:quinone oxidoreductase 2 (NQO2). The inhibitors identified from the screen exhibit a diverse range of scaffolds and the structure of one of the inhibitors, NSC13000 co-crystalized with NQO2, has been solved. This has been used to aid the generation of a structure/activity relationship between the computationally derived binding affinity and experimentally measured enzyme inhibitory potency. Many of the compounds are functionally active as inhibitors of NQO2 in cells at non toxic concentrations. To demonstrate this, advantage was taken of the NQO2-mediated toxicity of the chemotherapeutic drug CB1954. The toxicity of this drug is substantially reduced when the function of NQO2 is inhibited and many of the compounds achieve this in cells at nanomolar concentrations. The NQO2 inhibitors also attenuated TNF?-mediated, NF?B-driven transcriptional activity. The link between NQO2 and the regulation of NF?B was confirmed by using siRNA to NQO2 and by the observation that NRH, the cofactor for NQO2 enzyme activity, could regulate NF?B activity in an NQO2 dependent manner. NF?B is a potential therapeutic target and this study reveals an underlying mechanism that may exploitable for developing new anti-cancer drugs.

Nolan, Karen A.; Dunstan, Mark S.; Caraher, Mary C.; Scott, Katherine A.; Leys, David; Stratford, Ian J.

2011-01-01

8

Histamine modulates microglia function  

PubMed Central

Background Histamine is commonly acknowledged as an inflammatory mediator in peripheral tissues, leaving its role in brain immune responses scarcely studied. Therefore, our aim was to uncover the cellular and molecular mechanisms elicited by this molecule and its receptors in microglia-induced inflammation by evaluating cell migration and inflammatory mediator release. Methods Firstly, we detected the expression of all known histamine receptor subtypes (H1R, H2R, H3R and H4R), using a murine microglial cell line and primary microglia cell cultures from rat cortex, by real-time PCR analysis, immunocytochemistry and Western blotting. Then, we evaluated the role of histamine in microglial cell motility by performing scratch wound assays. Results were further confirmed using murine cortex explants. Finally, interleukin-1beta (IL-1?) and tumor necrosis factor-alpha (TNF-?) levels were evaluated by ELISA measurements to determine the role of histamine on the release of these inflammatory mediators. Results After 12 h of treatment, 100 ?M histamine and 10 ?g/ml histamine-loaded poly (lactic-co-glycolic acid) microparticles significantly stimulated microglia motility via H4R activation. In addition, migration involves ?5?1 integrins, and p38 and Akt signaling pathways. Migration of microglial cells was also enhanced in the presence of lipopolysaccharide (LPS, 100 ng/ml), used as a positive control. Importantly, histamine inhibited LPS-stimulated migration via H4R activation. Histamine or H4R agonist also inhibited LPS-induced IL-1? release in both N9 microglia cell line and hippocampal organotypic slice cultures. Conclusions To our knowledge, we are the first to show a dual role of histamine in the modulation of microglial inflammatory responses. Altogether, our data suggest that histamine per se triggers microglia motility, whereas histamine impedes LPS-induced microglia migration and IL-1? release. This last datum assigns a new putative anti-inflammatory role for histamine, acting via H4R to restrain exacerbated microglial responses under inflammatory challenge, which could have strong repercussions in the treatment of CNS disorders accompanied by microglia-derived inflammation.

2012-01-01

9

Triangular Clique Based Multilevel Approaches to Identify Protein Functional Modules  

Microsoft Academic Search

Identifying functional modules is believed to reveal most cellular processes. There have been many computational approaches to investigate the underlying biological structures (1, 5, 10, 13). A spectral clustering method plays a critical role identifying functional modules in a yeast protein-protein network in (10). One of major obstacles clustering algorithms face and deal with is the limited information on how

S. Oliveira; S. C. Seok

2006-01-01

10

Time-resolved metabolomics reveals metabolic modulation in rice foliage  

PubMed Central

Background To elucidate the interaction of dynamics among modules that constitute biological systems, comprehensive datasets obtained from "omics" technologies have been used. In recent plant metabolomics approaches, the reconstruction of metabolic correlation networks has been attempted using statistical techniques. However, the results were unsatisfactory and effective data-mining techniques that apply appropriate comprehensive datasets are needed. Results Using capillary electrophoresis mass spectrometry (CE-MS) and capillary electrophoresis diode-array detection (CE-DAD), we analyzed the dynamic changes in the level of 56 basic metabolites in plant foliage (Oryza sativa L. ssp. japonica) at hourly intervals over a 24-hr period. Unsupervised clustering of comprehensive metabolic profiles using Kohonen's self-organizing map (SOM) allowed classification of the biochemical pathways activated by the light and dark cycle. The carbon and nitrogen (C/N) metabolism in both periods was also visualized as a phenotypic linkage map that connects network modules on the basis of traditional metabolic pathways rather than pairwise correlations among metabolites. The regulatory networks of C/N assimilation/dissimilation at each time point were consistent with previous works on plant metabolism. In response to environmental stress, glutathione and spermidine fluctuated synchronously with their regulatory targets. Adenine nucleosides and nicotinamide coenzymes were regulated by phosphorylation and dephosphorylation. We also demonstrated that SOM analysis was applicable to the estimation of unidentifiable metabolites in metabolome analysis. Hierarchical clustering of a correlation coefficient matrix could help identify the bottleneck enzymes that regulate metabolic networks. Conclusion Our results showed that our SOM analysis with appropriate metabolic time-courses effectively revealed the synchronous dynamics among metabolic modules and elucidated the underlying biochemical functions. The application of discrimination of unidentified metabolites and the identification of bottleneck enzymatic steps even to non-targeted comprehensive analysis promise to facilitate an understanding of large-scale interactions among components in biological systems.

Sato, Shigeru; Arita, Masanori; Soga, Tomoyoshi; Nishioka, Takaaki; Tomita, Masaru

2008-01-01

11

NPARC Turbulence Module with Wall Functions.  

National Technical Information Service (NTIS)

The turbulence module recently developed for the NPARC code has been extended to include wall functions. The Van Driest transformation is used so that the wall functions can be applied to both incompressible and compressible flows. The module is equipped ...

J. Zhu T. H. Shih

1997-01-01

12

A rare variant in the osteoarthritis-associated locus GDF5 is functional and reveals a site that can be manipulated to modulate GDF5 expression.  

PubMed

Osteoarthritis (OA) is a polygenic disease characterized by cartilage loss, with the single-nucleotide polymorphism (SNP) rs143383 (C/T) influencing OA susceptibility across a range of ethnic groups. The SNP resides within the 5'-UTR of the growth and differentiation factor 5 gene (GDF5), with the OA-associated T-allele mediating reduced GDF5 expression. As GDF5 codes for a cartilage anabolic protein, this reduced expression may explain why the T-allele of rs143383 is an OA risk factor. Our deep sequencing of GDF5 identified a C/A transversion located -41?bp relative to the gene's transcription start site. This promoter variant is predicted to affect transcription factor binding and it may therefore highlight a regulatory site that could be exploited to manipulate GDF5 expression and alleviate the detrimental effect mediated by the T-allele of rs143383. Here, we describe our functional assessment of the -41?bp variant. Using reporter constructs we demonstrated that the transversion leads to increased gene expression to such a degree that the A-allele is able to compensate for the reduced expression mediated by the T-allele of rs143383. Using electrophoretic mobility shift assays we identified YY1 as a trans-acting factor that differentially binds to the alleles of the -41?bp variant, with more avid binding to allele A. Knockdown of YY1 led to a significant reduction in GDF5 expression, supporting YY1 as a GDF5 activator. In conclusion, we demonstrated that the -41?bp variant is functional and we have identified a regulatory region of GDF5 that can be exploited to overcome the OA genetic deficit mediated by the T-allele of rs143383. PMID:22929025

Dodd, Andrew W; Syddall, Catherine M; Loughlin, John

2012-08-29

13

A rare variant in the osteoarthritis-associated locus GDF5 is functional and reveals a site that can be manipulated to modulate GDF5 expression  

PubMed Central

Osteoarthritis (OA) is a polygenic disease characterized by cartilage loss, with the single-nucleotide polymorphism (SNP) rs143383 (C/T) influencing OA susceptibility across a range of ethnic groups. The SNP resides within the 5?-UTR of the growth and differentiation factor 5 gene (GDF5), with the OA-associated T-allele mediating reduced GDF5 expression. As GDF5 codes for a cartilage anabolic protein, this reduced expression may explain why the T-allele of rs143383 is an OA risk factor. Our deep sequencing of GDF5 identified a C/A transversion located ?41?bp relative to the gene's transcription start site. This promoter variant is predicted to affect transcription factor binding and it may therefore highlight a regulatory site that could be exploited to manipulate GDF5 expression and alleviate the detrimental effect mediated by the T-allele of rs143383. Here, we describe our functional assessment of the ?41?bp variant. Using reporter constructs we demonstrated that the transversion leads to increased gene expression to such a degree that the A-allele is able to compensate for the reduced expression mediated by the T-allele of rs143383. Using electrophoretic mobility shift assays we identified YY1 as a trans-acting factor that differentially binds to the alleles of the ?41?bp variant, with more avid binding to allele A. Knockdown of YY1 led to a significant reduction in GDF5 expression, supporting YY1 as a GDF5 activator. In conclusion, we demonstrated that the ?41?bp variant is functional and we have identified a regulatory region of GDF5 that can be exploited to overcome the OA genetic deficit mediated by the T-allele of rs143383.

Dodd, Andrew W; Syddall, Catherine M; Loughlin, John

2013-01-01

14

Functional and structural studies of the disulfide isomerase DsbC from the plant pathogen Xylella fastidiosa reveals a redox-dependent oligomeric modulation in vitro.  

PubMed

Xylella fastidiosa is a Gram-negative bacterium that grows as a biofilm inside the xylem vessels of susceptible plants and causes several economically relevant crop diseases. In the present study, we report the functional and low-resolution structural characterization of the X. fastidiosa disulfide isomerase DsbC (XfDsbC). DsbC is part of the disulfide bond reduction/isomerization pathway in the bacterial periplasm and plays an important role in oxidative protein folding. In the present study, we demonstrate the presence of XfDsbC during different stages of X. fastidiosa biofilm development. XfDsbC was not detected during X. fastidiosa planktonic growth; however, after administering a sublethal copper shock, we observed an overexpression of XfDsbC that also occurred during planktonic growth. These results suggest that X. fastidiosa can use XfDsbC in vivo under oxidative stress conditions similar to those induced by copper. In addition, using dynamic light scattering and small-angle X-ray scattering, we observed that the oligomeric state of XfDsbC in vitro may be dependent on the redox environment. Under reducing conditions, XfDsbC is present as a dimer, whereas a putative tetrameric form was observed under nonreducing conditions. Taken together, our findings demonstrate the overexpression of XfDsbC during biofilm formation and provide the first structural model of a bacterial disulfide isomerase in solution. PMID:22889056

Santos, Clelton A; Toledo, Marcelo A S; Trivella, Daniela B B; Beloti, Lilian L; Schneider, Dilaine R S; Saraiva, Antonio M; Crucello, Aline; Azzoni, Adriano R; Souza, Alessandra A; Aparicio, Ricardo; Souza, Anete P

2012-09-07

15

Perilymph Osmolality Modulates Cochlear Function  

PubMed Central

Objectives/Hypothesis The cochlear amplifier is required for the exquisite sensitivity of mammalian hearing. Outer hair cells underlie the cochlear amplifier and they are unique in that they maintain an intracellular turgor pressure. Changing the turgor pressure of an isolated outer hair cells through osmotic challenge modulates its ability to produce electromotile force. We sought to determine the effect of osmotic challenge on cochlear function. Study Design In vivo animal study. Methods Hypotonic and hypertonic artificial perilymph was perfused through the scala tympani of anesthetized guinea pigs. Cochlear function was assessed by measuring the compound action potential, distortion product otoacoustic emissions, the cochlear microphonic, and the endocochlear potential. Results Hypotonic perilymph decreased and hypertonic perilymph increased compound action potential and distortion product otoacoustic emission thresholds in a dose-dependent and reversible manner. The cochlear microphonic quadratic distortion product magnitude increased after hypotonic perfusion and decreased with hypertonic perfusion. There were no changes in the stimulus intensity growth curve of the low-frequency cochlear microphonic. The endocochlear potential was not affected by perilymph osmolality. Conclusions These data demonstrate that perilymph osmolality can modulate cochlear function and are consistent with what would be expected if outer hair cells turgor pressure changes the gain of the cochlear amplifier in vivo.

Choi, Chul-Hee; Oghalai, John S.

2013-01-01

16

The Modulation Transfer Function for Speech Intelligibility  

PubMed Central

We systematically determined which spectrotemporal modulations in speech are necessary for comprehension by human listeners. Speech comprehension has been shown to be robust to spectral and temporal degradations, but the specific relevance of particular degradations is arguable due to the complexity of the joint spectral and temporal information in the speech signal. We applied a novel modulation filtering technique to recorded sentences to restrict acoustic information quantitatively and to obtain a joint spectrotemporal modulation transfer function for speech comprehension, the speech MTF. For American English, the speech MTF showed the criticality of low modulation frequencies in both time and frequency. Comprehension was significantly impaired when temporal modulations <12 Hz or spectral modulations <4 cycles/kHz were removed. More specifically, the MTF was bandpass in temporal modulations and low-pass in spectral modulations: temporal modulations from 1 to 7 Hz and spectral modulations <1 cycles/kHz were the most important. We evaluated the importance of spectrotemporal modulations for vocal gender identification and found a different region of interest: removing spectral modulations between 3 and 7 cycles/kHz significantly increases gender misidentifications of female speakers. The determination of the speech MTF furnishes an additional method for producing speech signals with reduced bandwidth but high intelligibility. Such compression could be used for audio applications such as file compression or noise removal and for clinical applications such as signal processing for cochlear implants.

Elliott, Taffeta M.; Theunissen, Frederic E.

2009-01-01

17

Modulation of phagocytic cell function  

Microsoft Academic Search

Phagocytosis is an important factor in the defense of the host against all kinds of microorganisms. The process of phagocytosis of microorganisms by phagocytes can be separated into distinct but interrelated phases: adherence, chemotaxis, opsonization, attachment, ingestion, degranulation and killing. Phagocytosis is accompanied by an increase in oxygen metabolism in which H2O2 and activated oxygen species are generated. Modulation of

P. A. J. Henricks; J. Verhoef; F. P. Nijkamp

1986-01-01

18

Adrenal steroids as modulators of nerve cell function  

Microsoft Academic Search

Adrenal steroids modulate the function of nerve cells. Some, but not all actions of these steroids take place after binding to intracellular receptor systems and translocation of the steroid-receptor complex into the cell nucleus. Studies on the rat brain revealed heterogeneity of receptors. One population of receptor sites is present in abundance in extrahypothalamic limbic brain regions, e.g. neurons of

E. R. de Kloet

1984-01-01

19

Revealing electron delocalization through the source function.  

PubMed

The source function (SF) introduced in late 90s by Bader and Gatti quantifies the influence of each atom in a system in determining the amount of electron density at a given point, regardless of the atom's remote or close location with respect to the point. The SF may thus be attractive for studying directly in the real space somewhat elusive molecular properties, such as "electron conjugation" and "aromaticity", that lack rigorous definitions as they are not directly associated to quantum-mechanical observables. In this work, the results of a preliminary test aimed at understanding whether the SF descriptor is capable to reveal electron delocalization effects are corroborated by further examination of the previously investigated benzene, 1,3-cyclohexadiene, and cyclohexene series and by extending the analysis to some benchmark organic systems with different unsaturated bond patterns. The SF can actually reveal, order, and quantify ?-electron delocalization effects for formal double, single conjugated, and allylic bonds, in terms of the influence of distant atoms on the electron density at given bond critical points. In polycyclic aromatic hydrocarbons, the SF neatly reveals the mutual influence of the benzenoid subunits. In naphthalene it provides a rationale for the changes observed in the local aromatic character of one ring when the other is partially hydrogenated. The SF analysis describes instead biphenyl as made up by two weakly interacting benzene rings, only slightly perturbed by the combination of mutual steric and electronic effects. Eventually, a new SF-based indicator of local aromaticity is introduced, which shows excellent correlation with the aromatic index developed by Matta and Hernández-Trujillo, based on the delocalization indices. At variance with this latter and other commonly employed quantum-mechanical (local) aromaticity descriptors, the SF-based indicator does not require the knowledge of the pair density, nor the system wave function, being therefore promising for applications to experimentally derived charge density distributions. PMID:21761863

Monza, Emanuele; Gatti, Carlo; Lo Presti, Leonardo; Ortoleva, Emanuele

2011-07-15

20

Caffeine Modulates Attention Network Function.  

National Technical Information Service (NTIS)

The present work investigated the effects of caffeine (0 mg, 100 mg, 200 mg, 400 mg) on a flanker task designed to test Posner's three visual attention network functions: alerting, orienting, and executive control Posner, M. I. (2004). Cognitive Neuroscie...

C. R. Mahoney H. A. Tyalor H. R. Lieberman T. T. Brunye

2010-01-01

21

Quantification of Cell Edge Velocities and Traction Forces Reveals Distinct Motility Modules during Cell Spreading  

PubMed Central

Actin-based cell motility and force generation are central to immune response, tissue development, and cancer metastasis, and understanding actin cytoskeleton regulation is a major goal of cell biologists. Cell spreading is a commonly used model system for motility experiments – spreading fibroblasts exhibit stereotypic, spatially-isotropic edge dynamics during a reproducible sequence of functional phases: 1) During early spreading, cells form initial contacts with the surface. 2) The middle spreading phase exhibits rapidly increasing attachment area. 3) Late spreading is characterized by periodic contractions and stable adhesions formation. While differences in cytoskeletal regulation between phases are known, a global analysis of the spatial and temporal coordination of motility and force generation is missing. Implementing improved algorithms for analyzing edge dynamics over the entire cell periphery, we observed that a single domain of homogeneous cytoskeletal dynamics dominated each of the three phases of spreading. These domains exhibited a unique combination of biophysical and biochemical parameters – a motility module. Biophysical characterization of the motility modules revealed that the early phase was dominated by periodic, rapid membrane blebbing; the middle phase exhibited continuous protrusion with very low traction force generation; and the late phase was characterized by global periodic contractions and high force generation. Biochemically, each motility module exhibited a different distribution of the actin-related protein VASP, while inhibition of actin polymerization revealed different dependencies on barbed-end polymerization. In addition, our whole-cell analysis revealed that many cells exhibited heterogeneous combinations of motility modules in neighboring regions of the cell edge. Together, these observations support a model of motility in which regions of the cell edge exhibit one of a limited number of motility modules that, together, determine the overall motility function. Our data and algorithms are publicly available to encourage further exploration.

Cai, Yunfei; Xenias, Harry; Spielman, Ingrid; Shneidman, Anna V.; David, Lawrence A.; Dobereiner, Hans-Gunther; Wiggins, Chris H.; Sheetz, Michael P.

2008-01-01

22

Caffeine modulates attention network function.  

PubMed

The present work investigated the effects of caffeine (0mg, 100mg, 200mg, 400mg) on a flanker task designed to test Posner's three visual attention network functions: alerting, orienting, and executive control [Posner, M. I. (2004). Cognitive neuroscience of attention. New York, NY: Guilford Press]. In a placebo-controlled, double-blind study using a repeated-measures design, we found that the effects of caffeine on visual attention vary as a function of dose and the attention network under examination. Caffeine improved alerting and executive control function in a dose-response manner, asymptoting at 200mg; this effect is congruent with caffeine's adenosine-mediated effects on dopamine-rich areas of brain, and the involvement of these areas in alerting and the executive control of visual attention. Higher doses of caffeine also led to a marginally less efficient allocation of visual attention towards cued regions during task performance (i.e., orienting). Taken together, results of this study demonstrate that caffeine has differential effects on visual attention networks as a function of dose, and such effects have implications for hypothesized interactions of caffeine, adenosine and dopamine in brain areas mediating visual attention. PMID:19733954

Brunyé, Tad T; Mahoney, Caroline R; Lieberman, Harris R; Taylor, Holly A

2009-09-05

23

Caffeine Modulates Attention Network Function  

ERIC Educational Resources Information Center

|The present work investigated the effects of caffeine (0 mg, 100 mg, 200 mg, 400 mg) on a flanker task designed to test Posner's three visual attention network functions: alerting, orienting, and executive control [Posner, M. I. (2004). "Cognitive neuroscience of attention". New York, NY: Guilford Press]. In a placebo-controlled, double-blind…

Brunye, Tad T.; Mahoney, Caroline R.; Lieberman, Harris R.; Taylor, Holly A.

2010-01-01

24

Discovery of novel allosteric modulators of metabotropic glutamate receptor subtype 5 reveals chemical and functional diversity and in vivo activity in rat behavioral models of anxiolytic and antipsychotic activity.  

PubMed

Modulators of metabotropic glutamate receptor subtype 5 (mGluR5) may provide novel treatments for multiple central nervous system (CNS) disorders, including anxiety and schizophrenia. Although compounds have been developed to better understand the physiological roles of mGluR5 and potential usefulness for the treatment of these disorders, there are limitations in the tools available, including poor selectivity, low potency, and limited solubility. To address these issues, we developed an innovative assay that allows simultaneous screening for mGluR5 agonists, antagonists, and potentiators. We identified multiple scaffolds that possess diverse modes of activity at mGluR5, including both positive and negative allosteric modulators (PAMs and NAMs, respectively). 3-Fluoro-5-(3-(pyridine-2-yl)-1,2,4-oxadiazol-5-yl)benzonitrile (VU0285683) was developed as a novel selective mGluR5 NAM with high affinity for the 2-methyl-6-(phenylethynyl)-pyridine (MPEP) binding site. VU0285683 had anxiolytic-like activity in two rodent models for anxiety but did not potentiate phencyclidine-induced hyperlocomotor activity. (4-Hydroxypiperidin-1-yl)(4-phenylethynyl)phenyl)methanone (VU0092273) was identified as a novel mGluR5 PAM that also binds to the MPEP site. VU0092273 was chemically optimized to an orally active analog, N-cyclobutyl-6-((3-fluorophenyl)ethynyl)nicotinamide hydrochloride (VU0360172), which is selective for mGluR5. This novel mGluR5 PAM produced a dose-dependent reversal of amphetamine-induced hyperlocomotion, a rodent model predictive of antipsychotic activity. Discovery of structurally and functionally diverse allosteric modulators of mGluR5 that demonstrate in vivo efficacy in rodent models of anxiety and antipsychotic activity provide further support for the tremendous diversity of chemical scaffolds and modes of efficacy of mGluR5 ligands. In addition, these studies provide strong support for the hypothesis that multiple structurally distinct mGluR5 modulators have robust activity in animal models that predict efficacy in the treatment of CNS disorders. PMID:20923853

Rodriguez, Alice L; Grier, Mark D; Jones, Carrie K; Herman, Elizabeth J; Kane, Alexander S; Smith, Randy L; Williams, Richard; Zhou, Ya; Marlo, Joy E; Days, Emily L; Blatt, Tasha N; Jadhav, Satyawan; Menon, Usha N; Vinson, Paige N; Rook, Jerri M; Stauffer, Shaun R; Niswender, Colleen M; Lindsley, Craig W; Weaver, C David; Conn, P Jeffrey

2010-10-05

25

Discovery of Novel Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 5 Reveals Chemical and Functional Diversity and In Vivo Activity in Rat Behavioral Models of Anxiolytic and Antipsychotic ActivityS?  

PubMed Central

Modulators of metabotropic glutamate receptor subtype 5 (mGluR5) may provide novel treatments for multiple central nervous system (CNS) disorders, including anxiety and schizophrenia. Although compounds have been developed to better understand the physiological roles of mGluR5 and potential usefulness for the treatment of these disorders, there are limitations in the tools available, including poor selectivity, low potency, and limited solubility. To address these issues, we developed an innovative assay that allows simultaneous screening for mGluR5 agonists, antagonists, and potentiators. We identified multiple scaffolds that possess diverse modes of activity at mGluR5, including both positive and negative allosteric modulators (PAMs and NAMs, respectively). 3-Fluoro-5-(3-(pyridine-2-yl)-1,2,4-oxadiazol-5-yl)benzonitrile (VU0285683) was developed as a novel selective mGluR5 NAM with high affinity for the 2-methyl-6-(phenylethynyl)-pyridine (MPEP) binding site. VU0285683 had anxiolytic-like activity in two rodent models for anxiety but did not potentiate phencyclidine-induced hyperlocomotor activity. (4-Hydroxypiperidin-1-yl)(4-phenylethynyl)phenyl)methanone (VU0092273) was identified as a novel mGluR5 PAM that also binds to the MPEP site. VU0092273 was chemically optimized to an orally active analog, N-cyclobutyl-6-((3-fluorophenyl)ethynyl)nicotinamide hydrochloride (VU0360172), which is selective for mGluR5. This novel mGluR5 PAM produced a dose-dependent reversal of amphetamine-induced hyperlocomotion, a rodent model predictive of antipsychotic activity. Discovery of structurally and functionally diverse allosteric modulators of mGluR5 that demonstrate in vivo efficacy in rodent models of anxiety and antipsychotic activity provide further support for the tremendous diversity of chemical scaffolds and modes of efficacy of mGluR5 ligands. In addition, these studies provide strong support for the hypothesis that multiple structurally distinct mGluR5 modulators have robust activity in animal models that predict efficacy in the treatment of CNS disorders.

Rodriguez, Alice L.; Grier, Mark D.; Jones, Carrie K.; Herman, Elizabeth J.; Kane, Alexander S.; Smith, Randy L.; Williams, Richard; Zhou, Ya; Marlo, Joy E.; Days, Emily L.; Blatt, Tasha N.; Jadhav, Satyawan; Menon, Usha N.; Vinson, Paige N.; Rook, Jerri M.; Stauffer, Shaun R.; Niswender, Colleen M.; Lindsley, Craig W.; Weaver, C. David

2010-01-01

26

A Matrix-based Multilevel Approach to Identify Functional Protein Modules  

Microsoft Academic Search

Identifying functional modules is believed to reveal most cellular processes. There have been many computational approaches to investigate the underlying biological structures (2, 6, 15, 19, 22, 23). A spectral clustering method plays a critical role identifying functional modules in a yeast protein-protein network (19). We present an unweighted- graph version of a multilevel spectral algorithm which more accurately identies

Suely Oliveira; Sang-Cheol Seok

27

Functional analysis in Arabidopsis of FsPTP1, a tyrosine phosphatase from beechnuts, reveals its role as a negative regulator of ABA signaling and seed dormancy and suggests its involvement in ethylene signaling modulation.  

PubMed

By means of an RT-PCR approach we isolated a specific tyrosine phosphatase (FsPTP1) induced by abscisic acid (ABA) and correlated with seed dormancy in Fagus sylvatica seeds. To provide genetic evidence of FsPTP1 function in seed dormancy and ABA signal transduction pathway, we overexpressed this gene in Cape Verde Island ecotype of Arabidopsis thaliana, which shows the deepest degree of seed dormancy among Arabidopsis accessions. As a result, 35S:FsPTP1 transgenic seeds showed a reduced dormancy and insensitivity to ABA and osmotic stress conditions accompanied by a reduction in the level of expression of RAB18 and RD29, well-known ABA-responsive genes. Taken together, all these data are consistent with a role of this tyrosine phosphatase as a negative regulator of ABA signaling. In addition, phenotypes of FsPTP1 transgenic plants resemble those observed in ethylene constitutive mutants, accompanied by an increase in the level of expression of a key gene involved in ethylene signaling such as EIN2. All the data presented along the paper suggest that the effect of tyrosine phosphatases in ABA action during the transition from seed dormancy to germination may be through modulation of ethylene signaling. PMID:21567167

Alonso-Ramírez, Ana; Rodríguez, Dolores; Reyes, David; Jiménez, Jesús A; Nicolás, Gregorio; Nicolás, Carlos

2011-05-13

28

Multifunctional ferromagnetic disks for modulating cell function.  

PubMed

In this work, we focus on the methods for controlling cell function with ferromagnetic disk-shaped particles. We will first review the history of magnetically assisted modulation of cell behavior and applications of magnetic particles for studying physical properties of a cell. Then, we consider the biological applications of the microdisks such as the method for induction of cancer cell apoptosis, controlled drug release, hyperthermia and MRI imaging. PMID:23766544

Vitol, Elina A; Novosad, Valentyn; Rozhkova, Elena A

2012-11-01

29

Multifunctional ferromagnetic disks for modulating cell function  

PubMed Central

In this work, we focus on the methods for controlling cell function with ferromagnetic disk-shaped particles. We will first review the history of magnetically assisted modulation of cell behavior and applications of magnetic particles for studying physical properties of a cell. Then, we consider the biological applications of the microdisks such as the method for induction of cancer cell apoptosis, controlled drug release, hyperthermia and MRI imaging.

Vitol, Elina A.; Novosad, Valentyn; Rozhkova, Elena A.

2013-01-01

30

Knock-out models reveal new aquaporin functions.  

PubMed

Knockout mice have been informative in the discovery of unexpected biological functions of aquaporins. Knockout mice have confirmed the predicted roles of aquaporins in transepithelial fluid transport, as in the urinary concentrating mechanism and glandular fluid secretion. A less obvious, though predictable role of aquaporins is in tissue swelling under stress, as in the brain in stroke, tumor and infection. Phenotype analysis of aquaporin knockout mice has revealed several unexpected cellular roles of aquaporins whose mechanisms are being elucidated. Aquaporins facilitate cell migration, as seen in aquaporin-dependent tumor angiogenesis and tumor metastasis, by a mechanism that may involve facilitated water transport in lamellipodia of migrating cells. The ' aquaglyceroporins', aquaporins that transport both glycerol and water, regulate glycerol content in epidermis, fat and other tissues, and lead to a multiplicity of interesting consequences of gene disruption including dry skin, resistance to skin carcinogenesis, impaired cell proliferation and altered fat metabolism. An even more surprising role of a mammalian aquaporin is in neural signal transduction in the central nervous system. The many roles of aquaporins might be exploited for clinical benefit by modulation of aquaporin expression/function - as diuretics, and in the treatment of brain swelling, glaucoma, epilepsy, obesity and cancer. PMID:19096787

Verkman, Alan S

2009-01-01

31

Modulation transfer functions at Ka band  

NASA Astrophysics Data System (ADS)

The modulation transfer function (MTF) is often used to describe the modulation of the radar signal by the long waves. MTFs were measured at 35 GHz (Ka band) with a switched-beam vector slope gauge/scatterometer on the research platform NORDSEE as part of the SAXON-FPN experiment. Three independent measurements of the scattering were available for each height measurement. This provided the opportunity to average the time series to reduce the effects of fading noise and sea spikes, or, alternatively, to append the time series to achieve more degrees of freedom in the spectral estimates. For upwind measurements, the phase of the VV-polarized Ka-band MTF was always positive, which implies that the maximum of the radar return originates from the forward face of the long-scale waves. This phase increases with increasing wind speed. The magnitude of the MTF decreases with increasing wind speed.

Hesany, Vahid; Sistani, Bita; Salam, Asif; Haimov, Samuel; Gogineni, Prasad; Moore, Richard K.

32

Hierarchical structure and modules in the Escherichia coli transcriptional regulatory network revealed by a new top-down approach  

PubMed Central

Background Cellular functions are coordinately carried out by groups of genes forming functional modules. Identifying such modules in the transcriptional regulatory network (TRN) of organisms is important for understanding the structure and function of these fundamental cellular networks and essential for the emerging modular biology. So far, the global connectivity structure of TRN has not been well studied and consequently not applied for the identification of functional modules. Moreover, network motifs such as feed forward loop are recently proposed to be basic building blocks of TRN. However, their relationship to functional modules is not clear. Results In this work we proposed a top-down approach to identify modules in the TRN of E. coli. By studying the global connectivity structure of the regulatory network, we first revealed a five-layer hierarchical structure in which all the regulatory relationships are downward. Based on this regulatory hierarchy, we developed a new method to decompose the regulatory network into functional modules and to identify global regulators governing multiple modules. As a result, 10 global regulators and 39 modules were identified and shown to have well defined functions. We then investigated the distribution and composition of the two basic network motifs (feed forward loop and bi-fan motif) in the hierarchical structure of TRN. We found that most of these network motifs include global regulators, indicating that these motifs are not basic building blocks of modules since modules should not contain global regulators. Conclusion The transcriptional regulatory network of E. coli possesses a multi-layer hierarchical modular structure without feedback regulation at transcription level. This hierarchical structure builds the basis for a new and simple decomposition method which is suitable for the identification of functional modules and global regulators in the transcriptional regulatory network of E. coli. Analysis of the distribution of feed forward loops and bi-fan motifs in the hierarchical structure suggests that these network motifs are not elementary building blocks of functional modules in the transcriptional regulatory network of E. coli.

Ma, Hong-Wu; Buer, Jan; Zeng, An-Ping

2004-01-01

33

Differential Network Analysis Reveals Genetic Effects on Catalepsy Modules  

PubMed Central

We performed short-term bi-directional selective breeding for haloperidol-induced catalepsy, starting from three mouse populations of increasingly complex genetic structure: an F2 intercross, a heterogeneous stock (HS) formed by crossing four inbred strains (HS4) and a heterogeneous stock (HS-CC) formed from the inbred strain founders of the Collaborative Cross (CC). All three selections were successful, with large differences in haloperidol response emerging within three generations. Using a custom differential network analysis procedure, we found that gene coexpression patterns changed significantly; importantly, a number of these changes were concordant across genetic backgrounds. In contrast, absolute gene-expression changes were modest and not concordant across genetic backgrounds, in spite of the large and similar phenotypic differences. By inferring strain contributions from the parental lines, we are able to identify significant differences in allelic content between the selected lines concurrent with large changes in transcript connectivity. Importantly, this observation implies that genetic polymorphisms can affect transcript and module connectivity without large changes in absolute expression levels. We conclude that, in this case, selective breeding acts at the subnetwork level, with the same modules but not the same transcripts affected across the three selections.

Iancu, Ovidiu D.; Oberbeck, Denesa; Darakjian, Priscila; Kawane, Sunita; Erk, Jason; McWeeney, Shannon; Hitzemann, Robert

2013-01-01

34

Madagascar corals reveal Pacific multidecadal modulation of rainfall since 1708  

NASA Astrophysics Data System (ADS)

The Pacific Ocean modulates Australian and North American rainfall variability on multidecadal timescales, in concert with the Pacific Decadal Oscillation (PDO). It has been suggested that Pacific decadal variability may also influence Indian Ocean surface temperature and rainfall in a far-field response, similar to the El Niño Southern Oscillation (ENSO) on interannual timescales. However, instrumental records of rainfall are too short and too sparse to confidently assess such multidecadal climatic teleconnections. Here, we present four climate archives spanning the past 300 yr from giant Madagascar corals. We decouple 20th century human deforestation effects from rainfall induced soil erosion using spectral luminescence scanning and geochemistry. The corals provide the first evidence for Pacific decadal modulation of rainfall over the Western Indian Ocean. We find that positive PDO phases are associated with increased Indian Ocean temperatures and rainfall in Eastern Madagascar, while precipitation in Southern Africa and Eastern Australia declines. Consequently, the negative PDO phase that started in 1998 should lead to reduced rainfall over Eastern Madagascar and increased precipitation in Southern Africa and Eastern Australia. We conclude that the PDO has important implications for future multidecadal variability of African rainfall, where water resource management is increasingly important under the warming climate.

Grove, C. A.; Zinke, J.; Peeters, F.; Park, W.; Scheufen, T.; Kasper, S.; Randriamanantsoa, B.; McCulloch, M. T.; Brummer, G.-J. A.

2012-03-01

35

Optogenetic dissection reveals multiple rhythmogenic modules underlying locomotion.  

PubMed

Neural networks in the spinal cord known as central pattern generators produce the sequential activation of muscles needed for locomotion. The overall locomotor network architectures in limbed vertebrates have been much debated, and no consensus exists as to how they are structured. Here, we use optogenetics to dissect the excitatory and inhibitory neuronal populations and probe the organization of the mammalian central pattern generator. We find that locomotor-like rhythmic bursting can be induced unilaterally or independently in flexor or extensor networks. Furthermore, we show that individual flexor motor neuron pools can be recruited into bursting without any activity in other nearby flexor motor neuron pools. Our experiments differentiate among several proposed models for rhythm generation in the vertebrates and show that the basic structure underlying the locomotor network has a distributed organization with many intrinsically rhythmogenic modules. PMID:23798384

Hägglund, Martin; Dougherty, Kimberly J; Borgius, Lotta; Itohara, Shigeyoshi; Iwasato, Takuji; Kiehn, Ole

2013-06-24

36

Modulation of granulocyte functions by bacterial exotoxin and endotoxins.  

PubMed Central

The modulation of granulocyte functions by bacterial exotoxins (Streptolysin O, alveolysin, theta toxin) and endotoxins from salmonella and lipid A is described here. Incubation of polymorphonuclear granulocytes with thiol-activated toxins resulted in an increased leukotriene generation. Toxin-pretreated PMNs revealed an increased omega oxidation of LTB4, which may explain why toxin-stimulated cells release more LTC4 than LTB4. Furthermore, toxin-pretreated PMNs showed a decreased leukotriene generation on subsequent stimulation with the Ca-ionophore A 23187 or opsonized zymosan.

Bremm, K D; Konig, W; Thelestam, M; Alouf, J E

1987-01-01

37

Electrical neuroimaging reveals early generator modulation to emotional words  

Microsoft Academic Search

Functional electrical neuroimaging investigated incidental emotional word processing. Previous research suggests that the brain may differentially respond to the emotional content of linguistic stimuli pre-lexically (i.e., before distinguishing that these stimuli are words). We investigated the spatiotemporal brain mechanisms of this apparent paradox and in particular whether the initial differentiation of emotional stimuli is marked by different brain generator configurations

Stephanie Ortigue; Christoph M. Michel; Micah M. Murray; Christine Mohr; Serge Carbonnel; Theodor Landis

2004-01-01

38

Protein complexes and functional modules in molecular networks  

NASA Astrophysics Data System (ADS)

Proteins, nucleic acids, and small molecules form a dense network of molecular interactions in a cell. Molecules are nodes of this network, and the interactions between them are edges. The architecture of molecular networks can reveal important principles of cellular organization and function, similarly to the way that protein structure tells us about the function and organization of a protein. Computational analysis of molecular networks has been primarily concerned with node degree [Wagner, A. & Fell, D. A. (2001) Proc. R. Soc. London Ser. B 268, 1803-1810; Jeong, H., Tombor, B., Albert, R., Oltvai, Z. N. & Barabasi, A. L. (2000) Nature 407, 651-654] or degree correlation [Maslov, S. & Sneppen, K. (2002) Science 296, 910-913], and hence focused on single/two-body properties of these networks. Here, by analyzing the multibody structure of the network of protein-protein interactions, we discovered molecular modules that are densely connected within themselves but sparsely connected with the rest of the network. Comparison with experimental data and functional annotation of genes showed two types of modules: (i) protein complexes (splicing machinery, transcription factors, etc.) and (ii) dynamic functional units (signaling cascades, cell-cycle regulation, etc.). Discovered modules are highly statistically significant, as is evident from comparison with random graphs, and are robust to noise in the data. Our results provide strong support for the network modularity principle introduced by Hartwell et al. [Hartwell, L. H., Hopfield, J. J., Leibler, S. & Murray, A. W. (1999) Nature 402, C47-C52], suggesting that found modules constitute the "building blocks" of molecular networks.

Spirin, Victor; Mirny, Leonid A.

2003-10-01

39

Interferon modulates central nervous system function.  

PubMed

The interferons (IFNs) are an endogenous pleiotropic family of cytokines that perform fundamental physiological functions as well as protecting host organisms from disease and in maintaining homeostasis. This review covers the effects of endogenous IFN on the nervous system. It starts with the description of its receptors, followed how it modulate neuronal activity, mood, sleep, temperature, the endocrine system, the opioid system and how it regulate food consumption and the immune system. Similar to other multifunctional cytokines, an excessive or inappropriate activity of IFNs can cause toxicity and even death. Furthermore, IFNs are currently the major treatment modality for several malignant and non-malignant diseases such as chronic hepatitis C and B, multiple sclerosis, hematological malignancies, malignant melanoma, renal cell carcinoma, etc. PMID:22322149

Reyes-Vázquez, Cruz; Prieto-Gómez, Bertha; Dafny, Nachum

2011-10-08

40

Heterogeneity in Neutrophil Microparticles Reveals Distinct Proteome and Functional Properties*  

PubMed Central

Altered plasma neutrophil microparticle levels have recently been implicated in a number of vascular and inflammatory diseases, yet our understanding of their actions is very limited. Herein, we investigate the proteome of neutrophil microparticles in order to shed light on their biological actions. Stimulation of human neutrophils, either in suspension or adherent to an endothelial monolayer, led to the production of microparticles containing >400 distinct proteins with only 223 being shared by the two subsets. For instance, postadherent microparticles were enriched in alpha-2 macroglobulin and ceruloplasmin, whereas microparticles produced by neutrophils in suspension were abundant in heat shock 70 kDa protein 1. Annexin A1 and lactotransferrin were expressed in both microparticle subsets. We next determined relative abundance of these proteins in three types of human microparticle samples: healthy volunteer plasma, plasma of septic patients and skin blister exudates finding that these proteins were differentially expressed on neutrophil microparticles from these samples reflecting in part the expression profiles we found in vitro. Functional assessment of the neutrophil microparticles subsets demonstrated that in response to direct stimulation neutrophil microparticles produced reactive oxygen species and leukotriene B4 as well as locomoted toward a chemotactic gradient. Finally, we investigated the actions of the two neutrophil microparticles subsets described herein on target cell responses. Microarray analysis with human primary endothelial cells incubated with either microparticle subset revealed a discrete modulation of endothelial cell gene expression profile. These findings demonstrate that neutrophil microparticles are heterogenous and can deliver packaged information propagating the activation status of the parent cell, potentially exerting novel and fundamental roles both under homeostatic and disease conditions.

Dalli, Jesmond; Montero-Melendez, Trinidad; Norling, Lucy V; Yin, Xiaoke; Hinds, Charles; Haskard, Dorian; Mayr, Manuel; Perretti, Mauro

2013-01-01

41

Novel family of carbohydrate-binding modules revealed by the genome sequence of Spirochaeta thermophila DSM 6192.  

PubMed

Spirochaeta thermophila is a thermophilic, free-living, and cellulolytic anaerobe. The genome sequence data for this organism have revealed a high density of genes encoding enzymes from more than 30 glycoside hydrolase (GH) families and a noncellulosomal enzyme system for (hemi)cellulose degradation. Functional screening of a fosmid library whose inserts were mapped on the S. thermophila genome sequence allowed the functional annotation of numerous GH open reading frames (ORFs). Seven different GH ORFs from the S. thermophila DSM 6192 genome, all putative ?-glycanase ORFs according to sequence similarity analysis, contained a highly conserved novel GH-associated module of unknown function at their C terminus. Four of these GH enzymes were experimentally verified as xylanase, ?-glucanase, ?-glucanase/carboxymethylcellulase (CMCase), and CMCase. Binding experiments performed with the recombinantly expressed and purified GH-associated module showed that it represents a new carbohydrate-binding module (CBM) that binds to microcrystalline cellulose and is highly specific for this substrate. In the course of this work, the new CBM type was only detected in Spirochaeta, but recently we found sequences with detectable similarity to the module in the draft genomes of Cytophaga fermentans and Mahella australiensis, both of which are phylogenetically very distant from S. thermophila and noncellulolytic, yet inhabit similar environments. This suggests a possibly broad distribution of the module in nature. PMID:21685171

Angelov, Angel; Loderer, Christoph; Pompei, Susanne; Liebl, Wolfgang

2011-06-17

42

A Multilevel Approach to Identify Functional Modules in a Yeast Protein-Protein Interaction Network  

Microsoft Academic Search

\\u000a Identifying functional modules is believed to reveal most cellular processes. There have been many computational approaches\\u000a to investigate the underlying biological structures [9, 4, 10, 6]. A spectral clustering method plays a critical role identifying\\u000a functional modules in a yeast protein-protein network in [6, 4]. We present an unweighted-graph version of a multilevel spectral\\u000a algorithm which more accurately identifies protein

Suely Oliveira; Sang-cheol Seok

2006-01-01

43

Assessing the functional coherence of modules found in multiple-evidence networks from Arabidopsis  

Microsoft Academic Search

Background  Combining multiple evidence-types from different information sources has the potential to reveal new relationships in biological\\u000a systems. The integrated information can be represented as a relationship network, and clustering the network can suggest possible\\u000a functional modules. The value of such modules for gaining insight into the underlying biological processes depends on their\\u000a functional coherence. The challenges that we wish to

Artem Lysenko; Michael Defoin-Platel; Keywan Hassani-Pak; Jan Taubert; Charlie Hodgman; Christopher J. Rawlings; Mansoor Saqi

2011-01-01

44

Revealing conformational substates of lipidated N-Ras protein by pressure modulation  

PubMed Central

Regulation of protein function is often linked to a conformational switch triggered by chemical or physical signals. To evaluate such conformational changes and to elucidate the underlying molecular mechanisms of subsequent protein function, experimental identification of conformational substates and characterization of conformational equilibria are mandatory. We apply pressure modulation in combination with FTIR spectroscopy to reveal equilibria between spectroscopically resolved substates of the lipidated signaling protein N-Ras. Pressure has the advantage that its thermodynamic conjugate is volume, a parameter that is directly related to structure. The conformational dynamics of N-Ras in its different nucleotide binding states in the absence and presence of a model biomembrane was probed by pressure perturbation. We show that not only nucleotide binding but also the presence of the membrane has a drastic effect on the conformational dynamics and selection of conformational substates of the protein, and a new substate appearing upon membrane binding could be uncovered. Population of this new substate is accompanied by structural reorientations of the G domain, as also indicated by complementary ATR-FTIR and IRRAS measurements. These findings thus illustrate that the membrane controls signaling conformations by acting as an effective interaction partner, which has consequences for the G-domain orientation of membrane-associated N-Ras, which in turn is known to be critical for its effector and modulator interactions. Finally, these results provide insights into the influence of pressure on Ras-controlled signaling events in organisms living under extreme environmental conditions as they are encountered in the deep sea where pressures reach the kbar range.

Kapoor, Shobhna; Triola, Gemma; Vetter, Ingrid R.; Erlkamp, Mirko; Waldmann, Herbert; Winter, Roland

2012-01-01

45

VITAMIN E MODULATION OF VASCULAR FUNCTION  

Technology Transfer Automated Retrieval System (TEKTRAN)

Endothelium, a physical barrier between plasma and vascular smooth muscle, is an important modulator of vasomotor tone and coagulation and plays a crucial role in adhesion inhibition and platelets and leukocytes activation. Dietary antioxidants may modulate these endothelium-dependent vascular funct...

46

Estrogen receptor-? signaling modulates epithelial barrier function.  

PubMed

Impaired epithelial barrier function and estrogens are recognized as factors influencing inflammatory bowel disease (IBD) pathology and disease course. Estrogen receptor-? (ER?) is the most abundant estrogen receptor in the colon and a complete absence of ER? expression is associated with disrupted tight-junction formation and abnormal colonic architecture. The aim of this study was to determine whether ER? signaling has a role in the maintenance of epithelial permeability in the colon. ER? mRNA levels and colonic permeability were assessed in IL-10-deficient mice and HLA-B27 rats by RT-PCR and Ussing chambers. ER? expression and monolayer resistance were measured in HT-29 and T84 colonic epithelial monolayers by RT-PCR and electric cell-substrate impedance sensing. The effect of 17?-estradiol and an estrogen agonist [diarylpropionitrile (DPN)] and antagonist (ICI 182780) on epithelial resistance in T84 cells was measured. Expression of ER? and proinflammatory cytokines was investigated in colonic biopsies from IBD patients. Levels of ER? mRNA were decreased, whereas colonic permeability was increased, in IL-10-deficient mice and HLA-B27 transgenic rats prior to the onset of colitis. T84 cells demonstrated higher resistance and increased levels of ER? mRNA compared with HT-29 cells. 17?-estradiol and DPN induced increased epithelial resistance in T84 cells, whereas an ER? blocker prevented the increased resistance. Decreased ER? mRNA levels were observed in colonic biopsies from IBD patients. This study suggests a potential role for ER? signaling in the modulation of epithelial permeability and demonstrates reduced ER? mRNA in animal models of colitis and colon of patients with inflammatory bowel disease. PMID:21252046

Looijer-van Langen, Mirjam; Hotte, Naomi; Dieleman, Levinus A; Albert, Eric; Mulder, Chris; Madsen, Karen L

2011-01-20

47

GABAB receptor modulation of synaptic function  

PubMed Central

Neuromodulators have complex effects on both the presynaptic release and postsynaptic detection of neurotransmitters. Here we describe recent advances in our understanding of synaptic modulation by metabotropic GABAB receptors. By inhibiting multivesicular release from the presynaptic terminal, these receptors decrease the synaptic glutamate signal. GABAB receptors also inhibit the Ca2+ permeability of NMDA receptors to decrease Ca2+ signals in postsynaptic spines. These new findings highlight the importance of GABAB receptors in regulating many aspects of synaptic transmission. They also point to novel questions about the spatiotemporal dynamics and sources of synaptic modulation in the brain.

Chalifoux, Jason R.; Carter, Adam G.

2011-01-01

48

Searching for functional gene modules with interaction component models  

PubMed Central

Background Functional gene modules and protein complexes are being sought from combinations of gene expression and protein-protein interaction data with various clustering-type methods. Central features missing from most of these methods are handling of uncertainty in both protein interaction and gene expression measurements, and in particular capability of modeling overlapping clusters. It would make sense to assume that proteins may play different roles in different functional modules, and the roles are evidenced in their interactions. Results We formulate a generative probabilistic model for protein-protein interaction links and introduce two ways for including gene expression data into the model. The model finds interaction components, which can be interpreted as overlapping clusters or functional modules. We demonstrate the performance on two data sets of yeast Saccharomyces cerevisiae. Our methods outperform a representative set of earlier models in the task of finding biologically relevant modules having enriched functional classes. Conclusions Combining protein interaction and gene expression data with a probabilistic generative model improves discovery of modules compared to approaches based on either data source alone. With a fairly simple model we can find biologically relevant modules better than with alternative methods, and in addition the modules may be inherently overlapping in the sense that different interactions may belong to different modules.

2010-01-01

49

Revealing functionally coherent subsets using a spectral clustering and an information integration approach  

PubMed Central

Background Contemporary high-throughput analyses often produce lengthy lists of genes or proteins. It is desirable to divide the genes into functionally coherent subsets for further investigation, by integrating heterogeneous information regarding the genes. Here we report a principled approach for managing and integrating multiple data sources within the framework of graph-spectrum analysis in order to identify coherent gene subsets. Results We investigated several approaches to integrate information derived from different sources that reflect distinct aspects of gene functional relationships including: functional annotations of genes in the form of the Gene Ontology, co-mentioning of genes in the literature, and shared transcription factor binding sites among genes. Given a list of genes, we construct a graph containing the genes in each information space; then the graphs were kernel transformed so they could be integrated; finally functionally coherent subsets were identified using a spectral clustering algorithm. In a series of simulation experiments, known functionally coherent gene sets were mixed and recovered using our approach. Conclusions The results indicate that spectral clustering approaches are capable of recovering coherent gene modules even under noisy conditions, and that information integration serves to further enhance this capability. When applied to a real-world data set, our methods revealed biologically sensible modules, and highlighted the importance of information integration. The implementation of the statistical model is provided under the GNU general public license, as an installable Python module, at: http://code.google.com/p/spectralmix.

2012-01-01

50

Response Function of Modulated Grid Faraday Cup Plasma Instruments.  

National Technical Information Service (NTIS)

Modulated grid Faraday cup plasma analyzers are a very useful tool for making in situ measurements of space plasmas. One of their great attributes is that their simplicity permits their angular response function to be calculated theoretically. An expressi...

A. Barnett S. Olbert

1986-01-01

51

Measurement of Modulation Transfer Functions of Simulator Displays.  

National Technical Information Service (NTIS)

The theory and methodology necessary for measuring the Modulation Transfer Function (MTF) of flight simulator displays is presented. The mathematical development of the MTF from linear system theory is outlined. The two primary methods for measuring MTF, ...

G. R. Kelly

1992-01-01

52

Natural Selection on Functional Modules, a Genome-Wide Analysis  

PubMed Central

Classically, the functional consequences of natural selection over genomes have been analyzed as the compound effects of individual genes. The current paradigm for large-scale analysis of adaptation is based on the observed significant deviations of rates of individual genes from neutral evolutionary expectation. This approach, which assumed independence among genes, has not been able to identify biological functions significantly enriched in positively selected genes in individual species. Alternatively, pooling related species has enhanced the search for signatures of selection. However, grouping signatures does not allow testing for adaptive differences between species. Here we introduce the Gene-Set Selection Analysis (GSSA), a new genome-wide approach to test for evidences of natural selection on functional modules. GSSA is able to detect lineage specific evolutionary rate changes in a notable number of functional modules. For example, in nine mammal and Drosophilae genomes GSSA identifies hundreds of functional modules with significant associations to high and low rates of evolution. Many of the detected functional modules with high evolutionary rates have been previously identified as biological functions under positive selection. Notably, GSSA identifies conserved functional modules with many positively selected genes, which questions whether they are exclusively selected for fitting genomes to environmental changes. Our results agree with previous studies suggesting that adaptation requires positive selection, but not every mutation under positive selection contributes to the adaptive dynamical process of the evolution of species.

Serra, Francois; Arbiza, Leonardo; Dopazo, Joaquin; Dopazo, Hernan

2011-01-01

53

Modulators of the glucocorticoid receptor also regulate mineralocorticoid receptor function  

SciTech Connect

Modulators are proposed to be novel ether aminophosphoglycerides that stabilize unoccupied and occupied glucocorticoid receptor steroid binding and inhibit glucocorticoid receptor complex activation. Two isoforms, modulator 1 and modulator 2, have been purified from rat liver cytosol. Since the mineralocorticoid receptor is relatively resistant to activation, modulator's effect on rat distal colon mineralocorticoid receptor is relatively resistant to activation, modulator's effect on rat distal colon mineralocorticoid receptor function was examined. Double-reciprocal analysis showed linear kinetics, and mixing modulator isoforms together had additive effects on unoccupied and occupied receptor steroid binding stabilization and activation inhibition. Colon cytosol contained a low molecular weight, heat-stable factor(s) which inhibited receptor activation and stabilized occupied receptor steroid binding. Molybdate completely stabilized unoccupied mineralocorticoid receptor steroid binding and inhibited activation with half-maximal effects at 3-4 mM but only stabilized occupied receptor binding by {approximately}40%. These data indicate that (1) apparent physiologic concentrations of modulator stabilize mineralocorticoid receptor steroid binding and inhibit receptor activation, (2) an aldosterone-responsive tissue contains a modulator-like activity, and (3) molybdate mimics the effects of modulator.

Schulman, G. (Temple Univ., Philadelphia, PA (United States)); Bodine, P.V.; Litwack, G. (Fels Inst. for Cancer Research and Molecular Biology, Philadelphia, PA (United States))

1992-02-18

54

Ferrocene Functionalized Endocrine Modulators as Anticancer Agents  

NASA Astrophysics Data System (ADS)

We present here some of our studies on the synthesis and behaviour of ferrocenyl selective endocrine receptor modulators against cancer cells, particularly breast and prostate cancers. The proliferative/anti-proliferative effects of compounds based on steroidal and non-steroidal endocrine modulators have been extensively explored in vitro. Structure-activity relationship studies of such molecules, particularly the hydroxyferrocifens and ferrocene phenols, have shown the effect of (1) the presence and the length of the N,N-dimethylamino side chain, (2) the presence and position of the phenol group, (3) the role of the ferrocenyl moiety, (4) that of conjugation, (5) phenyl functionalisation and (6) the placement of the phenyl group. Compounds possessing a ferrocene moiety linked to a p-phenol by a conjugated ?-system are among the most potent of the series, with IC50 values ranging from 0.090 to 0.6µM on hormone independent breast cancer cells. Based on the SAR data and electrochemical studies, we have proposed an original mechanism to explain the unusual behaviour of these bioorganometallic species and coin the term "kronatropic" to qualify this effect, involving ROS production and bio-oxidation. In addition, the importance of formulation is underlined. We also discuss the behaviour of ferrocenyl androgens and anti-androgens for possible use against prostate cancers. In sum, ferrocene has proven to be a fascinating substituent due to its vast potential for oncology.

Hillard, Elizabeth A.; Vessières, Anne; Jaouen, Gerard

55

Exclusive Developmental Functions of gatae cis-Regulatory Modules in the Strongylocentrorus purpuratus Embryo  

PubMed Central

The gatae gene of Strongylocentrotus purpuratus is orthologous to vertebrate gata-4,5,6 genes. This gene is expressed in the endomesoderm in the blastula and later the gut of the embryo, and is required for normal development. A gatae BAC containing a GFP reporter knocked into exon one of the gene was able to reproduce all aspects of endogenous gatae expression in the embryo. To identify putative gatae cis-regulatory modules we carried out an interspecific sequence conservation analysis with respect to a Lytechinus variegatus gatae BAC, which revealed 25 conserved non-coding sequence patches. These were individually tested in gene transfer experiments, and two modules capable of driving localized reporter expression in the embryo were identified. Module 10 produces early expression in mesoderm and endoderm cells up to the early gastrula stage, while module 24 generates late endodermal expression at gastrula and pluteus stages. Module 10 was then deleted from the gatae BAC by reciprocal recombination, resulting in total loss of reporter expression in the time frame in which it is normally active. Similar deletion of module 24 led to ubiquitous GFP expression in the gastrula and pluteus. These results show that Module 10 is uniquely necessary and sufficient to account for the early phase of gatae expression during endomesoderm specification. In addition they imply a functional cis-regulatory module exclusion, whereby only a single module can associate with the basal promoter and drive gene expression at any given time.

Lee, Pei Yun; Nam, Jongmin; Davidson, Eric H.

2007-01-01

56

Epigenetic modulation of the immune function  

PubMed Central

Great efforts in the field of solid organ transplantation are being devoted to identifying biomarkers that allow a transplanted patient’s immune status to be established. Recently, it has been well documented that epigenetic mechanisms like DNA methylation and histone modifications regulate the expression of immune system-related genes, modifying the development of the innate and adaptive immune responses. An in-depth knowledge of these epigenetic mechanisms could modulate the immune response after transplantation and to develop new therapeutic strategies. Epigenetic modifiers, such as histone deacetylase (HDAC) inhibitors have considerable potential as anti-inflammatory and immunosuppressive agents, but their effect on transplantation has not hitherto been known. Moreover, the detection of epigenetic marks in key immune genes could be useful as biomarkers of rejection and progression among transplanted patients. Here, we describe recent discoveries concerning the epigenetic regulation of the immune system, and how this knowledge could be translated to the field of transplantation.

Suarez-Alvarez, Beatriz; Baragano Raneros, Aroa; Ortega, Francisco; Lopez-Larrea, Carlos

2013-01-01

57

Function and modulation of ?-containing GABAA receptors  

PubMed Central

???-containing GABAA receptors are 1) localized to extra- and peri-synaptic membranes, 2) exhibit a high sensitivity to GABA, 3) show little desensitization, and 4) are believed to be one of the primary mediators of tonic inhibition in the central nervous system. This type of signaling appears to play a key role in controlling cell excitability. This review article briefly summarizes recent knowledge on tonic GABA-mediated inhibition. We will also consider the mechanism of action of many clinically important drugs such as anxiolytics, anticonvulsants, and sedative/hypnotics and their effects on ?-containing GABA receptor activation. We will conclude that ???-containing GABAA receptors exhibit a relatively low efficacy that can be potentiated by endogenous modulators and anxiolytic agents. This scenario enables these particular GABA receptor combinations, upon neurosteroid exposure for example, to impart a profound effect on excitability in the central nervous system.

Zheleznova, Nadezhda N.; Sedelnikova, Anna; Weiss, David S.

2009-01-01

58

Forced Unfolding of the Fibronectin Type III Module Reveals a Tensile Molecular Recognition Switch  

NASA Astrophysics Data System (ADS)

The 10th type III module of fibronectin possesses a ? -sandwich structure consisting of seven ? -strands (A-G) that are arranged in two antiparallel sheets. It mediates cell adhesion to surfaces via its integrin binding motif, Arg78, Gly79, and Asp80 (RGD), which is placed at the apex of the loop connecting ? -strands F and G. Steered molecular dynamics simulations in which tension is applied to the protein's terminal ends reveal that the ? -strand G is the first to break away from the module on forced unfolding whereas the remaining fold maintains its structural integrity. The separation of strand G from the remaining fold results in a gradual shortening of the distance between the apex of the RGD-containing loop and the module surface, which potentially reduces the loop's accessibility to surface-bound integrins. The shortening is followed by a straightening of the RGD-loop from a tight ? -turn into a linear conformation, which suggests a further decrease of affinity and selectivity to integrins. The RGD-loop therefore is located strategically to undergo strong conformational changes in the early stretching stages of the module and thus constitutes a mechanosensitive control of ligand recognition.

Krammer, Andre; Lu, Hui; Isralewitz, Barry; Schulten, Klaus; Vogel, Viola

1999-02-01

59

A functional approach reveals community responses to disturbances.  

PubMed

Understanding the processes shaping biological communities under multiple disturbances is a core challenge in ecology and conservation science. Traditionally, ecologists have explored linkages between the severity and type of disturbance and the taxonomic structure of communities. Recent advances in the application of species traits, to assess the functional structure of communities, have provided an alternative approach that responds rapidly and consistently across taxa and ecosystems to multiple disturbances. Importantly, trait-based metrics may provide advanced warning of disturbance to ecosystems because they do not need species loss to be reactive. Here, we synthesize empirical evidence and present a theoretical framework, based on species positions in a functional space, as a tool to reveal the complex nature of change in disturbed ecosystems. PMID:23141923

Mouillot, David; Graham, Nicholas A J; Villéger, Sébastien; Mason, Norman W H; Bellwood, David R

2012-11-08

60

Discovering functional modules by identifying recurrent and mutually exclusive mutational patterns in tumors  

PubMed Central

Background Assays of multiple tumor samples frequently reveal recurrent genomic aberrations, including point mutations and copy-number alterations, that affect individual genes. Analyses that extend beyond single genes are often restricted to examining pathways, interactions and functional modules that are already known. Methods We present a method that identifies functional modules without any information other than patterns of recurrent and mutually exclusive aberrations (RME patterns) that arise due to positive selection for key cancer phenotypes. Our algorithm efficiently constructs and searches networks of potential interactions and identifies significant modules (RME modules) by using the algorithmic significance test. Results We apply the method to the TCGA collection of 145 glioblastoma samples, resulting in extension of known pathways and discovery of new functional modules. The method predicts a role for EP300 that was previously unknown in glioblastoma. We demonstrate the clinical relevance of these results by validating that expression of EP300 is prognostic, predicting survival independent of age at diagnosis and tumor grade. Conclusions We have developed a sensitive, simple, and fast method for automatically detecting functional modules in tumors based solely on patterns of recurrent genomic aberration. Due to its ability to analyze very large amounts of diverse data, we expect it to be increasingly useful when applied to the many tumor panels scheduled to be assayed in the near future.

2011-01-01

61

Conditional gene deletion reveals functional redundancy of GABAB receptors in peripheral nociceptors in vivo  

PubMed Central

Background ?-aminobutyric acid (GABA) is an important inhibitory neurotransmitter which mainly mediates its effects on neurons via ionotropic (GABAA) and metabotropic (GABAB) receptors. GABAB receptors are widely expressed in the central and the peripheral nervous system. Although there is evidence for a key function of GABAB receptors in the modulation of pain, the relative contribution of peripherally- versus centrally-expressed GABAB receptors is unclear. Results In order to elucidate the functional relevance of GABAB receptors expressed in peripheral nociceptive neurons in pain modulation we generated and analyzed conditional mouse mutants lacking functional GABAB(1) subunit specifically in nociceptors, preserving expression in the spinal cord and brain (SNS-GABAB(1)-/- mice). Lack of the GABAB(1) subunit precludes the assembly of functional GABAB receptor. We analyzed SNS-GABAB(1)-/- mice and their control littermates in several models of acute and neuropathic pain. Electrophysiological studies on peripheral afferents revealed higher firing frequencies in SNS-GABAB(1)-/- mice compared to corresponding control littermates. However no differences were seen in basal nociceptive sensitivity between these groups. The development of neuropathic and chronic inflammatory pain was similar across the two genotypes. The duration of nocifensive responses evoked by intraplantar formalin injection was prolonged in the SNS-GABAB(1)-/- animals as compared to their control littermates. Pharmacological experiments revealed that systemic baclofen-induced inhibition of formalin-induced nociceptive behaviors was not dependent upon GABAB(1) expression in nociceptors. Conclusion This study addressed contribution of GABAB receptors expressed on primary afferent nociceptive fibers to the modulation of pain. We observed that neither the development of acute and chronic pain nor the analgesic effects of a systematically-delivered GABAB agonist was significantly changed upon a specific deletion of GABAB receptors from peripheral nociceptive neurons in vivo. This lets us conclude that GABAB receptors in the peripheral nervous system play a less important role than those in the central nervous system in the regulation of pain.

2009-01-01

62

Genome-wide computational prediction of transcriptional regulatory modules reveals new insights into human gene expression  

Microsoft Academic Search

The identification of regulatory regions is one of the most important and challenging problems toward the functional annotation of the human genome. In higher eukaryotes, transcription-factor (TF) binding sites are often organized in clusters called cis-regulatory modules (CRM). While the prediction of individual TF-binding sites is a notoriously difficult problem, CRM prediction has proven to be somewhat more reliable. Starting

Mathieu Blanchette; Alain R. Bataille; Xiaoyu Chen; Christian Poitras; Josée Laganière; Céline Lefèbvre; Geneviève Deblois; Vincent Giguère; Vincent Ferretti; Dominique Bergeron; Benoit Coulombe; François Robert

2006-01-01

63

State-Related Changes in MEG Functional Connectivity Reveal the Task-Positive Sensorimotor Network  

PubMed Central

Functional connectivity measures applied to magnetoencephalography (MEG) data have the capacity to elucidate neuronal networks. However, the task-related modulation of these measures is essential to identifying the functional relevance of the identified network. In this study, we provide evidence for the efficacy of measuring “state-related” (i.e., task vs. rest) changes in MEG functional connectivity for revealing a sensorimotor network. We investigate changes in functional connectivity, measured as cortico-cortical coherence (CCC), between rest blocks and the performance of a visually directed motor task in a healthy cohort. Task-positive changes in CCC were interpreted in the context of any concomitant modulations in spectral power. Task-related increases in whole-head CCC relative to the resting state were identified between areas established as part of the sensorimotor network as well as frontal eye fields and prefrontal cortices, predominantly in the beta and gamma frequency bands. This study provides evidence for the use of MEG to identify task-specific functionally connected sensorimotor networks in a non-invasive, patient friendly manner.

Bardouille, Timothy; Boe, Shaun

2012-01-01

64

Glycosylation modulates arenavirus glycoprotein expression and function  

Microsoft Academic Search

The glycoprotein of lymphocytic choriomeningitis virus (LCMV) contains nine potential N-linked glycosylation sites. We investigated the function of these N-glycosylations by using alanine-scanning mutagenesis. All the available sites were occupied on GP1 and two of three on GP2. N-linked glycan mutations at positions 87 and 97 on GP1 resulted in reduction of expression and absence of cleavage and were necessary

Cyrille J. Bonhomme; Althea A. Capul; Elvin J. Lauron; Lydia H. Bederka; Kristeene A. Knopp; Michael J. Buchmeier

2011-01-01

65

Resting-State Brain Organization Revealed by Functional Covariance Networks  

PubMed Central

Background Brain network studies using techniques of intrinsic connectivity network based on fMRI time series (TS-ICN) and structural covariance network (SCN) have mapped out functional and structural organization of human brain at respective time scales. However, there lacks a meso-time-scale network to bridge the ICN and SCN and get insights of brain functional organization. Methodology and Principal Findings We proposed a functional covariance network (FCN) method by measuring the covariance of amplitude of low-frequency fluctuations (ALFF) in BOLD signals across subjects, and compared the patterns of ALFF-FCNs with the TS-ICNs and SCNs by mapping the brain networks of default network, task-positive network and sensory networks. We demonstrated large overlap among FCNs, ICNs and SCNs and modular nature in FCNs and ICNs by using conjunctional analysis. Most interestingly, FCN analysis showed a network dichotomy consisting of anti-correlated high-level cognitive system and low-level perceptive system, which is a novel finding different from the ICN dichotomy consisting of the default-mode network and the task-positive network. Conclusion The current study proposed an ALFF-FCN approach to measure the interregional correlation of brain activity responding to short periods of state, and revealed novel organization patterns of resting-state brain activity from an intermediate time scale.

Wang, Zhengge; Yuan, Cuiping; Jiao, Qing; Chen, Huafu; Biswal, Bharat B.; Lu, Guangming; Liu, Yijun

2011-01-01

66

Glycosylation modulates arenavirus glycoprotein expression and function  

SciTech Connect

The glycoprotein of lymphocytic choriomeningitis virus (LCMV) contains nine potential N-linked glycosylation sites. We investigated the function of these N-glycosylations by using alanine-scanning mutagenesis. All the available sites were occupied on GP1 and two of three on GP2. N-linked glycan mutations at positions 87 and 97 on GP1 resulted in reduction of expression and absence of cleavage and were necessary for downstream functions, as confirmed by the loss of GP-mediated fusion activity with T87A and S97A mutants. In contrast, T234A and E379N/A381T mutants impaired GP-mediated cell fusion without altered expression or processing. Infectivity via virus-like particles required glycans and a cleaved glycoprotein. Glycosylation at the first site within GP2, not normally utilized by LCMV, exhibited increased VLP infectivity. We also confirmed the role of the N-linked glycan at position 173 in the masking of the neutralizing epitope GP-1D. Taken together, our results indicated a strong relationship between fusion and infectivity.

Bonhomme, Cyrille J., E-mail: cbonhomm@uci.edu; Capul, Althea A., E-mail: acapul@uci.edu; Lauron, Elvin J., E-mail: elauron@chori.org; Bederka, Lydia H., E-mail: lbederka@uci.edu; Knopp, Kristeene A., E-mail: kknopp@uci.edu; Buchmeier, Michael J., E-mail: m.buchmeier@uci.ed

2011-01-20

67

Glycosylation modulates arenavirus glycoprotein expression and function  

PubMed Central

The glycoprotein of lymphocytic choriomeningitis virus (LCMV) contains nine potential N-linked glycosylation sites. We investigated the function of these N-glycosylations by using alanine-scanning mutagenesis. All the available sites were occupied on GP1 and two of three on GP2. N-linked glycan mutations at positions 87 and 97 on GP1 resulted in reduction of expression and absence of cleavage and were necessary for downstream functions, as confirmed by the loss of GP-mediated fusion activity with T87A, S97A mutants. In contrast, T234A and E379N/A381T mutants impaired GP-mediated cell fusion without altered expression or processing. Infectivity via virus-like particles required glycans and a cleaved glycoprotein. Glycosylation at the first site within GP2, not normally utilized by LCMV, exhibited increased VLP-infectivity. We also confirmed the role of the N-linked glycan at position 173 in the masking of the neutralizing epitope GP-1D. Taken together, our results indicated a strong relationship between fusion and infectivity.

Bonhomme, Cyrille J.; Capul, Althea A.; Lauron, Elvin J.; Bederka, Lydia H.; Knopp, Kristeene A.; Buchmeier, Michael J.

2010-01-01

68

Adiponectin modulates NK-cell function.  

PubMed

Adiponectin (APN) has been shown to exert antiinflammatory effects in various disease models but little is known concerning its regulation of NK-cell function. Here, we show that the majority of human CD56(dim) NK cells express surface Adiponectin receptor (AdipoR) 1 and 2 while most CD56(high) NK cells are AdipoR-negative. Toll-like receptor (TLR) ligand-induced IFN-? production was diminished by APN while it had no influence on NK-cell cytotoxicity. In contrast only a small subpopulation of murine NK cells expresses surface AdipoRs, but about 90% store them intracellularly. APN-deficient knockout (KO) mice had elevated frequencies of NK cells. However, cytotoxic degranulation of NK cells was decreased in APN knockout (APN-KO) animals. Accordingly, frequencies of CD11b(high) CD27(high) and CD94(high) effector NK cells and expression of NKG2D were lower in APN-KO mice. Upon CVB3 infection NK-cell function was restored in APN-KO mice. Our data suggest that in addition to its antiinflammatory effects APN also influences the numerical and differentiation status of NK cells, which may further impact the outcome of immune-mediated diseases in APN-KO mice. PMID:23401034

Wilk, Sabrina; Jenke, Alexander; Stehr, Jenny; Yang, Chin-An; Bauer, Sandra; Göldner, Katrin; Kotsch, Katja; Volk, Hans-Dieter; Poller, Wolfgang; Schultheiss, Heinz-Peter; Skurk, Carsten; Scheibenbogen, Carmen

2013-03-01

69

Gamma-tocotrienol modulated gene expression in senescent human diploid fibroblasts as revealed by microarray analysis.  

PubMed

The effect of ? -tocotrienol, a vitamin E isomer, in modulating gene expression in cellular aging of human diploid fibroblasts was studied. Senescent cells at passage 30 were incubated with 70? ? M of ? -tocotrienol for 24?h. Gene expression patterns were evaluated using Sentrix HumanRef-8 Expression BeadChip from Illumina, analysed using GeneSpring GX10 software, and validated using quantitative RT-PCR. A total of 100 genes were differentially expressed (P < 0.001) by at least 1.5 fold in response to ? -tocotrienol treatment. Amongst the genes were IRAK3, SelS, HSPA5, HERPUD1, DNAJB9, SEPR1, C18orf55, ARF4, RINT1, NXT1, CADPS2, COG6, and GLRX5. Significant gene list was further analysed by Gene Set Enrichment Analysis (GSEA), and the Normalized Enrichment Score (NES) showed that biological processes such as inflammation, protein transport, apoptosis, and cell redox homeostasis were modulated in senescent fibroblasts treated with ? -tocotrienol. These findings revealed that ? -tocotrienol may prevent cellular aging of human diploid fibroblasts by modulating gene expression. PMID:23634235

Makpol, Suzana; Zainuddin, Azalina; Chua, Kien Hui; Mohd Yusof, Yasmin Anum; Ngah, Wan Zurinah Wan

2013-03-24

70

Targeted Chemical Wedges Reveal the Role of Allosteric DNA Modulation in Protein -- DNA Assembly  

PubMed Central

The cooperative assembly of multiprotein complexes results from allosteric modulations of DNA structure as well as direct intermolecular contacts between proteins. Such cooperative binding plays a critical role in imparting exquisite sequence specificity on the homeobox transcription factor (Hox) family of developmental transcription factors. A well-characterized example includes the interaction of Hox proteins with extradenticle (Exd), a highly conserved DNA binding transcription factor. Although direct interactions are important, the contribution of indirect interactions toward cooperative assembly of Hox and Exd remains unresolved. Here we use minor groove binding polyamides as structural wedges to induce perturbations at specific base steps within the Exd binding site. We find that allosteric modulation of DNA structure contributes nearly 1.5 kcal/mol to the binding of Exd to DNA, even in the absence of direct Hox contacts. In contrast to previous studies, the sequence-targeted chemical wedges reveal the role of DNA geometry in cooperative assembly of Hox–Exd complexes. Programmable polyamides may well serve as general probes to investigate the role of DNA modulation in the cooperative and highly specific assembly of other protein–DNA complexes.

Moretti, Rocco; Donato, Leslie J.; Brezinski, Mary L.; Stafford, Ryan L.; Hoff, Helena; Thorson, Jon S.; Dervan, Peter B.; Ansari, Aseem Z.

2011-01-01

71

Soluble Axoplasm Enriched from Injured CNS Axons Reveals the Early Modulation of the Actin Cytoskeleton  

PubMed Central

Axon injury and degeneration is a common consequence of diverse neurological conditions including multiple sclerosis, traumatic brain injury and spinal cord injury. The molecular events underlying axon degeneration are poorly understood. We have developed a novel method to enrich for axoplasm from rodent optic nerve and characterised the early events in Wallerian degeneration using an unbiased proteomics screen. Our detergent-free method draws axoplasm into a dehydrated hydrogel of the polymer poly(2-hydroxyethyl methacrylate), which is then recovered using centrifugation. This technique is able to recover axonal proteins and significantly deplete glial contamination as confirmed by immunoblotting. We have used iTRAQ to compare axoplasm-enriched samples from naïve vs injured optic nerves, which has revealed a pronounced modulation of proteins associated with the actin cytoskeleton. To confirm the modulation of the actin cytoskeleton in injured axons we focused on the RhoA pathway. Western blotting revealed an augmentation of RhoA and phosphorylated cofilin in axoplasm-enriched samples from injured optic nerve. To investigate the localisation of these components of the RhoA pathway in injured axons we transected axons of primary hippocampal neurons in vitro. We observed an early modulation of filamentous actin with a concomitant redistribution of phosphorylated cofilin in injured axons. At later time-points, RhoA is found to accumulate in axonal swellings and also colocalises with filamentous actin. The actin cytoskeleton is a known sensor of cell viability across multiple eukaryotes, and our results suggest a similar role for the actin cytoskeleton following axon injury. In agreement with other reports, our data also highlights the role of the RhoA pathway in axon degeneration. These findings highlight a previously unexplored area of axon biology, which may open novel avenues to prevent axon degeneration. Our method for isolating CNS axoplasm also represents a new tool to study axon biology.

Garland, Patrick; Broom, Lucy J.; Quraishe, Shmma; Dalton, Paul D.; Skipp, Paul; Newman, Tracey A.; Perry, V. Hugh

2012-01-01

72

Progress of terahertz functional subwavelength devices -modulator, isolator and sensor  

NASA Astrophysics Data System (ADS)

Our recent important progress in terahertz (THz) functional devices based on photonic crystals and plasmonics was reviewed in this paper, involving THz modulator, isolator and sensor. For THz modulators, we demonstrate the transmission and modulation properties of a state conversion photonic crystals and a metal-semiconductor-metal plasmonic waveguide based on theoretical and experimental investigations. We also show the nonreciprocal transmission and enhancement mechanism of the structured metal/magneto-optical plasmonic waveguide and plasmonic lens for THz isolator and circulator. Moreover, a real-time quantitative THz microfluidic sensing based on photonic crystal pillar array is introduced by experimental results. These THz functional subwavelength devices exhibit great promising potential in THz application systems.

Fan, Fei; Chang, Sheng-Jiang

2013-08-01

73

Functional Metabolomics Reveals Novel Active Products in the DHA Metabolome  

PubMed Central

Endogenous mechanisms for successful resolution of an acute inflammatory response and the local return to homeostasis are of interest because excessive inflammation underlies many human diseases. In this review, we provide an update and overview of functional metabolomics that identified a new bioactive metabolome of docosahexaenoic acid (DHA). Systematic studies revealed that DHA was converted to DHEA-derived novel bioactive products as well as aspirin-triggered forms of protectins (AT-PD1). The new oxygenated DHEA-derived products blocked PMN chemotaxis, reduced P-selectin expression and platelet-leukocyte adhesion, and showed organ protection in ischemia/reperfusion injury. These products activated cannabinoid receptor (CB2 receptor) and not CB1 receptors. The AT-PD1 reduced neutrophil (PMN) recruitment in murine peritonitis. With human cells, AT-PD1 decreased transendothelial PMN migration as well as enhanced efferocytosis of apoptotic human PMN by macrophages. The recent findings reviewed here indicate that DHEA oxidative metabolism and aspirin-triggered conversion of DHA produce potent novel molecules with anti-inflammatory and organ-protective properties, opening the DHA metabolome functional roles.

Shinohara, Masakazu; Mirakaj, Valbona; Serhan, Charles N.

2012-01-01

74

Modeling Reveals Bistability and Low-Pass Filtering in the Network Module Determining Blood Stem Cell Fate  

PubMed Central

Combinatorial regulation of gene expression is ubiquitous in eukaryotes with multiple inputs converging on regulatory control elements. The dynamic properties of these elements determine the functionality of genetic networks regulating differentiation and development. Here we propose a method to quantitatively characterize the regulatory output of distant enhancers with a biophysical approach that recursively determines free energies of protein-protein and protein-DNA interactions from experimental analysis of transcriptional reporter libraries. We apply this method to model the Scl-Gata2-Fli1 triad—a network module important for cell fate specification of hematopoietic stem cells. We show that this triad module is inherently bistable with irreversible transitions in response to physiologically relevant signals such as Notch, Bmp4 and Gata1 and we use the model to predict the sensitivity of the network to mutations. We also show that the triad acts as a low-pass filter by switching between steady states only in response to signals that persist for longer than a minimum duration threshold. We have found that the auto-regulation loops connecting the slow-degrading Scl to Gata2 and Fli1 are crucial for this low-pass filtering property. Taken together our analysis not only reveals new insights into hematopoietic stem cell regulatory network functionality but also provides a novel and widely applicable strategy to incorporate experimental measurements into dynamical network models.

Narula, Jatin; Smith, Aileen M.; Gottgens, Berthold; Igoshin, Oleg A.

2010-01-01

75

Functional modules by relating protein interaction networks and gene expression  

Microsoft Academic Search

Genes and proteins are organized on the basis of their particular mutual relations or according to their interactions in cellular and genetic networks. These include metabolic or signaling pathways and protein interaction, regulatory or co-expression net- works. Integrating the information from the different types of networks may lead to the notion of a func- tional network and functional modules. To

Sabine Tornow; H. W. Mewes

2003-01-01

76

Weightlessness - a model to understand how gravity modulates cardiovascular function  

Microsoft Academic Search

Gravity stresses the cardiovascular system in humans by decreasing the blood supply to the heart. As a consequence of this, reflexes are constantly activated to increase heart rate, constrict the blood vessels and diminish the renal output of fluid. To explore how gravity modulates cardiovascular function, longterm weightlessness in space is a useful tool. Therefore, we have participated in space

Peter Norsk

77

Integrins: Sensors of Extracellular Matrix and Modulators of Cell Function  

Microsoft Academic Search

Integrins are a large family of transmembrane receptors for extracellular matrix (ECM) molecules. They play a critical role in organ morphogenesis, physiology and pathology, as they can modulate and control different cell functions, including adhesion, shape, polarity, growth, differentiation and motility. Integrins interact with ECM components via their extracellular domains, while their cytoplasmic domains play a pivotal role in mediating

Ambra Pozzi; Roy Zent

2003-01-01

78

Temporal modulation transfer functions in the barn owl (Tyto alba).  

PubMed

Barn owls (Tyto alba) have evolved several specializations in their auditory system to achieve the high sensory acuity required for prey capture, including superior processing of interaural time differences and phase coding in the auditory periphery. Here, we tested whether barn owls are capable of high temporal resolution that may be a prerequisite for the accuracy in binaural processing. Temporal resolution was measured psychoacoustically and demonstrated in temporal modulation transfer functions. Four barn owls were trained in an operant task with food reward to detect sinusoidal amplitude modulations within an 800-ms gated white-noise burst or 800-ms periods of modulation in continuous white noise (spectrum levels of -5 dB and 15 dB SPL). Within the range of tested amplitude modulation frequencies from 5 Hz to 1280 Hz, barn owls' detection thresholds were lowest at 10-20 Hz. This sensitivity corresponds to an intensity-difference limen of between 0.9 dB and 1.4 dB. For all conditions, temporal modulation transfer functions showed band-pass characteristics with a high-frequency cutoff in the range of 37 Hz to 92 Hz, corresponding to minimum integration times of 4.3 ms and 1.7 ms, respectively. In summary, these data indicate a temporal resolution in the owl's auditory system that is good, but not unusual, compared to other vertebrates. PMID:11913811

Dent, Michael L; Klump, Georg M; Schwenzfeier, Christian

2002-01-01

79

Response function of modulated grid Faraday cup plasma instruments  

NASA Astrophysics Data System (ADS)

Modulated grid Faraday cup plasma analyzers are a very useful tool for making in situ measurements of space plasmas. One of their great attributes is that their simplicity permits their angular response function to be calculated theoretically. An expression is derived for this response function by computing the trajectories of the charged particles inside the cup. The Voyager plasma science experiment is used as a specific example. Two approximations to the rigorous response function useful for data analysis are discussed. Multisensor analysis of solar wind data indicates that the formulas represent the true cup response function for all angles of incidence with a maximum error of only a few percent.

Barnett, A.; Olbert, S.

1986-10-01

80

Modulation of function and gated learning in a network memory  

SciTech Connect

Memory and learning are studied in a model neural network made from component cells with a variety of realistic intrinsic dynamic behaviors. Modulation of intrinsic cellular characteristics causes a network to switch between two entirely different modes of operation. In one mode the network acts as a selective, long-term associative memory, whereas in the other it is a nonselective, short-term latching memory. Such functional modulation can be used as a mechanism for initiating and terminating learning in a network associative memory.

Abbott, L.F. (Brandeis Univ., Waltham, MA (United States))

1990-12-01

81

Modulation of function and gated learning in a network memory.  

PubMed Central

Memory and learning are studied in a model neural network made from component cells with a variety of realistic intrinsic dynamic behaviors. Modulation of intrinsic cellular characteristics causes a network to switch between two entirely different modes of operation. In one mode the network acts as a selective, long-term associative memory, whereas in the other it is a nonselective, short-term latching memory. Such functional modulation can be used as a mechanism for initiating and terminating learning in a network associative memory. Images

Abbott, L F

1990-01-01

82

Amplitude modulation of atomic wave functions. Final report  

SciTech Connect

The major theoretical advance has been to show that one can modulate Rydberg wave functions using either of two methods: (1) the amplitude modulation technique which depends on autoionization to deplete part of the wave function, or (2) a phase modulation method, which uses a change in the core potential to create a localized phase shift in the wave function. Essentially, these two methods can both be seen as using the core potential to change the Rydberg wave function, using the imaginary part of the potential to do amplitude modulation, or using the real part of the potential to do phase modulation. This work will be published as the authors acquire experimental results which show the differences between the two methods. One of the results of this theoretical study is that the initial proposal to study Barium 6snd states had a significant flaw. Neither the autoionization time, nor the quantum defect shifts are very large in these cases. This means that the modulation is relatively small. This shows itself primarily in the difficulty of seeing significant population redistribution into different 6snd states. The authors intend to correct this in the next funding cycle either: (a) by using the more quickly decaying Ba 6pnf states to modulate 6snd states, or (b) by using Sr 5 snd states, as outlined in this report. Their first, low power experiments are complete. These experiments have used two pulses to do a temporal version of the Ramsey separated oscillatory fields excitation. The two pulses are generated by passing the single pulse through a Michelson-Morley interferometer, which is computer controlled to sweep one arm through 2.5 {micro}m in steps of 10 nm. The second pulse`s excitation interferes with that of the first pulse, and so the total excitation has a sinusoidal variation (with a time period equal to the optical period) on top of a constant background. The amplitude of the total variation should decay at half of the rate decay rate of the autoionizing state, so this produces a time-resolved measurement of the very rapid autoionization decay. Although this does not yet show that the atom stores modulations in the bound coherent state, it does demonstrate that the atom can be excited to an autoionizing state with high efficiency, and then brought back to a bound state at a later time. The second set of experiments takes the previous work to the strong coupling regime.

NONE

1998-11-01

83

Systematic identification of functional modules and cis-regulatory elements in Arabidopsis thaliana  

PubMed Central

Background Several large-scale gene co-expression networks have been constructed successfully for predicting gene functional modules and cis-regulatory elements in Arabidopsis (Arabidopsis thaliana). However, these networks are usually constructed and analyzed in an ad hoc manner. In this study, we propose a completely parameter-free and systematic method for constructing gene co-expression networks and predicting functional modules as well as cis-regulatory elements. Results Our novel method consists of an automated network construction algorithm, a parameter-free procedure to predict functional modules, and a strategy for finding known cis-regulatory elements that is suitable for consensus scanning without prior knowledge of the allowed extent of degeneracy of the motif. We apply the method to study a large collection of gene expression microarray data in Arabidopsis. We estimate that our co-expression network has ~94% of accuracy, and has topological properties similar to other biological networks, such as being scale-free and having a high clustering coefficient. Remarkably, among the ~300 predicted modules whose sizes are at least 20, 88% have at least one significantly enriched functions, including a few extremely significant ones (ribosome, p < 1E-300, photosynthetic membrane, p < 1.3E-137, proteasome complex, p < 5.9E-126). In addition, we are able to predict cis-regulatory elements for 66.7% of the modules, and the association between the enriched cis-regulatory elements and the enriched functional terms can often be confirmed by the literature. Overall, our results are much more significant than those reported by several previous studies on similar data sets. Finally, we utilize the co-expression network to dissect the promoters of 19 Arabidopsis genes involved in the metabolism and signaling of the important plant hormone gibberellin, and achieved promising results that reveal interesting insight into the biosynthesis and signaling of gibberellin. Conclusions The results show that our method is highly effective in finding functional modules from real microarray data. Our application on Arabidopsis leads to the discovery of the largest number of annotated Arabidopsis functional modules in the literature. Given the high statistical significance of functional enrichment and the agreement between cis-regulatory and functional annotations, we believe our Arabidopsis gene modules can be used to predict the functions of unknown genes in Arabidopsis, and to understand the regulatory mechanisms of many genes.

2011-01-01

84

Modulation of p53 binding to MDM2: computational studies reveal important roles of Tyr100  

PubMed Central

Background The tumor suppressor protein p53 is regulated by the ubiquitin ligase MDM2 which down-regulates p53. In tumours with overexpressed MDM2, the p53-MDM2 interaction can be interrupted by a peptide or small molecule to stabilize p53 as a therapeutic strategy. Structural and biochemical/mutagenesis data show that p53 has 3 hydrophobic residues F19, W23 and L26 that embed into the ligand binding pocket of MDM2 which is highly plastic in nature and can modulate its size to accommodate a variety of ligands. This binding pocket is primarily dependent on the orientation of a particular residue, Y100. We have studied the role of the dynamics of Y100 in p53 recognition. Results Molecular dynamics simulations show that the Y100 side chain can be in "open" or "closed" states with only the former enabling complex formation. When both p53 and MDM2 are in near native conformations, complex formation is rapid and is driven by the formation of a hydrogen bond between W23 of p53 and L54 of MDM2 or by the embedding of F19 of p53 into MDM2. The transition of Y100 from "closed" to "open" can increase the size of the binding site. Interconversions between these two states can be induced by the N-terminal region of MDM2 or by the conformations of the p53 peptides. Conclusion Molecular dynamics simulations have revealed how the binding of p53 to MDM2 is modulated by the conformational mobility of Y100 which is the gatekeeper residue in MDM2. The mobility of this residue can be modulated by the conformations of p53 and the Nterminal lid region of MDM2.

2009-01-01

85

Dissociable modulation of overt visual attention in valence and arousal revealed by topology of scan path.  

PubMed

Emotional stimuli have evolutionary significance for the survival of organisms; therefore, they are attention-grabbing and are processed preferentially. The neural underpinnings of two principle emotional dimensions in affective space, valence (degree of pleasantness) and arousal (intensity of evoked emotion), have been shown to be dissociable in the olfactory, gustatory and memory systems. However, the separable roles of valence and arousal in scene perception are poorly understood. In this study, we asked how these two emotional dimensions modulate overt visual attention. Twenty-two healthy volunteers freely viewed images from the International Affective Picture System (IAPS) that were graded for affective levels of valence and arousal (high, medium, and low). Subjects' heads were immobilized and eye movements were recorded by camera to track overt shifts of visual attention. Algebraic graph-based approaches were introduced to model scan paths as weighted undirected path graphs, generating global topology metrics that characterize the algebraic connectivity of scan paths. Our data suggest that human subjects show different scanning patterns to stimuli with different affective ratings. Valence salient stimuli (with neutral arousal) elicited faster and larger shifts of attention, while arousal salient stimuli (with neutral valence) elicited local scanning, dense attention allocation and deep processing. Furthermore, our model revealed that the modulatory effect of valence was linearly related to the valence level, whereas the relation between the modulatory effect and the level of arousal was nonlinear. Hence, visual attention seems to be modulated by mechanisms that are separate for valence and arousal. PMID:21494331

Ni, Jianguang; Jiang, Huihui; Jin, Yixiang; Chen, Nanhui; Wang, Jianhong; Wang, Zhengbo; Luo, Yuejia; Ma, Yuanye; Hu, Xintian

2011-04-06

86

Dissociable Modulation of Overt Visual Attention in Valence and Arousal Revealed by Topology of Scan Path  

PubMed Central

Emotional stimuli have evolutionary significance for the survival of organisms; therefore, they are attention-grabbing and are processed preferentially. The neural underpinnings of two principle emotional dimensions in affective space, valence (degree of pleasantness) and arousal (intensity of evoked emotion), have been shown to be dissociable in the olfactory, gustatory and memory systems. However, the separable roles of valence and arousal in scene perception are poorly understood. In this study, we asked how these two emotional dimensions modulate overt visual attention. Twenty-two healthy volunteers freely viewed images from the International Affective Picture System (IAPS) that were graded for affective levels of valence and arousal (high, medium, and low). Subjects' heads were immobilized and eye movements were recorded by camera to track overt shifts of visual attention. Algebraic graph-based approaches were introduced to model scan paths as weighted undirected path graphs, generating global topology metrics that characterize the algebraic connectivity of scan paths. Our data suggest that human subjects show different scanning patterns to stimuli with different affective ratings. Valence salient stimuli (with neutral arousal) elicited faster and larger shifts of attention, while arousal salient stimuli (with neutral valence) elicited local scanning, dense attention allocation and deep processing. Furthermore, our model revealed that the modulatory effect of valence was linearly related to the valence level, whereas the relation between the modulatory effect and the level of arousal was nonlinear. Hence, visual attention seems to be modulated by mechanisms that are separate for valence and arousal.

Ni, Jianguang; Jiang, Huihui; Jin, Yixiang; Chen, Nanhui; Wang, Jianhong; Wang, Zhengbo; Luo, Yuejia; Ma, Yuanye; Hu, Xintian

2011-01-01

87

Modulation of NMDA receptors in the cerebellum. II. Signaling pathways and physiological modulators regulating NMDA receptor function  

Microsoft Academic Search

NMDA receptors in cerebellum have specific characteristics that make their function and modulation different from those of\\u000a NMDA receptors in other brain areas. The properties of the NMDA receptor that modulate its function: Subunit composition,\\u000a post-translational modifications and synaptic localization are summarized in an accompanying article. In this review we summarize\\u000a how different signaling molecules modulate the function of NMDA

Ana Sanchez-Perez; Marta Llansola; Omar Cauli; Vicente Felipo

2005-01-01

88

Cholinergic modulation of cognition: Insights from human pharmacological functional neuroimaging  

PubMed Central

Evidence from lesion and cortical-slice studies implicate the neocortical cholinergic system in the modulation of sensory, attentional and memory processing. In this review we consider findings from sixty-three healthy human cholinergic functional neuroimaging studies that probe interactions of cholinergic drugs with brain activation profiles, and relate these to contemporary neurobiological models. Consistent patterns that emerge are: (1) the direction of cholinergic modulation of sensory cortex activations depends upon top-down influences; (2) cholinergic hyperstimulation reduces top-down selective modulation of sensory cortices; (3) cholinergic hyperstimulation interacts with task-specific frontoparietal activations according to one of several patterns, including: suppression of parietal-mediated reorienting; decreasing ‘effort’-associated activations in prefrontal regions; and deactivation of a ‘resting-state network’ in medial cortex, with reciprocal recruitment of dorsolateral frontoparietal regions during performance-challenging conditions; (4) encoding-related activations in both neocortical and hippocampal regions are disrupted by cholinergic blockade, or enhanced with cholinergic stimulation, while the opposite profile is observed during retrieval; (5) many examples exist of an ‘inverted-U shaped’ pattern of cholinergic influences by which the direction of functional neural activation (and performance) depends upon both task (e.g. relative difficulty) and subject (e.g. age) factors. Overall, human cholinergic functional neuroimaging studies both corroborate and extend physiological accounts of cholinergic function arising from other experimental contexts, while providing mechanistic insights into cholinergic-acting drugs and their potential clinical applications.

Bentley, Paul; Driver, Jon; Dolan, Raymond J.

2011-01-01

89

eg-level splitting in a layered perovskite manganite as revealed by charge modulation spectroscopy  

NASA Astrophysics Data System (ADS)

An orbital degree of freedom in Mott insulators gives strong impact on their phase transitions induced by the band-filling control or carrier doping. We have investigated the effect of electrostatic carrier doping on the electronic spectra for a layered Mott insulator Sr2MnO4 to reveal orbital-specific optical transitions. Sr2MnO4 is an n-type Mott insulator and its conduction band is composed of nearly degenerated eg orbitals dx2-y2 and d3z2-r2. The charge modulation spectra for a rectifying Sr2MnO4/Nb-doped SrTiO3 junction clearly revealed an optical transition at 1.7 eV, while a linear absorption spectrum is dominated by a transition at 2.0 eV. These are assigned to the transitions from O 2p to Mn d3z2-r2 and to dx2-y2, respectively. The accumulated charges with a density as high as 8×1013 cm-2 selectively occupy the nearly localized d3z2-r2 orbitals that hardly contribute to charge transport.

Nakamura, Masao; Kawasaki, Masashi; Tokura, Yoshinori

2012-09-01

90

Coexpression Analysis of Tomato Genes and Experimental Verification of Coordinated Expression of Genes Found in a Functionally Enriched Coexpression Module  

PubMed Central

Gene-to-gene coexpression analysis is a powerful approach to infer the function of uncharacterized genes. Here, we report comprehensive identification of coexpression gene modules of tomato (Solanum lycopersicum) and experimental verification of coordinated expression of module member genes. On the basis of the gene-to-gene correlation coefficient calculated from 67 microarray hybridization data points, we performed a network-based analysis. This facilitated the identification of 199 coexpression modules. A gene ontology annotation search revealed that 75 out of the 199 modules are enriched with genes associated with common functional categories. To verify the coexpression relationships between module member genes, we focused on one module enriched with genes associated with the flavonoid biosynthetic pathway. A non-enzyme, non-transcription factor gene encoding a zinc finger protein in this module was overexpressed in S. lycopersicum cultivar Micro-Tom, and expression levels of flavonoid pathway genes were investigated. Flavonoid pathway genes included in the module were up-regulated in the plant overexpressing the zinc finger gene. This result demonstrates that coexpression modules, at least the ones identified in this study, represent actual transcriptional coordination between genes, and can facilitate the inference of tomato gene function.

Ozaki, Soichi; Ogata, Yoshiyuki; Suda, Kunihiro; Kurabayashi, Atsushi; Suzuki, Tatsuya; Yamamoto, Naoki; Iijima, Yoko; Tsugane, Taneaki; Fujii, Takashi; Konishi, Chiaki; Inai, Shuji; Bunsupa, Somnuk; Yamazaki, Mami; Shibata, Daisuke; Aoki, Koh

2010-01-01

91

CXCR4-CCR5: A couple modulating T cell functions  

PubMed Central

Chemokines and their receptors direct leukocyte migration among blood, lymph and tissues. Evidence has recently accumulated that, besides their chemotactic functions, chemokine receptors are highly versatile players that fine tune immune responses. During human T cell activation by antigen-presenting cells, the chemokine receptors CCR5 and CXCR4 are recruited into the immunological synapse, where they deliver costimulatory signals. However, the molecular mechanisms allowing signaling versatility of chemokine receptors are unknown. Here, we describe the functional interaction between CXCR4 and CCR5 to exert specific biological functions and modulate T lymphocyte responses. We demonstrate that simultaneous expression and cooperation between CCR5 and CXCR4 are required for chemokine-induced T cell costimulation at the immunological synapse. In addition, we provide evidence for a physical association of the two receptors in a signaling complex that activates distinct T cell functions. We suggest that cooperation between receptors represents one key strategy for the functional plasticity of chemokines.

Contento, Rita Lucia; Molon, Barbara; Boularan, Cedric; Pozzan, Tullio; Manes, Santos; Marullo, Stefano; Viola, Antonella

2008-01-01

92

Pro-cognitive drug effects modulate functional brain network organization  

PubMed Central

Previous studies document that cholinergic and noradrenergic drugs improve attention, memory and cognitive control in healthy subjects and patients with neuropsychiatric disorders. In humans neural mechanisms of cholinergic and noradrenergic modulation have mainly been analyzed by investigating drug-induced changes of task-related neural activity measured with functional magnetic resonance imaging (fMRI). Endogenous neural activity has often been neglected. Further, although drugs affect the coupling between neurons, only a few human studies have explicitly addressed how drugs modulate the functional connectome, i.e., the functional neural interactions within the brain. These studies have mainly focused on synchronization or correlation of brain activations. Recently, there are some drug studies using graph theory and other new mathematical approaches to model the brain as a complex network of interconnected processing nodes. Using such measures it is possible to detect not only focal, but also subtle, widely distributed drug effects on functional network topology. Most important, graph theoretical measures also quantify whether drug-induced changes in topology or network organization facilitate or hinder information processing. Several studies could show that functional brain integration is highly correlated with behavioral performance suggesting that cholinergic and noradrenergic drugs which improve measures of cognitive performance should increase functional network integration. The purpose of this paper is to show that graph theory provides a mathematical tool to develop theory-driven biomarkers of pro-cognitive drug effects, and also to discuss how these approaches can contribute to the understanding of the role of cholinergic and noradrenergic modulation in the human brain. Finally we discuss the “global workspace” theory as a theoretical framework of pro-cognitive drug effects and argue that pro-cognitive effects of cholinergic and noradrenergic drugs might be related to higher network integration.

Giessing, Carsten; Thiel, Christiane M.

2012-01-01

93

Pro-cognitive drug effects modulate functional brain network organization.  

PubMed

Previous studies document that cholinergic and noradrenergic drugs improve attention, memory and cognitive control in healthy subjects and patients with neuropsychiatric disorders. In humans neural mechanisms of cholinergic and noradrenergic modulation have mainly been analyzed by investigating drug-induced changes of task-related neural activity measured with functional magnetic resonance imaging (fMRI). Endogenous neural activity has often been neglected. Further, although drugs affect the coupling between neurons, only a few human studies have explicitly addressed how drugs modulate the functional connectome, i.e., the functional neural interactions within the brain. These studies have mainly focused on synchronization or correlation of brain activations. Recently, there are some drug studies using graph theory and other new mathematical approaches to model the brain as a complex network of interconnected processing nodes. Using such measures it is possible to detect not only focal, but also subtle, widely distributed drug effects on functional network topology. Most important, graph theoretical measures also quantify whether drug-induced changes in topology or network organization facilitate or hinder information processing. Several studies could show that functional brain integration is highly correlated with behavioral performance suggesting that cholinergic and noradrenergic drugs which improve measures of cognitive performance should increase functional network integration. The purpose of this paper is to show that graph theory provides a mathematical tool to develop theory-driven biomarkers of pro-cognitive drug effects, and also to discuss how these approaches can contribute to the understanding of the role of cholinergic and noradrenergic modulation in the human brain. Finally we discuss the "global workspace" theory as a theoretical framework of pro-cognitive drug effects and argue that pro-cognitive effects of cholinergic and noradrenergic drugs might be related to higher network integration. PMID:22973209

Giessing, Carsten; Thiel, Christiane M

2012-08-28

94

Rbg1-Tma46 dimer structure reveals new functional domains and their role in polysome recruitment  

PubMed Central

Developmentally Regulated GTP-binding (DRG) proteins are highly conserved GTPases that associate with DRG Family Regulatory Proteins (DFRP). The resulting complexes have recently been shown to participate in eukaryotic translation. The structure of the Rbg1 GTPase, a yeast DRG protein, in complex with the C-terminal region of its DFRP partner, Tma46, was solved by X-ray diffraction. These data reveal that DRG proteins are multimodular factors with three additional domains, helix–turn–helix (HTH), S5D2L and TGS, packing against the GTPase platform. Surprisingly, the S5D2L domain is inserted in the middle of the GTPase sequence. In contrast, the region of Tma46 interacting with Rbg1 adopts an extended conformation typical of intrinsically unstructured proteins and contacts the GTPase and TGS domains. Functional analyses demonstrate that the various domains of Rbg1, as well as Tma46, modulate the GTPase activity of Rbg1 and contribute to the function of these proteins in vivo. Dissecting the role of the different domains revealed that the Rbg1 TGS domain is essential for the recruitment of this factor in polysomes, supporting further the implication of these conserved factors in translation.

Francis, Sandrea M.; Gas, Maria-Eugenia; Daugeron, Marie-Claire; Bravo, Jeronimo; Seraphin, Bertrand

2012-01-01

95

Rbg1-Tma46 dimer structure reveals new functional domains and their role in polysome recruitment.  

PubMed

Developmentally Regulated GTP-binding (DRG) proteins are highly conserved GTPases that associate with DRG Family Regulatory Proteins (DFRP). The resulting complexes have recently been shown to participate in eukaryotic translation. The structure of the Rbg1 GTPase, a yeast DRG protein, in complex with the C-terminal region of its DFRP partner, Tma46, was solved by X-ray diffraction. These data reveal that DRG proteins are multimodular factors with three additional domains, helix-turn-helix (HTH), S5D2L and TGS, packing against the GTPase platform. Surprisingly, the S5D2L domain is inserted in the middle of the GTPase sequence. In contrast, the region of Tma46 interacting with Rbg1 adopts an extended conformation typical of intrinsically unstructured proteins and contacts the GTPase and TGS domains. Functional analyses demonstrate that the various domains of Rbg1, as well as Tma46, modulate the GTPase activity of Rbg1 and contribute to the function of these proteins in vivo. Dissecting the role of the different domains revealed that the Rbg1 TGS domain is essential for the recruitment of this factor in polysomes, supporting further the implication of these conserved factors in translation. PMID:23002146

Francis, Sandrea M; Gas, María-Eugenia; Daugeron, Marie-Claire; Bravo, Jeronimo; Séraphin, Bertrand

2012-09-23

96

Compression of Flow Can Reveal Overlapping-Module Organization in Networks  

NASA Astrophysics Data System (ADS)

To better understand the organization of overlapping modules in large networks with respect to flow, we introduce the map equation for overlapping modules. In this information-theoretic framework, we use the correspondence between compression and regularity detection. The generalized map equation measures how well we can compress a description of flow in the network when we partition it into modules with possible overlaps. When we minimize the generalized map equation over overlapping network partitions, we detect modules that capture flow and determine which nodes at the boundaries between modules should be classified in multiple modules and to what degree. With a novel greedy-search algorithm, we find that some networks, for example, the neural network of the nematode Caenorhabditis elegans, are best described by modules dominated by hard boundaries, but that others, for example, the sparse European-roads network, have an organization of highly overlapping modules.

Viamontes Esquivel, Alcides; Rosvall, Martin

2011-10-01

97

Response function of modulated grid Faraday cup plasma instruments  

SciTech Connect

Modulated grid Faraday cup plasma analyzers are a very useful tool for making in situ measurements of space plasmas. One of their great attributes is that their simplicity permits their angular response function to be calculated theoretically. An expression is derived for this response function by computing the trajectories of the charged particles inside the cup. The Voyager Plasma Science (PLS) experiment is used as a specific example. Two approximations to the rigorous response function useful for data analysis are discussed. The theoretical formulas were tested by multi-sensor analysis of solar wind data. The tests indicate that the formulas represent the true cup response function for all angles of incidence with a maximum error of only a few percent.

Barnett, A.; Olbert, S.

1986-01-01

98

The response function of modulated grid Faraday cup plasma instruments  

NASA Astrophysics Data System (ADS)

Modulated grid Faraday cup plasma analyzers are a very useful tool for making in situ measurements of space plasmas. One of their great attributes is that their simplicity permits their angular response function to be calculated theoretically. An expression is derived for this response function by computing the trajectories of the charged particles inside the cup. The Voyager Plasma Science (PLS) experiment is used as a specific example. Two approximations to the rigorous response function useful for data analysis are discussed. The theoretical formulas were tested by multi-sensor analysis of solar wind data. The tests indicate that the formulas represent the true cup response function for all angles of incidence with a maximum error of only a few percent.

Barnett, A.; Olbert, S.

99

Thiolactone modulators of quorum sensing revealed through library design and screening  

PubMed Central

Quorum sensing (QS) is a process by which bacteria use small molecules or peptidic signals to assess their local population densities. At sufficiently high density, bacteria can alter gene expression levels to regulate group behaviors involved in a range of important and diverse phenotypes, including virulence factor production, biofilm formation, root nodulation, and bioluminescence. Gram-negative bacteria most commonly use N-acylated L-homoserine lactones (AHLs) as their QS signals. The AHL lactone ring is hydrolyzed relatively rapidly at biological pH, and the ring-opened product is QS inactive. We seek to identify AHL analogues with heightened hydrolytic stability, and thereby potentially heightened activity, for use as non-native modulators of bacterial QS. As part of this effort, we probed the utility of thiolactone analogues in the current study as QS agonists and antagonists in Gram-negative bacteria. A focused library of thiolactone analogs was designed and rapidly synthesized in solution. We examined the activity of the library as agonists and antagonists of LuxR-type QS receptors in Pseudomonas aeruginosa (LasR), Vibrio fischeri (LuxR), and Agrobacterium tumefaciens (TraR) using bacterial reporter strains. The thiolactone library contained several highly active compounds, including some of the most active LuxR inhibitors and the most active synthetic TraR agonist reported to date. Analysis of a representative thiolactone analog revealed that its hydrolysis half-life was almost double that of its parent AHL in bacterial growth medium.

McInnis, Christine E.; Blackwell, Helen E.

2011-01-01

100

Frequency Modulation Atomic Force Microscopy Reveals Individual Intermediates Associated with each Unfolded I27 Titin Domain  

PubMed Central

In this study, we apply a dynamic atomic force microscopy (AFM) technique, frequency modulation (FM) detection, to the mechanical unfolding of single titin I27 domains and make comparisons with measurements made using the AFM contact or static mode method. Static mode measurements revealed the well-known force transition occurring at 100–120 pN in the first unfolding peak, which was less clear, or more often absent, in the subsequent unfolding peaks. In contrast, some FM-AFM curves clearly resolved a force transition associated with each of the unfolding peaks irrespective of the number of observed unfolded domains. As expected for FM-AFM, the frequency shift response of the main unfolding peaks and their intermediates could only be detected when the oscillation amplitudes used were smaller than the interaction lengths being measured. It was also shown that the forces measured for the dynamical interaction of the FM-AFM technique were significantly lower than those measured using the static mode. This study highlights the potential for using dynamic AFM for investigating biological interactions, including protein unfolding and the detection of novel unfolding intermediates.

Higgins, Michael J.; Sader, John E.; Jarvis, Suzanne P.

2006-01-01

101

Postnatal Experience Modulates Functional Properties of Mouse Olfactory Sensory Neurons  

PubMed Central

Early experience considerably modulates the organization and function of all sensory systems. In the mammalian olfactory system, deprivation of the sensory inputs via neonatal, unilateral naris closure has been shown to induce structural, molecular, and functional changes from the olfactory epithelium to the olfactory bulb and cortex. However, it remains unknown how early experience shapes functional properties of individual olfactory sensory neurons (OSNs), the primary odor detectors in the nose. To address this question, we examined odorant response properties of mouse OSNs in both the closed and open nostril after four weeks of unilateral naris closure with age-matched untreated animals as control. Using patch-clamp technique on genetically-tagged OSNs with defined odorant receptors (ORs), we found that sensory deprivation increased the sensitivity of MOR23 neurons in the closed side while overexposure caused the opposite effect in the open side. We next analyzed the response properties including rise time, decay time, and adaptation induced by repeated stimulation in MOR23 and M71 neurons. Even though these two types of neurons showed distinct properties in dynamic range and response kinetics, sensory deprivation significantly slowed down the decay phase of odorant-induced transduction events in both types. Using western blotting and antibody staining, we confirmed upregulation of several signaling proteins in the closed side as compared with the open side. This study suggests that early experience modulates functional properties of OSNs, probably via modifying the signal transduction cascade.

He, Jiwei; Tian, Huikai; Lee, Anderson C.; Ma, Minghong

2012-01-01

102

Temporal modulation transfer functions in auditory receptor fibres of the locust ( Locusta migratoria L.)  

Microsoft Academic Search

The temporal resolution of auditory receptors of locusts was investigated by applying noise stimuli with sinusoidal amplitude modulations and by computing temporal modulation transfer functions. These transfer functions showed mostly bandpass characteristics, which are rarely found in other species at the level of receptors. From the upper cut-off frequencies of the modulation transfer functions the minimum integration times were calculated.

P. Prinz; B. Ronacher

2002-01-01

103

Module-based subnetwork alignments reveal novel transcriptional regulators in malaria parasite Plasmodium falciparum  

PubMed Central

Background Malaria causes over one million deaths annually, posing an enormous health and economic burden in endemic regions. The completion of genome sequencing of the causative agents, a group of parasites in the genus Plasmodium, revealed potential drug and vaccine candidates. However, genomics-driven target discovery has been significantly hampered by our limited knowledge of the cellular networks associated with parasite development and pathogenesis. In this paper, we propose an approach based on aligning neighborhood PPI subnetworks across species to identify network components in the malaria parasite P. falciparum. Results Instead of only relying on sequence similarities to detect functional orthologs, our approach measures the conservation between the neighborhood subnetworks in protein-protein interaction (PPI) networks in two species, P. falciparum and E. coli. 1,082 P. falciparum proteins were predicted as functional orthologs of known transcriptional regulators in the E. coli network, including general transcriptional regulators, parasite-specific transcriptional regulators in the ApiAP2 protein family, and other potential regulatory proteins. They are implicated in a variety of cellular processes involving chromatin remodeling, genome integrity, secretion, invasion, protein processing, and metabolism. Conclusions In this proof-of-concept study, we demonstrate that a subnetwork alignment approach can reveal previously uncharacterized members of the subnetworks, which opens new opportunities to identify potential therapeutic targets and provide new insights into parasite biology, pathogenesis and virulence. This approach can be extended to other systems, especially those with poor genome annotation and a paucity of knowledge about cellular networks.

2012-01-01

104

Fourth moments reveal the negativity of the Wigner function  

SciTech Connect

The presence of unique quantum correlations is the core of quantum-information processing and general quantum theory. We address the fundamental question of how quantum correlations of a generic quantum system can be probed using correlation functions defined for quasiprobability distributions. In particular, we discuss the possibility of probing the negativity of a quasiprobability by comparing moments of the Wigner function. We show that one must take at least the fourth moments to find the negativity in general and the eighth moments for states with a rotationally invariant Wigner function.

Bednorz, Adam [Faculty of Physics, University of Warsaw, Hoza 69, PL-00681 Warsaw (Poland); Belzig, Wolfgang [Fachbereich Physik, Universitaet Konstanz, D-78457 Konstanz (Germany)

2011-05-15

105

Nonoisotopic Assay for the Presynaptic Choline Transporter Reveals Capacity for Allosteric Modulation of Choline Uptake  

PubMed Central

Current therapies to enhance CNS cholinergic function rely primarily on extracellular acetylcholinesterase (AChE) inhibition, a pharmacotherapeutic strategy that produces dose-limiting side effects. The Na+-dependent, high-affinity choline transporter (CHT) is an unexplored target for cholinergic medication development. Although functional at the plasma membrane, CHT at steady-state is localized to synaptic vesicles such that vesicular fusion can support a biosynthetic response to neuronal excitation. To identify allosteric potentiators of CHT activity, we mapped endocytic sequences in the C-terminus of human CHT, identifying transporter mutants that exhibit significantly increased transport function. A stable HEK-293 cell line was generated from one of these mutants (CHT LV-AA) and used to establish a high-throughput screen (HTS) compatible assay based on the electrogenic nature of the transporter. We established that the addition of choline to these cells, at concentrations appropriate for high-affinity choline transport at presynaptic terminals, generates a hemicholinium-3 (HC-3)-sensitive, membrane depolarization that can be used for the screening of CHT inhibitors and activators. Using this assay, we discovered that staurosporine increased CHT LV-AA choline uptake activity, an effect mediated by a decrease in choline KM with no change in Vmax. As staurosporine did not change surface levels of CHT, nor inhibit HC-3 binding, we propose that its action is directly or indirectly allosteric in nature. Surprisingly, staurosporine reduced choline-induced membrane depolarization, suggesting that increased substrate coupling to ion gradients, arising at the expense of nonstoichiometric ion flow, accompanies a shift of CHT to a higher-affinity state. Our findings provide a new approach for the identification of CHT modulators that is compatible with high-throughput screening approaches and presents a novel model by which small molecules can enhance substrate flux through enhanced gradient coupling.

2012-01-01

106

Spectro-temporal modulation transfer functions and speech intelligibility.  

PubMed

Detection thresholds for spectral and temporal modulations are measured using broadband spectra with sinusoidally rippled profiles that drift up or down the log-frequency axis at constant velocities. Spectro-temporal modulation transfer functions (MTFs) are derived as a function of ripple peak density (omega cycles/octave) and drifting velocity (omega Hz). The MTFs exhibit a low-pass function with respect to both dimensions, with 50% bandwidths of about 16 Hz and 2 cycles/octave. The data replicate (as special cases) previously measured purely temporal MTFs (omega = 0) [Viemeister, J. Acoust. Soc. Am. 66, 1364-1380 (1979)] and purely spectral MTFs (omega = 0) [Green, in Auditory Frequency Selectivity (Plenum, Cambridge, 1986), pp. 351-359]. A computational auditory model is presented that exhibits spectro-temporal MTFs consistent with the salient trends in the data. The model is used to demonstrate the potential relevance of these MTFs to the assessment of speech intelligibility in noise and reverberant conditions. PMID:10573888

Chi, T; Gao, Y; Guyton, M C; Ru, P; Shamma, S

1999-11-01

107

Reticulon1-C modulates protein disulphide isomerase function.  

PubMed

Endoplasmic reticulum (ER) is the primary site for the synthesis and folding of secreted and membrane-bound proteins. Accumulation of unfolded and misfolded proteins in ER underlies a wide range of human neurodegenerative disorders. Hence, molecules regulating the ER stress response represent potential candidates as drug targets for tackling these diseases. Protein disulphide isomerase (PDI) is a chaperone involved in ER stress pathway, its activity being an important cellular defense against protein misfolding. Here, we demonstrate that human neuroblastoma SH-SY5Y cells overexpressing the reticulon protein 1-C (RTN1-C) reticulon family member show a PDI punctuate subcellular distribution identified as ER vesicles. This represents an event associated with a significant increase of PDI enzymatic activity. We provide evidence that the modulation of PDI localization and activity does not only rely upon ER stress induction or upregulation of its synthesis, but tightly correlates to an alteration in its nitrosylation status. By using different RTN1-C mutants, we demonstrate that the observed effects depend on RTN1-C N-terminal region and on the integrity of the microtubule network. Overall, our results indicate that RTN1-C induces PDI redistribution in ER vesicles, and concomitantly modulates its activity by decreasing the levels of its S-nitrosylated form. Thus RTN1-C represents a promising candidate to modulate PDI function. PMID:23559015

Bernardoni, P; Fazi, B; Costanzi, A; Nardacci, R; Montagna, C; Filomeni, G; Ciriolo, M R; Piacentini, M; Di Sano, F

2013-04-04

108

MAPK target networks in Arabidopsis thaliana revealed using functional protein microarrays.  

PubMed

Signaling through mitogen-activated protein kinases (MPKs) cascades is a complex and fundamental process in eukaryotes, requiring MPK-activating kinases (MKKs) and MKK-activating kinases (MKKKs). However, to date only a limited number of MKK-MPK interactions and MPK phosphorylation substrates have been revealed. We determined which Arabidopsis thaliana MKKs preferentially activate 10 different MPKs in vivo and used the activated MPKs to probe high-density protein microarrays to determine their phosphorylation targets. Our analyses revealed known and novel signaling modules encompassing 570 MPK phosphorylation substrates; these substrates were enriched in transcription factors involved in the regulation of development, defense, and stress responses. Selected MPK substrates were validated by in planta reconstitution experiments. A subset of activated and wild-type MKKs induced cell death, indicating a possible role for these MKKs in the regulation of cell death. Interestingly, MKK7- and MKK9-induced death requires Sgt1, a known regulator of cell death induced during plant innate immunity. Our predicted MKK-MPK phosphorylation network constitutes a valuable resource to understand the function and specificity of MPK signaling systems. PMID:19095804

Popescu, Sorina C; Popescu, George V; Bachan, Shawn; Zhang, Zimei; Gerstein, Mark; Snyder, Michael; Dinesh-Kumar, Savithramma P

2008-12-18

109

Flavivirus Replication Complex Assembly Revealed by DNAJC14 Functional Mapping  

PubMed Central

DNAJC14 is an Hsp40 family member that broadly modulates flavivirus replication. The mechanism by which DNAJC14 stoichiometrically participates in flavivirus replication complex (RC) formation is unknown; both reduced and elevated levels result in replication inhibition. Using yellow fever virus (YFV), we demonstrate that DNAJC14 redistributes and clusters with YFV nonstructural proteins via a transmembrane domain and a newly identified membrane-binding domain (MBD), which both mediate targeting to detergent-resistant membranes. Furthermore, the RC and DNAJC14 reside as part of a protein interaction network that remains after 1% Triton solubilization. Mutagenesis studies demonstrate that entry into this protein interaction network requires the DNAJC14 C-terminal self-interaction domain. Fusion of the DNAJC14 MBD and self-interaction domain with another Hsp40 family protein is sufficient to confer YFV-inhibitory activity. Our findings support a novel model of DNAJC14 action that includes specific membrane targeting of both DNAJC14 and YFV replication proteins, the formation of protein interactions, and a microdomain-specific chaperone event leading to RC formation. This process alters the properties of the RC membrane and results in the formation of a protein scaffold that maintains the RC.

Yi, Zhigang; Yuan, Zhenghong; Rice, Charles M.

2012-01-01

110

Prethermalization revealed by the relaxation dynamics of full distribution functions  

NASA Astrophysics Data System (ADS)

We detail the experimental observation of the non-equilibrium many-body phenomenon prethermalization. We study the dynamics of a rapidly and coherently split one-dimensional Bose gas. An analysis based on the use of full quantum mechanical probability distributions of matter wave interference contrast reveals that the system evolves toward a quasi-steady state. This state, which can be characterized by an effective temperature, is not the final thermal equilibrium state. We compare the evolution of the system to an integrable Tomonaga-Luttinger liquid model, and show that the system dephases to a prethermalized state rather than undergoing thermalization toward a final thermal equilibrium state.

Adu Smith, D.; Gring, M.; Langen, T.; Kuhnert, M.; Rauer, B.; Geiger, R.; Kitagawa, T.; Mazets, I.; Demler, E.; Schmiedmayer, J.

2013-07-01

111

Functional brain connectivity as revealed by singular spectrum analysis.  

PubMed

Correlation based measures have widely been used to characterize brain connectivity. In this paper, a new approach based on singular spectrum analysis is proposed to characterize brain connectivity. It is obtained by deriving the common basis vector of two or more trajectory matrices associated with functional brain responses. This approach has the advantage illustrating the existence of joint variations of the functional brain responses and to characterize the correlation structure. The performance of the method are illustrated on both simulated autoregressive data and real fMRI data. PMID:23367097

Seghouane, Abd-Krim; Shah, Adnan

2012-01-01

112

Revealing Topological Organization of Human Brain Functional Networks with Resting-State Functional near Infrared Spectroscopy  

PubMed Central

Background The human brain is a highly complex system that can be represented as a structurally interconnected and functionally synchronized network, which assures both the segregation and integration of information processing. Recent studies have demonstrated that a variety of neuroimaging and neurophysiological techniques such as functional magnetic resonance imaging (MRI), diffusion MRI and electroencephalography/magnetoencephalography can be employed to explore the topological organization of human brain networks. However, little is known about whether functional near infrared spectroscopy (fNIRS), a relatively new optical imaging technology, can be used to map functional connectome of the human brain and reveal meaningful and reproducible topological characteristics. Results We utilized resting-state fNIRS (R-fNIRS) to investigate the topological organization of human brain functional networks in 15 healthy adults. Brain networks were constructed by thresholding the temporal correlation matrices of 46 channels and analyzed using graph-theory approaches. We found that the functional brain network derived from R-fNIRS data had efficient small-world properties, significant hierarchical modular structure and highly connected hubs. These results were highly reproducible both across participants and over time and were consistent with previous findings based on other functional imaging techniques. Conclusions Our results confirmed the feasibility and validity of using graph-theory approaches in conjunction with optical imaging techniques to explore the topological organization of human brain networks. These results may expand a methodological framework for utilizing fNIRS to study functional network changes that occur in association with development, aging and neurological and psychiatric disorders.

Zhao, Tengda; Shu, Ni; He, Yong

2012-01-01

113

Functionally guided alignment of protein interaction networks for module detection  

PubMed Central

Motivation: Functional module detection within protein interaction networks is a challenging problem due to the sparsity of data and presence of errors. Computational techniques for this task range from purely graph theoretical approaches involving single networks to alignment of multiple networks from several species. Current network alignment methods all rely on protein sequence similarity to map proteins across species. Results: Here we carry out network alignment using a protein functional similarity measure. We show that using functional similarity to map proteins across species improves network alignment in terms of functional coherence and overlap with experimentally verified protein complexes. Moreover, the results from functional similarity-based network alignment display little overlap (<15%) with sequence similarity-based alignment. Our combined approach integrating sequence and function-based network alignment alongside graph clustering properties offers a 200% increase in coverage of experimental datasets and comparable accuracy to current network alignment methods. Availability: Program binaries and source code is freely available at http://www.stats.ox.ac.uk/research/bioinfo/resources Contact: ali@stats.ox.ac.uk Supplementary Information: Supplementary data are available at Bioinformatics online.

Ali, Waqar; Deane, Charlotte M.

2009-01-01

114

Microscale laser surgery reveals adaptive function of male intromittent genitalia  

Microsoft Academic Search

The leading hypothesis for the evolution of male genital complexity proposes that genital traits evolve in response to post-insemination sexual selection; that is, via cryptic female choice or sperm competition. Here, we describe a laser ablation technique for high-precision manipulation of microscale body parts of insects, and employ it to discern the adaptive function of a rapidly evolving and taxonomically

Michal Polak; Arash Rashed

2010-01-01

115

Simulation of modulation transfer function using a rendering method.  

PubMed

We propose a novel simulation method based on rendering to evaluate the modulation transfer function (MTF) of optical imaging systems. The new simulation method corresponds to an experimental measurement of the MTF using imaging resolution test charts, and therefore allows an analysis of the resolving power of shift-variant optical systems that are difficult to evaluate with conventional methods based on the point spread function (PSF). Furthermore, the effects of stray light, such as from reflection or scattering, on the imaging performance can be analyzed. In contrast to methods based on illumination optics using Monte Carlo methods, the proposed method calculates the intensities on an image surface with rendering techniques used in three-dimensional computer graphics (3D CG), which results in calculations that are faster and have a higher precision. The proposed method is highly effective in analyzing the MTF of optical imaging systems through simulations. PMID:23546121

Horiuchi, Shuma; Yoshida, Shuhei; Yamamoto, Manabu

2013-03-25

116

Patching the glia reveals the functional organisation of the brain.  

PubMed

The neuroglia was initially conceived by Rudolf Virchow as a non-cellular connective tissue holding neurones together. In 1894, Carl Ludwig Schleich proposed a hypothesis of fully integrated and interconnected neuronal-glial circuits as a substrate for brain function. This hypothesis received direct experimental support only hundred years later, after several physiological techniques, and most notably the patch-clamp method, were applied to glial cells. These experiments have demonstrated the existence of active and bi-directional neuronal-glial communications, integrating neuronal networks and glial syncytium into one functional circuit. The data accumulated during last 15 years prompt rethinking of the neuronal doctrine towards more inclusive concept, which regards both neurones and glia as equally responsible for information processing in the brain. PMID:16775706

Verkhratsky, Alexei

2006-06-15

117

Patching the glia reveals the functional organisation of the brain  

Microsoft Academic Search

The neuroglia was initially conceived by Rudolf Virchow as a non-cellular connective tissue holding neurones together. In\\u000a 1894, Carl Ludwig Schleich proposed a hypothesis of fully integrated and interconnected neuronal-glial circuits as a substrate\\u000a for brain function. This hypothesis received direct experimental support only hundred years later, after several physiological\\u000a techniques, and most notably the patch-clamp method, were applied to

Alexei Verkhratsky

2006-01-01

118

Immunoglobulin Structure and Function as Revealed by Electron Microscopy  

Microsoft Academic Search

Electron–microscopic (EM) analysis preceded crystallographic analysis [1, 2]of Igs by over a decade and was for a time the only direct way of analyzing their 3–D molecular structure. Once the X–ray structures were deduced, the role of EM gradually shifted from gross structural analysis to the addressing of more sophisticated structural and functional questions. EM remains a vital adjunct to

Kenneth H. Roux

1999-01-01

119

Genome-wide association and functional follow-up reveals new loci for kidney function.  

PubMed

Chronic kidney disease (CKD) is an important public health problem with a genetic component. We performed genome-wide association studies in up to 130,600 European ancestry participants overall, and stratified for key CKD risk factors. We uncovered 6 new loci in association with estimated glomerular filtration rate (eGFR), the primary clinical measure of CKD, in or near MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80. Morpholino knockdown of mpped2 and casp9 in zebrafish embryos revealed podocyte and tubular abnormalities with altered dextran clearance, suggesting a role for these genes in renal function. By providing new insights into genes that regulate renal function, these results could further our understanding of the pathogenesis of CKD. PMID:22479191

Pattaro, Cristian; Köttgen, Anna; Teumer, Alexander; Garnaas, Maija; Böger, Carsten A; Fuchsberger, Christian; Olden, Matthias; Chen, Ming-Huei; Tin, Adrienne; Taliun, Daniel; Li, Man; Gao, Xiaoyi; Gorski, Mathias; Yang, Qiong; Hundertmark, Claudia; Foster, Meredith C; O'Seaghdha, Conall M; Glazer, Nicole; Isaacs, Aaron; Liu, Ching-Ti; Smith, Albert V; O'Connell, Jeffrey R; Struchalin, Maksim; Tanaka, Toshiko; Li, Guo; Johnson, Andrew D; Gierman, Hinco J; Feitosa, Mary; Hwang, Shih-Jen; Atkinson, Elizabeth J; Lohman, Kurt; Cornelis, Marilyn C; Johansson, Åsa; Tönjes, Anke; Dehghan, Abbas; Chouraki, Vincent; Holliday, Elizabeth G; Sorice, Rossella; Kutalik, Zoltan; Lehtimäki, Terho; Esko, Tõnu; Deshmukh, Harshal; Ulivi, Sheila; Chu, Audrey Y; Murgia, Federico; Trompet, Stella; Imboden, Medea; Kollerits, Barbara; Pistis, Giorgio; Harris, Tamara B; Launer, Lenore J; Aspelund, Thor; Eiriksdottir, Gudny; Mitchell, Braxton D; Boerwinkle, Eric; Schmidt, Helena; Cavalieri, Margherita; Rao, Madhumathi; Hu, Frank B; Demirkan, Ayse; Oostra, Ben A; de Andrade, Mariza; Turner, Stephen T; Ding, Jingzhong; Andrews, Jeanette S; Freedman, Barry I; Koenig, Wolfgang; Illig, Thomas; Döring, Angela; Wichmann, H-Erich; Kolcic, Ivana; Zemunik, Tatijana; Boban, Mladen; Minelli, Cosetta; Wheeler, Heather E; Igl, Wilmar; Zaboli, Ghazal; Wild, Sarah H; Wright, Alan F; Campbell, Harry; Ellinghaus, David; Nöthlings, Ute; Jacobs, Gunnar; Biffar, Reiner; Endlich, Karlhans; Ernst, Florian; Homuth, Georg; Kroemer, Heyo K; Nauck, Matthias; Stracke, Sylvia; Völker, Uwe; Völzke, Henry; Kovacs, Peter; Stumvoll, Michael; Mägi, Reedik; Hofman, Albert; Uitterlinden, Andre G; Rivadeneira, Fernando; Aulchenko, Yurii S; Polasek, Ozren; Hastie, Nick; Vitart, Veronique; Helmer, Catherine; Wang, Jie Jin; Ruggiero, Daniela; Bergmann, Sven; Kähönen, Mika; Viikari, Jorma; Nikopensius, Tiit; Province, Michael; Ketkar, Shamika; Colhoun, Helen; Doney, Alex; Robino, Antonietta; Giulianini, Franco; Krämer, Bernhard K; Portas, Laura; Ford, Ian; Buckley, Brendan M; Adam, Martin; Thun, Gian-Andri; Paulweber, Bernhard; Haun, Margot; Sala, Cinzia; Metzger, Marie; Mitchell, Paul; Ciullo, Marina; Kim, Stuart K; Vollenweider, Peter; Raitakari, Olli; Metspalu, Andres; Palmer, Colin; Gasparini, Paolo; Pirastu, Mario; Jukema, J Wouter; Probst-Hensch, Nicole M; Kronenberg, Florian; Toniolo, Daniela; Gudnason, Vilmundur; Shuldiner, Alan R; Coresh, Josef; Schmidt, Reinhold; Ferrucci, Luigi; Siscovick, David S; van Duijn, Cornelia M; Borecki, Ingrid; Kardia, Sharon L R; Liu, Yongmei; Curhan, Gary C; Rudan, Igor; Gyllensten, Ulf; Wilson, James F; Franke, Andre; Pramstaller, Peter P; Rettig, Rainer; Prokopenko, Inga; Witteman, Jacqueline C M; Hayward, Caroline; Ridker, Paul; Parsa, Afshin; Bochud, Murielle; Heid, Iris M; Goessling, Wolfram; Chasman, Daniel I; Kao, W H Linda; Fox, Caroline S

2012-03-29

120

Microscale laser surgery reveals adaptive function of male intromittent genitalia  

PubMed Central

The leading hypothesis for the evolution of male genital complexity proposes that genital traits evolve in response to post-insemination sexual selection; that is, via cryptic female choice or sperm competition. Here, we describe a laser ablation technique for high-precision manipulation of microscale body parts of insects, and employ it to discern the adaptive function of a rapidly evolving and taxonomically important genital trait: the intromittent claw-like genital spines of male Drosophila bipectinata Duda. We demonstrate experimentally and unambiguously that the genital spines of this species function to mechanically couple the genitalia together. The excision of the spines by laser ablation sharply reduced the ability of males both to copulate and to compete against rival males for mates. When spineless males did succeed to copulate, their insemination success and fertilization rate were not statistically different from controls, at odds with the post-insemination sexual selection hypothesis of genital function and evolution. The results provide direct experimental support for the hypothesis that genital traits evolve in response to sexual selection occurring prior to insemination.

Polak, Michal; Rashed, Arash

2010-01-01

121

Functional network analysis reveals differences in the semantic priming task.  

PubMed

The recent years have seen the emergence of graph theoretical analysis of complex, functional brain networks estimated from neurophysiological measurements. The research has mainly focused on the graph characterization of the resting-state/default network, and its potential for clinical application. Functional resting-state networks usually display the characteristics of small-world networks and their statistical properties have been observed to change due to pathological conditions or aging. In the present paper we move forward in the application of graph theoretical tools in functional connectivity by investigating high-level cognitive processing in healthy adults, in a manner similar to that used in psychological research in the framework of event-related potentials (ERPs). More specifically we aim at investigating how graph theoretical approaches can help to discover systematic and task-dependent differences in high-level cognitive processes such as language perception. We will show that such an approach is feasible and that the results coincide well with the findings from neuroimaging studies. PMID:21376754

Schinkel, Stefan; Zamora-López, Gorka; Dimigen, Olaf; Sommer, Werner; Kurths, Jürgen

2011-03-03

122

Novel Functions of Photoreceptor Guanylate Cyclases Revealed by Targeted Deletion  

PubMed Central

Targeted deletion of membrane guanylyl cyclases (GCs) has yielded new information concerning their function. Here, we summarize briefly recent results of laboratory generated non-photoreceptor GC knockouts characterized by complex phenotypes affecting the vasculature, heart, brain, kidney and other tissues. The main emphasis of the review, however, addresses the two GCs expressed in retinal photoreceptors, termed GC-E and GC-F. Naturally occurring GC-E (GUCY2D) null alleles in human and chicken are associated with an early onset blinding disorder, termed ‘Leber Congenital Amaurosis type 1’ (LCA-1), characterized by extinguished scotopic and photopic ERGs, and retina degeneration. In mouse, a GC-E null genotype produces a recessive cone dystrophy, while rods remain functional. Rod function is supported by the presence of GC-F (Gucy2f), a close relative of GC-E. Deletion of Gucy2f has very little effect on rod and cone physiology and survival. However, a GC-E/GC-F double knockout (GCdko) phenotypically resembles human LCA-1 with extinguished ERGs and rod/cone degneration. In GCdko rods, PDE6 and GCAPs are absent in outer segments. In contrast, GC-E-/- cones lack proteins of the entire phototransduction cascade. These results suggest that GC-E may participate in transport of peripheral membrane proteins from the endoplasmic reticulum (ER) to the outer segments.

Karan, Sukanya; Frederick, Jeanne M.; Baehr, Wolfgang

2010-01-01

123

Effects of the modulation of microbiota on the gastrointestinal immune system and bowel function.  

PubMed

The gastrointestinal tract harbors a tremendous number and variety of commensal microbiota. The intestinal mucosa simultaneously absorbs essential nutrients and protects against detrimental antigens or pathogenic microbiota as the first line of defense. Beneficial interactions between the host and microbiota are key requirements for host health. Although the gut microbiota has been previously studied in the context of inflammatory diseases, it has recently become clear that this microbial environment has a beneficial role during normal homeostasis, by modulating the immune system or bowel motor function. Recent studies revealed that microbiota, including their metabolites, modulate key signaling pathways involved in the inflammation of the mucosa or the neurotransmitter system in the gut-brain axis. The underlying molecular mechanisms of host-microbiota interactions are still unclear; however, manipulation of microbiota by probiotics or prebiotics is becoming increasingly recognized as an important therapeutic option, especially for the treatment of the dysfunction or inflammation of the intestinal tract. PMID:24070265

Kanauchi, Osamu; Andoh, Akira; Mitsuyama, Keiichi

2013-10-15

124

Forced expression of dystrophin deletion constructs reveals structure- function correlations  

PubMed Central

Dystrophin plays an important role in skeletal muscle by linking the cytoskeleton and the extracellular matrix. The amino terminus of dystrophin binds to actin and possibly other components of the subsarcolemmal cytoskeleton, while the carboxy terminus associates with a group of integral and peripheral membrane proteins and glycoproteins that are collectively known as the dystrophin-associated protein (DAP) complex. We have generated transgenic/mdx mice expressing "full-length" dystrophin constructs, but with consecutive deletions within the COOH- terminal domains. These mice have enabled analysis of the interaction between dystrophin and members of the DAP complex and the effects that perturbing these associations have on the dystrophic process. Deletions within the cysteine-rich region disrupt the interaction between dystrophin and the DAP complex, leading to a severe dystrophic pathology. These deletions remove the beta-dystroglycan-binding site, which leads to a parallel loss of both beta-dystroglycan and the sarcoglycan complex from the sarcolemma. In contrast, deletion of the alternatively spliced domain and the extreme COOH terminus has no apparent effect on the function of dystrophin when expressed at normal levels. The proteins resulting from these latter two deletions supported formation of a completely normal DAP complex, and their expression was associated with normal muscle morphology in mdx mice. These data indicate that the cysteine-rich domain is critical for functional activity, presumably by mediating a direct interaction with beta-dystroglycan. However, the remainder of the COOH terminus is not required for assembly of the DAP complex.

1996-01-01

125

Molecular dissection of botulinum neurotoxin reveals interdomain chaperone function.  

PubMed

Clostridium botulinum neurotoxin (BoNT) is a multi-domain protein made up of the approximately 100 kDa heavy chain (HC) and the approximately 50 kDa light chain (LC). The HC can be further subdivided into two halves: the N-terminal translocation domain (TD) and the C-terminal Receptor Binding Domain (RBD). We have investigated the minimal requirements for channel activity and LC translocation. We utilize a cellular protection assay and a single channel/single molecule LC translocation assay to characterize in real time the channel and chaperone activities of BoNT/A truncation constructs in Neuro 2A cells. The unstructured, elongated belt region of the TD is demonstrated to be dispensable for channel activity, although may be required for productive LC translocation. We show that the RBD is not necessary for channel activity or LC translocation, however it dictates the pH threshold of channel insertion into the membrane. These findings indicate that each domain functions as a chaperone for the others in addition to their individual functions, working in concert to achieve productive intoxication. PMID:23396042

Fischer, Audrey; Montal, Mauricio

2013-02-05

126

Global Analysis of ATM Polymorphism Reveals Significant Functional Constraint  

PubMed Central

ATM, the gene that is mutated in ataxia-telangiectasia, is associated with cerebellar degeneration, abnormal proliferation of small blood vessels, and cancer. These clinically important manifestations have stimulated interest in defining the sequence variation in the ATM gene. Therefore, we undertook a comprehensive survey of sequence variation in ATM in diverse human populations. The protein-encoding exons of the gene (9,168 bp) and the adjacent intron and untranslated sequences (14,661 bp) were analyzed in 93 individuals from seven major human populations. In addition, the coding sequence was analyzed in one chimpanzee, one gorilla, one orangutan, and one Old World monkey. In human ATM, 88 variant sites were discovered by denaturing high-performance liquid chromatography, which is 96%–100% sensitive for detection of DNA sequence variation. ATM was compared to 14 other autosomal genes for nucleotide diversity. The noncoding regions of ATM had diversity values comparable to other genes, but the coding regions had very low diversity, especially in the last 29% of the protein sequence. A test of the neutral evolution hypothesis, through use of the Hudson/Kreitman/Aguadé statistic, revealed that this region of the human ATM gene was significantly constrained relative to that of the orangutan, the Old World monkey, and the mouse, but not relative to that of the chimpanzee or the gorilla. ATM displayed extensive linkage disequilibrium, consistent with suppression of meiotic recombination at this locus. Seven haplotypes were defined. Two haplotypes accounted for 82% of all chromosomes analyzed in all major populations; two others carrying the same D126E missense polymorphism accounted for 33% of chromosomes in Africa but were never observed outside of Africa. The high frequency of this polymorphism may be due either to a population expansion within Africa or to selective pressure.

Thorstenson, Yvonne R.; Shen, Peidong; Tusher, Virginia G.; Wayne, Tierney L.; Davis, Ronald W.; Chu, Gilbert; Oefner, Peter J.

2001-01-01

127

Involvement of oxidative and nitrosative stress in modulation of gene expression and functional responses by IFNgamma.  

PubMed

IFNgamma is a potent immunomodulator which plays important roles in host defense. IFNgamma modulates transcription of growth-related genes [N-myc downstream regulator 1, growth arrest and DNA damage inducible gamma and inhibitor of DNA binding 2 (Id2)], which is followed by increased growth suppression in the mouse hepatoma cell line, H6. Further studies revealed modulation of genes involved in oxidative and nitrosative stress (iNos, gp91phox and Catalase) and increased generation of reactive oxygen species (ROS) and reactive nitrogen intermediates (RNIs) upon IFNgamma treatment. High amounts of ROS and RNI are responsible for IFNgamma-mediated reduction in cell growth as this process is blocked, using either diphenylene iodonium (DPI), an inhibitor of flavin-containing NADPH oxidases, or N-methyl L-arginine (LNMA), an inhibitor of nitric oxide synthase. Based on studies with LNMA and DPI, IFNgamma-modulated genes can be categorized into two distinct sets: oxidative and nitrosative stress independent (transporter associated with antigen processing 2, Cd80, Lmp10 and Icosl) and oxidative and nitrosative stress dependent (iNos, gp91phox, Catalase and Id2). In addition, DPI or LNMA blocked IFNgamma-induced activation of Ras, demonstrating the involvement of oxidative and nitrosative stress. Manumycin A, a farnesyl transferase inhibitor, blocked Ras activation and reduced NADPH oxidase activity and ROS amounts leading to increased cell growth in the presence of IFNgamma. Notably, the IFNgamma-induced MHC class I levels are not modulated in cells treated with DPI, LNMA or manumycin A. Together, these results delineate the role of high amounts of ROS, RNI and Ras activation in modulating expression of some genes and, thereby, function by IFNgamma. The implications of these results during modulation of immune responses by IFNgamma are discussed. PMID:17606979

Prasanna, S Jyothi; Saha, Banishree; Nandi, Dipankar

2007-07-02

128

Dolphin whistles: a functional misnomer revealed by heliox breathing.  

PubMed

Delphinids produce tonal whistles shaped by vocal learning for acoustic communication. Unlike terrestrial mammals, delphinid sound production is driven by pressurized air within a complex nasal system. It is unclear how fundamental whistle contours can be maintained across a large range of hydrostatic pressures and air sac volumes. Two opposing hypotheses propose that tonal sounds arise either from tissue vibrations or through actual whistle production from vortices stabilized by resonating nasal air volumes. Here, we use a trained bottlenose dolphin whistling in air and in heliox to test these hypotheses. The fundamental frequency contours of stereotyped whistles were unaffected by the higher sound speed in heliox. Therefore, the term whistle is a functional misnomer as dolphins actually do not whistle, but form the fundamental frequency contour of their tonal calls by pneumatically induced tissue vibrations analogous to the operation of vocal folds in terrestrial mammals and the syrinx in birds. This form of tonal sound production by nasal tissue vibrations has probably evolved in delphinids to enable impedance matching to the water, and to maintain tonal signature contours across changes in hydrostatic pressures, air density and relative nasal air volumes during dives. PMID:21900314

Madsen, P T; Jensen, F H; Carder, D; Ridgway, S

2011-09-07

129

Structural and Functional Studies of the Rap1 C-Terminus Reveal Novel Separation-of-Function Mutants  

SciTech Connect

The yeast Rap1 protein plays an important role in transcriptional silencing and in telomere length homeostasis. Rap1 mediates silencing at the HM loci and at telomeres by recruiting the Sir3 and Sir4 proteins to chromatin via a Rap1 C-terminal domain, which also recruits the telomere length regulators, Rif1 and Rif2. We report the 1.85 {angstrom} resolution crystal structure of the Rap1 C-terminus, which adopts an all-helical fold with no structural homologues. The structure was used to engineer surface mutations in Rap1, and the effects of these mutations on silencing and telomere length regulation were assayed in vivo. Our surprising finding was that there is no overlap between mutations affecting mating-type and telomeric silencing, suggesting that Rap1 plays distinct roles in silencing at the silent mating-type loci and telomeres. We also found novel Rap1 phenotypes and new separation-of-function mutants, which provide new tools for studying Rap1 function. Yeast two-hybrid studies were used to determine how specific mutations affect recruitment of Sir3, Rif1, and Rif2. A comparison of the yeast two-hybrid and functional data reveals patterns of protein interactions that correlate with each Rap1 phenotype. We find that Sir3 interactions are important for telomeric silencing, but not mating type silencing, and that Rif1 and Rif2 interactions are important in different subsets of telomeric length mutants. Our results show that the role of Rap1 in silencing differs between the HM loci and the telomeres and offer insight into the interplay between HM silencing, telomeric silencing, and telomere length regulation. These findings suggest a model in which competition and multiple recruitment events modulate silencing and telomere length regulation.

Feeser, Elizabeth A.; Wolberger, Cynthia (JHU-MED)

2010-02-19

130

Beta function measurement in the Tevatron using quadrupole gradient modulation  

SciTech Connect

Early in Run2, there was an effort to compare the different emittance measurements in the Tevatron (flying wires and synchrotron light) and understand the origin of the observed differences. To measure the beta function at a few key locations near the instruments, air-core quadrupoles were installed. By modulating the gradient of these magnets and measuring the effect on the tune, the lattice parameters can be extracted. Initially, the results seem to disagree with other methods. At the time, the lattice was strongly coupled due to a skew component in the main dipoles, caused by sagging of the cryostat. After a large fraction of the superconducting magnets were shimmed to remove a strong skew quadrupole component, the results now agree with the theoretical values to within 20%.

Jansson, A.; Lebrun, P.; Volk, J.T.; /Fermilab

2005-05-01

131

Modulation transfer function of antenna-coupled infrared detector arrays.  

PubMed

Individual antenna-coupled IR bolometers have recently been demonstrated at wavelengths near 10 ?m. If focal-plane arrays (FPA's) of antenna-coupled detectors can be fabricated, enhancement of IR-imager performance is possible. A first step in the design process is to analyze the image-quality potential of antenna-coupled, FPA-based imagers in terms of the modulation transfer function (MTF). The key step in our analysis is development of a cross-talk MTF that accounts for the electromagnetic coupling between adjacent antennas in the FPA. We find that electromagnetic cross talk will not be a significant image-quality factor in antenna-coupled IR FPA's. PMID:21127627

Boreman, G D; Dogariu, A; Christodoulou, C; Kotter, D

1996-11-01

132

Role of sex hormones in the modulation of cholangiocyte function  

PubMed Central

Over the last years, cholangiocytes, the cells that line the biliary tree, have been considered an important object of study for their biological properties which involves bile formation, proliferation, injury repair, fibrosis and angiogenesis. Cholangiocyte proliferation occurs in all pathologic conditions of liver injury where it is associated with inflammation and regeneration. During these processes, biliary cells start to secrete different cytokines, growth factors, neuropeptides and hormones which represent potential mechanisms for cross talk with other liver cells. Several studies suggest that hormones, and in particular, sex hormones, play a fundamental role in the modulation of the growth of this compartment in the injured liver which functionally conditions the progression of liver disease. Understanding the mechanisms of action and the intracellular pathways of these compounds on cholangiocyte pathophysiology will provide new potential strategies for the management of chronic liver diseases. The purpose of this review is to summarize the recent findings on the role of sex hormones in cholangiocyte proliferation and biology.

Mancinelli, Romina; Onori, Paolo; DeMorrow, Sharon; Francis, Heather; Glaser, Shannon; Franchitto, Antonio; Carpino, Guido; Alpini, Gianfranco; Gaudio, Eugenio

2010-01-01

133

Spleen lymphocyte function modulated by a cocoa-enriched diet.  

PubMed

Previous studies have shown the down-regulating in vitro effect of cocoa flavonoids on lymphocyte and macrophage activation. In the present paper, we report the capacity of a long-term rich cocoa diet to modulate macrophage cytokine secretion and lymphocyte function in young rats. Weaned rats received natural cocoa (4% or 10% food intake), containing 32 mg flavonoids/g, for 3 weeks. Spleen immune function was then evaluated through the analysis of lymphocyte composition, their proliferative response and their ability to secrete cytokines and Ig. In addition, the status of activated peritoneal macrophages was established through tumour necrosis factor (TNF)-alpha secretion. The richest cocoa diet (10%) caused a reduction of TNF-alpha secretion by peritoneal macrophages showing anti-inflammatory activity. Similarly, although a 10% cocoa diet increased lymphocyte proliferation rate, it down-regulated T helper 2 (Th2)-related cytokines and decreased Ig secretion. These changes were accompanied by an increase in spleen B cell proportion and a decrease in Th cell percentage. In summary, these results demonstrate the functional activity of a cocoa-high dosage in down-regulating the immune response that might be beneficial in hypersensitivity and autoimmunity. PMID:17565606

Ramiro-Puig, E; Pérez-Cano, F J; Ramírez-Santana, C; Castellote, C; Izquierdo-Pulido, M; Permanyer, J; Franch, A; Castell, M

2007-06-12

134

Posterior Association Networks and Functional Modules Inferred from Rich Phenotypes of Gene Perturbations  

PubMed Central

Combinatorial gene perturbations provide rich information for a systematic exploration of genetic interactions. Despite successful applications to bacteria and yeast, the scalability of this approach remains a major challenge for higher organisms such as humans. Here, we report a novel experimental and computational framework to efficiently address this challenge by limiting the ‘search space’ for important genetic interactions. We propose to integrate rich phenotypes of multiple single gene perturbations to robustly predict functional modules, which can subsequently be subjected to further experimental investigations such as combinatorial gene silencing. We present posterior association networks (PANs) to predict functional interactions between genes estimated using a Bayesian mixture modelling approach. The major advantage of this approach over conventional hypothesis tests is that prior knowledge can be incorporated to enhance predictive power. We demonstrate in a simulation study and on biological data, that integrating complementary information greatly improves prediction accuracy. To search for significant modules, we perform hierarchical clustering with multiscale bootstrap resampling. We demonstrate the power of the proposed methodologies in applications to Ewing's sarcoma and human adult stem cells using publicly available and custom generated data, respectively. In the former application, we identify a gene module including many confirmed and highly promising therapeutic targets. Genes in the module are also significantly overrepresented in signalling pathways that are known to be critical for proliferation of Ewing's sarcoma cells. In the latter application, we predict a functional network of chromatin factors controlling epidermal stem cell fate. Further examinations using ChIP-seq, ChIP-qPCR and RT-qPCR reveal that the basis of their genetic interactions may arise from transcriptional cross regulation. A Bioconductor package implementing PAN is freely available online at http://bioconductor.org/packages/release/bioc/html/PANR.html.

Wang, Xin; Castro, Mauro A.

2012-01-01

135

Screen for Chemical Modulators of Autophagy Reveals Novel Therapeutic Inhibitors of mTORC1 Signaling  

PubMed Central

Background Mammalian target of rapamycin complex 1 (mTORC1) is a protein kinase that relays nutrient availability signals to control numerous cellular functions including autophagy, a process of cellular self-eating activated by nutrient depletion. Addressing the therapeutic potential of modulating mTORC1 signaling and autophagy in human disease requires active chemicals with pharmacologically desirable properties. Methodology/Principal Findings Using an automated cell-based assay, we screened a collection of >3,500 chemicals and identified three approved drugs (perhexiline, niclosamide, amiodarone) and one pharmacological reagent (rottlerin) capable of rapidly increasing autophagosome content. Biochemical assays showed that the four compounds stimulate autophagy and inhibit mTORC1 signaling in cells maintained in nutrient-rich conditions. The compounds did not inhibit mTORC2, which also contains mTOR as a catalytic subunit, suggesting that they do not inhibit mTOR catalytic activity but rather inhibit signaling to mTORC1. mTORC1 inhibition and autophagosome accumulation induced by perhexiline, niclosamide or rottlerin were rapidly reversed upon drug withdrawal whereas amiodarone inhibited mTORC1 essentially irreversibly. TSC2, a negative regulator of mTORC1, was required for inhibition of mTORC1 signaling by rottlerin but not for mTORC1 inhibition by perhexiline, niclosamide and amiodarone. Transient exposure of immortalized mouse embryo fibroblasts to these drugs was not toxic in nutrient-rich conditions but led to rapid cell death by apoptosis in starvation conditions, by a mechanism determined in large part by the tuberous sclerosis complex protein TSC2, an upstream regulator of mTORC1. By contrast, transient exposure to the mTORC1 inhibitor rapamycin caused essentially irreversible mTORC1 inhibition, sustained inhibition of cell growth and no selective cell killing in starvation. Conclusion/Significance The observation that drugs already approved for human use can reversibly inhibit mTORC1 and stimulate autophagy should greatly facilitate the preclinical and clinical testing of mTORC1 inhibition for indications such as tuberous sclerosis, diabetes, cardiovascular disease and cancer.

Donohue, Elizabeth; Tsang, Trevor C. F.; Lajoie, Patrick; Proud, Christopher G.; Nabi, Ivan R.; Roberge, Michel

2009-01-01

136

Casein Kinase 1 Proteomics Reveal Prohibitin 2 Function in Molecular Clock  

PubMed Central

Throughout the day, clock proteins synchronize changes in animal physiology (e.g., wakefulness and appetite) with external cues (e.g., daylight and food). In vertebrates, both casein kinase 1 delta and epsilon (CK1? and CK1?) regulate these circadian changes by phosphorylating other core clock proteins. In addition, CK1 can regulate circadian-dependent transcription in a non-catalytic manner, however, the mechanism is unknown. Furthermore, the extent of functional redundancy between these closely related kinases is debated. To further advance knowledge about CK1? and CK1? mechanisms of action in the biological clock, we first carried out proteomic analysis of both kinases in human cells. Next, we tested interesting candidates in a cell-based circadian readout which resulted in the discovery of PROHIBITIN 2 (PHB2) as a modulator of period length. Decreasing the expression of PHB2 increases circadian-driven transcription, thus revealing PHB2 acts as an inhibitor in the molecular clock. While stable binding of PHB2 to either kinase was not detected, knocking down CK1? expression increases PHB2 protein levels and, unexpectedly, knocking down CK1? decreases PHB2 transcript levels. Thus, isolating CK1 protein complexes led to the identification of PHB2 as an inhibitor of circadian transcription. Furthermore, we show that CK1? and CK1? differentially regulate the expression of PHB2.

Kategaya, Lorna S.; Hilliard, Aisha; Zhang, Louying; Asara, John M.; Ptacek, Louis J.; Fu, Ying-Hui

2012-01-01

137

APECED-causing mutations in AIRE reveal the functional domains of the protein.  

PubMed

A defective form of the AIRE protein causes autoimmune destruction of target organs by disturbing the immunological tolerance of patients with a rare monogenic disease, autoimmune polyendocrinopathy (APE)-candidiasis (C)-ectodermal dystrophy (ED), APECED. Recently, experiments on knockout mice revealed that AIRE controls autoimmunity by regulating the transcription of peripheral tissue-restricted antigens in thymic medullary epithelial cells. Thus, AIRE provides a unique model for molecular studies of organ-specific autoimmunity. In order to analyze the molecular and cellular consequences of 16 disease-causing mutations in vitro, we studied the subcellular localization, transactivation capacity, homomultimerization, and complex formation of several mutant AIRE polypeptides. Most of the mutations altered the nucleus-cytoplasm distribution of AIRE and disturbed its association with nuclear dots and cytoplasmic filaments. While the PHD zinc fingers were necessary for the transactivation capacity of AIRE, other regions of AIRE also modulated this function. Consequently, most of the mutations decreased transactivation. The HSR domain was responsible for the homomultimerization activity of AIRE; all the missense mutations of the HSR and the SAND domains decreased this activity, but those in other domains did not. The AIRE protein was present in soluble high-molecular-weight complexes. Mutations in the HSR domain and deletion of PHD zinc fingers disturbed the formation of these complexes. In conclusion, we propose an in vitro model in which AIRE transactivates transcription through heteromeric molecular interactions that are regulated by homomultimerization and conditional localization of AIRE in the nucleus or in the cytoplasm. PMID:14974083

Halonen, Maria; Kangas, Hannele; Rüppell, Taina; Ilmarinen, Tanja; Ollila, Juha; Kolmer, Meelis; Vihinen, Mauno; Palvimo, Jorma; Saarela, Jani; Ulmanen, Ismo; Eskelin, Petra

2004-03-01

138

A hub-attachment based method to detect functional modules from confidence-scored protein interactions and expression profiles  

Microsoft Academic Search

BACKGROUND: Many research results show that the biological systems are composed of functional modules. Members in the same module usually have common functions. This is useful information to understand how biological systems work. Therefore, detecting functional modules is an important research topic in the post-genome era. One of functional module detecting methods is to find dense regions in Protein-Protein Interaction

Chia-Hao Chin; Shu-Hwa Chen; Chin-Wen Ho; Ming-Tat Ko; Chung-Yen Lin

2010-01-01

139

Masking release for words in amplitude-modulated noise as a function of modulation rate and task  

PubMed Central

For normal-hearing listeners, masked speech recognition can improve with the introduction of masker amplitude modulation. The present experiments tested the hypothesis that this masking release is due in part to an interaction between the temporal distribution of cues necessary to perform the task and the probability of those cues temporally coinciding with masker modulation minima. Stimuli were monosyllabic words masked by speech-shaped noise, and masker modulation was introduced via multiplication with a raised sinusoid of 2.5–40 Hz. Tasks included detection, three-alternative forced-choice identification, and open-set identification. Overall, there was more masking release associated with the closed than the open-set tasks. The best rate of modulation also differed as a function of task; whereas low modulation rates were associated with best performance for the detection and three-alternative identification tasks, performance improved with modulation rate in the open-set task. This task-by-rate interaction was also observed when amplitude-modulated speech was presented in a steady masker, and for low- and high-pass filtered speech presented in modulated noise. These results were interpreted as showing that the optimal rate of amplitude modulation depends on the temporal distribution of speech cues and the information required to perform a particular task.

Buss, Emily; Whittle, Lisa N.; Grose, John H.; Hall, Joseph W.

2009-01-01

140

Transcriptome analysis of a cnidarian – dinoflagellate mutualism reveals complex modulation of host gene expression  

Microsoft Academic Search

BACKGROUND: Cnidarian – dinoflagellate intracellular symbioses are one of the most important mutualisms in the marine environment. They form the trophic and structural foundation of coral reef ecosystems, and have played a key role in the evolutionary radiation and biodiversity of cnidarian species. Despite the prevalence of these symbioses, we still know very little about the molecular modulators that initiate,

Mauricio Rodriguez-Lanetty; Wendy S Phillips; Virginia M Weis

2006-01-01

141

Identification and analysis of evolutionarily cohesive functional modules in protein networks  

Microsoft Academic Search

The increasing number of sequenced genomes makes it possible to infer the evolutionary history of functional modules, i.e., groups of proteins that contribute jointly to the same cellular function in a given species. Here we identify and analyze those prokaryotic functional modules, whose composition remains largely unchanged during evolution, and study their properties. Such \\

Mónica Campillos; Christian von Mering; Lars Juhl Jensen; Peer Bork

2006-01-01

142

Analysis of her1 and her7 Mutants Reveals a Spatio Temporal Separation of the Somite Clock Module  

PubMed Central

Somitogenesis is controlled by a genetic network consisting of an oscillator (clock) and a gradient (wavefront). The “hairy and Enhancer of Split”- related (her) genes act downstream of the Delta/Notch (D/N) signaling pathway, and are crucial components of the segmentation clock. Due to genome duplication events, the zebrafish genome, possesses two gene copies of the mouse Hes7 homologue: her1 and her7. To better understand the functional consequences of this gene duplication, and to determine possible independent roles for these two genes during segmentation, two zebrafish mutants her1hu2124 and her7hu2526 were analyzed. In the course of embryonic development, her1hu2124 mutants exhibit disruption of the three anterior-most somite borders, whereas her7hu2526 mutants display somite border defects restricted to somites 8 (+/?3) to 17 (+/?3) along the anterior-posterior axis. Analysis of the molecular defects in her1hu2124 mutants reveals a her1 auto regulatory feedback loop during early somitogenesis that is crucial for correct patterning and independent of her7 oscillation. This feedback loop appears to be restricted to early segmentation, as cyclic her1 expression is restored in her1hu2124 embryos at later stages of development. Moreover, only the anterior deltaC expression pattern is disrupted in the presomitic mesoderm of her1hu2124 mutants, while the posterior expression pattern of deltaC remains unaltered. Together, this data indicates the existence of an independent and genetically separable anterior and posterior deltaC clock modules in the presomitic mesdorm (PSM).

Choorapoikayil, Suma; Gajewski, Martin

2012-01-01

143

Knockdown and overexpression of NR1 modulates NMDA receptor function  

PubMed Central

The N-methyl-D-aspartate receptor (NMDAR) is critically involved in learning and memory, neuronal survival, as well as neuroexcitotoxicity and seizures. We hypothesize that even mild reductions in the numbers of hippocampal NMDARs could impair learning and memory, whereas increasing receptor activity would facilitate learning but reduce seizure threshold. We developed novel gene transfer strategies assisted by an adeno-associated viral vector 1/2 to bi-directionally modulate expression levels of the NR1 protein in rat hippocampus. Functional consequences of the altered NR1 expression were examined in the acute seizure model, and on normal processes of fear memory and neurogenesis. We found that knocking down NR1 protected against seizures at the expense of impaired learning, as predicted. Paradoxically, NR1 overexpression not only increased fear memory and neurogenesis, but also delayed onset of more severe seizures. In conclusion, the observed consequences of NR1 knockdown and overexpression underscore NMDAR requirement for neuronal plasticity, and are in agreement with its dichotomous functions.

Kalev-Zylinska, Maggie L.; Symes, Wymond; Young, Deborah; During, Matthew J.

2010-01-01

144

Surface tunability of nanoparticles in modulating platelet functions.  

PubMed

Metallic nanoparticles are attractive candidates as MRI contrast agents and mediators for drug delivery, diagnostics, and therapy. Direct contact and exposure to blood circulation is common in many such applications. The consequent thrombotic response may therefore be important to study. The main objective of the present work was to study how platelet functions were changed in the presence of different nano-surface or surface capping, which may provide a measure for the safety of a nanoparticle, and also assess the use of such nanoparticles in platelet modulation. Aggregometry, ATP release reaction, flow cytometry and immune-blotting studies were performed to study platelet response to different nano-particles (iron oxide, gold and silver). For each nanoparticle surface conjugation (capping) was varied. It was found that citric acid functionalized iron oxide nanoparticles have anti-platelet activity, with a decrease in aggregation, tyrosine phosphorylation level, and granule release. On the other hand in other cases (e.g. gold nanoparticles) pro-aggregatory response was observed in the presence of nanoparticles and, in some cases, the nanoparticles behaved neutrally (e.g. for starch-coated iron oxide nanoparticles). Therefore, nanoparticles can induce antiplatelet or a pro-aggregatory response, or remain neutral depending on surface capping. A related observation is that antiplatelet drugs can be made more potent by nanoparticle conjugation. PMID:22033068

Deb, Suryyani; Raja, S O; Dasgupta, Anjan Kr; Sarkar, Rajkumar; Chattopadhyay, Asoke P; Chaudhuri, Utpal; Guha, Pradipta; Sardar, Partha

2011-10-26

145

Modulation transfer function measurement of scanning reflectance microscopes.  

PubMed

Real-time medical imaging systems such as reflectance confocal microscopes and optical coherence microscopes are being tested in multiple-patient and multiple-center clinical trials. The modulation transfer function (MTF) of these systems at any given time influences the image information content and can affect the interpretation of the images. MTF is difficult to measure in real-time scanning systems when imaging at the Nyquist limit. We describe a measurement technique similar to the electronic imaging resolution standards ISO-12233 (electronic cameras) that can be applied to scanned spot imaging systems with asynchronous pixel clocks. This technique requires the acquisition of a single image of a reflective stripe object. An asynchronous pixel clock induces subpixel jitter in the edge location. The jitter is removed using a Fourier method, and an oversampled edge response function is calculated using algorithms developed in MATLAB. This technique provides fast, simple to use, and repeatable full-width at half maximum lateral resolution and MTF measurements based on only one test image. We present the results for reflectance confocal microscopes operating at 0.9 numerical aperture. PMID:17994880

Wang, Zhao; Glazowski, Christopher E; Zavislan, James M

146

SPIN90 phosphorylation modulates spine structure and synaptic function.  

PubMed

The correct rearrangement of postsynaptic components in dendritic spines is important for driving changes of spine structure and synaptic function. SPIN90 plays an essential role in many cellular processes including actin polymerization, endocytosis, growth cone formation and dendritic spine morphogenesis. Here, we demonstrate that SPIN90, which is a binding partner of PSD95 and Shank in spines, is targeted to synapses and leads to enhanced synaptic activity in neurons. We show, using in vitro and in vivo kinase assays, that SPIN90 is tyrosine phosphorylated by Src kinase. SPIN90 that was tyrosine-phosphorylated by Src was targeted to dendritic spines in cultured hippocampal neurons. Moreover, a SPIN90 phospho-deficient mutant was unable to accumulate at dendritic spines whereas SPIN90 WT and a phospho-mimicking mutant were localized at spines and bound PSD95 and Shank with increased efficiency. Consistent with these findings, hippocampal neurons that overexpressed SPIN90 WT or a phospho-mimicking mutant had enlarged spine heads, leading to enhanced postsynaptic function in terms of both amplitude and frequency. Together, our findings show that SPIN90 modulates synaptic activity in neurons as a result of its phosphorylation. PMID:23342115

Cho, In Ha; Kim, Dae Hwan; Lee, Min-Jung; Bae, Jeomil; Lee, Kun Ho; Song, Woo Keun

2013-01-14

147

Acute Modulations in Permeability Barrier Function Regulate Epidermal Cornification  

PubMed Central

Stratum corneum comprises corneocytes, derived from outer stratum granulosum during terminal differentiation, embedded in a lipid-enriched extracellular matrix, secreted from epidermal lamellar bodies. Permeability barrier insults stimulate rapid secretion of preformed lamellar bodies from the outer stratum granulosum, regulated through modulations in ionic gradients and serine protease (SP)/protease-activated receptor type 2 (PAR2) signaling. Because corneocytes are also required for barrier function, we hypothesized that corneocyte formation could also be regulated by barrier function. Barrier abrogation by two unrelated methods initiated a wave of cornification, assessed as TdT-mediated dUTP nick end-labeling-positive cells in stratum granulosum and newly cornified cells by electron microscopy. Because cornification was blocked by occlusion, corneocytes formed specifically in response to barrier, rather than injury or cell replacement, requirements. SP inhibitors and hyperacidification (which decreases SP activity) blocked cornification after barrier disruption. Similarly, cornification was delayed in PAR2?/? mice. Although classical markers of apoptosis [poly(ADP-ribose)polymerase and caspase (Casp)-3] remained unchanged, barrier disruption activated Casp-14. Moreover, the pan-Casp inhibitor Z-VAD-FMK delayed cornification, and corneocytes were structurally aberrant in Casp14?/? mice. Thus, permeability barrier requirements coordinately drive both the generation of the stratum corneum lipid-enriched extracellular matrix and the transformation of granular cells into corneocytes, in an SP- and Casp-14-dependent manner, signaled by PAR2.

Demerjian, Marianne; Hachem, Jean-Pierre; Tschachler, Erwin; Denecker, Geertrui; Declercq, Wim; Vandenabeele, Peter; Mauro, Theodora; Hupe, Melanie; Crumrine, Debra; Roelandt, Truus; Houben, Evi; Elias, Peter M.; Feingold, Kenneth R.

2008-01-01

148

Functional modulation of human delta opioid receptor by neuropeptide FF  

PubMed Central

Background Neuropeptide FF (NPFF) plays a role in physiological pain sensation and opioid analgesia. For example, NPFF potentiates opiate-induced analgesia and the delta opioid receptor antagonist naltrindole inhibits NPFF-induced antinociception. The nature of the interactions between NPFF and opioid receptors seems to be complex and the molecular mechanisms behind the observed physiological effects are not known. Results We used a stable Chinese hamster ovary cell line expressing c-MYC-tagged human delta opioid receptor to study the interactions at the molecular level. Our results imply that NPFF can directly modulate the activation of delta opioid receptor in the absence of NPFF receptors. The modulatory effect, though only moderate, was consistently detected with several methods. The agonist-induced receptor trafficking was changed in the presence of (1DMe)NPYF, a stable NPFF-analogue. (1DMe)NPYF enhanced the receptor activation and recovery; opioid antagonists inhibited the effects, indicating that they were delta opioid receptor-mediated. The binding experiments with a novel ligand, Terbium-labeled deltorphin I, showed that (1DMe)NPYF modulated the binding of delta opioid receptor ligands. The levels of phosphorylated mitogen-activated protein kinase and intracellular cAMP were studied to clarify the effects of NPFF on the opioid signaling mechanisms. Application of (1DMe)NPYF together with a delta opioid receptor agonist enhanced the signaling via both pathways studied. Concomitantly to the receptor trafficking, the time-course of the activation of the signaling was altered. Conclusion In addition to working via indirect mechanisms on the opioid systems, NPFF may exert a direct modulatory effect on the delta opioid receptor. NPFF may be a multi-functional neuropeptide that regulates several neuronal systems depending on the site of action.

Anko, Minna-Liisa; Panula, Pertti

2005-01-01

149

Nuclear Technology. Course 30: Mechanical Inspection. Module 30-2, Pump Functional Testing.  

ERIC Educational Resources Information Center

This second in a series of eight modules for a course titled Mechanical Inspection describes typical pump functional tests which are performed after pump installation and prior to release of the plant for unrestricted power operation. The module follows a typical format that includes the following sections: (1) introduction, (2) module

Wasel, Ed; Espy, John

150

Ocean Wave-Radar Modulation Transfer Functions From the West Coast Experiment  

Microsoft Academic Search

Short gravity-capillary waves, the equilibrium, or the steady state excitations of the ocean surface are modulated by longer ocean waves. These short waves are the predominant microwave scatterers on the ocean surface under many viewing conditions so that the modulation is readily measured with CW Doppler radar used as a two-scale wave probe. Modulation transfer functions (the ratio of the

J. W. Wright; W. J. Plant; W. C. Keller; W. L. Jones

1980-01-01

151

Differentiation-Inducing Factor-1 and -2 Function also as Modulators for Dictyostelium Chemotaxis  

PubMed Central

Background In the early stages of development of the cellular slime mold Dictyostelium discoideum, chemotaxis toward cAMP plays a pivotal role in organizing discrete cells into a multicellular structure. In this process, a series of signaling molecules, such as G-protein-coupled cell surface receptors for cAMP, phosphatidylinositol metabolites, and cyclic nucleotides, function as the signal transducers for controlling dynamics of cytoskeleton. Differentiation-inducing factor-1 and -2 (DIF-1 and DIF-2) were originally identified as the factors (chlorinated alkylphenones) that induce Dictyostelium stalk cell differentiation, but it remained unknown whether the DIFs had any other physiologic functions. Methodology/Principal Findings To further elucidate the functions of DIFs, in the present study we investigated their effects on chemotaxis under various conditions. Quite interestingly, in shallow cAMP gradients, DIF-1 suppressed chemotaxis whereas DIF-2 promoted it greatly. Analyses with various mutants revealed that DIF-1 may inhibit chemotaxis, at least in part, via GbpB (a phosphodiesterase) and a decrease in the intracellular cGMP concentration ([cGMP]i). DIF-2, by contrast, may enhance chemotaxis, at least in part, via RegA (another phosphodiesterase) and an increase in [cGMP]i. Using null mutants for DimA and DimB, the transcription factors that are required for DIF-dependent prestalk differentiation, we also showed that the mechanisms for the modulation of chemotaxis by DIFs differ from those for the induction of cell differentiation by DIFs, at least in part. Conclusions/Significance Our findings indicate that DIF-1 and DIF-2 function as negative and positive modulators for Dictyostelium chemotaxis, respectively. To our knowledge, this is the first report in any organism of physiologic modulators (small molecules) for chemotaxis having differentiation-inducing activity.

Kuwayama, Hidekazu; Kubohara, Yuzuru

2009-01-01

152

MYC2 Differentially Modulates Diverse Jasmonate-Dependent Functions in Arabidopsis[W  

PubMed Central

The Arabidopsis thaliana basic helix-loop-helix Leu zipper transcription factor (TF) MYC2/JIN1 differentially regulates jasmonate (JA)-responsive pathogen defense (e.g., PDF1.2) and wound response (e.g., VSP) genes. In this study, genome-wide transcriptional profiling of wild type and mutant myc2/jin1 plants followed by functional analyses has revealed new roles for MYC2 in the modulation of diverse JA functions. We found that MYC2 negatively regulates Trp and Trp-derived secondary metabolism such as indole glucosinolate biosynthesis during JA signaling. Furthermore, MYC2 positively regulates JA-mediated resistance to insect pests, such as Helicoverpa armigera, and tolerance to oxidative stress, possibly via enhanced ascorbate redox cycling and flavonoid biosynthesis. Analyses of MYC2 cis binding elements and expression of MYC2-regulated genes in T-DNA insertion lines of a subset of MYC2–regulated TFs suggested that MYC2 might modulate JA responses via differential regulation of an intermediate spectrum of TFs with activating or repressing roles in JA signaling. MYC2 also negatively regulates its own expression, and this may be one of the mechanisms used in fine-tuning JA signaling. Overall, these results provide new insights into the function of MYC2 and the transcriptional coordination of the JA signaling pathway.

Dombrecht, Bruno; Xue, Gang Ping; Sprague, Susan J.; Kirkegaard, John A.; Ross, John J.; Reid, James B.; Fitt, Gary P.; Sewelam, Nasser; Schenk, Peer M.; Manners, John M.; Kazan, Kemal

2007-01-01

153

Structure and function of the SWIRM domain, a conserved protein module found in chromatin regulatory complexes.  

PubMed

The SWIRM domain is a module found in the Swi3 and Rsc8 subunits of SWI/SNF-family chromatin remodeling complexes, and the Ada2 and BHC110/LSD1 subunits of chromatin modification complexes. Here we report the high-resolution crystal structure of the SWIRM domain from Swi3 and characterize the in vitro and in vivo function of the SWIRM domains from Saccharomyces cerevisiae Swi3 and Rsc8. The Swi3 SWIRM forms a four-helix bundle containing a pseudo 2-fold axis and a helix-turn-helix motif commonly found in DNA-binding proteins. We show that the Swi3 SWIRM binds free DNA and mononucleosomes with high and comparable affinity and that a subset of Swi3 substitution mutants that display growth defects in vivo also show impaired DNA-binding activity in vitro, consistent with a nucleosome targeting function of this domain. Genetic and biochemical studies also reveal that the Rsc8 and Swi3 SWIRM domains are essential for the proper assembly and in vivo functions of their respective complexes. Together, these studies identify the SWIRM domain as an essential multifunctional module for the regulation of gene expression. PMID:16461455

Da, Guoping; Lenkart, Jeffrey; Zhao, Kehao; Shiekhattar, Ramin; Cairns, Bradley R; Marmorstein, Ronen

2006-02-03

154

Advanced ATM-layer function MCM-D module for ATM wide-area network  

Microsoft Academic Search

This paper describes a high-performance and cost-effective MCM-D module for an ATM-layer function device. The MCM-D module is fabricated on a Si-substrate using the stacking RAM technique to reduce module size. The MCM has a 4-layer Si substrate, a high-performance ASIC, 8 high-speed SRAMs, and an FPGA. By using the stacking RAM technique, MCM-D module size was reduced to 50.8

Tomoaki Kawamura; Naoaki Yamanaka; Katsumi Kaizu

1997-01-01

155

Purification of a Tat-associated kinase reveals a TFIIH complex that modulates HIV1 transcription  

Microsoft Academic Search

The Tat protein is a transcriptional activator which is required for efficient human immunodeficiency virus 1 (HIV-1) gene expression Tat stimulates HIV–1 transcriptional elongation by increasing the processivity of RNA polymerase II. To address whether Tat-mediated effects on HIV–1 gene expression are due to modulation in the phosphorylation of the RNA polymerase II C–terminal domain (CTD), we developed a purification

León F. García-Martínez; Gopinath Mavankal; John M. Neveu; Dmitri Ivanov; Richard B. Gaynor

1997-01-01

156

Expression QTL Modules as Functional Components Underlying Higher-Order Phenotypes  

PubMed Central

Systems genetics studies often involve the mapping of numerous regulatory relations between genetic loci and expression traits. These regulatory relations form a bipartite network consisting of genetic loci and expression phenotypes. Modular network organizations may arise from the pleiotropic and polygenic regulation of gene expression. Here we analyzed the expression QTL (eQTL) networks derived from expression genetic data of yeast and mouse liver and found 65 and 98 modules respectively. Computer simulation result showed that such modules rarely occurred in randomized networks with the same number of nodes and edges and same degree distribution. We also found significant within-module functional coherence. The analysis of genetic overlaps and the evidences from biomedical literature have linked some eQTL modules to physiological phenotypes. Functional coherence within the eQTL modules and genetic overlaps between the modules and physiological phenotypes suggests that eQTL modules may act as functional units underlying the higher-order phenotypes.

Bao, Lei; Xia, Xuefeng; Cui, Yan

2010-01-01

157

A comprehensive analysis of prognostic signatures reveals the high predictive capacity of the Proliferation, Immune response and RNA splicing modules in breast cancer  

PubMed Central

Introduction Several gene expression signatures have been proposed and demonstrated to be predictive of outcome in breast cancer. In the present article we address the following issues: Do these signatures perform similarly? Are there (common) molecular processes reported by these signatures? Can better prognostic predictors be constructed based on these identified molecular processes? Methods We performed a comprehensive analysis of the performance of nine gene expression signatures on seven different breast cancer datasets. To better characterize the functional processes associated with these signatures, we enlarged each signature by including all probes with a significant correlation to at least one of the genes in the original signature. The enrichment of functional groups was assessed using four ontology databases. Results The classification performance of the nine gene expression signatures is very similar in terms of assigning a sample to either a poor outcome group or a good outcome group. Nevertheless the concordance in classification at the sample level is low, with only 50% of the breast cancer samples classified in the same outcome group by all classifiers. The predictive accuracy decreases with the number of poor outcome assignments given to a sample. The best classification performance was obtained for the group of patients with only good outcome assignments. Enrichment analysis of the enlarged signatures revealed 11 functional modules with prognostic ability. The combination of the RNA-splicing and immune modules resulted in a classifier with high prognostic performance on an independent validation set. Conclusions The study revealed that the nine signatures perform similarly but exhibit a large degree of discordance in prognostic group assignment. Functional analyses indicate that proliferation is a common cellular process, but that other functional categories are also enriched and show independent prognostic ability. We provide new evidence of the potentially promising prognostic impact of immunity and RNA-splicing processes in breast cancer.

Reyal, Fabien; van Vliet, Martin H; Armstrong, Nicola J; Horlings, Hugo M; de Visser, Karin E; Kok, Marlen; Teschendorff, Andrew E; Mook, Stella; van 't Veer, Laura; Caldas, Carlos; Salmon, Remy J; Vijver, Marc J van de; Wessels, Lodewyk FA

2008-01-01

158

Identification and characterization of the lysobactin biosynthetic gene cluster reveals mechanistic insights into an unusual termination module architecture.  

PubMed

Lysobactin (katanosin B) is a macrocyclic depsipeptide, displaying high antibacterial activity against human pathogens. In this work, we have identified and characterized the entire biosynthetic gene cluster responsible for lysobactin assembly. Sequential analysis of the Lysobacter sp. ATCC 53042 genome revealed the lysobactin gene cluster to encode two multimodular nonribosomal peptide synthetases. As the number of modules found within the synthetases LybA and LybB directly correlates with the primary sequence of lysobactin, a linear logic of lysobactin biosynthesis is proposed. Investigation of adenylation domain specificities in vitro confirmed the direct association between the synthetases and lysobactin biosynthesis. Furthermore, an unusual tandem thioesterase architecture of the LybB termination module was identified. Biochemical characterization of the individual thioesterases in vitro provides evidence that solely penultimate thioesterase domain mediates the cyclization and simultaneous release of lysobactin. PMID:21609846

Hou, Jie; Robbel, Lars; Marahiel, Mohamed A

2011-05-27

159

Modulation of apoptotic pathways of macrophages by surface-functionalized multi-walled carbon nanotubes.  

PubMed

Biomedical applications of carbon nanotubes (CNTs) often involve improving their hydrophilicity and dispersion in biological media by modifying them through noncovalent or covalent functionalization. However, the potential adverse effects of surface-functionalized CNTs have not been well characterized. In this study, we functionalized multi-walled CNTs (MWCNTs) via carboxylation, to produce MWCNTs-COOH, and via poly (ethylene glycol) linking, to produce MWCNTs-PEG. We used these functionalized MWCNTs to study the effect of surface functionalization on MWCNTs-induced toxicity to macrophages, and elucidate the underlying mechanisms of action. Our results revealed that MWCNTs-PEG were less cytotoxic and were associated with less apoptotic cell death of macrophages than MWCNTs-COOH. Additionally, MWCNTs-PEG induced less generation of reactive oxygen species (ROS) involving less activation of NADPH oxidase compared with MWCNTs-COOH, as evidenced by membrane translocation of p47(phox) and p67(phox) in macrophages. The less cytotoxic and apoptotic effect of MWCNTs-PEG compared with MWCNTs-COOH resulted from the lower cellular uptake of MWCNTs-PEG, which resulted in less activation of oxidative stress-responsive pathways, such as p38 mitogen-activated protein kinases (MAPK) and nuclear factor (NF)-?B. These results demonstrate that surface functionalization of CNTs may alter ROS-mediated cytotoxic and apoptotic response by modulating apoptotic signaling pathways. Our study thus provides new insights into the molecular basis for the surface properties affecting CNTs toxicity. PMID:23755279

Jiang, Yuanqin; Zhang, Honggang; Wang, Yange; Chen, Min; Ye, Shefang; Hou, Zhenqing; Ren, Lei

2013-06-06

160

Allosteric modulation and functional selectivity of G protein-coupled receptors.  

PubMed

Agonists of a single G protein-coupled receptor (GPCR) may activate distinct signaling pathways. Functional selectivity, an emerging concept with therapeutic relevance for GPCRs, may be due to conformational selection or stabilization with respect to particular agonists, receptor dimerization, variable expression levels of GPCRs and downstream signaling molecules, and allosteric modulation. Allosteric modulators may have potential advantages over orthosteric ligands, including greater selectivity and safety. This review focuses on functional selectivity resulting from allosteric modulation. PMID:23687514

Gao, Zhan-Guo; Jacobson, Kenneth A

2013-01-01

161

Form and Function: An Organic Chemistry Module. Teacher's Guide.  

ERIC Educational Resources Information Center

|This teacher's guide is designed to provide science teachers with the necessary guidance and suggestions for teaching organic chemistry. In this book, the diverse field of organic chemistry modules is introduced. The material in this book can be integrated with the other modules in a sequence that helps students to see that chemistry is a unified…

Jarvis, Bruce; Mazzocchi, Paul; Hearle, Robert

162

Glycoside hydrolases and glycosyltransferases: families and functional modules  

Microsoft Academic Search

The past year has witnessed the expected increase in the number of solved structures of glycoside hydrolases and glycosyltransferases, and their constitutive modules. These structures show that, while glycoside hydrolases display an extraordinary variety of folds, glycosyltransferases and carbohydrate-binding modules appear to belong to a much smaller number of folding families.

Yves Bourne; Bernard Henrissat

2001-01-01

163

Exploring Tomato Gene Functions Based on Coexpression Modules Using Graph Clustering and Differential Coexpression Approaches1[C][W][OA  

PubMed Central

Gene-to-gene coexpression analysis provides fundamental information and is a promising approach for predicting unknown gene functions in plants. We investigated various associations in the gene expression of tomato (Solanum lycopersicum) to predict unknown gene functions in an unbiased manner. We obtained more than 300 microarrays from publicly available databases and our own hybridizations, and here, we present tomato coexpression networks and coexpression modules. The topological characteristics of the networks were highly heterogenous. We extracted 465 total coexpression modules from the data set by graph clustering, which allows users to divide a graph effectively into a set of clusters. Of these, 88% were assigned systematically by Gene Ontology terms. Our approaches revealed functional modules in the tomato transcriptome data; the predominant functions of coexpression modules were biologically relevant. We also investigated differential coexpression among data sets consisting of leaf, fruit, and root samples to gain further insights into the tomato transcriptome. We now demonstrate that (1) duplicated genes, as well as metabolic genes, exhibit a small but significant number of differential coexpressions, and (2) a reversal of gene coexpression occurred in two metabolic pathways involved in lycopene and flavonoid biosynthesis. Independent experimental verification of the findings for six selected genes was done using quantitative real-time polymerase chain reaction. Our findings suggest that differential coexpression may assist in the investigation of key regulatory steps in metabolic pathways. The approaches and results reported here will be useful to prioritize candidate genes for further functional genomics studies of tomato metabolism.

Fukushima, Atsushi; Nishizawa, Tomoko; Hayakumo, Mariko; Hikosaka, Shoko; Saito, Kazuki; Goto, Eiji; Kusano, Miyako

2012-01-01

164

Modulation of T-cell function by type I interferon.  

PubMed

Production of type I interferon (IFN-?/?) is a common cellular response to virus infection. IFN-?/? has a dual role in combating infection, triggering innate antiviral mechanisms and stimulating the generation of an adaptive immune response. This review focuses on the effects of IFN-?/? on one particular immune cell type, the T cell, and the impact of IFN-?/?-mediated signalling in T cells on the immune response. The critical role of T-cell responsiveness to IFN-?/? for the generation of productive T-cell responses after infections with certain viruses in vivo is discussed in the context of in vitro experiments investigating the mechanisms by which IFN-?/? modifies T-cell function. These studies reveal complex effects of IFN-?/? on T cells, with the consequences of exposure to IFN-?/? depending on the context of other signals received by the T cell. PMID:22391814

Tough, David F

2012-03-06

165

Proteomic analysis reveals virus-specific Hsp25 modulation in cardiac myocytes  

PubMed Central

Viruses frequently infect the heart but clinical myocarditis is rare, suggesting that the cardiac antiviral response is uniquely effective. Indeed, the Type I interferon (IFN) response is cardiac cell type-specific and provides one integrated network of protection for the heart. Here, a proteomic approach was used to identify additional proteins that may be involved in the cardiac antiviral response. Reovirus-induced murine myocarditis reflects direct viral damage to cardiac cells, and offers an excellent system for study. Primary cultures of murine cardiac myocytes were infected with myocarditic or non-myocarditic reovirus strains, and whole cell lysates were compared by two-dimensional difference gel electrophoresis (2D-DIGE) and matrix-assisted laser desorption / ionization – time-of-flight (MALDI-TOF/TOF) tandem mass spectrometry. Results were quantitative and reproducible, and demonstrated that whole proteome changes clustered according to viral pathogenic phenotype. Moreover, the data suggest that the heat shock protein Hsp25 is modulated differentially by myocarditic and non-myocarditic reoviruses and may play a role in the cardiac antiviral response. Members of seven virus families modulate Hsp25 or Hsp27 expression in a variety of cell types, suggesting that Hsp25 participation in the antiviral response may be widespread. However, results here provide the first evidence for a virus-induced decrease in Hsp25/27, and suggest that viruses may have evolved a mechanism to subvert this protective response, as they have for IFN.

Li, Lianna; Sevinsky, Joel R.; Rowland, Megan D.; Bundy, Jonathan L.; Stephenson, James L.; Sherry, Barbara

2010-01-01

166

The DAVID Gene Functional Classification Tool: a novel biological module-centric algorithm to functionally analyze large gene lists  

PubMed Central

The DAVID Gene Functional Classification Tool uses a novel agglomeration algorithm to condense a list of genes or associated biological terms into organized classes of related genes or biology, called biological modules. This organization is accomplished by mining the complex biological co-occurrences found in multiple sources of functional annotation. It is a powerful method to group functionally related genes and terms into a manageable number of biological modules for efficient interpretation of gene lists in a network context.

Huang, Da Wei; Sherman, Brad T; Tan, Qina; Collins, Jack R; Alvord, W Gregory; Roayaei, Jean; Stephens, Robert; Baseler, Michael W; Lane, H Clifford; Lempicki, Richard A

2007-01-01

167

Genomic insights of protein arginine methyltransferase Hmt1 binding reveals novel regulatory functions  

PubMed Central

Background Protein arginine methylation is a post-translational modification involved in important biological processes such as transcription and RNA processing. This modification is catalyzed by both type I and II protein arginine methyltransferases (PRMTs). One of the most conserved type I PRMTs is PRMT1, the homolog of which is Hmt1 in Saccharomyces cerevisiae. Hmt1 has been shown to play a role in various gene expression steps, such as promoting the dynamics of messenger ribonucleoprotein particle (mRNP) biogenesis, pre-mRNA splicing, and silencing of chromatin. To determine the full extent of Hmt1’s involvement during gene expression, we carried out a genome-wide location analysis for Hmt1. Results A comprehensive genome-wide binding profile for Hmt1 was obtained by ChIP-chip using NimbleGen high-resolution tiling microarrays. Of the approximately 1000 Hmt1-binding sites found, the majority fall within or proximal to an ORF. Different occupancy patterns of Hmt1 across genes with different transcriptional rates were found. Interestingly, Hmt1 occupancy is found at a number of other genomic features such as tRNA and snoRNA genes, thereby implicating a regulatory role in the biogenesis of these non-coding RNAs. RNA hybridization analysis shows that Hmt1 loss-of-function mutants display higher steady-state tRNA abundance relative to the wild-type. Co-immunoprecipitation studies demonstrate that Hmt1 interacts with the TFIIIB component Bdp1, suggesting a mechanism for Hmt1 in modulating RNA Pol III transcription to regulate tRNA production. Conclusions The genome-wide binding profile of Hmt1 reveals multiple potential new roles for Hmt1 in the control of eukaryotic gene expression, especially in the realm of non-coding RNAs. The data obtained here will provide an important blueprint for future mechanistic studies on the described occupancy relationship for genomic features bound by Hmt1.

2012-01-01

168

Temperature-Induced Protein Secretion by Leishmania mexicana Modulates Macrophage Signalling and Function  

PubMed Central

Protozoan parasites of genus Leishmania are the causative agents of leishmaniasis. These digenetic microorganisms undergo a marked environmental temperature shift (TS) during transmission from the sandfly vector (ambient temperature, 25–26°C) to the mammalian host (37°C). We have observed that this TS induces a rapid and dramatic increase in protein release from Leishmania mexicana (cutaneous leishmaniasis) within 4 h. Proteomic identification of the TS-induced secreted proteins revealed 72 proteins, the majority of which lack a signal peptide and are thus thought to be secreted via nonconventional mechanisms. Interestingly, this protein release is accompanied by alterations in parasite morphology including an augmentation in the budding of exovesicles from its surface. Here we show that the exoproteome of L. mexicana upon TS induces cleavage and activation of the host protein tyrosine phosphatases, specifically SHP-1 and PTP1-B, in a murine bone-marrow-derived macrophage cell line. Furthermore, translocation of prominent inflammatory transcription factors, namely NF-?B and AP-1 is altered. The exoproteome also caused inhibition of nitric oxide production, a crucial leishmanicidal function of the macrophage. Overall, our results provide strong evidence that within early moments of interaction with the mammalian host, L. mexicana rapidly releases proteins and exovesicles that modulate signalling and function of the macrophage. These modulations can result in attenuation of the inflammatory response and deactivation of the macrophage aiding the parasite in the establishment of infection.

Hassani, Kasra; Antoniak, Elisabeth; Jardim, Armando; Olivier, Martin

2011-01-01

169

The structure of a Streptomyces avermitilis ?-L-rhamnosidase reveals a novel carbohydrate-binding module CBM67 within the six-domain arrangement.  

PubMed

?-L-rhamnosidases hydrolyze ?-linked L-rhamnosides from oligosaccharides or polysaccharides. We determined the crystal structure of the glycoside hydrolase family 78 Streptomyces avermitilis ?-L-rhamnosidase (SaRha78A) in its free and L-rhamnose complexed forms, which revealed the presence of six domains N, D, E, F, A, and C. In the ligand complex, L-rhamnose was bound in the proposed active site of the catalytic module, revealing the likely catalytic mechanism of SaRha78A. Glu(636) is predicted to donate protons to the glycosidic oxygen, and Glu(895) is the likely catalytic general base, activating the nucleophilic water, indicating that the enzyme operates through an inverting mechanism. Replacement of Glu(636) and Glu(895) resulted in significant loss of ?-rhamnosidase activity. Domain D also bound L-rhamnose in a calcium-dependent manner, with a KD of 135 ?m. Domain D is thus a non-catalytic carbohydrate binding module (designated SaCBM67). Mutagenesis and structural data identified the amino acids in SaCBM67 that target the features of L-rhamnose that distinguishes it from the other major sugars present in plant cell walls. Inactivation of SaCBM67 caused a substantial reduction in the activity of SaRha78A against the polysaccharide composite gum arabic, but not against aryl rhamnosides, indicating that SaCBM67 contributes to enzyme function against insoluble substrates. PMID:23486481

Fujimoto, Zui; Jackson, Adam; Michikawa, Mari; Maehara, Tomoko; Momma, Mitsuru; Henrissat, Bernard; Gilbert, Harry J; Kaneko, Satoshi

2013-03-13

170

Ciprofloxacin enhances T cell function by modulating interleukin activities.  

PubMed Central

Ciprofloxacin (CIP) is a quinolone carboxylic acid derivative with a broad spectrum of antibacterial activity. CIP (0.1-30 micrograms/ml) enhanced DNA synthesis of mouse spleen cells and human peripheral blood lymphocytes (PBL) that had been activated with T cell mitogens or with alloantigens. In addition, CIP increased the amount of IL-2 found in the supernatants of phytohaemagglutinin (PHA)-stimulated human PBL. The presence of CIP in the medium (0.3-10 micrograms/ml) increased the levels of IL-1 found in the culture supernatants of adherence-enriched mouse macrophages, human monocyte/macrophages and a human monocytic cell line stimulated with lipopolysaccharide. In contrast there was no effect of CIP on the release of IL-1 by freshly isolated human monocytes or by cells of the keratinocyte line, A431. CIP alone had no influence on the basal release of IL-2 by NOB-1 cells, a T cell line that responds to IL-1 with an increase in IL-2 synthesis, but, in combination with recombinant IL-1, CIP significantly enhanced the release of IL-2 by these cells. The results of this study suggest that CIP modulates the immune response at two levels--the production of IL-2 by activated T cells and the production of IL-1 by activated monocyte/macrophages. However, CIP did not affect the primary antibody response in vitro or in vivo against sheep erythrocytes and ovalbumin respectively. Thus the enhancing action of ciprofloxacin on the immune system appears to be restricted to T cell function and macrophage/T cell interactions.

Stunkel, K G; Hewlett, G; Zeiler, H J

1991-01-01

171

Modulation of Human Mineralocorticoid Receptor Function by Protein Kinase A  

Microsoft Academic Search

The mineralocorticoid receptor (MR) acts as a li- gand-dependent transcription factor modulating specific gene expression in sodium-transporting epithelia. Physiological evidence suggest a cross- talk between the cAMP- and aldosterone-signaling pathways. We provide evidence that protein kinase A (PKA), a major mediator of signal transduction pathways, modulates transcriptional activity of the human MR (hMR). Using transient transfection as- says in HepG2

Charbel Massaad; Nathalie Houard; Marc Lombes

1999-01-01

172

Functions, aberrations, and advances for chromatin modulation in cancer.  

PubMed

Cancer initiation and progression is causally connected to genome and epigenome deregulations. Epigenetic deregulations (such as DNA methylation, histone modifications, and miRNA-based modulation) have been increasingly reported in tumorigenesis and different chromatin-modulating enzymes have been discovered and classified and their aberrations connected to cancer. A better insight into alterations occurring on chromatin enzymes and their impact in cancer thus represents a crucial step in exploiting epigenetic targeting in cancer prevention and treatment. PMID:24114483

Conte, Mariarosaria; Altucci, Lucia

2014-01-01

173

Isolation of highly persistent mutants of Salmonella enterica serovar typhimurium reveals a new toxin-antitoxin module.  

PubMed

Bacterial persistence is characterized by the ability of a subpopulation within bacterial cultures to survive exposure to antibiotics and other lethal treatments. The surviving persisters are not the result of genetic changes but represent epigenetic variants that are in a physiological state where growth is inhibited. Since characterization of persisters has been performed mainly in Escherichia coli K-12, we sought to identify mechanisms of persistence in the pathogen Salmonella enterica serovar Typhimurium. Isolation of new highly persistent mutants revealed that the shpAB locus (Salmonella high persistence) imparted a 3- to 4-order-of-magnitude increase in survival after ampicillin exposure throughout its growth phase and protected the population against exposure to multiple antibiotics. Genetic characterization revealed that shpAB is a newly discovered toxin-antitoxin (TA) module. The high-persistence phenotype was attributed to a nonsense mutation in the 3' end of the shpB gene encoding an antitoxin protein. Characteristic of other TA modules, shpAB is autoregulated, and high persistence depends on the Lon protease. PMID:23204462

Slattery, Andrew; Victorsen, Alec H; Brown, April; Hillman, Kai; Phillips, Gregory J

2012-11-30

174

A novel subgradient-based optimization algorithm for blockmodel functional module identification  

PubMed Central

Functional module identification in biological networks may provide new insights into the complex interactions among biomolecules for a better understanding of cellular functional organization. Most of existing functional module identification methods are based on the optimization of network modularity and cluster networks into groups of nodes within which there are a higher-than-expectation number of edges. However, module identification simply based on this topological criterion may not discover certain kinds of biologically meaningful modules within which nodes are sparsely connected but have similar interaction patterns with the rest of the network. In order to unearth more biologically meaningful functional modules, we propose a novel efficient convex programming algorithm based on the subgradient method with heuristic path generation to solve the problem in a recently proposed framework of blockmodel module identification. We have implemented our algorithm for large-scale protein-protein interaction (PPI) networks, including Saccharomyces cerevisia and Homo sapien PPI networks collected from the Database of Interaction Proteins (DIP) and Human Protein Reference Database (HPRD). Our experimental results have shown that our algorithm achieves comparable network clustering performance in comparison to the more time-consuming simulated annealing (SA) optimization. Furthermore, preliminary results for identifying fine-grained functional modules in both biological networks and the comparison with the commonly adopted Markov Clustering (MCL) algorithm have demonstrated the potential of our algorithm to discover new types of modules, within which proteins are sparsely connected but with significantly enriched biological functionalities.

2013-01-01

175

Radiation inactivation reveals discrete cation binding sites that modulate dihydropyridine binding sites  

SciTech Connect

In low ionic strength buffer (5 mM Tris.HCl), the binding of (3H) nitrendipine to dihydropyridine calcium antagonist binding sites of mouse forebrain membranes is increased by both Na{sup +} and Ca{sup 2+}. Radiation inactivation was used to determine the target size of ({sup 3}H)nitrendipine binding sites in 5 mM Tris.HCl buffer, in the presence and absence of these cations. After irradiation, ({sup 3}H) nitrendipine binding in buffer with or without Na+ was diminished, due to a loss of binding sites and also to an increase in Kd. After accounting for radiation effects on the dissociation constant, the target size for the nitrendipine binding site in buffer was 160-170 kDa and was 170-180 kDa in the presence of sodium. In the presence of calcium ions, ({sup 3}H)nitrendipine binding showed no radiation effects on Kd and yielded a target size of 150-170 kDa. These findings suggest, as in the case of opioid receptors, the presence of high molecular weight membrane components that modulate cation-induced alterations in radioligand binding to dihydropyridine binding sites.

Bolger, G.T.; Skolnick, P.; Kempner, E.S. (National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD (USA))

1989-08-01

176

Unrestrained erythroblast development in Nix?/? mice reveals a mechanism for apoptotic modulation of erythropoiesis  

PubMed Central

Normal production of RBCs requires that the antiapoptotic protein Bcl-xl be induced at end stages of differentiation in response to erythropoietin (Epo) signaling. The critical proapoptotic pathways inhibited by Bcl-xl in erythroblasts are unknown. We used gene targeting in the mouse to evaluate the BH3-only factor Nix, which is transcriptionally up-regulated during Epo-stimulated in vitro erythrocyte differentiation. Nix null mice are viable and fertile. Peripheral blood counts revealed a profound reticulocytosis and thrombocytosis despite normal serum Epo levels and blood oxygen tension. Nix null mice exhibited massive splenomegaly, with splenic and bone marrow erythroblastosis and reduced apoptosis in vivo during erythrocyte maturation. Hematopoietic progenitor populations were unaffected. Cultured Nix null erythroid cells were hypersensitive to Epo and resistant to apoptosis stimulated by cytokine deprivation and calcium ionophore. Transcriptional profiling of Nix null spleens revealed increased expression of cell cycle and erythroid genes, including Bcl-xl, and diminished expression of cell death and B cell-related genes. Thus, cell-autonomous Nix-mediated apoptosis in opposition to the Epo-induced erythroblast survival pathway appears indispensable for regulation of erythrocyte production and maintenance of hematological homeostasis. These results suggest that physiological codependence and coordinated regulation of pro- and antiapoptotic Bcl2 family members may represent a general regulatory paradigm in hematopoiesis.

Diwan, Abhinav; Koesters, Andrew G.; Odley, Amy M.; Pushkaran, Suvarnamala; Baines, Christopher P.; Spike, Benjamin T.; Daria, Diedre; Jegga, Anil G.; Geiger, Hartmut; Aronow, Bruce J.; Molkentin, Jeffery D.; Macleod, Kay F.; Kalfa, Theodosia A.; Dorn, Gerald W.

2007-01-01

177

Unrestrained erythroblast development in Nix-/- mice reveals a mechanism for apoptotic modulation of erythropoiesis.  

PubMed

Normal production of RBCs requires that the antiapoptotic protein Bcl-xl be induced at end stages of differentiation in response to erythropoietin (Epo) signaling. The critical proapoptotic pathways inhibited by Bcl-xl in erythroblasts are unknown. We used gene targeting in the mouse to evaluate the BH3-only factor Nix, which is transcriptionally up-regulated during Epo-stimulated in vitro erythrocyte differentiation. Nix null mice are viable and fertile. Peripheral blood counts revealed a profound reticulocytosis and thrombocytosis despite normal serum Epo levels and blood oxygen tension. Nix null mice exhibited massive splenomegaly, with splenic and bone marrow erythroblastosis and reduced apoptosis in vivo during erythrocyte maturation. Hematopoietic progenitor populations were unaffected. Cultured Nix null erythroid cells were hypersensitive to Epo and resistant to apoptosis stimulated by cytokine deprivation and calcium ionophore. Transcriptional profiling of Nix null spleens revealed increased expression of cell cycle and erythroid genes, including Bcl-xl, and diminished expression of cell death and B cell-related genes. Thus, cell-autonomous Nix-mediated apoptosis in opposition to the Epo-induced erythroblast survival pathway appears indispensable for regulation of erythrocyte production and maintenance of hematological homeostasis. These results suggest that physiological codependence and coordinated regulation of pro- and antiapoptotic Bcl2 family members may represent a general regulatory paradigm in hematopoiesis. PMID:17420462

Diwan, Abhinav; Koesters, Andrew G; Odley, Amy M; Pushkaran, Suvarnamala; Baines, Christopher P; Spike, Benjamin T; Daria, Diedre; Jegga, Anil G; Geiger, Hartmut; Aronow, Bruce J; Molkentin, Jeffery D; Macleod, Kay F; Kalfa, Theodosia A; Dorn, Gerald W

2007-04-09

178

Modulation of working memory function by motivation through loss-aversion.  

PubMed

Cognitive performance is affected by motivation. Few studies, however, have investigated the neural mechanisms of the influence of motivation through potential monetary punishment on working memory. We employed functional MRI during a delayed recognition task that manipulated top-down control demands with added monetary incentives to some trials in the form of potential losses of bonus money. Behavioral performance on the task was influenced by loss-threatening incentives in the form of faster and more accurate performance. As shown previously, we found enhancement of activity for relevant stimuli occurs throughout all task periods (e.g., stimulus encoding, maintenance, and response) in both prefrontal and visual association cortex. Further, these activation patterns were enhanced for trials with possible monetary loss relative to nonincentive trials. During the incentive cue, the amygdala and striatum showed significantly greater activation when money was at a possible loss on the trial. We also evaluated patterns of functional connectivity between regions responsive to monetary consequences and prefrontal areas responsive to the task. This analysis revealed greater delay period connectivity between and the left insula and prefrontal cortex with possible monetary loss relative to nonincentive trials. Overall, these results reveal that incentive motivation can modulate performance on working memory tasks through top-down signals via amplification of activity within prefrontal and visual association regions selective to processing the perceptual inputs of the stimuli to be remembered. PMID:22113962

Krawczyk, Daniel C; D'Esposito, Mark

2011-11-24

179

Altered baseline brain activity in children with ADHD revealed by resting-state functional MRI  

Microsoft Academic Search

In children with attention deficit hyperactivity disorder (ADHD), functional neuroimaging studies have revealed abnormalities in various brain regions, including prefrontal-striatal circuit, cerebellum, and brainstem. In the current study, we used a new marker of functional magnetic resonance imaging (fMRI), amplitude of low-frequency (0.01–0.08Hz) fluctuation (ALFF) to investigate the baseline brain function of this disorder. Thirteen boys with ADHD (13.0±1.4 years)

Zang Yu-Feng; He Yong; Zhu Chao-Zhe; Cao Qing-Jiu; Sui Man-Qiu; Liang Meng; Tian Li-Xia; Jiang Tian-Zi; Wang Yu-Feng

2007-01-01

180

Motif module map reveals enforcement of aging by continual NF B activity  

Microsoft Academic Search

Aging is characterized by specific alterations in gene expression, but their underlying mechanisms and functional consequences are not well understood. Here we develop a systematic approach to identify combinatorial cis-regulatory motifs that drive age-dependent gene expression across different tissues and organisms. Integrated analysis of 365 microarrays spanning nine tissue types predicted fourteen motifs as major regulators of age-dependent gene expression

Adam S. Adler; Saurabh Sinha; Tiara L. A. Kawahara; Jennifer Y. Zhang; Eran Segal; Howard Y. Chang

2007-01-01

181

A Common Evolutionary Origin for Tailed-Bacteriophage Functional Modules and Bacterial Machineries  

PubMed Central

Summary: Bacteriophages belonging to the order Caudovirales possess a tail acting as a molecular nanomachine used during infection to recognize the host cell wall, attach to it, pierce it, and ensure the high-efficiency delivery of the genomic DNA to the host cytoplasm. In this review, we provide a comprehensive analysis of the various proteins constituting tailed bacteriophages from a structural viewpoint. To this end, we had in mind to pinpoint the resemblances within and between functional modules such as capsid/tail connectors, the tails themselves, or the tail distal host recognition devices, termed baseplates. This comparison has been extended to bacterial machineries embedded in the cell wall, for which shared molecular homology with phages has been recently revealed. This is the case for the type VI secretion system (T6SS), an inverted phage tail at the bacterial surface, or bacteriocins. Gathering all these data, we propose that a unique ancestral protein fold may have given rise to a large number of bacteriophage modules as well as to some related bacterial machinery components.

Veesler, David; Cambillau, Christian

2011-01-01

182

NSP-Cas protein structures reveal a promiscuous interaction module in cell signaling  

SciTech Connect

Members of the novel SH2-containing protein (NSP) and Crk-associated substrate (Cas) protein families form multidomain signaling platforms that mediate cell migration and invasion through a collection of distinct signaling motifs. Members of each family interact via their respective C-terminal domains, but the mechanism of this association has remained enigmatic. Here we present the crystal structures of the C-terminal domain from the NSP protein BCAR3 and the complex of NSP3 with p130Cas. BCAR3 adopts the Cdc25-homology fold of Ras GTPase exchange factors, but it has a 'closed' conformation incapable of enzymatic activity. The structure of the NSP3-p130Cas complex reveals that this closed conformation is instrumental for interaction of NSP proteins with a focal adhesion-targeting domain present in Cas proteins. This enzyme-to-adaptor conversion enables high-affinity, yet promiscuous, interactions between NSP and Cas proteins and represents an unprecedented mechanistic paradigm linking cellular signaling networks.

Mace, P.D.; Robinson, H.; Wallez, Y.; Dobaczewska, M. K.; Lee, J. J.; Pasquale, E. B.; Riedl, S. J.

2011-12-01

183

STED Nanoscopy Reveals Molecular Details of Cholesterol- and Cytoskeleton-Modulated Lipid Interactions in Living Cells  

PubMed Central

Details about molecular membrane dynamics in living cells, such as lipid-protein interactions, are often hidden from the observer because of the limited spatial resolution of conventional far-field optical microscopy. The superior spatial resolution of stimulated emission depletion (STED) nanoscopy can provide new insights into this process. The application of fluorescence correlation spectroscopy (FCS) in focal spots continuously tuned down to 30 nm in diameter distinguishes between free and anomalous molecular diffusion due to, for example, transient binding of lipids to other membrane constituents, such as lipids and proteins. We compared STED-FCS data recorded on various fluorescent lipid analogs in the plasma membrane of living mammalian cells. Our results demonstrate details about the observed transient formation of molecular complexes. The diffusion characteristics of phosphoglycerolipids without hydroxyl-containing headgroups revealed weak interactions. The strongest interactions were observed with sphingolipid analogs, which showed cholesterol-assisted and cytoskeleton-dependent binding. The hydroxyl-containing headgroup of gangliosides, galactosylceramide, and phosphoinositol assisted binding, but in a much less cholesterol- and cytoskeleton-dependent manner. The observed anomalous diffusion indicates lipid-specific transient hydrogen bonding to other membrane molecules, such as proteins, and points to a distinct connectivity of the various lipids to other membrane constituents. This strong interaction is different from that responsible for forming cholesterol-dependent, liquid-ordered domains in model membranes.

Mueller, V.; Ringemann, C.; Honigmann, A.; Schwarzmann, G.; Medda, R.; Leutenegger, M.; Polyakova, S.; Belov, V.N.; Hell, S.W.; Eggeling, C.

2011-01-01

184

Modulation of cell function in the calcium messenger system  

Microsoft Academic Search

A consideration of hormone and neurotransmitter action as an information transfer sequence leads to the conclusion that there are two mechanisms by which the intracellular messengers calcium and cAMP, binding to their respective intracellular receptor proteins, modulate the behavior of specific response elements within the cell. These two mechanisms are those of increasing the amplitude of a particular messenger, and

Howard Rasmussen; David M. Waisman

185

Modulation of Cell Structure and Function in Response to Substrate Stiffness and External Forces  

Microsoft Academic Search

The mechanical balance maintained between the cell and its environment forms the basis of tissue formation, cohesion and homeostasis. Cells are able to sense the mechanical characteristics of the extracellular medium and to modulate their function accordingly. Furthermore, cells are able to modulate the mechanical properties of their environment in response to intracellular signals. In this article we review recent

Martial Hervy

2010-01-01

186

Modulation-doped semiconductor nanowires: Functional building blocks for nanoelectronics and nanophotonics  

Microsoft Academic Search

The synthetic implementation of designed nanostructures is central to advances in the field of nanoscience and nanotechnology. Modulation of the composition of nanostructures during growth could encode information or function in a manner analogous to biological systems and independent of the constraints of lithography. This thesis presents the synthesis and characterization of modulation-doped nanowires with the structural and electrical properties

Chen Yang

2006-01-01

187

The Autocorrelation Function and Power Spectrum of PCM\\/FM with Random Binary Modulating Waveforms  

Microsoft Academic Search

This paper presents the derivation of exact expressions for the autocorrelation function and power spectrum of PCM\\/FM or FSK when the frequency modulating waveform is a random sequence of binary pulses of length T. The problem treated is that of true frequency modulation of an oscillator, a process which, except for a few special cases, generates waveforms and spectra different

M. G. Pelchat

1964-01-01

188

Evidence that family 35 carbohydrate binding modules display conserved specificity but divergent function  

Microsoft Academic Search

Enzymes that hydrolyze complex carbohydrates play important roles in numerous biological processes that result in the maintenance of marine and terrestrial life. These enzymes often contain noncatalytic carbohydrate binding modules (CBMs) that have important substrate-targeting functions. In general, there is a tight correlation between the ligands recognized by bacterial CBMs and the substrate specificity of the appended catalytic modules. Through

Cedric Montanier; Alicia Lammerts van Bueren; Claire Dumon; James E. Flint; Marcia A. Correia; Jose A. Prates; Susan J. Firbank; Richard J. Lewis; Gilles G. Grondin; Mariana G. Ghinet; Tracey M. Gloster; Cecile Herve; J. Paul Knox; Brian G. Talbot; Johan P. Turkenburg; Janne Kerovuo; Ryszard Brzezinski; Carlos M. G. A. Fontes; Gideon J. Davies; Alisdair B. Boraston; Harry J. Gilbert

2009-01-01

189

Scaling behavior in turbulent Rayleigh-Bénard convection revealed by conditional structure functions.  

PubMed

We show that the nature of the scaling behavior can be revealed by studying the conditional structure functions evaluated at given values of the locally averaged thermal dissipation rate. These conditional structure functions have power-law dependence on the value of the locally averaged thermal dissipation rate, and such dependence for the Bolgiano-Obukhov scaling is different from the other scaling behaviors. Our analysis of experimental measurements verifies the power-law dependence and reveals the Bolgiano-Obukhov scaling behavior at the center of the bottom plate of the convection cell. PMID:23410424

Ching, Emily S C; Tsang, Yue-Kin; Fok, T N; He, Xiaozhou; Tong, Penger

2013-01-03

190

Impact of Lipid Raft Integrity on 5-HT3 Receptor Function and its Modulation by Antidepressants  

PubMed Central

Because of the biochemical colocalization of the 5-HT3 receptor and antidepressants within raft-like domains and their antagonistic effects at this ligand-gated ion channel, we investigated the impact of lipid raft integrity for 5-HT3 receptor function and its modulation by antidepressants. Treatment with methyl-?-cyclodextrine (M?CD) markedly reduced membrane cholesterol levels and caused a more diffuse membrane distribution of the lipid raft marker protein flotillin-1 indicating lipid raft impairment. Both amplitude and charge of serotonin evoked cation currents were diminished following cholesterol depletion by either M?CD or simvastatin (Sim), whereas the functional antagonistic properties of the antidepressants desipramine (DMI) and fluoxetine (Fluox) at the 5-HT3 receptor were retained. Although both the 5-HT3 receptor and flotillin-1 were predominantly found in raft-like domains in western blots following sucrose density gradient centrifugation, immunocytochemistry revealed only a coincidental degree of colocalization of these two proteins. These findings and the persistence of the antagonistic effects of DMI and Fluox against 5-HT3 receptors after lipid raft impairment indicate that their modulatory effects are likely mediated through non-raft 5-HT3 receptors, which are not sufficiently detected by means of sucrose density gradient centrifugation. In conclusion, lipid raft integrity appears to be important for 5-HT3 receptor function in general, whereas it is not a prerequisite for the antagonistic properties of antidepressants such as DMI and Fluox at this ligand-gated ion channel.

Nothdurfter, Caroline; Tanasic, Sascha; Di Benedetto, Barbara; Rammes, Gerhard; Wagner, Eva-Maria; Kirmeier, Thomas; Ganal, Vanessa; Kessler, Julia S; Rein, Theo; Holsboer, Florian; Rupprecht, Rainer

2010-01-01

191

Impact of lipid raft integrity on 5-HT3 receptor function and its modulation by antidepressants.  

PubMed

Because of the biochemical colocalization of the 5-HT(3) receptor and antidepressants within raft-like domains and their antagonistic effects at this ligand-gated ion channel, we investigated the impact of lipid raft integrity for 5-HT(3) receptor function and its modulation by antidepressants. Treatment with methyl-beta-cyclodextrine (MbetaCD) markedly reduced membrane cholesterol levels and caused a more diffuse membrane distribution of the lipid raft marker protein flotillin-1 indicating lipid raft impairment. Both amplitude and charge of serotonin evoked cation currents were diminished following cholesterol depletion by either MbetaCD or simvastatin (Sim), whereas the functional antagonistic properties of the antidepressants desipramine (DMI) and fluoxetine (Fluox) at the 5-HT(3) receptor were retained. Although both the 5-HT(3) receptor and flotillin-1 were predominantly found in raft-like domains in western blots following sucrose density gradient centrifugation, immunocytochemistry revealed only a coincidental degree of colocalization of these two proteins. These findings and the persistence of the antagonistic effects of DMI and Fluox against 5-HT(3) receptors after lipid raft impairment indicate that their modulatory effects are likely mediated through non-raft 5-HT(3) receptors, which are not sufficiently detected by means of sucrose density gradient centrifugation. In conclusion, lipid raft integrity appears to be important for 5-HT(3) receptor function in general, whereas it is not a prerequisite for the antagonistic properties of antidepressants such as DMI and Fluox at this ligand-gated ion channel. PMID:20200506

Nothdurfter, Caroline; Tanasic, Sascha; Di Benedetto, Barbara; Rammes, Gerhard; Wagner, Eva-Maria; Kirmeier, Thomas; Ganal, Vanessa; Kessler, Julia S; Rein, Theo; Holsboer, Florian; Rupprecht, Rainer

2010-03-03

192

The connectivity of functional cores reveals different degrees of segregation and integration in the brain at rest.  

PubMed

The principles of functional specialization and integration in the resting brain are implemented in a complex system of specialized networks that share some degree of interaction. Recent studies have identified wider functional modules compared to previously defined networks and reported a small-world architecture of brain activity in which central nodes balance the pressure to evolve segregated pathways with the integration of local systems. The accurate identification of such central nodes is crucial but might be challenging for several reasons, e.g. inter-subject variability and physiological/pathological network plasticity, and recent works reported partially inconsistent results concerning the properties of these cortical hubs. Here, we applied a whole-brain data-driven approach to extract cortical functional cores and examined their connectivity from a resting state fMRI experiment on healthy subjects. Two main statistically significant cores, centered on the posterior cingulate cortex and the supplementary motor area, were extracted and their functional connectivity maps, thresholded at three statistical levels, revealed the presence of two complex systems. One system is consistent with the default mode network (DMN) and gradually connects to visual regions, the other centered on motor regions and gradually connects to more sensory-specific portions of cortex. These two large scale networks eventually converged to regions belonging to the medial aspect of the DMN, potentially allowing inter-network interactions. PMID:23220493

de Pasquale, Francesco; Sabatini, Umberto; Della Penna, Stefania; Sestieri, Carlo; Caravasso, Chiara Falletta; Formisano, Rita; Péran, Patrice

2012-12-06

193

Development and SAR of functionally selective allosteric modulators of GABAA receptors.  

PubMed

Positive modulators at the benzodiazepine site of ?2- and ?3-containing GABA(A) receptors are believed to be anxiolytic. Through oocyte voltage clamp studies, we have discovered two series of compounds that are positive modulators at ?2-/?3-containing GABA(A) receptors and that show no functional activity at ?1-containing GABA(A) receptors. We report studies to improve this functional selectivity and ultimately deliver clinical candidates. The functional SAR of cinnolines and quinolines that are positive allosteric modulators of the ?2- and ?3-containing GABA(A) receptors, while simultaneously neutral antagonists at ?1-containing GABA(A) receptors, is described. Such functionally selective modulators of GABA(A) receptors are expected to be useful in the treatment of anxiety and other psychiatric illnesses. PMID:21498079

Alhambra, Cristobal; Becker, Chris; Blake, Timothy; Chang, Amy Hui-Fang; Damewood, James R; Daniels, Thalia; Dembofsky, Bruce T; Gurley, David A; Hall, James E; Herzog, Keith J; Horchler, Carey L; Ohnmacht, Cyrus J; Schmiesing, Richard Jon; Dudley, Adam; Ribadeneira, Maria D; Knappenberger, Katherine S; Maciag, Carla; Stein, Mark M; Chopra, Maninder; Liu, Xiaodong F; Christian, Edward P; Arriza, Jeffrey L; Chapdelaine, Marc J

2011-03-29

194

An improved FORTRAN program for calculating modulation transfer functions: concise communication.  

PubMed

An improved FORTRAN II program for calculating modulation transfer functions (MTFs) is presented. The program features (A) simplified input-data specifications; (B) a conversational mode of use; and (C) graphic printout of the MTF curve. PMID:830835

Benedetto, A R; Nusynowitz, M L

1977-01-01

195

Tethering toxins and peptide ligands for modulation of neuronal function  

PubMed Central

Tethering genetically encoded peptide toxins or ligands close to their point of activity at the cell plasma membrane provides a new approach to the study of cell networks and neuronal circuits, as it allows selective targeting of specific cell populations, enhances the working concentration of the ligand or blocker peptide, and permits the engineering of a large variety of t-peptides (e.g., including use of fluorescent markers, viral vectors and point mutation variants). This review describes the development of tethered toxins and peptides derived from the identification of the cell surface nAChR modulator lynx1, the existence of related endogenous cell surface modulators of nAChR and AMPA receptors, and the application of the t-toxin and t-neuropeptide technology to the dissection of neuronal circuits in metazoans.

Ibanez-Tallon, Ines; Nitabach, Michael N.

2011-01-01

196

Involvement of oxidative and nitrosative stress in modulation of gene expression and functional responses by IFN  

Microsoft Academic Search

IFNg is a potent immunomodulator which plays important roles in host defense. IFNg modulates transcription of growth-related genes (N-myc downstream regulator 1, growth arrest and DNA damage inducible g and inhibitor of DNA binding 2 (Id2)), which is followed by increased growth suppression in the mouse hepatoma cell line, H6. Further studies revealed modulation of genes involved in oxidative and

S. Jyothi Prasanna; Banishree Saha; Dipankar Nandi

2007-01-01

197

A role for phospholipid polyunsaturation in modulating membrane protein function  

Microsoft Academic Search

Visual transduction is one of the best characterized G protein—coupled signalling systems. In addition, about 50% of the disk\\u000a membrane phospholipid acyl chains are 22:6n-3, making this system ideal for determining the role of polyunsaturation in modulating\\u000a membrane-signalling systems. The extent of formation of metarhodopsin II (MII), the G protein—activating photointermediate\\u000a of rhodopsin, was studied in phospholipid vesicles composed of

Burton J. Litman; Drake C. Mitchell

1996-01-01

198

An in silico method for detecting overlapping functional modules from composite biological networks  

PubMed Central

Background The ever-increasing flow of gene expression and protein-protein interaction (PPI) data has assisted in understanding the dynamics of the cell. The detection of functional modules is the first step in deciphering the apparent modularity of biological networks. However, most network-partitioning algorithms consider only the topological aspects and ignore the underlying functional relationships. Results In the current study we integrate proteomics and microarray data of yeast, in the form of a weighted PPI graph. We partition the enriched PPI network with the novel DetMod algorithm and we identify 335 modules. One of the main advantages of DetMod is that it manages to capture the inter-module cross-talk by allowing a controlled degree of overlap among the detected modules. The obtained modules are densely connected in terms of protein interactions, while their members share up to a high degree similar biological process GO terms. Moreover, known protein complexes are largely incorporated in the assessed modules. Finally, we display the prevalence of our method against modules resulting from other computational approaches. Conclusion The successful integration of heterogeneous data and the concept of the proposed algorithm provide confident functional modules. We also proved that our approach is superior to methods restricted to PPI data only.

Maraziotis, Ioannis A; Dimitrakopoulou, Konstantina; Bezerianos, Anastasios

2008-01-01

199

Development and SAR of functionally selective allosteric modulators of GABA A receptors  

Microsoft Academic Search

Positive modulators at the benzodiazepine site of ?2- and ?3-containing GABAA receptors are believed to be anxiolytic. Through oocyte voltage clamp studies, we have discovered two series of compounds that are positive modulators at ?2-\\/?3-containing GABAA receptors and that show no functional activity at ?1-containing GABAA receptors. We report studies to improve this functional selectivity and ultimately deliver clinical candidates.

Cristobal Alhambra; Chris Becker; Timothy Blake; James R. Damewood; Thalia Daniels; Bruce T. Dembofsky; David A. Gurley; James E. Hall; Keith J. Herzog; Carey L. Horchler; Cyrus J. Ohnmacht; Richard Jon Schmiesing; Adam Dudley; Maria D. Ribadeneira; Katherine S. Knappenberger; Carla Maciag; Mark M. Stein; Maninder Chopra; Xiaodong F. Liu; Edward P. Christian; Jeffrey L. Arriza; Marc J. Chapdelaine

2011-01-01

200

Androgens modulate structure and function of the suprachiasmatic nucleus brain clock.  

PubMed

Gonadal hormones can modulate circadian rhythms in rodents and humans, and androgen receptors are highly localized within the core region of the mouse suprachiasmatic nucleus (SCN) brain clock. Although androgens are known to modulate neural plasticity in other CNS compartments, the role of androgens and their receptors on plasticity in the SCN is unexplored. In the present study, we ask whether androgens influence the structure and function of the mouse SCN by examining the effects of gonadectomy (GDX) on the structure of the SCN circuit and its responses to light, including induction of clock genes and behavioral phase shifting. We found that after GDX, glial fibrillary acidic protein increased with concomitant decreases in the expression of the synaptic proteins synaptophysin and postsynaptic density 95. We also found that GDX exerts effects on the molecular and behavioral responses to light that are phase dependent. In late night [circadian time (CT)21], GDX increased light-induced mPer1 but not mPer2 expression compared with intact (INT) controls. In contrast, in early night (CT13.5), GDX decreased light induced mPer2 but had no effect on mPer1. At CT13.5, GDX animals also showed larger phase delays than did INT. Treatment of GDX animals with the nonaromatizable androgen dihydrotestosterone restored glial fibrillary acidic protein, postsynaptic density 95, and synaptophysin in the SCN and reinstated the INT pattern of molecular and behavioral responses to light. Together, the results reveal a role for androgens in regulating circuitry in the mouse SCN, with functional consequences for clock gene expression and behavioral responses to photic phase resetting stimuli. PMID:21363939

Karatsoreos, Ilia N; Butler, Matthew P; Lesauter, Joseph; Silver, Rae

2011-03-01

201

Pharmacological, antioxidant, genotoxic studies and modulation of rat splenocyte functions by Cyperus rotundus extracts  

PubMed Central

Background Cyperus rotundus Linn. (Cyperaceae) is a Tunisian medicinal plant used in folkloric (traditional) medicine to treat stomach disorders and inflammatory diseases. The present study explored the analgesic, anti-inflammatory and genotoxic activities of extracts from the aerial parts of C. rotundus. The antioxidant capacity and the modulation of splenocyte functions by these extracts were also investigated in mice. The phytochemical analysis was carried out using standard methods. Methods Aqueous, ethyl acetate, methanol and TOF-enriched extracts (300, 150, and 50??g/ml) were evaluated for their analgesic and anti-inflammatory activities. 4, 2, and 1?mg/ml of each extract were tested to investigate their effect on lipid peroxidation. The genotoxic study was monitored by measuring the structural chromosome aberrations of mice treated with 300?mg/kg of extract. The proliferation of lymphocytes in the absence and presence of mitogens was assessed at a concentration range 1–1000??g/ml. Results The tested extracts were able to decrease the mouse ear oedema induced by xylene. Furthermore, it was shown that the same extracts reduced the number of abdominal contractions caused by acetic acid in mice, revealing the peripheral analgesic activity of these extracts. It is worth noting that mice treated with doses up to 300?mg/kg b.w. of Cyperus rotundus extracts did not exhibit any toxicity. The tested extracts significantly enhance lymphocyte proliferation at 1?mg/ml. Conclusions It appears that C. rotundus extracts contain potent components such as flavonoids that may potentially be useful for modulating the immune cell functions, provoking analgesic, anti-inflammatory and antioxidant effects.

2013-01-01

202

A scale of functional divergence for yeast duplicated genes revealed from analysis of the protein-protein interaction network  

Microsoft Academic Search

BACKGROUND: Studying the evolution of the function of duplicated genes usually implies an estimation of the extent of functional conservation\\/divergence between duplicates from comparison of actual sequences. This only reveals the possible molecular function of genes without taking into account their cellular function(s). We took into consideration this latter dimension of gene function to approach the functional evolution of duplicated

Anaïs Baudot; Bernard Jacq; Christine Brun

2004-01-01

203

Modulation of T Cell Metabolism and Function through Calcium Signaling  

PubMed Central

As a vital second messenger in the activation of lymphocytes, the divalent cation Ca2+ plays numerous roles in adaptive immune responses. Importantly, Ca2+ signaling is essential for T cell activation, tolerance of self-antigens, and homeostasis. Supporting the essential role of Ca2+ signaling in T cell biology, the Ca2+ regulated protein phosphatase calcineurin is a key target of pharmacologic inhibition for preventing allograft rejection and for autoimmune therapy. Recent studies have highlighted the unique role of Stim1 and Orai1/2 proteins in the regulation of store-operated/calcium release activated calcium (CRAC) channels in the context of T cells. While Ca2+ is known to modulate T cell activation via effects on calcineurin and its target, nuclear factor of activated T cells (NFAT), this second messenger also regulates other pathways, including protein kinase C, calmodulin kinases, and cytoskeletal proteins. Ca2+ also modulates the unique metabolic changes that occur during in distinct T cell stages and subsets. Herein, we discuss the means by which Ca2+ mobilization modulates cellular metabolism following T cell receptor ligation. Further, we highlight the crosstalk between mitochondrial metabolism, reactive oxygen species (ROS) generation, and CRAC channel activity. As a target of mitochondrial ROS and Ca2+ regulation, we describe the involvement of the serine/threonine kinase DRAK2 in the context of these processes. Given the important roles for Ca2+ dependent signaling and cellular metabolism in adaptive immune responses, the crosstalk between these pathways is likely to be important for the regulation of T cell activation, tolerance, and homeostasis.

Fracchia, Kelley M.; Pai, Christine Y.; Walsh, Craig M.

2013-01-01

204

Synthesizing genome-wide association studies and expression microarray reveals novel genes that act in the human growth plate to modulate height.  

PubMed

Previous meta-analysis of genome-wide association (GWA) studies has identified 180 loci that influence adult height. However, each GWA locus typically comprises a set of contiguous genes, only one of which presumably modulates height. We reasoned that many of the causative genes within these loci influence height because they are expressed in and function in the growth plate, a cartilaginous structure that causes bone elongation and thus determines stature. Therefore, we used expression microarray studies of mouse and rat growth plate, human disease databases and a mouse knockout phenotype database to identify genes within the GWAS loci that are likely required for normal growth plate function. Each of these approaches identified significantly more genes within the GWA height loci than at random genomic locations (P < 0.0001 each), supporting the validity of the approach. The combined analysis strongly implicates 78 genes in growth plate function, including multiple genes that participate in PTHrP-IHH, BMP and CNP signaling, and many genes that have not previously been implicated in the growth plate. Thus, this analysis reveals a large number of novel genes that regulate human growth plate chondrogenesis and thereby contribute to the normal variations in human adult height. The analytic approach developed for this study may be applied to GWA studies for other common polygenic traits and diseases, thus providing a new general strategy to identify causative genes within GWA loci and to translate genetic associations into mechanistic biological insights. PMID:22914739

Lui, Julian C; Nilsson, Ola; Chan, Yingleong; Palmer, Cameron D; Andrade, Anenisia C; Hirschhorn, Joel N; Baron, Jeffrey

2012-08-21

205

Rasd1 Modulates the Coactivator Function of NonO in the Cyclic AMP Pathway  

PubMed Central

All living organisms exhibit autonomous daily physiological and behavioural rhythms to help them synchronize with the environment. Entrainment of circadian rhythm is achieved via activation of cyclic AMP (cAMP) and mitogen-activated protein kinase signaling pathways. NonO (p54nrb) is a multifunctional protein involved in transcriptional activation of the cAMP pathway and is involved in circadian rhythm control. Rasd1 is a monomeric G protein implicated to play a pivotal role in potentiating both photic and nonphotic responses of the circadian rhythm. In this study, we have identified and validated NonO as an interacting partner of Rasd1 via affinity pulldown, co-immunoprecipitation and indirect immunofluorescence studies. The GTP-hydrolysis activity of Rasd1 is required for the functional interaction. Functional interaction of Rasd1-NonO in the cAMP pathway was investigated via reporter gene assays, chromatin immunoprecipitation and gene knockdown. We showed that Rasd1 and NonO interact at the CRE-site of specific target genes. These findings reveal a novel mechanism by which the coregulator activity of NonO can be modulated.

Ong, Shufen Angeline; Tan, Jen Jen; Tew, Wai Loon; Chen, Ken-Shiung

2011-01-01

206

Cadmium modulates adipocyte functions in metallothionein-null mice.  

PubMed

Our previous study has demonstrated that exposure to cadmium (Cd), a toxic heavy metal, causes a reduction of adipocyte size and the modulation of adipokine expression. To further investigate the significance of the Cd action, we studied the effect of Cd on the white adipose tissue (WAT) of metallothionein null (MT(-/-)) mice, which cannot form atoxic Cd-MT complexes and are used for evaluating Cd as free ions, and wild type (MT(+/+)) mice. Cd administration more significantly reduced the adipocyte size of MT(-/-) mice than that of MT(+/+) mice. Cd exposure also induced macrophage recruitment to WAT with an increase in the expression level of Ccl2 (MCP-1) in the MT(-/-) mice. The in vitro exposure of Cd to adipocytes induce triglyceride release into culture medium, decrease in the expression levels of genes involved in fatty acid synthesis and lipid hydrolysis at 24h, and at 48h increase in phosphorylation of the lipid-droplet-associated protein perilipin, which facilitates the degradation of stored lipids in adipocytes. Therefore, the reduction in adipocyte size by Cd may arise from an imbalance between lipid synthesis and lipolysis. In addition, the expression levels of leptin, adiponectin and resistin decreased in adipocytes. Taken together, exposure to Cd may induce unusually small adipocytes and modulate the expression of adipokines differently from the case of physiologically small adipocytes, and may accelerate the risk of developing insulin resistance and type 2 diabetes. PMID:23921151

Kawakami, Takashige; Nishiyama, Kaori; Kadota, Yoshito; Sato, Masao; Inoue, Masahisa; Suzuki, Shinya

2013-08-03

207

Modulation of the barrier function of the skin.  

PubMed

Transport of xenobiotics across the stratum corneum, the rate-controlling membrane of skin, is slow and the mechanism appears complex. However, the basic transfer is controlled by fundamental physicochemical concepts, the predominant of which are partition (K), diffusion (D) and solubility (C(s)). In order to change the rate of penetration it is therefore clear that it is these parameters that should be targeted. In most instances enhancement strategies are adopted to improve D, K or C(s), however there are instances in which permeation reduction may be beneficial. Examples include the topical application of sunscreens or insect repellents. This publication demonstrates the way in which modulation effects can be assessed and the difficulties involved in determining which of the physicochemical parameter(s) are being affected. If the formulation influences more than one, synergism can often be seen. Advances in computer modelling have provided an insight into the mechanisms of action of some of the chemical enhancers at a molecular level. Enhanced skin absorption has been reported for the delivery of macromolecules such as insulin (associated with transfersomes) or DNA (as a DOTAP complex). The barrier property of the skin must be modulated for this to be achieved. However the precise mechanisms of action have not been elucidated. PMID:11509910

Hadgraft, J

2001-01-01

208

Global protein profiling reveals anti-EGFR monoclonal antibody 806-modulated proteins in A431 tumor xenografts.  

PubMed

Abstract An important mediator of tumorigenesis, the epidermal growth factor receptor (EGFR) is expressed in almost all non-transformed cell types, associated with tumor progression, angiogenesis and metastasis. The significance of the EGFR as a cancer therapeutic target is underscored by the clinical development of several different classes of EGFR antagonists, including monoclonal antibodies (mAb) and tyrosine kinase inhibitors. Extensive preclinical studies have demonstrated the anti-tumor effects of mAb806 against tumor xenografts overexpressing EGFR. EGF stimulation of A431 cells induces rapid tyrosine phosphorylation of intracellular signalling proteins which regulate cell proliferation and apoptosis. Detailed understanding of the intracellular signalling pathways and components modulated by mAbs (such as mAb806) to EGFR, and other growth factor receptors, remain limited. The use of fluorescence 2D difference gel electrophoresis (2D DIGE), coupled with sensitive MS-based protein profiling in A431 tumor (epidermoid carcinoma) xenografts, in combination with mAb806, revealed proteins modulating endocytosis, cell architecture, apoptosis, cell signalling pathways and cell cycle regulation, including Dynamin-1-like protein, cofilin-1 protein, and 14-3-3 protein zeta/delta. Further, we report various proteins, including Interferon-induced protein 53 (IFI53), and Oncogene EMS1 (EMS1) which have roles in the tumor microenvironment, regulating cancer cell invasiveness, angiogenesis and formation of metastases. These findings contribute to understanding the underlying biological processes associated with mAb806 therapy of EGFR-positive tumors, and identifying further potential protein markers that may contribute in assessment of the treatment response. PMID:23957735

Lee, Sze Ting; Ji, Hong; Greening, David W; Speirs, Robert W H; Rigopoulos, Angela; Pillay, Vinochani; Murone, Carmel; Vitali, Angela; Stühler, Kai; Johns, Terrance G; Corner, Georgia A; Mariadason, John M; Simpson, Richard J; Scott, Andrew M

2013-08-20

209

Structure of an Arrestin2-clathrin Complex Reveals a Novel Clathrin Binding Domain that Modulates Receptor Trafficking  

SciTech Connect

Non-visual arrestins play a pivotal role as adaptor proteins in regulating the signaling and trafficking of multiple classes of receptors. Although arrestin interaction with clathrin, AP-2, and phosphoinositides contributes to receptor trafficking, little is known about the configuration and dynamics of these interactions. Here, we identify a novel interface between arrestin2 and clathrin through x-ray diffraction analysis. The intrinsically disordered clathrin binding box of arrestin2 interacts with a groove between blades 1 and 2 in the clathrin {beta}-propeller domain, whereas an 8-amino acid splice loop found solely in the long isoform of arrestin2 (arrestin2L) interacts with a binding pocket formed by blades 4 and 5 in clathrin. The apposition of the two binding sites in arrestin2L suggests that they are exclusive and may function in higher order macromolecular structures. Biochemical analysis demonstrates direct binding of clathrin to the splice loop in arrestin2L, whereas functional analysis reveals that both binding domains contribute to the receptor-dependent redistribution of arrestin2L to clathrin-coated pits. Mutagenesis studies reveal that the clathrin binding motif in the splice loop is (L/I){sub 2}GXL. Taken together, these data provide a framework for understanding the dynamic interactions between arrestin2 and clathrin and reveal an essential role for this interaction in arrestin-mediated endocytosis.

Kang, D.; Kern, R; Puthenveedu, M; von Zastrow, M; Williams, J; Benovic, J

2009-01-01

210

Modulation of NMDA receptor function: implications for vertebrate neural development  

Microsoft Academic Search

The NMDA subtype of glutamate receptor is hypothesized to mediate synaptic competition in the developing brain by stabilizing converging synapses that have correlated activity patterns. Disruption of NMDA receptor function during development interferes with synapse elimination and sensory map formation. Moreover, many studies indicate that NMDA receptor function is high during times of synaptic rearrangement. In this review, a corollary

A. J. SCHEETZ; MARTHA CONSTANTIN-PATON

1994-01-01

211

Functional Redundancy Patterns Reveal Non-Random Assembly Rules in a Species-Rich Marine Assemblage  

PubMed Central

The relationship between species and the functional diversity of assemblages is fundamental in ecology because it contains key information on functional redundancy, and functionally redundant ecosystems are thought to be more resilient, resistant and stable. However, this relationship is poorly understood and undocumented for species-rich coastal marine ecosystems. Here, we used underwater visual censuses to examine the patterns of functional redundancy for one of the most diverse vertebrate assemblages, the coral reef fishes of New Caledonia, South Pacific. First, we found that the relationship between functional and species diversity displayed a non-asymptotic power-shaped curve, implying that rare functions and species mainly occur in highly diverse assemblages. Second, we showed that the distribution of species amongst possible functions was significantly different from a random distribution up to a threshold of ?90 species/transect. Redundancy patterns for each function further revealed that some functions displayed fast rates of increase in redundancy at low species diversity, whereas others were only becoming redundant past a certain threshold. This suggested non-random assembly rules and the existence of some primordial functions that would need to be fulfilled in priority so that coral reef fish assemblages can gain a basic ecological structure. Last, we found little effect of habitat on the shape of the functional-species diversity relationship and on the redundancy of functions, although habitat is known to largely determine assemblage characteristics such as species composition, biomass, and abundance. Our study shows that low functional redundancy is characteristic of this highly diverse fish assemblage, and, therefore, that even species-rich ecosystems such as coral reefs may be vulnerable to the removal of a few keystone species.

Guillemot, Nicolas; Kulbicki, Michel; Chabanet, Pascale; Vigliola, Laurent

2011-01-01

212

Joint independent component analysis of structural and functional images reveals complex patterns of functional reorganisation in stroke aphasia.  

PubMed

Previous functional activation studies in patients with aphasia have mostly relied on standard group comparisons of aphasic patients with healthy controls, which are biased towards regions showing the most consistent effects and disregard variability within groups. Groups of aphasic patients, however, show considerable variability with respect to lesion localisation and extent. Here, we use a novel method, joint independent component analysis (jICA), which allowed us to investigate abnormal patterns of functional activation with O(15)-PET during lexical decision in aphasic patients after middle cerebral artery stroke and to directly relate them to lesion information from structural MRI. Our results demonstrate that with jICA we could detect a network of compensatory increases in activity within bilateral anterior inferior temporal areas (BA20), which was not revealed by standard group comparisons. In addition, both types of analyses, jICA and group comparison, showed increased activity in the right posterior superior temporal gyrus in aphasic patients. Further, whereas standard analyses revealed no decreases in activation, jICA identified that left perisylvian lesions were associated with decreased activation of left posterior inferior frontal cortex, damaged in most patients, and extralesional remote decreases of activity within polar parts of the inferior temporal gyrus (BA38/20) and the occipital cortex (BA19). Taken together, our results demonstrate that jICA may be superior in revealing complex patterns of functional reorganisation in aphasia. PMID:19524049

Specht, Karsten; Zahn, Roland; Willmes, Klaus; Weis, Susanne; Holtel, Christiane; Krause, Bernd J; Herzog, Hans; Huber, Walter

2009-06-11

213

Functional roles of a tetraloop/receptor interacting module in a cyclic di-GMP riboswitch.  

PubMed

Riboswitches are a class of structural RNAs that regulate transcription and translation through specific recognition of small molecules. Riboswitches are attractive not only as drug targets for novel antibiotics but also as modular tools for controlling gene expression. Sequence comparison of a class of riboswitches that sense cyclic di-GMP (type-I c-di-GMP riboswitches) revealed that this type of riboswitch frequently shows a GAAA loop/receptor interaction between P1 and P3 elements. In the crystal structures of a type-I c-di-GMP riboswitch from Vibrio cholerae (the Vc2 riboswitch), the GNRA loop/receptor interaction assembled P2 and P3 stems to organize a ligand-binding pocket. In this study, the functional importance of the GAAA loop-receptor interaction in the Vc2 riboswitch was examined. A series of variant Vc2 riboswitches with mutations in the GAAA loop/receptor interaction were assayed for their switching abilities. In mutants with mutations in the P2 GAAA loop, expression of the reporter gene was reduced to approximately 40%?-?60% of that in the wild-type. However, mutants in which the P3 receptor motif was substituted with base pairs were as active as the wild-type. These results suggested that the GAAA loop/receptor interaction does not simply establish the RNA 3D structure but docking of P2 GAAA loop reduces the flexibility of the GAAA receptor motif in the P3 element. This mechanism was supported by a variant riboswitch bearing a theophylline aptamer module in P3 the structural rigidity of which could be modulated by the small molecule theophylline. PMID:22074990

Fujita, Yuki; Tanaka, Takahiro; Furuta, Hiroyuki; Ikawa, Yoshiya

2011-11-09

214

Leucine and citrulline modulate muscle function in malnourished aged rats  

Microsoft Academic Search

Protein energy malnutrition in the elderly causes preferential loss of muscle mass which is associated with poor functional\\u000a states. Leucine and citrulline are able to stimulate muscle protein synthesis in aged rats but no study has been undertaken\\u000a to evaluate their effect on muscle function. Sprague–Dawley male rats aged 23 months were used in the experiment. Part of\\u000a them were subjected

Cécile Faure; Agathe Raynaud-Simon; Arnaud Ferry; Valérie Daugé; Luc Cynober; Christian Aussel; Christophe Moinard

215

Angiogenesis and vascular functions in modulation of obesity, adipose metabolism, and insulin sensitivity.  

PubMed

White and brown adipose tissues are hypervascularized and the adipose vasculature displays phenotypic and functional plasticity to coordinate with metabolic demands of adipocytes. Blood vessels not only supply nutrients and oxygen to nourish adipocytes, they also serve as a cellular reservoir to provide adipose precursor and stem cells that control adipose tissue mass and function. Multiple signaling molecules modulate the complex interplay between the vascular system and the adipocytes. Understanding fundamental mechanisms by which angiogenesis and vasculatures modulate adipocyte functions may provide new therapeutic options for treatment of obesity and metabolic disorders by targeting the adipose vasculature. PMID:24035587

Cao, Yihai

2013-09-12

216

[The assessment of modulated radiofrequence electromagnetic radiation on cognitive function in rats of different ages].  

PubMed

The modulated radiofrequence electromagnetic radiation influence on cognitive function of male uninbred Wister rat exposed at the age of sexual maturation (2 months) and at the age of morphofunctional maturity (3.5 months) was examined. Animals were subjected to pulse electromagnetic radiation (925 MHz) modulated as a GSM standard with the power density 1.2 mW/cm2 for 10 minutes every day for 12 days. At day 8 of exposure the cognitive function were examined with the Morris water maze. In the result of investigation it was determines that modulated radiofrequence electromagnetic radiation at the sexual maturation age did not affect the spatial learning and improve the visual orientation performance. Modulated radiofrequence electromagnetic exposure of animals at the sex maturity age did not affect the visual performance and improve the spatial performance of male rats. PMID:17867503

Priakhin, E A; Triapitsyna, G A; Andreev, S S; Kolomiets, I A; Polevik, N D; Akleev, A V

217

The rice hydroperoxide lyase OsHPL3 functions in defense responses by modulating the oxylipin pathway.  

PubMed

As important signal molecules, jasmonates (JAs) and green leaf volatiles (GLVs) play diverse roles in plant defense responses against insect pests and pathogens. However, how plants employ their specific defense responses by modulating the levels of JA and GLVs remains unclear. Here, we describe identification of a role for the rice HPL3 gene, which encodes a hydroperoxide lyase (HPL), OsHPL3/CYP74B2, in mediating plant-specific defense responses. The loss-of-function mutant hpl3-1 produced disease-resembling lesions spreading through the whole leaves. A biochemical assay revealed that OsHPL3 possesses intrinsic HPL activity, hydrolyzing hydroperoxylinolenic acid to produce GLVs. The hpl3-1 plants exhibited enhanced induction of JA, trypsin proteinase inhibitors and other volatiles, but decreased levels of GLVs including (Z)-3-hexen-1-ol. OsHPL3 positively modulates resistance to the rice brown planthopper [BPH, Nilaparvata lugens (Stål)] but negatively modulates resistance to the rice striped stem borer [SSB, Chilo suppressalis (Walker)]. Moreover, hpl3-1 plants were more attractive to a BPH egg parasitoid, Anagrus nilaparvatae, than the wild-type, most likely as a result of increased release of BPH-induced volatiles. Interestingly, hpl3-1 plants also showed increased resistance to bacterial blight (Xanthomonas oryzae pv. oryzae). Collectively, these results indicate that OsHPL3, by affecting the levels of JA, GLVs and other volatiles, modulates rice-specific defense responses against different invaders. PMID:22519706

Tong, Xiaohong; Qi, Jinfeng; Zhu, Xudong; Mao, Bizeng; Zeng, Longjun; Wang, Baohui; Li, Qun; Zhou, Guoxin; Xu, Xiaojing; Lou, Yonggen; He, Zuhua

2012-06-18

218

Double-blind intervention trial on modulation of ozone effects on pulmonary function by antioxidant supplements  

Microsoft Academic Search

The aim of this study was to investigate whether the acute effects of ozone on lung function could be modulated by antioxidant vitamin supplementation in a placebo-controlled study. Lung function was measured in Dutch bicyclists (n = 38) before and after each training session on a number of occasions (n = 380) during the summer of 1996. The vitamin group

Linda Grievink; Aletta G. Zijlstra; Xiaodong Ke; Bert Brunekreef

1999-01-01

219

Genetic Interaction Maps in Escherichia coli Reveal Functional Crosstalk among Cell Envelope Biogenesis Pathways  

PubMed Central

As the interface between a microbe and its environment, the bacterial cell envelope has broad biological and clinical significance. While numerous biosynthesis genes and pathways have been identified and studied in isolation, how these intersect functionally to ensure envelope integrity during adaptive responses to environmental challenge remains unclear. To this end, we performed high-density synthetic genetic screens to generate quantitative functional association maps encompassing virtually the entire cell envelope biosynthetic machinery of Escherichia coli under both auxotrophic (rich medium) and prototrophic (minimal medium) culture conditions. The differential patterns of genetic interactions detected among >235,000 digenic mutant combinations tested reveal unexpected condition-specific functional crosstalk and genetic backup mechanisms that ensure stress-resistant envelope assembly and maintenance. These networks also provide insights into the global systems connectivity and dynamic functional reorganization of a universal bacterial structure that is both broadly conserved among eubacteria (including pathogens) and an important target.

Vlasblom, James; Gagarinova, Alla; Phanse, Sadhna; Graham, Chris; Yousif, Fouad; Ding, Huiming; Xiong, Xuejian; Nazarians-Armavil, Anaies; Alamgir, Md; Ali, Mehrab; Pogoutse, Oxana; Pe'er, Asaf; Arnold, Roland; Michaut, Magali; Parkinson, John; Golshani, Ashkan; Whitfield, Chris; Wodak, Shoshana J.; Moreno-Hagelsieb, Gabriel; Greenblatt, Jack F.; Emili, Andrew

2011-01-01

220

Genetic interaction maps in Escherichia coli reveal functional crosstalk among cell envelope biogenesis pathways.  

PubMed

As the interface between a microbe and its environment, the bacterial cell envelope has broad biological and clinical significance. While numerous biosynthesis genes and pathways have been identified and studied in isolation, how these intersect functionally to ensure envelope integrity during adaptive responses to environmental challenge remains unclear. To this end, we performed high-density synthetic genetic screens to generate quantitative functional association maps encompassing virtually the entire cell envelope biosynthetic machinery of Escherichia coli under both auxotrophic (rich medium) and prototrophic (minimal medium) culture conditions. The differential patterns of genetic interactions detected among > 235,000 digenic mutant combinations tested reveal unexpected condition-specific functional crosstalk and genetic backup mechanisms that ensure stress-resistant envelope assembly and maintenance. These networks also provide insights into the global systems connectivity and dynamic functional reorganization of a universal bacterial structure that is both broadly conserved among eubacteria (including pathogens) and an important target. PMID:22125496

Babu, Mohan; Díaz-Mejía, J Javier; Vlasblom, James; Gagarinova, Alla; Phanse, Sadhna; Graham, Chris; Yousif, Fouad; Ding, Huiming; Xiong, Xuejian; Nazarians-Armavil, Anaies; Alamgir, Md; Ali, Mehrab; Pogoutse, Oxana; Pe'er, Asaf; Arnold, Roland; Michaut, Magali; Parkinson, John; Golshani, Ashkan; Whitfield, Chris; Wodak, Shoshana J; Moreno-Hagelsieb, Gabriel; Greenblatt, Jack F; Emili, Andrew

2011-11-17

221

The Chlamydomonas genome reveals the evolution of key animal and plant functions.  

PubMed

Chlamydomonas reinhardtii is a unicellular green alga whose lineage diverged from land plants over 1 billion years ago. It is a model system for studying chloroplast-based photosynthesis, as well as the structure, assembly, and function of eukaryotic flagella (cilia), which were inherited from the common ancestor of plants and animals, but lost in land plants. We sequenced the approximately 120-megabase nuclear genome of Chlamydomonas and performed comparative phylogenomic analyses, identifying genes encoding uncharacterized proteins that are likely associated with the function and biogenesis of chloroplasts or eukaryotic flagella. Analyses of the Chlamydomonas genome advance our understanding of the ancestral eukaryotic cell, reveal previously unknown genes associated with photosynthetic and flagellar functions, and establish links between ciliopathy and the composition and function of flagella. PMID:17932292

Merchant, Sabeeha S; Prochnik, Simon E; Vallon, Olivier; Harris, Elizabeth H; Karpowicz, Steven J; Witman, George B; Terry, Astrid; Salamov, Asaf; Fritz-Laylin, Lillian K; Maréchal-Drouard, Laurence; Marshall, Wallace F; Qu, Liang-Hu; Nelson, David R; Sanderfoot, Anton A; Spalding, Martin H; Kapitonov, Vladimir V; Ren, Qinghu; Ferris, Patrick; Lindquist, Erika; Shapiro, Harris; Lucas, Susan M; Grimwood, Jane; Schmutz, Jeremy; Cardol, Pierre; Cerutti, Heriberto; Chanfreau, Guillaume; Chen, Chun-Long; Cognat, Valérie; Croft, Martin T; Dent, Rachel; Dutcher, Susan; Fernández, Emilio; Fukuzawa, Hideya; González-Ballester, David; González-Halphen, Diego; Hallmann, Armin; Hanikenne, Marc; Hippler, Michael; Inwood, William; Jabbari, Kamel; Kalanon, Ming; Kuras, Richard; Lefebvre, Paul A; Lemaire, Stéphane D; Lobanov, Alexey V; Lohr, Martin; Manuell, Andrea; Meier, Iris; Mets, Laurens; Mittag, Maria; Mittelmeier, Telsa; Moroney, James V; Moseley, Jeffrey; Napoli, Carolyn; Nedelcu, Aurora M; Niyogi, Krishna; Novoselov, Sergey V; Paulsen, Ian T; Pazour, Greg; Purton, Saul; Ral, Jean-Philippe; Riaño-Pachón, Diego Mauricio; Riekhof, Wayne; Rymarquis, Linda; Schroda, Michael; Stern, David; Umen, James; Willows, Robert; Wilson, Nedra; Zimmer, Sara Lana; Allmer, Jens; Balk, Janneke; Bisova, Katerina; Chen, Chong-Jian; Elias, Marek; Gendler, Karla; Hauser, Charles; Lamb, Mary Rose; Ledford, Heidi; Long, Joanne C; Minagawa, Jun; Page, M Dudley; Pan, Junmin; Pootakham, Wirulda; Roje, Sanja; Rose, Annkatrin; Stahlberg, Eric; Terauchi, Aimee M; Yang, Pinfen; Ball, Steven; Bowler, Chris; Dieckmann, Carol L; Gladyshev, Vadim N; Green, Pamela; Jorgensen, Richard; Mayfield, Stephen; Mueller-Roeber, Bernd; Rajamani, Sathish; Sayre, Richard T; Brokstein, Peter; Dubchak, Inna; Goodstein, David; Hornick, Leila; Huang, Y Wayne; Jhaveri, Jinal; Luo, Yigong; Martínez, Diego; Ngau, Wing Chi Abby; Otillar, Bobby; Poliakov, Alexander; Porter, Aaron; Szajkowski, Lukasz; Werner, Gregory; Zhou, Kemin; Grigoriev, Igor V; Rokhsar, Daniel S; Grossman, Arthur R

2007-10-12

222

Functional biogeography of ocean microbes revealed through non-negative matrix factorization.  

PubMed

The direct "metagenomic" sequencing of genomic material from complex assemblages of bacteria, archaea, viruses and microeukaryotes has yielded new insights into the structure of microbial communities. For example, analysis of metagenomic data has revealed the existence of previously unknown microbial taxa whose spatial distributions are limited by environmental conditions, ecological competition, and dispersal mechanisms. However, differences in genotypes that might lead biologists to designate two microbes as taxonomically distinct need not necessarily imply differences in ecological function. Hence, there is a growing need for large-scale analysis of the distribution of microbial function across habitats. Here, we present a framework for investigating the biogeography of microbial function by analyzing the distribution of protein families inferred from environmental sequence data across a global collection of sites. We map over 6,000,000 protein sequences from unassembled reads from the Global Ocean Survey dataset to [Formula: see text] protein families, generating a protein family relative abundance matrix that describes the distribution of each protein family across sites. We then use non-negative matrix factorization (NMF) to approximate these protein family profiles as linear combinations of a small number of ecological components. Each component has a characteristic functional profile and site profile. Our approach identifies common functional signatures within several of the components. We use our method as a filter to estimate functional distance between sites, and find that an NMF-filtered measure of functional distance is more strongly correlated with environmental distance than a comparable PCA-filtered measure. We also find that functional distance is more strongly correlated with environmental distance than with geographic distance, in agreement with prior studies. We identify similar protein functions in several components and suggest that functional co-occurrence across metagenomic samples could lead to future methods for de-novo functional prediction. We conclude by discussing how NMF, and other dimension reduction methods, can help enable a macroscopic functional description of marine ecosystems. PMID:23049741

Jiang, Xingpeng; Langille, Morgan G I; Neches, Russell Y; Elliot, Marie; Levin, Simon A; Eisen, Jonathan A; Weitz, Joshua S; Dushoff, Jonathan

2012-09-18

223

Functional Biogeography of Ocean Microbes Revealed through Non-Negative Matrix Factorization  

PubMed Central

The direct “metagenomic” sequencing of genomic material from complex assemblages of bacteria, archaea, viruses and microeukaryotes has yielded new insights into the structure of microbial communities. For example, analysis of metagenomic data has revealed the existence of previously unknown microbial taxa whose spatial distributions are limited by environmental conditions, ecological competition, and dispersal mechanisms. However, differences in genotypes that might lead biologists to designate two microbes as taxonomically distinct need not necessarily imply differences in ecological function. Hence, there is a growing need for large-scale analysis of the distribution of microbial function across habitats. Here, we present a framework for investigating the biogeography of microbial function by analyzing the distribution of protein families inferred from environmental sequence data across a global collection of sites. We map over 6,000,000 protein sequences from unassembled reads from the Global Ocean Survey dataset to protein families, generating a protein family relative abundance matrix that describes the distribution of each protein family across sites. We then use non-negative matrix factorization (NMF) to approximate these protein family profiles as linear combinations of a small number of ecological components. Each component has a characteristic functional profile and site profile. Our approach identifies common functional signatures within several of the components. We use our method as a filter to estimate functional distance between sites, and find that an NMF-filtered measure of functional distance is more strongly correlated with environmental distance than a comparable PCA-filtered measure. We also find that functional distance is more strongly correlated with environmental distance than with geographic distance, in agreement with prior studies. We identify similar protein functions in several components and suggest that functional co-occurrence across metagenomic samples could lead to future methods for de-novo functional prediction. We conclude by discussing how NMF, and other dimension reduction methods, can help enable a macroscopic functional description of marine ecosystems.

Neches, Russell Y.; Elliot, Marie; Levin, Simon A.; Eisen, Jonathan A.; Weitz, Joshua S.; Dushoff, Jonathan

2012-01-01

224

Manganese-Enhanced MRI Reveals Structural and Functional Changes in the Cortex of Bassoon Mutant Mice  

Microsoft Academic Search

Manganese-enhanced magnetic resonance imaging (ME-MRI) was used to analyze the brain architecture in mice lacking the functional presynaptic active zone protein Bassoon. Anatomical characteriza- tion revealed a significant increase in the total brain volume in Bassoon mutants as compared with wild-type mice, which is mainly caused by changes in cortex and hippocampus volume. The measured enlargement in cortical volume coincides

Frank Angenstein; Heiko G. Niessen; J. Goldschmidt; H. Lison; W. D. Altrock; E. D. Gundelfinger; H. Scheich

2006-01-01

225

Modelling NifH2 protein of Clostridium pasteurianum reveals clues about its physiological function.  

PubMed

Clostridium pasteurianum is an anaerobic free-living nitrogen fixer. As a unique feature, the organism contains five extra nifH-like genes in addition to nifH1. Detailed analysis with respect to the structure and function of the nifH-like gene products is missing due to the lack of information about the presence of their translation products in the cell. Recent work indicates that the nifH2 gene is transcribed and translated into a polypeptide of expected size in nitrogen-fixing cells of C. pasteurianum and is regulated both at the transcriptional and translational levels. However, the current data do not reveal the physiological function of the NifH2 protein. In this study, we have used computer tools and the NifH1 of C. pasteurianum as the template to predict a possible tertiary structure and assign a putative function for NifH2 protein. A comparison of the structures of the NifH1 and modelled NifH2 revealed similarities in the polypeptide conformations for both monomers. Analysis of the properties of nucleotide binding, dimer interacting and cluster containing regions did not reveal major differences between NifH1 and modelled NifH2, although minor differences were observed. Rigid docking results revealed the possibility of formation of a NifH1-NifH2 heterodimer as well as formation of a NifH2 homodimer. We, therefore, propose that NifH2 can form a dimer with NifH1, albeit less efficiently and may function as a regulatory Fe-protein. PMID:16495101

Kasap, Murat

2006-02-21

226

Revealing molecular-level surface structure of amyloid fibrils in liquid by means of frequency modulation atomic force microscopy  

NASA Astrophysics Data System (ADS)

We have investigated the surface structure of islet amyloid polypeptide (IAPP) fibrils and ?-synuclein protofibrils in liquid by means of frequency modulation atomic force microscopy (FM-AFM). Ångström-resolution FM-AFM imaging of isolated macromolecules in liquid is demonstrated for the first time. Individual ?-strands aligned perpendicular to the fibril axis with a spacing of 0.5 nm are resolved in FM-AFM images, which confirms cross-? structure of IAPP fibrils in real space. FM-AFM images also reveal the existence of 4 nm periodic domains along the axis of IAPP fibrils. Stripe features with 0.5 nm spacing are also found in images of ?-synuclein protofibrils. However, in contrast to the case for IAPP fibrils, the stripes are oriented 30° from the axis, suggesting the possibility of ?-strand alignment in protofibrils different from that in mature fibrils or the regular arrangement of thioflavin T molecules present during the fibril preparation aligned at the surface of the protofibrils.

Fukuma, Takeshi; Mostaert, Anika S.; Serpell, Louise C.; Jarvis, Suzanne P.

2008-09-01

227

Synaptic function and modulation of glycine receptor channels in the hypoglossal nucleus  

Microsoft Academic Search

In this review, we discuss the function and modulation of chloride-selective glycine receptor (GlyR) channels, some genetic\\u000a diseases originated from dysfunction of GlyRs, and modulation of glycinergic synapses by intracellular calcium (Ca2+) with particular attention on the motoneurons of the hypoglossal nucleus. This motor nucleus is a brainstem structure implicated\\u000a in the command of coordinated movements during oral behavioral phenomena,

P. Bregestovski; M. Mukhtarov

2007-01-01

228

Cross and Iso oriented surrounds modulate the contrast response function: The effect of surround contrast  

Microsoft Academic Search

The detectability and appearance of visual targets can be modulated by surround stimuli. In this study we asked how cross- and iso-oriented surrounds modulate contrast detection and discrimination in foveal vision. We systematically measured the Threshold-versus-Contrast (TvC) functions over a wide range of pedestal and surround contrasts. Our results show that cross-oriented surrounds lower the contrast threshold over the entire

Dennis M. Levi

2003-01-01

229

C-element: A New Clustering Algorithm to Find High Quality Functional Modules in PPI Networks  

PubMed Central

Graph clustering algorithms are widely used in the analysis of biological networks. Extracting functional modules in protein-protein interaction (PPI) networks is one such use. Most clustering algorithms whose focuses are on finding functional modules try either to find a clique like sub networks or to grow clusters starting from vertices with high degrees as seeds. These algorithms do not make any difference between a biological network and any other networks. In the current research, we present a new procedure to find functional modules in PPI networks. Our main idea is to model a biological concept and to use this concept for finding good functional modules in PPI networks. In order to evaluate the quality of the obtained clusters, we compared the results of our algorithm with those of some other widely used clustering algorithms on three high throughput PPI networks from Sacchromyces Cerevisiae, Homo sapiens and Caenorhabditis elegans as well as on some tissue specific networks. Gene Ontology (GO) analyses were used to compare the results of different algorithms. Each algorithm's result was then compared with GO-term derived functional modules. We also analyzed the effect of using tissue specific networks on the quality of the obtained clusters. The experimental results indicate that the new algorithm outperforms most of the others, and this improvement is more significant when tissue specific networks are used.

Ghasemi, Mahdieh; Rahgozar, Maseud; Bidkhori, Gholamreza; Masoudi-Nejad, Ali

2013-01-01

230

C-element: A New Clustering Algorithm to Find High Quality Functional Modules in PPI Networks.  

PubMed

Graph clustering algorithms are widely used in the analysis of biological networks. Extracting functional modules in protein-protein interaction (PPI) networks is one such use. Most clustering algorithms whose focuses are on finding functional modules try either to find a clique like sub networks or to grow clusters starting from vertices with high degrees as seeds. These algorithms do not make any difference between a biological network and any other networks. In the current research, we present a new procedure to find functional modules in PPI networks. Our main idea is to model a biological concept and to use this concept for finding good functional modules in PPI networks. In order to evaluate the quality of the obtained clusters, we compared the results of our algorithm with those of some other widely used clustering algorithms on three high throughput PPI networks from Sacchromyces Cerevisiae, Homo sapiens and Caenorhabditis elegans as well as on some tissue specific networks. Gene Ontology (GO) analyses were used to compare the results of different algorithms. Each algorithm's result was then compared with GO-term derived functional modules. We also analyzed the effect of using tissue specific networks on the quality of the obtained clusters. The experimental results indicate that the new algorithm outperforms most of the others, and this improvement is more significant when tissue specific networks are used. PMID:24039752

Ghasemi, Mahdieh; Rahgozar, Maseud; Bidkhori, Gholamreza; Masoudi-Nejad, Ali

2013-09-05

231

Serotonin modulates muscle function in the medicinal leech Hirudo verbana.  

PubMed

The body wall muscles of sanguivorous leeches power mechanically diverse behaviours: suction feeding, crawling and swimming. These require longitudinal muscle to exert force over an extremely large length range, from 145 to 46 per cent of the mean segmental swimming length. Previous data, however, suggest that leech body wall muscle has limited capacity for force production when elongated. Serotonin (5-HT) alters the passive properties of the body wall and stimulates feeding. We hypothesized that 5-HT may also have a role in allowing force production in elongated muscle by changing the shape of the length-tension relationship (LTR). LTRs were measured from longitudinal muscle strips in vitro in physiological saline with and without the presence of 10 µM 5-HT. The LTR was much broader than previously measured for leech muscle. Rather than shifting the LTR, 5-HT reduced passive muscle tonus and increased active stress at all lengths. In addition to modulating leech behaviour and passive mechanical properties, 5-HT probably enhances muscle force and work production during locomotion and feeding. PMID:21561963

Gerry, Shannon P; Ellerby, David J

2011-05-11

232

Modulation of baroreflex function by rosiglitazone in prediabetic hyperglycemic rats.  

PubMed

Baroreflex sensitivity (BRS) is abnormal in the prediabetic state. This study was conducted to determine effects of chronic rosiglitazone (RSG), an insulin sensitizer, on BRS in prediabetic hyperglycemic (PDH) rats induced by nicotinamide and streptozotocin. The fasting and postprandial blood glucose levels were 5.6-6.9 and 7.8-11.0 mmol/l, respectively. Rats were treated with RSG or saline for 12 weeks. BRS response to phenylephrine (PE-BRS) or sodium nitroprusside (NP-BRS) was determined by linear regression method. Cardiac sympathetic and parasympathetic influences were determined by autonomic blockades. In the saline-treated PDH rats, PE-BRS was enhanced early at week 4 and became greater at week 12. Abnormalities in NP-BRS and cardiac autonomic influences were found only after week 12. Four weeks of RSG treatment normalized blood glucose levels but not PE-BRS. All altered cardiovascular variables were completely restored by 12 weeks of RSG treatment. The correlation between BRS and blood glucose levels in saline-treated PDH rats was significant at week 12, but no correlation was found in RSG-treated rats. In conclusion, hyperglycemia, even in the prediabetic state, may play a role in BRS abnormalities. RSG treatment early in the prediabetic state may normalize BRS via cardiac autonomic modulation, besides its anti-hyperglycemic action. PMID:22881223

Hong, L-Z; Chan, Y-C; Wang, M-F; Wang, J-Y; Hung, S-W; Tsai, C-I; Tseng, C-J

2012-08-08

233

Functional Expression of an Arachnid Sodium Channel Reveals Residues Responsible for Tetrodotoxin Resistance in Invertebrate Sodium Channels*  

PubMed Central

Tetrodotoxin (TTX) is a potent blocker of voltage-gated sodium channels, but not all sodium channels are equally sensitive to inhibition by TTX. The molecular basis of differential TTX sensitivity of mammalian sodium channels has been largely elucidated. In contrast, our knowledge about the sensitivity of invertebrate sodium channels to TTX remains poor, in part because of limited success in functional expression of these channels. In this study, we report the functional characterization in Xenopus oocytes of the first non-insect, invertebrate voltage-gated sodium channel from the varroa mite (Varroa destructor), an ecto-parasite of the honeybee. This arachnid sodium channel activates and inactivates rapidly with half-maximal activation at ?18 mV and half-maximal fast inactivation at ?29 mV. Interestingly, this arachnid channel showed surprising TTX resistance. TTX blocked this channel with an IC50 of 1 ?m. Subsequent site-directed mutagenesis revealed two residues, Thr-1674 and Ser-1967, in the pore-forming region of domains III and IV, respectively, which were responsible for the observed resistance to inhibition by TTX. Furthermore, sequence comparison and additional amino acid substitutions suggested that sequence polymorphisms at these two positions could be a widespread mechanism for modulating TTX sensitivity of sodium channels in diverse invertebrates.

Du, Yuzhe; Nomura, Yoshiko; Liu, Zhiqi; Huang, Zachary Y.; Dong, Ke

2009-01-01

234

Functional expression of an arachnid sodium channel reveals residues responsible for tetrodotoxin resistance in invertebrate sodium channels.  

PubMed

Tetrodotoxin (TTX) is a potent blocker of voltage-gated sodium channels, but not all sodium channels are equally sensitive to inhibition by TTX. The molecular basis of differential TTX sensitivity of mammalian sodium channels has been largely elucidated. In contrast, our knowledge about the sensitivity of invertebrate sodium channels to TTX remains poor, in part because of limited success in functional expression of these channels. In this study, we report the functional characterization in Xenopus oocytes of the first non-insect, invertebrate voltage-gated sodium channel from the varroa mite (Varroa destructor), an ecto-parasite of the honeybee. This arachnid sodium channel activates and inactivates rapidly with half-maximal activation at -18 mV and half-maximal fast inactivation at -29 mV. Interestingly, this arachnid channel showed surprising TTX resistance. TTX blocked this channel with an IC(50) of 1 microM. Subsequent site-directed mutagenesis revealed two residues, Thr-1674 and Ser-1967, in the pore-forming region of domains III and IV, respectively, which were responsible for the observed resistance to inhibition by TTX. Furthermore, sequence comparison and additional amino acid substitutions suggested that sequence polymorphisms at these two positions could be a widespread mechanism for modulating TTX sensitivity of sodium channels in diverse invertebrates. PMID:19828457

Du, Yuzhe; Nomura, Yoshiko; Liu, Zhiqi; Huang, Zachary Y; Dong, Ke

2009-10-14

235

Functional traits reveal processes driving natural afforestation at large spatial scales.  

PubMed

An understanding of the processes governing natural afforestation over large spatial scales is vital for enhancing forest carbon sequestration. Models of tree species occurrence probability in non-forest vegetation could potentially identify the primary variables determining natural afforestation. However, inferring processes governing afforestation using tree species occurrence is potentially problematic, since it is impossible to know whether observed occurrences are due to recruitment or persistence of existing trees following disturbance. Plant functional traits have the potential to reveal the processes by which key environmental and land cover variables influence afforestation. We used 10,061 survey plots to identify the primary environmental and land cover variables influencing tree occurrence probability in non-forest vegetation in New Zealand. We also examined how these variables influenced diversity of functional traits linked to plant ecological strategy and dispersal ability. Mean annual temperature was the most important environmental predictor of tree occurrence. Local woody cover and distance to forest were the most important land cover variables. Relationships between these variables and ecological strategy traits revealed a trade-off between ability to compete for light and colonize sites that were marginal for tree occurrence. Biotically dispersed species occurred less frequently with declining temperature and local woody cover, suggesting that abiotic stress limited their establishment and that biotic dispersal did not increase ability to colonize non-woody vegetation. Functional diversity for ecological strategy traits declined with declining temperature and woody cover and increasing distance to forest. Functional diversity for dispersal traits showed the opposite trend. This suggests that low temperatures and woody cover and high distance to forest may limit tree species establishment through filtering on ecological strategy traits, but not on dispersal traits. This study shows that 'snapshot' survey plot data, combined with functional trait data, may reveal the processes driving tree species establishment in non-forest vegetation over large spatial scales. PMID:24058664

Mason, Norman W H; Wiser, Susan K; Richardson, Sarah J; Thorsen, Michael J; Holdaway, Robert J; Dray, Stéphane; Thomson, Fiona J; Carswell, Fiona E

2013-09-18

236

Functional Traits Reveal Processes Driving Natural Afforestation at Large Spatial Scales  

PubMed Central

An understanding of the processes governing natural afforestation over large spatial scales is vital for enhancing forest carbon sequestration. Models of tree species occurrence probability in non-forest vegetation could potentially identify the primary variables determining natural afforestation. However, inferring processes governing afforestation using tree species occurrence is potentially problematic, since it is impossible to know whether observed occurrences are due to recruitment or persistence of existing trees following disturbance. Plant functional traits have the potential to reveal the processes by which key environmental and land cover variables influence afforestation. We used 10,061 survey plots to identify the primary environmental and land cover variables influencing tree occurrence probability in non-forest vegetation in New Zealand. We also examined how these variables influenced diversity of functional traits linked to plant ecological strategy and dispersal ability. Mean annual temperature was the most important environmental predictor of tree occurrence. Local woody cover and distance to forest were the most important land cover variables. Relationships between these variables and ecological strategy traits revealed a trade-off between ability to compete for light and colonize sites that were marginal for tree occurrence. Biotically dispersed species occurred less frequently with declining temperature and local woody cover, suggesting that abiotic stress limited their establishment and that biotic dispersal did not increase ability to colonize non-woody vegetation. Functional diversity for ecological strategy traits declined with declining temperature and woody cover and increasing distance to forest. Functional diversity for dispersal traits showed the opposite trend. This suggests that low temperatures and woody cover and high distance to forest may limit tree species establishment through filtering on ecological strategy traits, but not on dispersal traits. This study shows that ‘snapshot’ survey plot data, combined with functional trait data, may reveal the processes driving tree species establishment in non-forest vegetation over large spatial scales.

Mason, Norman W. H.; Wiser, Susan K.; Richardson, Sarah J.; Thorsen, Michael J.; Holdaway, Robert J.; Dray, Stephane; Thomson, Fiona J.; Carswell, Fiona E.

2013-01-01

237

Mesocortical dopamine modulation of executive functions: beyond working memory  

Microsoft Academic Search

Rationale  Dopamine (DA) neurotransmission in the prefrontal cortex (PFC) is known to play an essential role in mediating executive functions such as the working memory. DA exerts these effects by acting on D1 receptors because blockade or stimulation of these receptors in the PFC can impair performance on delayed response tasks. However, comparatively less is known about dopaminergic mechanisms that mediate

Stan B. Floresco; Orsolya Magyar

2006-01-01

238

Salmonella Effectors: Important players modulating host cell function during infection  

PubMed Central

Summary Salmonella enterica serovar Typhimurium (S. Typhimurium) is a Gram-negative facultative foodborne pathogen that causes gastroenteritis in humans. This bacterium has evolved a sophisticated machinery to alter host cell function critical to its virulence capabilities. Central to S. Typhimurium pathogenesis are two Type three secretion systems (T3SS) encoded within pathogenicity islands SPI-1 and SPI-2 that are responsible for the secretion and translocation of a set of bacterial proteins termed effectors into host cells with the intention of altering host cell physiology for bacterial entry and survival. Thus, once delivered by the T3SS, the secreted effectors play critical roles in manipulating the host cell to allow for bacteria invasion, induction of inflammatory responses, and the assembly of an intracellular protective niche created for bacterial survival and replication. Emerging evidence indicates that these effectors are modular proteins consisting of distinct functional domains/motifs that are utilized by the bacteria to activate intracellular signaling pathways modifying host cell function. Also, recently reported are the dual functionality of secreted effectors and the concept of “terminal reassortment”. Herein, we highlight some of the nascent concepts regarding Salmonella effectors in the context infection.

Agbor, Terence A.; McCormick, Beth A.

2012-01-01

239

Imaging how attention modulates pain in humans using functional MRI  

Microsoft Academic Search

Summary Current clinical and experimental literature strongly supports the phenomenon of reduced pain perception whilst attention is distracted away from noxious stimuli. This study used functional MRI to elucidate the under- lying neural systems and mechanisms involved. An ana- logue of the Stroop task, the counting Stroop, was used as a cognitive distraction task whilst subjects received intermittent painful thermal

Susanna J. Bantick; Richard G. Wise; Alexander Ploghaus; Stuart Clare; Stephen M. Smith; Irene Tracey

2002-01-01

240

T-cadherin modulates hepatocyte functions in vitro  

Microsoft Academic Search

Primary hepatocytes from several differ- ent species rapidly lose viability and phenotypic func- tions on isolation from their native microenvironment of the liver. Stromal cells derived from both within and outside the liver can induce phenotypic functions in primary hepatocytes in vitro; however, the molecular mediators underlying this \\

Salman R. Khetani; Alice A. Chen; Barbara Ranscht; Sangeeta N. Bhatia

2008-01-01

241

Modulation of macrophage and B cell function by glycosaminoglycans  

Microsoft Academic Search

There is increasing evidence that the behavior of antigen-presenting cells may be regu- lated, in part, by the surrounding microenviron- ment. Components of the microenvironment of solid tissues that might influence antigen-presenting cell functions include glycosaminoglycans. We pre- viously showed that heparan sulfate glycosaminogly- cans activate macrophages, leading to profound alterations in T cell responses. Here we demon- strate the

Lucile E. Wrenshall; R. Brian Stevens; Frank B. Cerra; Jeffrey L. Platt

1999-01-01

242

A new type of very low-power modulated laser: soft-tissue changes induced in osteoarthritic patients revealed by sonography.  

PubMed

Patients with symptomatic osteoarthritis of the cervical spine were studied by ultrasound examination. The region of interest was the soft connective tissue layer above the right and the left superior trapezium that revealed a significant difference in thickness between the left and right side. The aching side was treated with a new type of very low-power, modulated laser for 3 min. Immediately after application, the sonographic examination revealed a significant symmetrization of the subcutaneous tissue. PMID:11146897

Baratto, L; Capra, R; Farinelli, M; Monteforte, P; Morasso, P; Rovetta, G

2000-01-01

243

Cannabinoids and bone: endocannabinoids modulate human osteoclast function in vitro  

PubMed Central

BACKGROUND AND PURPOSE Both CB1 and CB2 cannabinoid receptors have been shown to play a role in bone metabolism. Crucially, previous studies have focussed on the effects of cannabinoid ligands in murine bone cells. This study aimed to investigate the effects of cannabinoids on human bone cells in vitro. EXPERIMENTAL APPROACH Quantitative RT-PCR was used to determine expression of cannabinoid receptors and liquid chromatography-electrospray ionization tandem mass spectrometry was used to determine the presence of endocannabinoids in human bone cells. The effect of cannabinoids on human osteoclast formation, polarization and resorption was determined by assessing the number of cells expressing ?v?3 or with F-actin rings, or measurement of resorption area. KEY RESULTS Human osteoclasts express both CB1 and CB2 receptors. CB2 expression was significantly higher in human monocytes compared to differentiated osteoclasts. Furthermore, the differentiation of human osteoclasts from monocytes was associated with a reduction in 2-AG levels and an increase in anandamide (AEA) levels. Treatment of osteoclasts with LPS significantly increased levels of AEA. Nanomolar concentrations of AEA and the synthetic agonists CP 55 940 and JWH015 stimulated human osteoclast polarization and resorption; these effects were attenuated in the presence of CB1 and/or CB2 antagonists. CONCLUSIONS AND IMPLICATIONS Low concentrations of cannabinoids activate human osteoclasts in vitro. There is a dynamic regulation of the expression of the CB2 receptor and the production of the endocannabinoids during the differentiation of human bone cells. These data suggest that small molecules modulating the endocannabinoid system could be important therapeutics in human bone disease. LINKED ARTICLES This article is part of a themed section on Cannabinoids in Biology and Medicine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-8. To view Part I of Cannabinoids in Biology and Medicine visit http://dx.doi.org/10.1111/bph.2011.163.issue-7

Whyte, LS; Ford, L; Ridge, SA; Cameron, GA; Rogers, MJ; Ross, RA

2012-01-01

244

Genetic Diversity of Coastal Bottlenose Dolphins Revealed by Structurally and Functionally Diverse Hemoglobins  

PubMed Central

Studies of structure-function relationships in the respiratory proteins of marine mammals revealed unexpected variations in the number and types of hemoglobins (Hbs) present in coastal bottlenose dolphins, Tursiops truncatus. We obtained blood samples from free-ranging coastal bottlenose dolphins as a component of capture-release studies. We found that the oxygen-binding functions of bottlenose dolphin blood are poised between effector-saturated and unsaturated levels, enabling exercise-dependent shifts in oxygen transfer functions. Isolated bottlenose dolphin Hbs showed elevated pH sensitivities (Bohr effects) and appreciably lower oxygen affinities than adult human Hb in the absence of allosteric effectors. These properties may be an adaptive modification that enhance oxygen delivery during diving episodes when oxygen tensions and effector levels are low. The Hbs of individual dolphins showed similar oxygen affinities, responses to effectors, and expression of heme-heme interaction in oxygen binding, but differed in their redox potentials and rates of autoxidation. The heterogeneity suggested by these functional variations in Hbs of individual dolphins was born out by variations in the molecular weights and numbers of their ? and ? globin chains. Although coastal bottlenose dolphins were expected to have a single type of Hb, the mass differences observed revealed considerable genetic diversity. There were multiple Hb forms in some individuals and differences in Hb patterns among individuals within the same community.

Remington, Nicole; Stevens, Robert D.; Wells, Randall S.; Hohn, Aleta; Dhungana, Suraj; Taboy, Celine H.; Crumbliss, Alvin L.; Henkens, Robert; Bonaventura, Celia

2007-01-01

245

Bicarbonate modulates oxidative and functional damage in ischemia-reperfusion.  

PubMed

The carbon dioxide/bicarbonate (CO(2)/HCO(3)(-)) pair is the main biological pH buffer. However, its influence on biological processes, and in particular redox processes, is still poorly explored. Here we study the effect of CO(2)/HCO(3)(-) on ischemic injury in three distinct models (cardiac HL-1 cells, perfused rat heart, and Caenorhabditis elegans). We found that, although various concentrations of CO(2)/HCO(3)(-) do not affect function under basal conditions, ischemia-reperfusion or similar insults in the presence of higher CO(2)/HCO(3)(-) resulted in greater functional loss associated with higher oxidative damage in all models. Because the effect of CO(2)/HCO(3)(-) was observed in all models tested, we believe this buffer is an important determinant of oxidative damage after ischemia-reperfusion. PMID:23195687

Queliconi, Bruno B; Marazzi, Thire B M; Vaz, Sandra M; Brookes, Paul S; Nehrke, Keith; Augusto, Ohara; Kowaltowski, Alicia J

2012-11-27

246

Identifying responsive functional modules from protein-protein interaction network  

Microsoft Academic Search

Proteins interact with each other within a cell, and those interactions give rise to the biological function and dynamical\\u000a behavior of cellular systems. Generally, the protein interactions are temporal, spatial, or condition dependent in a specific\\u000a cell, where only a small part of interactions usually take place under certain conditions. Recently, although a large amount\\u000a of protein interaction data have

Zikai Wu; Xingming Zhao; Luonan Chen

2009-01-01

247

Annexin I modulates cell functions by controlling intracellular calcium release  

Microsoft Academic Search

Annexin I is an intracellular protein in search of a function. Ex vivo it has calcium- and phospholipid-binding properties. To evaluate its role in vivo, MCF-7 cells were stably transfected with annexin I in sense or antisense orientations. In cells overexpressing annexin I, calcium release was abro- gated on stimulation of purinergic or bradykinin receptors, whereas non-transfected cells or cells

BRIGITTE M. FREY; BERNHARD F. X. REBER; BANNIKUPPE S. VISHWANATH; GENEVIEVE ESCHER; FELIX J. FREY

248

Quantum Theta Functions and Gabor Frames for Modulation Spaces  

Microsoft Academic Search

Representations of the celebrated Heisenberg commutation relations in quantum mechanics (and their exponentiated versions)\\u000a form the starting point for a number of basic constructions, both in mathematics and mathematical physics (geometric quantization,\\u000a quantum tori, classical and quantum theta functions) and signal analysis (Gabor analysis). In this paper we will try to bridge\\u000a the two communities, represented by the two co-authors:

Franz Luef; Yuri I. Manin

2009-01-01

249

Heteromeric MT1/MT2 Melatonin Receptors Modulate Photoreceptor Function.  

PubMed

The formation of G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptor (GPCR) heteromers enables signaling diversification and holds great promise for improved drug selectivity. Most studies of these oligomerization events have been conducted in heterologous expression systems, and in vivo validation is lacking in most cases, thus questioning the physiological significance of GPCR heteromerization. The melatonin receptors MT1 and MT2 exist as homomers and heteromers when expressed in cultured cells. We showed that melatonin MT1/MT2 heteromers mediated the effect of melatonin on the light sensitivity of rod photoreceptors in mice. This effect of melatonin involved activation of the heteromer-specific phospholipase C and protein kinase C (PLC/PKC) pathway and was abolished in MT1(-/-) or MT2(-/-) mice, as well as in mice overexpressing a nonfunctional MT2 mutant that interfered with the formation of functional MT1/MT2 heteromers in photoreceptor cells. Not only does this study establish an essential role of melatonin receptor heteromers in retinal function, it also provides in vivo support for the physiological importance of GPCR heteromerization. Thus, the MT1/MT2 heteromer complex may provide a specific pharmacological target to improve photoreceptor function. PMID:24106342

Baba, Kenkichi; Benleulmi-Chaachoua, Abla; Journé, Anne-Sophie; Kamal, Maud; Guillaume, Jean-Luc; Dussaud, Sébastien; Gbahou, Florence; Yettou, Katia; Liu, Cuimei; Contreras-Alcantara, Susana; Jockers, Ralf; Tosini, Gianluca

2013-10-08

250

Physical Motif Clustering within Intrinsically Disordered Nucleoporin Sequences Reveals Universal Functional Features.  

PubMed

Bioinformatics of disordered proteins is especially challenging given high mutation rates for homologous proteins and that functionality may not be strongly related to sequence. Here we have performed a novel bioinformatic analysis, based on the spatial clustering of physically relevant features such as binding motifs and charges within disordered proteins, on thousands of Nuclear Pore Complex (NPC) FG motif containing proteins (FG nups). The biophysical mechanism by which FG nups regulate nucleocytoplasmic transport has remained elusive. Our analysis revealed a set of highly conserved spatial features in the sequence structure of individual FG nups, such as the separation, localization, and ordering of FG motifs and charged residues along the protein chain. These functionally conserved features provide insight into the particular biophysical mechanisms responsible for regulation of nucleocytoplasmic traffic in the NPC, strongly constraining current models. Additionally this method allows us to identify potentially functionally analogous disordered proteins across distantly related species. PMID:24066078

Ando, David; Colvin, Michael; Rexach, Michael; Gopinathan, Ajay

2013-09-16

251

Physical Motif Clustering within Intrinsically Disordered Nucleoporin Sequences Reveals Universal Functional Features  

PubMed Central

Bioinformatics of disordered proteins is especially challenging given high mutation rates for homologous proteins and that functionality may not be strongly related to sequence. Here we have performed a novel bioinformatic analysis, based on the spatial clustering of physically relevant features such as binding motifs and charges within disordered proteins, on thousands of Nuclear Pore Complex (NPC) FG motif containing proteins (FG nups). The biophysical mechanism by which FG nups regulate nucleocytoplasmic transport has remained elusive. Our analysis revealed a set of highly conserved spatial features in the sequence structure of individual FG nups, such as the separation, localization, and ordering of FG motifs and charged residues along the protein chain. These functionally conserved features provide insight into the particular biophysical mechanisms responsible for regulation of nucleocytoplasmic traffic in the NPC, strongly constraining current models. Additionally this method allows us to identify potentially functionally analogous disordered proteins across distantly related species.

Ando, David; Colvin, Michael; Rexach, Michael; Gopinathan, Ajay

2013-01-01

252

Functional Influence-Based Approach to Identify Overlapping Modules in Biological Networks  

Microsoft Academic Search

\\u000a The inherent, dynamic, and structural behaviors of complex biological networks in a topological perspective have been widely\\u000a studied recently. These studies have attempted to discover hidden functional knowledge on a system level since biological\\u000a networks provide insights into the underlying mechanisms of biological processes and molecular functions within a cell. Functional\\u000a modules can be identified from biological networks as a

Young-Rae Cho; Aidong Zhang

253

Menstrual cycle phase modulates reward-related neural function in women  

PubMed Central

There is considerable evidence from animal studies that the mesolimbic and mesocortical dopamine systems are sensitive to circulating gonadal steroid hormones. Less is known about the influence of estrogen and progesterone on the human reward system. To investigate this directly, we used functional MRI and an event-related monetary reward paradigm to study women with a repeated-measures, counterbalanced design across the menstrual cycle. Here we show that during the midfollicular phase (days 4–8 after onset of menses) women anticipating uncertain rewards activated the orbitofrontal cortex and amygdala more than during the luteal phase (6–10 days after luteinizing hormone surge). At the time of reward delivery, women in the follicular phase activated the midbrain, striatum, and left fronto-polar cortex more than during the luteal phase. These data demonstrate augmented reactivity of the reward system in women during the midfollicular phase when estrogen is unopposed by progesterone. Moreover, investigation of between-sex differences revealed that men activated ventral putamen more than women during anticipation of uncertain rewards, whereas women more strongly activated the anterior medial prefrontal cortex at the time of reward delivery. Correlation between brain activity and gonadal steroid levels also revealed that the amygdalo-hippocampal complex was positively correlated with estradiol level, regardless of menstrual cycle phase. Together, our findings provide evidence of neurofunctional modulation of the reward system by gonadal steroid hormones in humans and establish a neurobiological foundation for understanding their impact on vulnerability to drug abuse, neuropsychiatric diseases with differential expression across males and females, and hormonally mediated mood disorders.

Dreher, Jean-Claude; Schmidt, Peter J.; Kohn, Philip; Furman, Daniella; Rubinow, David; Berman, Karen Faith

2007-01-01

254

Discrimination of interaural phase differences in the envelopes of sinusoidally amplitude-modulated 4kHz tones as a function of modulation depth  

Microsoft Academic Search

Psychometric functions were measured for the discrimination of the interaural phase difference (IPD) of the envelope of a sinusoidally amplitude-modulated (SAM) 4-kHz pure tone for modulation frequencies of 128 and 300 Hz and modulation depths (m) of 0.2, 0.6, 0.9, and 1.0. Contrary to recent modeling assumptions, it was found that a constant change in normalized interaural envelope correlation, with

Mark A. Stellmack; Neal F. Viemeister; Andrew J. Byrne

2005-01-01

255

IL-28A (IFN-?2) modulates lung DC function to promote Th1 immune skewing and suppress allergic airway disease  

PubMed Central

IL-28 (IFN-?) cytokines exhibit potent antiviral and antitumor function but their full spectrum of activities remains largely unknown. Recently, IL-28 cytokine family members were found to be profoundly down-regulated in allergic asthma. We now reveal a novel role of IL-28 cytokines in inducing type 1 immunity and protection from allergic airway disease. Treatment of wild-type mice with recombinant or adenovirally expressed IL-28A ameliorated allergic airway disease, suppressed Th2 and Th17 responses and induced IFN-?. Moreover, abrogation of endogenous IL-28 cytokine function in IL-28R??/? mice exacerbated allergic airway inflammation by augmenting Th2 and Th17 responses, and IgE levels. Central to IL-28A immunoregulatory activity was its capacity to modulate lung CD11c+ dendritic cell (DC) function to down-regulate OX40L, up-regulate IL-12p70 and promote Th1 differentiation. Consistently, IL-28A-mediated protection was absent in IFN-??/? mice or after IL-12 neutralization and could be adoptively transferred by IL-28A-treated CD11c+ cells. These data demonstrate a critical role of IL-28 cytokines in controlling T cell responses in vivo through the modulation of lung CD11c+ DC function in experimental allergic asthma.

Koltsida, Ourania; Hausding, Michael; Stavropoulos, Athanasios; Koch, Sonja; Tzelepis, George; Ubel, Caroline; Kotenko, Sergei V; Sideras, Paschalis; Lehr, Hans A; Tepe, Marcus; Klucher, Kevin M; Doyle, Sean E; Neurath, Markus F; Finotto, Susetta; Andreakos, Evangelos

2011-01-01

256

Yeast gain-of-function mutations reveal structure-function relationships conserved among different subfamilies of transient receptor potential channels.  

PubMed

Transient receptor potential (TRP) channels found in animals, protists, and fungi are primary chemo-, thermo-, or mechanosensors. Current research emphasizes the characteristics of individual channels in each animal TRP subfamily but not the mechanisms common across subfamilies. A forward genetic screen of the TrpY1, the yeast TRP channel, recovered gain-of-function (GOF) mutations with phenotype in vivo and in vitro. Single-channel patch-clamp analyses of these GOF-mutant channels show prominent aberrations in open probability and channel kinetics. These mutations revealed functionally important aromatic amino acid residues in four locations: at the intracellular end of the fifth transmembrane helix (TM5), at both ends of TM6, and at the immediate extension of TM6. These aromatics have counterparts in most TRP subfamilies. The one in TM5 (F380L) aligns precisely with an exceptional Drosophila mutant allele (F550I) that causes constitutive activity in the canonical TRP channel, resulting in rapid and severe retinal degeneration beyond mere loss of phototaxis. Thus, this phenylalanine maintains the balance of various functional states (conformations) of a channel for insect phototransduction as well as one for fungal mechanotransduction. This residue is among a small cluster of phenylalanines found in all known subfamilies of TRP channels. This unique case illustrates that GOF mutations can reveal structure-function principles that can be generalized across different TRP subfamilies. It appears that the conserved aromatics in the four locations have conserved functions in most TRP channels. The possible mechanistic roles of these aromatics and the further use of yeast genetics to dissect TRP channels are discussed. PMID:18042709

Su, Zhenwei; Zhou, Xinliang; Haynes, W John; Loukin, Stephen H; Anishkin, Andriy; Saimi, Yoshiro; Kung, Ching

2007-11-27

257

Maps of protein structure space reveal a fundamental relationship between protein structure and function  

PubMed Central

To study the protein structure–function relationship, we propose a method to efficiently create three-dimensional maps of structure space using a very large dataset of > 30,000 Structural Classification of Proteins (SCOP) domains. In our maps, each domain is represented by a point, and the distance between any two points approximates the structural distance between their corresponding domains. We use these maps to study the spatial distributions of properties of proteins, and in particular those of local vicinities in structure space such as structural density and functional diversity. These maps provide a unique broad view of protein space and thus reveal previously undescribed fundamental properties thereof. At the same time, the maps are consistent with previous knowledge (e.g., domains cluster by their SCOP class) and organize in a unified, coherent representation previous observation concerning specific protein folds. To investigate the function–structure relationship, we measure the functional diversity (using the Gene Ontology controlled vocabulary) in local structural vicinities. Our most striking finding is that functional diversity varies considerably across structure space: The space has a highly diverse region, and diversity abates when moving away from it. Interestingly, the domains in this region are mostly alpha/beta structures, which are known to be the most ancient proteins. We believe that our unique perspective of structure space will open previously undescribed ways of studying proteins, their evolution, and the relationship between their structure and function.

Osadchy, Margarita; Kolodny, Rachel

2011-01-01

258

Characterization of homologs of the small RNA SgrS reveals diversity in function.  

PubMed

SgrS is a small RNA (sRNA) that requires the RNA chaperone Hfq for its function. SgrS is a unique dual-function sRNA with a base pairing function that regulates mRNA targets and an mRNA function that allows production of the 43-amino-acid protein SgrT. SgrS is expressed when non-metabolizable sugars accumulate intracellularly (glucose-phosphate stress) and is required to allow Escherichia coli cells to recover from stress. In this study, homologs of SgrS were used to complement an E. coli sgrS mutant in order elucidate the physiological relevance of differences among homologs. These analyses revealed that the base pairing function of E. coli and Yersinia pestis SgrS homologs is critical for rescue from glucose-phosphate stress. In contrast, base pairing-deficient SgrS homologs from Salmonella typhimurium, Erwinia carotovora and Klebsiella pneumoniae rescue E. coli cells from stress despite their failure to regulate target mRNAs. Compared with E. coli SgrS, S. typhimurium SgrS produces more SgrT and this rescues cell growth even when the base pairing function is inactivated. Genetic evidence suggests that a secondary structure in the E. coli SgrS 5' region inhibits sgrT translation. This structure is not present in S. typhimurium SgrS, which explains its higher level of SgrT production. PMID:19620214

Wadler, Caryn S; Vanderpool, Carin K

2009-07-20

259

Structural fragment clustering reveals novel structural and functional motifs in ?-helical transmembrane proteins  

PubMed Central

Background A large proportion of an organism's genome encodes for membrane proteins. Membrane proteins are important for many cellular processes, and several diseases can be linked to mutations in them. With the tremendous growth of sequence data, there is an increasing need to reliably identify membrane proteins from sequence, to functionally annotate them, and to correctly predict their topology. Results We introduce a technique called structural fragment clustering, which learns sequential motifs from 3D structural fragments. From over 500,000 fragments, we obtain 213 statistically significant, non-redundant, and novel motifs that are highly specific to ?-helical transmembrane proteins. From these 213 motifs, 58 of them were assigned to function and checked in the scientific literature for a biological assessment. Seventy percent of the motifs are found in co-factor, ligand, and ion binding sites, 30% at protein interaction interfaces, and 12% bind specific lipids such as glycerol or cardiolipins. The vast majority of motifs (94%) appear across evolutionarily unrelated families, highlighting the modularity of functional design in membrane proteins. We describe three novel motifs in detail: (1) a dimer interface motif found in voltage-gated chloride channels, (2) a proton transfer motif found in heme-copper oxidases, and (3) a convergently evolved interface helix motif found in an aspartate symporter, a serine protease, and cytochrome b. Conclusions Our findings suggest that functional modules exist in membrane proteins, and that they occur in completely different evolutionary contexts and cover different binding sites. Structural fragment clustering allows us to link sequence motifs to function through clusters of structural fragments. The sequence motifs can be applied to identify and characterize membrane proteins in novel genomes.

2010-01-01

260

In Vivo Analysis of Lrig Genes Reveals Redundant and Independent Functions in the Inner Ear  

PubMed Central

Lrig proteins are conserved transmembrane proteins that modulate a variety of signaling pathways from worm to humans. In mammals, there are three family members – Lrig1, Lrig2, and Lrig3 – that are defined by closely related extracellular domains with a similar arrangement of leucine rich repeats and immunoglobulin domains. However, the intracellular domains show little homology. Lrig1 inhibits EGF signaling through internalization and degradation of ErbB receptors. Although Lrig3 can also bind ErbB receptors in vitro, it is unclear whether Lrig2 and Lrig3 exhibit similar functions to Lrig1. To gain insights into Lrig gene functions in vivo, we compared the expression and function of the Lrigs in the inner ear, which offers a sensitive system for detecting effects on morphogenesis and function. We find that all three family members are expressed in the inner ear throughout development, with Lrig1 and Lrig3 restricted to subsets of cells and Lrig2 expressed more broadly. Lrig1 and Lrig3 overlap prominently in the developing vestibular apparatus and simultaneous removal of both genes disrupts inner ear morphogenesis. This suggests that these two family members act redundantly in the otic epithelium. In contrast, although Lrig1 and Lrig2 are frequently co-expressed, Lrig1?/?;Lrig2?/? double mutant ears show no enhanced structural abnormalities. At later stages, Lrig1 expression is sustained in non-sensory tissues, whereas Lrig2 levels are enhanced in neurons and sensory epithelia. Consistent with these distinct expression patterns, Lrig1 and Lrig2 mutant mice exhibit different forms of impaired auditory responsiveness. Notably, Lrig1?/?;Lrig2?/? double mutant mice display vestibular deficits and suffer from a more severe auditory defect that is accompanied by a cochlear innervation phenotype not present in single mutants. Thus, Lrig genes appear to act both redundantly and independently, with Lrig2 emerging as the most functionally distinct family member.

del Rio, Tony; Nishitani, Allison M.; Yu, Wei-Ming; Goodrich, Lisa V.

2013-01-01

261

Two-dimensional gel electrophoresis revealed antipsychotic drugs induced protein expression modulations in C6 glioma cells.  

PubMed

The efficacy and side effects of long-term administration of antipsychotic drugs (APDs) may be attributed to drug-induced change in protein expression in brain cells. Glial cells are non-neuronal cells that can provide nutrients and physiological support to neuronal cells. Glial cells are believed to participate in neurotransmission, neurons' early development, and guiding migration of neurons. Accumulated clinical data also indicate relationships between disturbance of glial cells' function and various psychotic diseases including schizophrenia. We used two-dimensional gel electrophoresis coupled with MALDI-TOF/TOF mass spectrometry protein identification to analyze differentially expressed proteins in haloperidol-, risperidone-, and clozapine-treated C6 glioma cells. We found that the expression of pericentrin, glial fibrillary acidic protein, Rho GDP-dissociation inhibitor 1, anionic trypsin-1, peroxiredoxin-1, and parvalbumin were regulated by each of the three APDs. Western blot analysis supported the findings. Real-time quantitative PCR detected changed transcriptions of those proteins. Protein and gene expression of N-cadherin in C6 cells were affected by haloperidol and clozapine but not risperidone. In addition, regulatory effects of clozapine on the glyceraldehyde 3-phosphate dehydrogenase gene were observed in C6 cells. This may be the first study to uncover how APD-modulated genes may cause protein expression changes and affect ARHGDIA-mediated regulation of Rho GTPase family proteins in glial cells. PMID:22960606

Chen, Mao-Liang

2012-08-31

262

Modulation of the Akt pathway reveals a novel link with PERK/eIF2?, which is relevant during hypoxia.  

PubMed

The unfolded protein response (UPR) and the Akt signaling pathway share several regulatory functions and have the capacity to determine cell outcome under specific conditions. However, both pathways have largely been studied independently. Here, we asked whether the Akt pathway regulates the UPR. To this end, we used a series of chemical compounds that modulate PI3K/Akt pathway and monitored the activity of the three UPR branches: PERK, IRE1 and ATF6. The antiproliferative and antiviral drug Akt-IV strongly and persistently activated all three branches of the UPR. We present evidence that activation of PERK/eIF2? requires Akt and that PERK is a direct Akt target. Chemical activation of this novel Akt/PERK pathway by Akt-IV leads to cell death, which was largely dependent on the presence of PERK and IRE1. Finally, we show that hypoxia-induced activation of eIF2? requires Akt, providing a physiologically relevant condition for the interaction between Akt and the PERK branch of the UPR. These data suggest the UPR and the Akt pathway signal to one another as a means of controlling cell fate. PMID:23922774

Blaustein, Matías; Pérez-Munizaga, Daniela; Sánchez, Manuel Alejandro; Urrutia, Carolina; Grande, Alicia; Risso, Guillermo; Srebrow, Anabella; Alfaro, Jennifer; Colman-Lerner, Alejandro

2013-07-29

263

Modulation of the Akt Pathway Reveals a Novel Link with PERK/eIF2?, which Is Relevant during Hypoxia  

PubMed Central

The unfolded protein response (UPR) and the Akt signaling pathway share several regulatory functions and have the capacity to determine cell outcome under specific conditions. However, both pathways have largely been studied independently. Here, we asked whether the Akt pathway regulates the UPR. To this end, we used a series of chemical compounds that modulate PI3K/Akt pathway and monitored the activity of the three UPR branches: PERK, IRE1 and ATF6. The antiproliferative and antiviral drug Akt-IV strongly and persistently activated all three branches of the UPR. We present evidence that activation of PERK/eIF2? requires Akt and that PERK is a direct Akt target. Chemical activation of this novel Akt/PERK pathway by Akt-IV leads to cell death, which was largely dependent on the presence of PERK and IRE1. Finally, we show that hypoxia-induced activation of eIF2? requires Akt, providing a physiologically relevant condition for the interaction between Akt and the PERK branch of the UPR. These data suggest the UPR and the Akt pathway signal to one another as a means of controlling cell fate.

Sanchez, Manuel Alejandro; Urrutia, Carolina; Grande, Alicia; Risso, Guillermo; Srebrow, Anabella; Alfaro, Jennifer; Colman-Lerner, Alejandro

2013-01-01

264

Integrative genomic and functional analyses reveal neuronal subtype differentiation bias in human embryonic stem cell lines  

PubMed Central

The self-renewal and differentiation potential of human embryonic stem cells (hESCs) suggests that hESCs could be used for regenerative medicine, especially for restoring neuronal functions in brain diseases. However, the functional properties of neurons derived from hESC are largely unknown. Moreover, because hESCs were derived under diverse conditions, the possibility arises that neurons derived from different hESC lines exhibit distinct properties, but this possibility remains unexplored. To address these issues, we developed a protocol that allows stepwise generation from hESCs of cultures composed of ?70–80% human neurons that exhibit spontaneous synaptic network activity. Comparison of neurons derived from the well characterized HSF1 and HSF6 hESC lines revealed that HSF1- but not HSF6-derived neurons exhibit forebrain properties. Accordingly, HSF1-derived neurons initially form primarily GABAergic synaptic networks, whereas HSF6-derived neurons initially form glutamatergic networks. microRNA profiling revealed significant expression differences between the two hESC lines, suggesting that microRNAs may influence their distinct differentiation properties. These observations indicate that although both HSF1 and HSF6 hESCs differentiate into functional neurons, the two hESC lines exhibit distinct differentiation potentials, suggesting that they are preprogrammed. Information on hESC line-specific differentiation biases is crucial for neural stem cell therapy and establishment of novel disease models using hESCs.

Wu, Hao; Xu, Jun; Pang, Zhiping P.; Ge, Weihong; Kim, Kevin J.; Blanchi, Bruno; Chen, Caifu; Sudhof, Thomas C.; Sun, Yi E.

2007-01-01

265

High-Throughput Chemical Screen Identifies a Novel Potent Modulator of Cellular Circadian Rhythms and Reveals CKI? as a Clock Regulatory Kinase  

PubMed Central

The circadian clock underlies daily rhythms of diverse physiological processes, and alterations in clock function have been linked to numerous pathologies. To apply chemical biology methods to modulate and dissect the clock mechanism with new chemical probes, we performed a circadian screen of ?120,000 uncharacterized compounds on human cells containing a circadian reporter. The analysis identified a small molecule that potently lengthens the circadian period in a dose-dependent manner. Subsequent analysis showed that the compound also lengthened the period in a variety of cells from different tissues including the mouse suprachiasmatic nucleus, the central clock controlling behavioral rhythms. Based on the prominent period lengthening effect, we named the compound longdaysin. Longdaysin was amenable for chemical modification to perform affinity chromatography coupled with mass spectrometry analysis to identify target proteins. Combined with siRNA-mediated gene knockdown, we identified the protein kinases CKI?, CKI?, and ERK2 as targets of longdaysin responsible for the observed effect on circadian period. Although individual knockdown of CKI?, CKI?, and ERK2 had small period effects, their combinatorial knockdown dramatically lengthened the period similar to longdaysin treatment. We characterized the role of CKI? in the clock mechanism and found that CKI?-mediated phosphorylation stimulated degradation of a clock protein PER1, similar to the function of CKI?. Longdaysin treatment inhibited PER1 degradation, providing insight into the mechanism of longdaysin-dependent period lengthening. Using larval zebrafish, we further demonstrated that longdaysin drastically lengthened circadian period in vivo. Taken together, the chemical biology approach not only revealed CKI? as a clock regulatory kinase but also identified a multiple kinase network conferring robustness to the clock. Longdaysin provides novel possibilities in manipulating clock function due to its ability to simultaneously inhibit several key components of this conserved network across species.

Hirota, Tsuyoshi; Lee, Jae Wook; Lewis, Warren G.; Zhang, Eric E.; Breton, Ghislain; Liu, Xianzhong; Garcia, Michael; Peters, Eric C.; Etchegaray, Jean-Pierre; Traver, David; Schultz, Peter G.; Kay, Steve A.

2010-01-01

266

Integrative network analysis reveals active microRNAs and their functions in gastric cancer  

PubMed Central

Background MicroRNAs (miRNAs) are a class of endogenous, small and highly conserved noncoding RNAs that control gene expression either by degradation of target mRNAs or by inhibition of protein translation. They play important roles in cancer progression. A single miRNA can provoke a chain reaction and further affect protein interaction network (PIN). Therefore, we developed a novel integrative approach to identify the functional roles and the regulated PIN of oncomirs. Results We integrated the expression profiles of miRNA and mRNA with the human PIN to reveal miRNA-regulated PIN in specific biological conditions. The potential functions of miRNAs were determined by functional enrichment analysis and the activities of miRNA-regulated PINs were evaluated by the co-expression of protein-protein interactions (PPIs). The function of a specific miRNA, miR-148a, was further examined by clinical data analysis and cell-based experiments. We uncovered several miRNA-regulated networks which were enriched with functions related to cancer progression. One miRNA, miR-148a, was identified and its function is to decrease tumor proliferation and metastasis through its regulated PIN. Furthermore, we found that miR-148a could reduce the invasiveness, migratory and adhesive activities of gastric tumor cells. Most importantly, elevated miR-148a level in gastric cancer tissues was strongly correlated with distant metastasis, organ and peritoneal invasion and reduced survival rate. Conclusions This study provides a novel method to identify active oncomirs and their potential functions in gastric cancer progression. The present data suggest that miR-148a could be a potential prognostic biomarker of gastric cancer and function as a tumor suppressor through repressing the activity of its regulated PIN.

2011-01-01

267

Calcium handling proteins: structure, function, and modulation by exercise.  

PubMed

Heart failure is a serious public health issue with a growing prevalence, and it is related with the aging of the population. Hypertension is identified as the main precursor of left ventricular hypertrophy and therefore can lead to diastolic dysfunction and heart failure. Scientific studies have confirmed the beneficial effects of the physical exercise by reducing the blood pressure and improving the functional status of the heart in hypertension. Several proteins are involved in the mobilization of calcium during the coupling excitation-contraction process in the heart among those are sarcoplasmic reticulum Ca(2+)-ATPase, phospholamban, calsequestrin, sodium-calcium exchanger, L-type calcium's channel, and ryanodine receptors. Our goal is to address the beneficial effects of exercise on the calcium handling proteins in a heart with hypertension. PMID:23436107

Locatelli, Jamille; de Assis, Leonardo V M; Isoldi, Mauro C

2013-02-24

268

Narcissism: its function in modulating self-conscious emotions.  

PubMed

This study focused on the functional aspects of narcissism in regulating self-conscious emotions (guilt, shame, hubristic pride, and achievement-oriented pride) as well as two other attribution styles (externalization and detachment). The authors investigated Japanese university students (N = 452) with regard to their self-conscious emotions using the Test of Self-Conscious Affect-3 (TOSCA-3) and their narcissistic personality using the short version of Narcissistic Personality Inventory (NPI-S). Structural equation modeling was used for the analysis. The authors found that narcissism led individuals to feel achievement-oriented pride, hubristic pride, externalization, and detachment, but inhibited feelings of shame. It did not have a significant effect on guilt. Shame-proneness prompted hubristic pride and externalization. Guilt-proneness inclined an individual toward achievement-oriented pride, but deterred externalization. In this article, the authors present and interpret these results in detail and then discuss how they can be utilized in psychotherapy. PMID:22988899

Uji, Masayo; Nagata, Toshiaki; Kitamura, Toshinori

2012-01-01

269

N-Glycans Modulate the Function of Human Corticosteroid-Binding Globulin*  

PubMed Central

Human corticosteroid-binding globulin (CBG), a heavily glycosylated protein containing six N-linked glycosylation sites, transports cortisol and other corticosteroids in blood circulation. Here, we investigate the biological importance of the N-glycans of CBG derived from human serum by performing a structural and functional characterization of CBG N-glycosylation. Liquid chromatography-tandem MS-based glycoproteomics and glycomics combined with exoglycosidase treatment revealed 26 complex type N-glycoforms, all of which were terminated with ?2,3-linked neuraminic acid (NeuAc) residues. The CBG N-glycans showed predominantly bi- and tri-antennary branching, but higher branching was also observed. N-glycans from all six N-glycosylation sites were identified with high site occupancies (70.5–99.5%) and glycoforms from all sites contained a relatively low degree of core-fucosylation (0–34.9%). CBG showed site-specific glycosylation and the site-to-site differences in core-fucosylation and branching could be in silico correlated with the accessibility to the individual glycosylation sites on the maturely folded protein. Deglycosylated and desialylated CBG analogs were generated to investigate the biological importance of CBG N-glycans. As a functional assay, MCF-7 cells were challenged with native and glycan-modified CBG and the amount of cAMP, which is produced as a quantitative response upon CBG binding to its cell surface receptor, was used to evaluate the CBG:receptor interaction. The removal of both CBG N-glycans and NeuAc residues increased the production of cAMP significantly. This confirms that N-glycans are involved in the CBG:receptor interaction and indicates that the modulation is performed by steric and/or electrostatic means through the terminal NeuAc residues.

Sumer-Bayraktar, Zeynep; Kolarich, Daniel; Campbell, Matthew P.; Ali, Sinan; Packer, Nicolle H.; Thaysen-Andersen, Morten

2011-01-01

270

Structure-function insights of membrane and soluble proteins revealed by electron crystallography.  

PubMed

Electron crystallography is emerging as an important method in solving protein structures. While it has found extensive applications in the understanding of membrane protein structure and function at a wide range of resolutions, from revealing oligomeric arrangements to atomic models, electron crystallography has also provided invaluable information on the soluble ?/?-tubulin which could not be obtained by any other method to date. Examples of critical insights from selected structures of membrane proteins as well as ?/?-tubulin are described here, demonstrating the vast potential of electron crystallography that is first beginning to unfold. PMID:23132078

Dreaden, Tina M; Devarajan, Bharanidharan; Barry, Bridgette A; Schmidt-Krey, Ingeborg

2013-01-01

271

Inflammation Modulates Human HDL Composition and Function in vivo  

PubMed Central

Objectives Inflammation may directly impair HDL functions, in particular reverse cholesterol transport (RCT), but limited data support this concept in humans. Methods and Results We employed low-dose human endotoxemia to assess the effects of inflammation on HDL and RCT-related parameters in vivo. Endotoxemia induced remodelling of HDL with depletion of pre-?1a HDL particles determined by 2-D gel electrophoresis (-32.2 ± 9.3% at 24h, p<0.05) as well as small (-23.0 ± 5.1%, p<0.01, at 24h) and medium (-57.6 ± 8.0% at 16h, p<0.001) HDL estimated by nuclear magnetic resonance (NMR). This was associated with induction of class II secretory phospholipase A2 (~36 fold increase) and suppression of lecithin:cholesterol acyltransferase activity (-20.8 ± 3.4% at 24h, p<0.01) and cholesterol ester transfer protein mass (-22.2 ± 6.8% at 24h, p<0.001). The HDL fraction, isolated following endotoxemia, had reduced capacity to efflux cholesterol in vitro from SR-BI and ABCA1, but not ABCG1 transporter cell models. Conclusions These data support the concept that “atherogenic-HDL dysfunction” and impaired RCT occur in human inflammatory syndromes, largely independent of changes in plasma HDL-C and ApoA-I levels.

de la Llera Moya, Margarita; McGillicuddy, Fiona C; Hinkle, Christine C; Byrne, Michael; Joshi, Michelle R; Nguyen, Vihn; Tabita-Martinez, Jennifer; Wolfe, Megan L; Badellino, Karen; Pruscino, Leticia; Mehta, Nehal N; Asztalos, Bela F; Reilly, Muredach P

2012-01-01

272

MR and GR functional SNPs may modulate tobacco smoking susceptibility.  

PubMed

A number of studies have demonstrated that stress is involved in all aspects of smoking behavior, including initiation, maintenance and relapse. The mineralocorticoid (MR) and glucocorticoid (GR) receptors are expressed in several brain areas and play a key role in negative feedback of the hypothalamic-pituitary-adrenal (HPA) axis. As nicotine increases the activation of the HPA axis, we wondered if functional SNPs (single nucleotide polymorphisms) in MR and GR coding genes (NR3C2 rs5522 and NR3C1 rs6198, respectively) may be involved in smoking susceptibility. The sample included 627 volunteers, of which 514 were never-smokers and 113 lifetime smokers. We report an interaction effect between rs5522 and rs6198 SNPs. The odds ratio (OR) for the presence of the NR3C2 rs5522 Val allele in NR3C1 rs6198 G carriers was 0.18 (P = 0.007), while in rs6198 G noncarriers the OR was 1.83 (P = 0.027). We also found main effects of the NR3C1 rs6198 G allele on number of cigarettes smoked per day (P = 0.027) and in total score of the Fagerström Test for Nicotine Dependence (P = 0.007). These findings are consistent with a possible link between NR3C2 and NR3C1 polymorphisms and smoking behavior and provide a first partial replication for a nominally significant GWAS finding between NR3C2 and tobacco smoking. PMID:23543128

Rovaris, Diego L; Mota, Nina R; de Azeredo, Lucas A; Cupertino, Renata B; Bertuzzi, Guilherme P; Polina, Evelise R; Contini, Verônica; Kortmann, Gustavo L; Vitola, Eduardo S; Grevet, Eugenio H; Grassi-Oliveira, Rodrigo; Callegari-Jacques, Sidia M; Bau, Claiton H D

2013-03-31

273

Genetic modulation of energy metabolism in birds through mitochondrial function  

PubMed Central

Despite their central importance for the evolution of physiological variation, the genetic mechanisms that determine energy expenditure in animals have largely remained unstudied. We used quantitative genetics to confirm that both mass-specific and whole-organism basal metabolic rate (BMR) were heritable in a captive-bred population of stonechats (Saxicola torquata spp.) founded on birds from three wild populations (Europe, Africa and Asia) that differed in BMR. This argues that BMR is at least partially under genetic control by multiple unknown nuclear loci each with a limited effect on the phenotype. We then tested for a genetic effect on BMR based on mitochondrial–nuclear coadaptation using hybrids between ancestral populations with high and low BMR (Europe–Africa and Asia–Europe), with different parental configurations (femalehigh–malelow or femalelow–malehigh) within each combination of populations. Hybrids with different parental configurations have on average identical mixtures of nuclear DNA, but differ in mitochondrial DNA because it is inherited only from the mother. Mass-specific BMR differed between hybrids with different parental configurations, implying that the combination of mitochondrial and nuclear DNA affected metabolic rate. Therefore, our findings implicate mitochondrial function as an important regulator of energy metabolism. In combination with the substantial heritabilities of metabolic rate, and corroborated by genetic differences in the mitochondrial genome, these results set the stage for further investigations of a genetic control mechanism involving both mitochondrial and nuclear genes determining metabolic rate at the whole-organism level.

Tieleman, B. Irene; Versteegh, Maaike A.; Fries, Anthony; Helm, Barbara; Dingemanse, Niels J.; Gibbs, H. Lisle; Williams, Joseph B.

2009-01-01

274

Leptin as a Modulator of Neuroendocrine Function in Humans  

PubMed Central

Leptin, a peptide hormone secreted by adipocytes in proportion of the amount of energy stored in fat, plays a central role in regulating human energy homeostasis. In addition, leptin plays a significant permissive role in the physiological regulation of several neuroendocrine axes, including the hypothalamic-pituitary-gonadal, -thyroid, -growth hormone, and -adrenal axes. Decreased levels of leptin, also known as hypoleptinemia, signal to the brain a state of energy deprivation. Hypoleptinemia can be a congenital or acquired condition, and is associated with alterations of the aforementioned axes aimed at promoting survival. More specifically, gonadotropin levels decrease and become less pulsatile under conditions of energy deprivation, and these changes can be at least partially reversed through leptin administration in physiological replacement doses. Similarly, leptin deficiency is associated with thyroid axis abnormalities including abnormal levels of thyrotropin-releasing hormone, and leptin administration may at least partially attenuate this effect. Leptin deficiency results in decreased insulin-like growth factor 1 levels which can be partially ameliorated through leptin administration, and leptin appears to have a much more pronounced effect on the growth of rodents than that of humans. Similarly, adrenal axis function is regulated more tightly by low leptin in rodents than in humans. In addition to congenital leptin deficiency, conditions that may be associated with decreased leptin levels include hypothalamic amenorrhea, anorexia nervosa, and congenital or acquired lipodystrophy syndromes. Accumulating evidence from proof of concept studies suggests that leptin administration, in replacement doses, may ameliorate neuroendocrine abnormalities in individuals who suffer from these conditions.

Khan, Sami M.; Hamnvik, Ole-Petter R.; Brinkoetter, Mary

2012-01-01

275

Modulation of immune function by dietary lectins in rheumatoid arthritis.  

PubMed

Despite the almost universal clinical observation that inflammation of the gut is frequently associated with inflammation of the joints and vice versa, the nature of this relationship remains elusive. In the present review, we provide evidence for how the interaction of dietary lectins with enterocytes and lymphocytes may facilitate the translocation of both dietary and gut-derived pathogenic antigens to peripheral tissues, which in turn causes persistent peripheral antigenic stimulation. In genetically susceptible individuals, this antigenic stimulation may ultimately result in the expression of overt rheumatoid arthritis (RA) via molecular mimicry, a process whereby foreign peptides, similar in structure to endogenous peptides, may cause antibodies or T-lymphocytes to cross-react with both foreign and endogenous peptides and thereby break immunological tolerance. By eliminating dietary elements, particularly lectins, which adversely influence both enterocyte and lymphocyte structure and function, it is proposed that the peripheral antigenic stimulus (both pathogenic and dietary) will be reduced and thereby result in a diminution of disease symptoms in certain patients with RA. PMID:10884708

Cordain, L; Toohey, L; Smith, M J; Hickey, M S

2000-03-01

276

Modulation-doped semiconductor nanowires: Functional building blocks for nanoelectronics and nanophotonics  

NASA Astrophysics Data System (ADS)

The synthetic implementation of designed nanostructures is central to advances in the field of nanoscience and nanotechnology. Modulation of the composition of nanostructures during growth could encode information or function in a manner analogous to biological systems and independent of the constraints of lithography. This thesis presents the synthesis and characterization of modulation-doped nanowires with the structural and electrical properties of modulated regions are completely defined during synthesis, and efforts of developing conventional and quantum electronic and photonic based on modulation-doped nanowires. We describe the successful synthesis of modulation-doped silicon nanowires using the nanocluster-catalyzed vapor-liquid-solid growth processes. The pure axial elongation without radial overcoating during the growth process was achieved with the introduction of a local substrate heater and use of a hydrogen atmosphere and verified by High-resolution transmission electron microscopy studies. Scanning gate microscopy shows that the key properties of the modulated structures, including the number, size and period of the differentially doped regions, are defined in a controllable manner during synthesis, and moreover, that feature sizes to less than 50 nm are possible. These modulation-doped nanowires provide the potential for essential device function to be defined during synthesis not lithography. First, a lithography-free approach is developed for addressing individual nanowires in an array when the nanowires have different dopant modulation sequences and implemented in a 2x2 modulation-doped silicon nanowire field-effect transistor array. Second, encoding of single and coupled double quantum dot (QD) structures is achieved in modulation-doped nanowires. Low temperature transport studies demonstrate that QD sizes of single QD structures as well as the interaction between two QDs of double QD structures can be controlled by synthesis. Third, this general synthesis approach is extended to a novel p-i-n nanowire structure, in which both dopant type and concentration are modulated. Spatial photocurrent measurements demonstrate the potential of the application for single nanowire avalanche photodetectors, and being integrated with other essential nanophotonic elements for integrated systems. Fundamentally, studies of the impact ionization coefficients of electrons and holes in silicon nanowires suggest possible longer optical phonon mean free path than that in bulk due to the phonon confinement effect. Lastly, two other types of nanowire heterostructures, branched nanowires and atomic sharp metal/semiconductor nanowire heterostructures are also developed through synthesis via a multi-step metal-catalyzed chemical vapor deposition method, and chemical conversion of semiconductor nanowire, respectively. Their implementations for nanoelectronic device elements are also discussed.

Yang, Chen

277

Global Functional Map of the p23 Molecular Chaperone Reveals an Extensive Cellular Network  

PubMed Central

Summary In parallel with evolutionary developments, the Hsp90 molecular chaperone system shifted from a simple prokaryotic factor into an expansive network that includes a variety of cochaperones. We have taken high-throughput genomic and proteomic approaches to better understand the abundant yeast p23 cochaperone Sba1. Our work revealed an unexpected p23 network that displayed considerable independence from known Hsp90 clients. Additionally, our data uncovered a broad nuclear role for p23, contrasting with the historical dogma of restricted cytosolic activities for molecular chaperones. Validation studies demonstrated that yeast p23 was required for proper Golgi function, ribosome biogenesis and was necessary for efficient DNA repair from a wide range of mutagens. Notably, mammalian p23 had conserved roles in these pathways as well as being necessary for proper cell mobility. Taken together, our work demonstrates that the p23 chaperone serves a broad physiological network and functions both in conjunction with and sovereign to Hsp90.

Echtenkamp, Frank J.; Zelin, Elena; Oxelmark, Ellinor; Woo, Joyce I.; Andrews, Brenda J.; Garabedian, Michael; Freeman, Brian C.

2011-01-01

278

Bite of the Cats: Relationships between Functional Integration and Mechanical Performance as Revealed by Mandible Geometry.  

PubMed

Cat-like carnivorous mammals represent a relatively homogeneous group of species whose morphology appears constrained by exclusive adaptations for meat eating. We present the most comprehensive data set of extant and extinct cat-like species to test for evolutionary transformations in size, shape and mechanical performance, that is, von Mises stress and surface traction, of the mandible. Size and shape were both quantified by means of geometric morphometrics, whereas mechanical performance was assessed applying finite element models to 2D geometry of the mandible. Additionally, we present the first almost complete composite phylogeny of cat-like carnivorans for which well-preserved mandibles are known, including representatives of 35 extant and 59 extinct species of Felidae, Nimravidae, and Barbourofelidae. This phylogeny was used to test morphological differentiation, allometry, and covariation of mandible parts within and among clades. After taking phylogeny into account, we found that both allometry and mechanical variables exhibit a significant impact on mandible shape. We also tested whether mechanical performance was linked to morphological integration. Mechanical stress at the coronoid process is higher in sabertoothed cats than in any other clade. This is strongly related to the high degree of covariation within modules of sabertooths mandibles. We found significant correlation between integration at the clade level and per-clade averaged stress values, on both original data and by partialling out interclade allometry from shapes when calculating integration. This suggests a strong interaction between natural selection and the evolution of developmental and functional modules at the clade level. [Comparative methods; felidae mandible; finite element analysis; geometric morphometrics; morphological integration; sabertooth; structural performance]. PMID:23925509

Piras, Paolo; Maiorino, Leonardo; Teresi, Luciano; Meloro, Carlo; Lucci, Federico; Kotsakis, Tassos; Raia, Pasquale

2013-08-06

279

Fatty Acid (FFA) Transport in Cardiomyocytes Revealed by Imaging Unbound FFA Is Mediated by an FFA Pump Modulated by the CD36 Protein*  

PubMed Central

Free fatty acid (FFA) transport across the cardiomyocyte plasma membrane is essential to proper cardiac function, but the role of membrane proteins and FFA metabolism in FFA transport remains unclear. Metabolism is thought to maintain intracellular FFA at low levels, providing the driving force for FFA transport, but intracellular FFA levels have not been measured directly. We report the first measurements of the intracellular unbound FFA concentrations (FFAi) in cardiomyocytes. The fluorescent indicator of FFA, ADIFAB (acrylodan-labeled rat intestinal fatty acid-binding protein), was microinjected into isolated cardiomyocytes from wild type (WT) and FAT/CD36 null C57B1/6 mice. Quantitative imaging of ADIFAB fluorescence revealed the time courses of FFA influx and efflux. For WT mice, rate constants for efflux (?0.02 s?1) were twice influx, and steady state FFAi were more than 3-fold larger than extracellular unbound FFA (FFAo). The concentration gradient and the initial rate of FFA influx saturated with increasing FFAo. Similar characteristics were observed for oleate, palmitate, and arachidonate. FAT/CD36 null cells revealed similar characteristics, except that efflux was 2–3-fold slower than WT cells. Rate constants determined with intracellular ADIFAB were confirmed by measurements of intracellular pH. FFA uptake by suspensions of cardiomyocytes determined by monitoring FFAo using extracellular ADIFAB confirmed the influx rate constants determined from FFAi measurements and demonstrated that rates of FFA transport and etomoxir-sensitive metabolism are regulated independently. We conclude that FFA influx in cardiac myocytes is mediated by a membrane pump whose transport rate constants may be modulated by FAT/CD36.

Carley, Andrew N.; Kleinfeld, Alan M.

2011-01-01

280

Advanced Glycation End Products Are Direct Modulators of ?-Cell Function  

PubMed Central

OBJECTIVE Excess accumulation of advanced glycation end products (AGEs) contributes to aging and chronic diseases. We aimed to obtain evidence that exposure to AGEs plays a role in the development of type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS The effect of AGEs was examined on insulin secretion by MIN6N8 cells and mouse islets and in vivo in three separate rodent models: AGE-injected or high AGE–fed Sprague-Dawley rats and nonobese diabetic (NODLt) mice. Rodents were also treated with the AGE-lowering agent alagebrium. RESULTS ?-Cells exposed to AGEs displayed acute glucose-stimulated insulin secretory defects, mitochondrial abnormalities including excess superoxide generation, a decline in ATP content, loss of MnSOD activity, reduced calcium flux, and increased glucose uptake, all of which were improved with alagebrium treatment or with MnSOD adenoviral overexpression. Isolated mouse islets exposed to AGEs had decreased glucose-stimulated insulin secretion, increased mitochondrial superoxide production, and depletion of ATP content, which were improved with alagebrium or with MnTBAP, an SOD mimetic. In rats, transient or chronic exposure to AGEs caused progressive insulin secretory defects, superoxide generation, and ?-cell death, ameliorated with alagebrium. NODLt mice had increased circulating AGEs in association with an increase in islet mitochondrial superoxide generation, which was prevented by alagebrium, which also reduced the incidence of autoimmune diabetes. Finally, at-risk children who progressed to T1D had higher AGE concentrations than matched nonprogressors. CONCLUSIONS These findings demonstrate that AGEs directly cause insulin secretory defects, most likely by impairing mitochondrial function, which may contribute to the development of T1D.

Coughlan, Melinda T.; Yap, Felicia Y.T.; Tong, David C.K.; Andrikopoulos, Sofianos; Gasser, Anna; Thallas-Bonke, Vicki; Webster, Diane E.; Miyazaki, Jun-ichi; Kay, Thomas W.; Slattery, Robyn M.; Kaye, David M.; Drew, Brian G.; Kingwell, Bronwyn A.; Fourlanos, Spiros; Groop, Per-Henrik; Harrison, Leonard C.; Knip, Mikael; Forbes, Josephine M.

2011-01-01

281

Remote sensing image restoration with modulation transfer function compensation technology in-orbit  

NASA Astrophysics Data System (ADS)

In order to improve the characteristic of light-duty of space optical remote sensors and the quality of remote sensing images. A novel means was designed. It is used for remote sensing image restoration in-orbit that based on the modulation transfer function compensation (MTFC). The principle of the modulation transfer function compensation in-orbit was given, and the control system in-orbit of the modulation transfer function compensation was designed. The modulation transfer function curve was obtained by direct measurement in laboratory. The remote sensing image restoration was realized by constrained least square filter. The indexes including mean, standard deviation, edge intensity and others are used to evaluate the quality of remote sensing image restoration. The results show that the evaluation indicators of the restored image are better than the original image, and the MTF at Nyquist frequency is increased to 0.1635 from 0.1501. It totally satisfies the requirement for real-time remote sensing image restoration in-orbit, and significantly improves the image quality.

Mu, Xin; Xu, Shuyan; Li, Guangxin; Hu, Jun

2013-03-01

282

Preliminary Probabilistic Safety Assessment of Chinese Dual Functional Lithium Lead Test Blanket Module System for ITER  

Microsoft Academic Search

A dual functional lithium lead (DFLL) test blanket module (TBM) concept for testing in International Thermonuclear Experimental Reactor (ITER) has been proposed. The safety assessment of DFL-TBM has been carried out applying the Probabilistic Safety Assessment (PSA) approach. The accident sequences have been modeled and quantified through the event tree technique, which allows identifying all possible combinations of success or

L. Hu; Y. Wu; J. Wang; S. WangandFDSTeam

2007-01-01

283

Growing functional modules from a seed protein via integration of protein interaction and gene expression data  

Microsoft Academic Search

BACKGROUND: Nowadays modern biology aims at unravelling the strands of complex biological structures such as the protein-protein interaction (PPI) networks. A key concept in the organization of PPI networks is the existence of dense subnetworks (functional modules) in them. In recent approaches clustering algorithms were applied at these networks and the resulting subnetworks were evaluated by estimating the coverage of

Ioannis A. Maraziotis; Konstantina Dimitrakopoulou; Anastasios Bezerianos

2007-01-01

284

Modulation Transfer Functions of the Photographic Material Developer System, Determined with a Bar Test-Object.  

National Technical Information Service (NTIS)

A study has been made of the modulation-transfer functions (MTF) of two photographic materials of different types with the use of a specially shaped bar test-object. Only when a developer with a high buffer capacity is employed is the MTF invariant with r...

Y. N. Gorokhovski A. L. Kuznetsova

1974-01-01

285

Measurement of MODIS optics effective focal length, distortion, and modulation transfer function  

NASA Astrophysics Data System (ADS)

A combination MODIS optics characteristics, short back focal length, and relatively distorting optics, has required major revisions in techniques used earlier to characterize effective focal length (EFL) and modulation transfer function (MTF) in the thematic mapper (TM) project. This paper compares measurement approaches used to characterize TM optics and revised methodology intended to characterize MODIS optics at an integration and assembly level.

Thurlow, Paul E.; Cline, Richard W.

1993-08-01

286

Relevance of Dietary Lipids as Modulators of Immune Functions in Cells Infected with Listeria monocytogenes  

Microsoft Academic Search

Nutritional status may have significant importance for the immune system, and particularly, unsaturated fatty acids may serve as modulators of immune functions. Clinical and epidemiological studies have demon- strated that fatty acids are involved in the reduction of the inflammatory processes that occur in diseases characterized by an overactivation of the immune system. At the same time, an increase in

M. A. Puertollano; M. A. de Pablo; G. Alvarez de Cienfuegos

2002-01-01

287

The impact of physical training on endocrine modulation, muscle physiology and sexual functions in elderly men  

Microsoft Academic Search

With rapidly growing geriatric population and with the improvement in quality of life, sexuality is becoming an increasingly important aspect of aging. This paper is dealing with the investigation of the role of physical training program of moderate intensity on endocrine modulation, skeletal muscle physiology, improvement of depression and of sexual function in elderly men.

C. R. Revnic; A. S. Nica; F. Revnic

2007-01-01

288

The Plasticizer Di(2-ethylhexyl) Phthalate Modulates ??-Aminobutyric Acid Type A and Glycine Receptor Function  

Microsoft Academic Search

INTRODUCTION: Intravenous (IV) fluid bags made of polyvinyl chloride (PVC) often contain the plasticizer di(2-ethylhexyl) phthalate (DEHP) to make the PVC flexible. Phthalate esters have been reported to inhibit neuronal nicotinic acetylcholine receptors, which are sensitive to many inhaled anesthetics. This raises the possi- bility that DEHP might modulate the function of other cys-loop receptors, such as -amino butyric acid

Liya Yang; Pavle S. Milutinovic; Robert J. Brosnan; Edmond I Eger; James M. Sonner

2007-01-01

289

Moire modulation transfer function of alexandrite rods and their thresholds as lasers  

SciTech Connect

We show that there is a simple correlation between the modulation transfer function (MTF) of alexandrite laser rods and the thresholds of these rods as cw lasers. Thus the MTF provides a novel and important way to evaluate material (before or after fabrication) for use in solid-state lasers. This approach should be generally applicable to all solid-state laser materials.

Kafri, O.; Samelson, H.; Chin, T.; Heller, D.F.

1986-04-01

290

Angiotensin converting enzyme inhibitor modulates glomerular function and structure by distinct mechanisms  

Microsoft Academic Search

Angiotensin converting enzyme inhibitor modulates glomerular function and structure by distinct mechanisms. Rats with puromycin aminonucleoside (PAN) nephrosis were given either angiotensin I converting enzyme inhibitor (ACEI), angiotensin II type 1 receptor antagonist (Ang IIRA), or no treatment for four weeks and were then monitored for an additional 12 weeks. In untreated PAN rats, proteinuria reached a maximum at two

Ryojiro Tanaka; Valentina Kon; Toshimasa Yoshioka; Iekuni Ichikawa; Agnes Fogo

1994-01-01

291

Progress in the structural understanding of voltage-gated calcium channel (CaV) function and modulation.  

PubMed

Voltage-gated calcium channels (CaVs) are large, transmembrane multiprotein complexes that couple membrane depolarization to cellular calcium entry. These channels are central to cardiac action potential propagation, neurotransmitter and hormone release, muscle contraction, and calcium-dependent gene transcription. Over the past six years, the advent of high-resolution structural studies of CaV components from different isoforms and CaV modulators has begun to reveal the architecture that underlies the exceptionally rich feedback modulation that controls CaV action. These descriptions of CaV molecular anatomy have provided new, structure-based insights into the mechanisms by which particular channel elements affect voltage-dependent inactivation (VDI), calcium?dependent inactivation (CDI), and calcium?dependent facilitation (CDF). The initial successes have been achieved through structural studies of soluble channel domains and modulator proteins and have proven most powerful when paired with biochemical and functional studies that validate ideas inspired by the structures. Here, we review the progress in this growing area and highlight some key open challenges for future efforts. PMID:21139419

Minor, Daniel L; Findeisen, Felix

292

Progress in the structural understanding of voltage-gated calcium channel (CaV) function and modulation  

PubMed Central

Voltage-gated calcium channels (CaVs) are large, transmembrane multiprotein complexes that couple membrane depolarization to cellular calcium entry. These channels are central to cardiac action potential propagation, neurotransmitter and hormone release, muscle contraction and calcium-dependent gene transcription. Over the past six years, the advent of high-resolution structural studies of CaV components from different isoforms and CaV modulators has begun to reveal the architecture that underlies the exceptionally rich feedback modulation that controls CaV action. These descriptions of CaV molecular anatomy have provided new, structure-based insights into the mechanisms by which particular channel elements affect voltage-dependent inactivation (VDI), calcium-dependent inactivation (CDI) and calcium-dependent facilitation (CDF). The initial successes have been achieved through structural studies of soluble channel domains and modulator proteins and have proven most powerful when paired with biochemical and functional studies that validate ideas inspired by the structures. Here, we review the progress in this growing area and highlight some key open challenges for future efforts.

Findeisen, Felix

2010-01-01

293

Thermodynamic Characterization of a Triheme Cytochrome Family from Geobacter sulfurreducens Reveals Mechanistic and Functional Diversity  

PubMed Central

Abstract A family of five periplasmic triheme cytochromes (PpcA-E) was identified in Geobacter sulfurreducens, where they play a crucial role by driving electron transfer from the cytoplasm to the cell exterior and assisting the reduction of extracellular acceptors. The thermodynamic characterization of PpcA using NMR and visible spectroscopies was previously achieved under experimental conditions identical to those used for the triheme cytochrome c7 from Desulfuromonas acetoxidans. Under such conditions, attempts to obtain NMR data were complicated by the relatively fast intermolecular electron exchange. This work reports the detailed thermodynamic characterization of PpcB, PpcD, and PpcE under optimal experimental conditions. The thermodynamic characterization of PpcA was redone under these new conditions to allow a proper comparison of the redox properties with those of other members of this family. The heme reduction potentials of the four proteins are negative, differ from each other, and cover different functional ranges. These reduction potentials are strongly modulated by heme-heme interactions and by interactions with protonated groups (the redox-Bohr effect) establishing different cooperative networks for each protein, which indicates that they are designed to perform different functions in the cell. PpcA and PpcD appear to be optimized to interact with specific redox partners involving e?/H+ transfer via different mechanisms. Although no evidence of preferential electron transfer pathway or e?/H+ coupling was found for PpcB and PpcE, the difference in their working potential ranges suggests that they may also have different physiological redox partners. This is the first study, to our knowledge, to characterize homologous cytochromes from the same microorganism and provide evidence of their different mechanistic and functional properties. These findings provide an explanation for the coexistence of five periplasmic triheme cytochromes in G. sulfurreducens.

Morgado, Leonor; Bruix, Marta; Pessanha, Miguel; Londer, Yuri Y.; Salgueiro, Carlos A.

2010-01-01

294

Spectroscopic Functions of Multi-Stacked Metallic Plates with Modulated Slit Arrays  

NASA Astrophysics Data System (ADS)

We show that a spectroscopic function can be achieved by an artificial combination of very thin metallic plates with modulated cut-through slit arrays by simulation using the finite-difference time-domain method. The novel function is based on the remarkable frequency dependences of optical phased array effects, i.e., the phase variations of optical waves threading through the slit arrays in multi-stacked metallic plates. We also present methods to enhance the phase shift.

Tokuda, Yasunori; Sakaguchi, Koichiro; Nishihara, Toshiki; Takano, Keisuke; Fukushima, Takehiro; Hangyo, Masanori

2013-06-01

295

Modulation of P-glycoprotein function by amlodipine derivatives in brain microvessel endothelial cells of rats  

Microsoft Academic Search

Aim:To investigate whether the amlodipine derivatives, CJX1 and CJX2, have a modulative effect on P-glycoprotein (P-gp) function in rat brain microvessel endothelial cells (RBMEC).Methods:Isolated RBMEC were cultured in DMEM\\/F12 (1:1) medium. The amount of intracellular rhodamine (Rh123) was determined, using a fluorescence spectrophotometer, to evaluate the function of P-gp.Results:The accumulation of Rh123 in RBMEC was potentiated in a concentration dependent

Bian-sheng Ji; Ling He; Guo-qing Liu

2005-01-01

296

Inferring modules of functionally interacting proteins using the Bond Energy Algorithm  

PubMed Central

Background Non-homology based methods such as phylogenetic profiles are effective for predicting functional relationships between proteins with no considerable sequence or structure similarity. Those methods rely heavily on traditional similarity metrics defined on pairs of phylogenetic patterns. Proteins do not exclusively interact in pairs as the final biological function of a protein in the cellular context is often hold by a group of proteins. In order to accurately infer modules of functionally interacting proteins, the consideration of not only direct but also indirect relationships is required. In this paper, we used the Bond Energy Algorithm (BEA) to predict functionally related groups of proteins. With BEA we create clusters of phylogenetic profiles based on the associations of the surrounding elements of the analyzed data using a metric that considers linked relationships among elements in the data set. Results Using phylogenetic profiles obtained from the Cluster of Orthologous Groups of Proteins (COG) database, we conducted a series of clustering experiments using BEA to predict (upper level) relationships between profiles. We evaluated our results by comparing with COG's functional categories, And even more, with the experimentally determined functional relationships between proteins provided by the DIP and ECOCYC databases. Our results demonstrate that BEA is capable of predicting meaningful modules of functionally related proteins. BEA outperforms traditionally used clustering methods, such as k-means and hierarchical clustering by predicting functional relationships between proteins with higher accuracy. Conclusion This study shows that the linked relationships of phylogenetic profiles obtained by BEA is useful for detecting functional associations between profiles and extending functional modules not found by traditional methods. BEA is capable of detecting relationship among phylogenetic patterns by linking them through a common element shared in a group. Additionally, we discuss how the proposed method may become more powerful if other criteria to classify different levels of protein functional interactions, as gene neighborhood or protein fusion information, is provided.

Watanabe, Ryosuke LA; Morett, Enrique; Vallejo, Edgar E

2008-01-01

297

Molecular mechanisms of COMPLEXIN fusion clamp function in synaptic exocytosis revealed in a new Drosophila mutant.  

PubMed

The COMPLEXIN (CPX) proteins play a critical role in synaptic vesicle fusion and neurotransmitter release. Previous studies demonstrated that CPX functions in both activation of evoked neurotransmitter release and inhibition/clamping of spontaneous synaptic vesicle fusion. Here we report a new cpx mutant in Drosophila melanogaster, cpx(1257), revealing spatially defined and separable pools of CPX which make distinct contributions to the activation and clamping functions. In cpx(1257), lack of only the last C-terminal amino acid of CPX is predicted to disrupt prenylation and membrane targeting of CPX. Immunocytochemical analysis established localization of wild-type CPX to active zone (AZ) regions containing neurotransmitter release sites as well as broader presynaptic membrane compartments including synaptic vesicles. Parallel biochemical studies confirmed CPX membrane association and demonstrated robust binding interactions of CPX with all three SNAREs. This is in contrast to the cpx(1257) mutant, in which AZ localization of CPX persists but general membrane localization and, surprisingly, the bulk of CPX-SNARE protein interactions are abolished. Furthermore, electrophysiological analysis of neuromuscular synapses revealed interesting differences between cpx(1257) and a cpx null mutant. The cpx null exhibited a marked decrease in the EPSC amplitude, slowed EPSC rise and decay times and an increased mEPSC frequency with respect to wild-type. In contrast, cpx(1257) exhibited a wild-type EPSC with an increased mEPSC frequency and thus a selective failure to clamp spontaneous release. These results indicate that spatially distinct and separable interactions of CPX with presynaptic membranes and SNARE proteins mediate separable activation and clamping functions of CPX in neurotransmitter release. PMID:23769723

Iyer, Janani; Wahlmark, Christopher J; Kuser-Ahnert, Giselle A; Kawasaki, Fumiko

2013-06-11

298

Reduction of IMRT beam complexity through the use of beam modulation penalties in the objective function  

SciTech Connect

Inverse planned intensity modulated radiation therapy (IMRT) has become commonplace in treatment centers across the world. Due to the implications of beam complexity on treatment planning, delivery, and quality assurance, several methods have been proposed to reduce the complexity. These methods include beamlet intensity restrictions, smoothing procedures, and direct aperture optimization. Many of these methods typically sacrifice target coverage and/or normal tissue sparing in return for increased beam smoothness and delivery efficiency. In the present work, we penalize beam modulation in the inverse planning cost function to reduce beam complexity and increase delivery efficiency, while maintaining dosimetric quality. Three modulation penalties were tested: two that penalized deviation from Savitzky-Golay filtered versions of the optimized beams, and one that penalized the plan intensity map variation (a measure of overall beam modulation). The modulation penalties were applied at varying weights in a weighted sum objective (or cost) function to investigate their ability to reduce beam complexity while preserving IMRT plan quality. The behavior of the penalties was characterized on a CT phantom, and then clinical optimization comparisons were performed in the brain, prostate, and head/neck. Comparisons were made between (i) plans with a baseline cost function (ii) plans with a baseline cost function employing maximum beamlet intensity limits, and (iii) plans with each of the modulation penalties added to the baseline cost function. Plan analysis was based upon dose-volume histograms, relevant dose metrics, beam modulation, and monitor units required for step and shoot delivery. Each of the techniques yielded improvements over a baseline cost function in terms of MU reduction. In most cases, this was achieved with minimal change to the plan DVHs and metrics. In all cases, an acceptable plan was reached with each of the methods while reducing MU substantially. Each individual method has merit as a tool for reducing IMRT beam complexity and could be easily applied in the clinic to improve overall inverse plan quality. However, the penalty based upon the plan intensity map variation consistently produced the most delivery-efficient plans with the fewest computations.

Matuszak, Martha M.; Larsen, Edward W.; Fraass, Benedick A. [Department of Radiation Oncology and Department of Nuclear Engineering and Radiological Sciences, University of Michigan, Ann Arbor, Michigan 48109 (United States); Department of Nuclear Engineering and Radiological Sciences, University of Michigan, Ann Arbor, Michigan 48109 (United States); Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan 48109 (United States)

2007-02-15

299

Photon-Number Distribution and Wigner Function of Generalized Photon-Modulated Coherent State  

NASA Astrophysics Data System (ADS)

In this paper, we present the generalized photon-modulated coherent state (GPMCS) generated by repeatedly operating the combination of Bosonic creation and annihilation operators on the coherent state. It is found that the GPMCS is a Hermite-excited coherent state and its normalization factor is related to single-variable Hermite polynomials. Furthermore, some significant quantum statistical properties of the GPMCS are investigated, such as photon-number distribution (PND) and the Wigner function (WF). We find that the WF of the GPMCS has negative values when the generalized photon-modulation exists, which implies the nonclassical properties of the GPMCS.

Zhou, Jun; Wang, Shuai; Song, Jun; Fan, Hong-Yi

300

50-Gb/s NRZ and RZ Modulator Driver ICs Based on Functional Distributed Circuits  

NASA Astrophysics Data System (ADS)

We have developed two modulator driver ICs that are based on the functional distributed circuit (FDC) topology for over 40-Gb/s optical transmission systems using InP HBT technology. The FDC topology enables both a wide bandwidth amplifier and high-speed digital functions. The none-return-to-zero (NRZ) driver IC, which is integrated with a D-type flip-flop, exhibits 2.6-Vp-p (differential output: 5.2Vp-p) output-voltage swings with a high signal quality at 43 and 50Gb/s. The return-to-zero (RZ) driver IC, which is integrated with a NRZ to RZ converter, produces 2.4-Vp-p (differential output: 4.8Vp-p) output-voltage swings and excellent eye openings at 43 and 50Gb/s. Furthermore, we conducted electro-optical modulation experiments using the developed modulator driver ICs and a dual drive LiNbO3 Mach-Zehnder modulator. We were able to obtain NRZ and RZ clear optical eye openings with low jitters and sufficient extinction ratios of more than 12dB, at 43 and 50Gb/s. These results indicate that the FDC has the potential to achieve a large output voltage and create high-speed functional ICs for over-40-Gb/s transmission systems.

Suzuki, Yasuyuki; Mamada, Masayuki

301

Intermediate closed state for glycine receptor function revealed by cysteine cross-linking  

PubMed Central

Pentameric ligand-gated ion channels (pLGICs) mediate signal transmission by coupling the binding of extracellular ligands to the opening of their ion channel. Agonist binding elicits activation and desensitization of pLGICs, through several conformational states, that are, thus far, incompletely characterized at the structural level. We previously reported for GLIC, a prokaryotic pLGIC, that cross-linking of a pair of cysteines at both sides of the extracellular and transmembrane domain interface stabilizes a locally closed (LC) X-ray structure. Here, we introduced the homologous pair of cysteines on the human ?1 glycine receptor. We show by electrophysiology that cysteine cross-linking produces a gain-of-function phenotype characterized by concomitant constitutive openings, increased agonist potency, and equalization of efficacies of full and partial agonists. However, it also produces a reduction of maximal currents at saturating agonist concentrations without change of the unitary channel conductance, an effect reversed by the positive allosteric modulator propofol. The cross-linking thus favors a unique closed state distinct from the resting and longest-lived desensitized states. Fitting the data according to a three-state allosteric model suggests that it could correspond to a LC conformation. Its plausible assignment to a gating intermediate or a fast-desensitized state is discussed. Overall, our data show that relative movement of two loops at the extracellular-transmembrane interface accompanies orthosteric agonist-mediated gating.

Prevost, Marie S.; Moraga-Cid, Gustavo; Van Renterghem, Catherine; Edelstein, Stuart J.; Changeux, Jean-Pierre; Corringer, Pierre-Jean

2013-01-01

302

Distinct Properties of Human HMGN5 Reveal a Rapidly Evolving but Functionally Conserved Nucleosome Binding Protein ?  

PubMed Central

The HMGN family is a family of nucleosome-binding architectural proteins that affect the structure and function of chromatin in vertebrates. We report that the HMGN5 variant, encoded by a gene located on chromosome X, is a rapidly evolving protein with an acidic C-terminal domain that differs among vertebrate species. We found that the intranuclear organization and nucleosome interactions of human HMGN5 are distinct from those of mouse HMGN5 and that the C-terminal region of the protein is the main determinant of the chromatin interaction properties. Despite their apparent differences, both mouse and human HMGN5 proteins interact with histone H1, reduce its chromatin residence time, and can induce large-scale chromatin decompaction in living cells. Analysis of HMGN5 mutants suggests that distinct domains in HMGN5 affect specific steps in the interaction of H1 with chromatin. Elevated levels of either human or mouse HMGN5 affect the transcription of numerous genes, most in a variant-specific manner. Our study identifies HMGN5 as a rapidly evolving vertebrate nuclear protein with species-specific properties. HMGN5 has a highly disordered structure, binds dynamically to nucleosome core particles, modulates the binding of H1 to chromatin, reduces the compaction of the chromatin fiber, and affects transcription.

Malicet, Cedric; Rochman, Mark; Postnikov, Yuri; Bustin, Michael

2011-01-01

303

Intermediate closed state for glycine receptor function revealed by cysteine cross-linking.  

PubMed

Pentameric ligand-gated ion channels (pLGICs) mediate signal transmission by coupling the binding of extracellular ligands to the opening of their ion channel. Agonist binding elicits activation and desensitization of pLGICs, through several conformational states, that are, thus far, incompletely characterized at the structural level. We previously reported for GLIC, a prokaryotic pLGIC, that cross-linking of a pair of cysteines at both sides of the extracellular and transmembrane domain interface stabilizes a locally closed (LC) X-ray structure. Here, we introduced the homologous pair of cysteines on the human ?1 glycine receptor. We show by electrophysiology that cysteine cross-linking produces a gain-of-function phenotype characterized by concomitant constitutive openings, increased agonist potency, and equalization of efficacies of full and partial agonists. However, it also produces a reduction of maximal currents at saturating agonist concentrations without change of the unitary channel conductance, an effect reversed by the positive allosteric modulator propofol. The cross-linking thus favors a unique closed state distinct from the resting and longest-lived desensitized states. Fitting the data according to a three-state allosteric model suggests that it could correspond to a LC conformation. Its plausible assignment to a gating intermediate or a fast-desensitized state is discussed. Overall, our data show that relative movement of two loops at the extracellular-transmembrane interface accompanies orthosteric agonist-mediated gating. PMID:24085847

Prevost, Marie S; Moraga-Cid, Gustavo; Van Renterghem, Catherine; Edelstein, Stuart J; Changeux, Jean-Pierre; Corringer, Pierre-Jean

2013-10-01

304

Functional modulation of vascular adhesion protein-1 by a novel splice variant.  

PubMed

Vascular Adhesion Protein-1 (VAP-1) is an endothelial adhesion molecule belonging to the primary amine oxidases. Upon inflammation it takes part in the leukocyte extravasation cascade facilitating transmigration of leukocytes into the inflamed tissue. Screening of a human lung cDNA library revealed the presence of an alternatively spliced shorter transcript of VAP-1, VAP-1?3. Here, we have studied the functional and structural characteristics of VAP-1?3, and show that the mRNA for this splice variant is expressed in most human tissues studied. In comparison to the parent molecule this carboxy-terminally truncated isoform lacks several of the amino acids important in the formation of the enzymatic groove of VAP-1. In addition, the conserved His684, which takes part in coordinating the active site copper, is missing from VAP-1?3. Assays using the prototypic amine substrates methylamine and benzylamine demonstrated that VAP-1?3 is indeed devoid of the semicarbazide-sensitive amine oxidase (SSAO) activity characteristic to VAP-1. When VAP-1?3-cDNA is transfected into cells stably expressing VAP-1, the surface expression of the full-length molecule is reduced. Furthermore, the SSAO activity of the co-transfectants is diminished in comparison to transfectants expressing only VAP-1. The observed down-regulation of both the expression and enzymatic activity of VAP-1 may result from a dominant-negative effect caused by heterodimerization between VAP-1 and VAP-1?3, which was detected in co-immunoprecipitation studies. This alternatively spliced transcript adds thus to the repertoire of potential regulatory mechanisms through which the cell-surface expression and enzymatic activity of VAP-1 can be modulated. PMID:23349812

Kaitaniemi, Sam; Grön, Kirsi; Elovaara, Heli; Salmi, Marko; Jalkanen, Sirpa; Elima, Kati

2013-01-18

305

Functional Modulation of Vascular Adhesion Protein-1 by a Novel Splice Variant  

PubMed Central

Vascular Adhesion Protein-1 (VAP-1) is an endothelial adhesion molecule belonging to the primary amine oxidases. Upon inflammation it takes part in the leukocyte extravasation cascade facilitating transmigration of leukocytes into the inflamed tissue. Screening of a human lung cDNA library revealed the presence of an alternatively spliced shorter transcript of VAP-1, VAP-1?3. Here, we have studied the functional and structural characteristics of VAP-1?3, and show that the mRNA for this splice variant is expressed in most human tissues studied. In comparison to the parent molecule this carboxy-terminally truncated isoform lacks several of the amino acids important in the formation of the enzymatic groove of VAP-1. In addition, the conserved His684, which takes part in coordinating the active site copper, is missing from VAP-1?3. Assays using the prototypic amine substrates methylamine and benzylamine demonstrated that VAP-1?3 is indeed devoid of the semicarbazide-sensitive amine oxidase (SSAO) activity characteristic to VAP-1. When VAP-1?3-cDNA is transfected into cells stably expressing VAP-1, the surface expression of the full-length molecule is reduced. Furthermore, the SSAO activity of the co-transfectants is diminished in comparison to transfectants expressing only VAP-1. The observed down-regulation of both the expression and enzymatic activity of VAP-1 may result from a dominant-negative effect caused by heterodimerization between VAP-1 and VAP-1?3, which was detected in co-immunoprecipitation studies. This alternatively spliced transcript adds thus to the repertoire of potential regulatory mechanisms through which the cell-surface expression and enzymatic activity of VAP-1 can be modulated.

Kaitaniemi, Sam; Gron, Kirsi; Elovaara, Heli; Salmi, Marko; Jalkanen, Sirpa; Elima, Kati

2013-01-01

306

Gas7-Deficient Mouse Reveals Roles in Motor Function and Muscle Fiber Composition during Aging  

PubMed Central

Background Growth arrest-specific gene 7 (Gas7) has previously been shown to be involved in neurite outgrowth in vitro; however, its actual role has yet to be determined. To investigate the physiological function of Gas7 in vivo, here we generated a Gas7-deficient mouse strain with a labile Gas7 mutant protein whose functions are similar to wild-type Gas7. Methodology/Principal Findings Our data show that aged Gas7-deficient mice have motor activity defects due to decreases in the number of spinal motor neurons and in muscle strength, of which the latter may be caused by changes in muscle fiber composition as shown in the soleus. In cross sections of the soleus of Gas7-deficient mice, gross morphological features and levels of myosin heavy chain I (MHC I) and MHC II markers revealed significantly fewer fast fibers. In addition, we found that nerve terminal sprouting, which may be associated with slow and fast muscle fiber composition, was considerably reduced at neuromuscular junctions (NMJ) during aging. Conclusions/Significance These findings indicate that Gas7 is involved in motor neuron function associated with muscle strength maintenance.

Huang, Bo-Tsang; Chang, Pu-Yuan; Su, Ching-Hua; Chao, Chuck C.-K.; Lin-Chao, Sue

2012-01-01

307

Comparative Proteomics Reveal Fundamental Structural and Functional Differences between the Two Progeny Phenotypes of a Baculovirus  

PubMed Central

The replication of lepidopteran baculoviruses is characterized by the production of two progeny phenotypes: the occlusion-derived virus (ODV), which establishes infection in midgut cells, and the budded virus (BV), which disseminates infection to different tissues within a susceptible host. To understand the structural, and hence functional, differences between BV and ODV, we employed multiple proteomic methods to reveal the protein compositions and posttranslational modifications of the two phenotypes of Helicoverpa armigera nucleopolyhedrovirus. In addition, Western blotting and quantitative mass spectrometry were used to identify the localization of proteins in the envelope or nucleocapsid fractions. Comparative protein portfolios of BV and ODV showing the distribution of 54 proteins, encompassing the 21 proteins shared by BV and ODV, the 12 BV-specific proteins, and the 21 ODV-specific proteins, were obtained. Among the 11 ODV-specific envelope proteins, 8 either are essential for or contribute to oral infection. Twenty-three phosphorylated and 6 N-glycosylated viral proteins were also identified. While the proteins that are shared by the two phenotypes appear to be important for nucleocapsid assembly and trafficking, the structural and functional differences between the two phenotypes are evidently characterized by the envelope proteins and posttranslational modifications. This comparative proteomics study provides new insight into how BV and ODV are formed and why they function differently.

Hou, Dianhai; Zhang, Leike; Deng, Fei; Fang, Wei; Wang, Ranran; Liu, Xijia; Rayner, Simon; Chen, Xinwen; Wang, Hualin

2013-01-01

308

Prokaryotic Caspase Homologs: Phylogenetic Patterns and Functional Characteristics Reveal Considerable Diversity  

PubMed Central

Caspases accomplish initiation and execution of apoptosis, a programmed cell death process specific to metazoans. The existence of prokaryotic caspase homologs, termed metacaspases, has been known for slightly more than a decade. Despite their potential connection to the evolution of programmed cell death in eukaryotes, the phylogenetic distribution and functions of these prokaryotic metacaspase sequences are largely uncharted, while a few experiments imply involvement in programmed cell death. Aiming at providing a more detailed picture of prokaryotic caspase homologs, we applied a computational approach based on Hidden Markov Model search profiles to identify and functionally characterize putative metacaspases in bacterial and archaeal genomes. Out of the total of 1463 analyzed genomes, merely 267 (18%) were identified to contain putative metacaspases, but their taxonomic distribution included most prokaryotic phyla and a few archaea (Euryarchaeota). Metacaspases were particularly abundant in Alphaproteobacteria, Deltaproteobacteria and Cyanobacteria, which harbor many morphologically and developmentally complex organisms, and a distinct correlation was found between abundance and phenotypic complexity in Cyanobacteria. Notably, Bacillus subtilis and Escherichia coli, known to undergo genetically regulated autolysis, lacked metacaspases. Pfam domain architecture analysis combined with operon identification revealed rich and varied configurations among the metacaspase sequences. These imply roles in programmed cell death, but also e.g. in signaling, various enzymatic activities and protein modification. Together our data show a wide and scattered distribution of caspase homologs in prokaryotes with structurally and functionally diverse sub-groups, and with a potentially intriguing evolutionary role. These features will help delineate future characterizations of death pathways in prokaryotes.

Asplund-Samuelsson, Johannes; Bergman, Birgitta; Larsson, John

2012-01-01

309

Acid modulates the squamous epithelial barrier function by modulating the localization of claudins in the superficial layers.  

PubMed

Acid is a major cause of gastro-esophageal reflux disease. However, the influence of acid on the esophageal stratified epithelial barrier function and tight junction (TJ) proteins is not fully understood. Here, we explore the influence of acid on barrier function and TJ proteins using a newly developed model of the esophageal-like squamous epithelial cell layers that employs an air-liquid interface (ALI) system. Barrier function was determined by measuring trans-epithelial electrical resistance (TEER) and diffusion of paracellular tracers. TJ-related protein (claudin-1, claudin-4, occludin and ZO-1) expression and localization was examined by immunofluorescent staining, and by western blotting of 1% NP-40 soluble and insoluble fractions. We also examined the influence of acid (pH 2-4) on the barrier created by these cells. The in vitro ALI culture system showed a tight barrier (1500-2500 ?·cm(2)) with the expression of claudin-1, claudin-4, occludin and ZO-1 in the superficial layers. Claudin-1, claudin-4, occludin and ZO-1 were detected as dots and whisker-like lines in the superficial layers, and as a broad line in the suprabasal layers. These localization patterns are similar to those in the human esophagus. On day 7 under ALI culture, TJ proteins were detected in the superficial layers with functional properties, including decreased permeability and increased TEER. Dilated intercellular spaces were detected at the suprabasal cell layers even under the control conditions of ALI cells. pH 2 acid on the apical side significantly reduced the TEER in ALI-cultured cells. This decrease in TEER by the acid was in parallel with the decreased amount of detergent-insoluble claudin-4. Claudin-4 delocalization was confirmed by immunofluorescent staining. In conclusion, TJs are located in the superficial layers of the esophagus, and acid stimulation disrupts barrier function, at least in part by modulating the amount and localization of claudin-4 in the superficial layers. PMID:21912379

Oshima, Tadayuki; Koseki, Junichi; Chen, Xin; Matsumoto, Takayuki; Miwa, Hiroto

2011-09-12

310

Functional Architecture of the Inferior Colliculus Revealed with Voltage-Sensitive Dyes  

PubMed Central

We used optical imaging with voltage-sensitive dyes to investigate the spatio-temporal dynamics of synaptically evoked activity in brain slices of the inferior colliculus (IC). Responses in transverse slices which preserve cross-frequency connections and in modified sagittal slices that preserve connections within frequency laminae were evoked by activating the lateral lemniscal tract. Comparing activity between small and large populations of cells revealed response areas in the central nucleus of the IC that were similar in magnitude but graded temporally. In transverse sections, these response areas are summed to generate a topographic response profile. Activity through the commissure to the contralateral IC required an excitation threshold that was reached when GABAergic inhibition was blocked. Within laminae, module interaction created temporal homeostasis. Diffuse activity evoked by a single lemniscal shock re-organized into distinct spatial and temporal compartments when stimulus trains were used, and generated a directional activity profile within the lamina. Using different stimulus patterns to activate subsets of microcircuits in the central nucleus of the IC, we found that localized responses evoked by low-frequency stimulus trains spread extensively when train frequency was increased, suggesting recruitment of silent microcircuits. Long stimulus trains activated a circuit specific to post-inhibitory rebound neurons. Rebound microcircuits were defined by a focal point of initiation that spread to an annular ring that oscillated between inhibition and excitation. We propose that much of the computing power of the IC is derived from local circuits, some of which are cell-type specific. These circuits organize activity within and across frequency laminae, and are critical in determining the stimulus-selectivity of auditory coding.

Chandrasekaran, Lakshmi; Xiao, Ying; Sivaramakrishnan, Shobhana

2013-01-01

311

A novel functional module detection algorithm for protein-protein interaction networks  

PubMed Central

Background The sparse connectivity of protein-protein interaction data sets makes identification of functional modules challenging. The purpose of this study is to critically evaluate a novel clustering technique for clustering and detecting functional modules in protein-protein interaction networks, termed STM. Results STM selects representative proteins for each cluster and iteratively refines clusters based on a combination of the signal transduced and graph topology. STM is found to be effective at detecting clusters with a diverse range of interaction structures that are significant on measures of biological relevance. The STM approach is compared to six competing approaches including the maximum clique, quasi-clique, minimum cut, betweeness cut and Markov Clustering (MCL) algorithms. The clusters obtained by each technique are compared for enrichment of biological function. STM generates larger clusters and the clusters identified have p-values that are approximately 125-fold better than the other methods on biological function. An important strength of STM is that the percentage of proteins that are discarded to create clusters is much lower than the other approaches. Conclusion STM outperforms competing approaches and is capable of effectively detecting both densely and sparsely connected, biologically relevant functional modules with fewer discards.

Hwang, Woochang; Cho, Young-Rae; Zhang, Aidong; Ramanathan, Murali

2006-01-01

312

Research in the modulation transfer function (MTF) measurement of InGaAs focal plane arrays  

NASA Astrophysics Data System (ADS)

The Modulation Transfer Function (MTF) of an opto-electrical device is defined as the ratio of the system output modulation to the input modulation, which describes the performance of the imaging system in the Fourier domain. Accurate measurement of the MTF is often obtained by analyzing the high-quality image of a special target reproduced by the optical system with known MTF. To evaluate the MTF of short-wave infrared InGaAs focal plane arrays (FPAs), we develop a laboratory system with high precision and automation based on the slit scan method. An 8*1 linear InGaAs FPAs is then measured by this test set-up for the first time to evaluate the MTF of each pixel at room temperature. The results show a good MTF repeatability and uniformity of the 8*1 InGaAs FPAs. The relationship between the MTF and illumination is also discussed.

Xu, Zhonghua; Fang, Jiaxiong

2012-10-01

313

Gustatory Imagery Reveals Functional Connectivity from the Prefrontal to Insular Cortices Traced with Magnetoencephalography  

PubMed Central

Our experience and prejudice concerning food play an important role in modulating gustatory information processing; gustatory memory stored in the central nervous system influences gustatory information arising from the peripheral nervous system. We have elucidated the mechanism of the “top-down” modulation of taste perception in humans using functional magnetic resonance imaging (fMRI) and demonstrated that gustatory imagery is mediated by the prefrontal (PFC) and insular cortices (IC). However, the temporal order of activation of these brain regions during gustatory imagery is still an open issue. To explore the source of “top-down” signals during gustatory imagery tasks, we analyzed the temporal activation patterns of activated regions in the cerebral cortex using another non-invasive brain imaging technique, magnetoencephalography (MEG). Gustatory imagery tasks were presented by words (Letter G-V) or pictures (Picture G-V) of foods/beverages, and participants were requested to recall their taste. In the Letter G-V session, 7/9 (77.8%) participants showed activation in the IC with a latency of 401.7±34.7 ms (n?=?7) from the onset of word exhibition. In 5/7 (71.4%) participants who exhibited IC activation, the PFC was activated prior to the IC at a latency of 315.2±56.5 ms (n?=?5), which was significantly shorter than the latency to the IC activation. In the Picture G-V session, the IC was activated in 6/9 (66.7%) participants, and only 1/9 (11.1%) participants showed activation in the PFC. There was no significant dominance between the right and left IC or PFC during gustatory imagery. These results support those from our previous fMRI study in that the Letter G-V session rather than the Picture G-V session effectively activates the PFC and IC and strengthen the hypothesis that the PFC mediates “top-down” control of retrieving gustatory information from the storage of long-term memories and in turn activates the IC.

Kobayashi, Masayuki; Sasabe, Tetsuya; Shigihara, Yoshihito; Tanaka, Masaaki; Watanabe, Yasuyoshi

2011-01-01

314

Revealing the Functions of the Transketolase Enzyme Isoforms in Rhodopseudomonas palustris Using a Systems Biology Approach  

PubMed Central

Background Rhodopseudomonas palustris (R. palustris) is a purple non-sulfur anoxygenic phototrophic bacterium that belongs to the class of proteobacteria. It is capable of absorbing atmospheric carbon dioxide and converting it to biomass via the process of photosynthesis and the Calvin–Benson–Bassham (CBB) cycle. Transketolase is a key enzyme involved in the CBB cycle. Here, we reveal the functions of transketolase isoforms I and II in R. palustris using a systems biology approach. Methodology/Principal Findings By measuring growth ability, we found that transketolase could enhance the autotrophic growth and biomass production of R. palustris. Microarray and real-time quantitative PCR revealed that transketolase isoforms I and II were involved in different carbon metabolic pathways. In addition, immunogold staining demonstrated that the two transketolase isoforms had different spatial localizations: transketolase I was primarily associated with the intracytoplasmic membrane (ICM) but transketolase II was mostly distributed in the cytoplasm. Comparative proteomic analysis and network construction of transketolase over-expression and negative control (NC) strains revealed that protein folding, transcriptional regulation, amino acid transport and CBB cycle-associated carbon metabolism were enriched in the transketolase I over-expressed strain. In contrast, ATP synthesis, carbohydrate transport, glycolysis-associated carbon metabolism and CBB cycle-associated carbon metabolism were enriched in the transketolase II over-expressed strain. Furthermore, ATP synthesis assays showed a significant increase in ATP synthesis in the transketolase II over-expressed strain. A PEPCK activity assay showed that PEPCK activity was higher in transketolase over-expressed strains than in the negative control strain. Conclusions/Significance Taken together, our results indicate that the two isoforms of transketolase in R. palustris could affect photoautotrophic growth through both common and divergent metabolic mechanisms.

Hu, Chia-Wei; Chang, Ya-Ling; Chen, Shiang Jiuun; Kuo-Huang, Ling-Long; Liao, James C.; Huang, Hsuan-Cheng; Juan, Hsueh-Fen

2011-01-01

315

Proteomics reveals distinct forms of functional crosstalk between proteolysis and phosphorylation during apoptosis  

PubMed Central

Caspase proteases are principal mediators of apoptosis, where they cleave hundreds of proteins. Phosphorylation also plays an important role in apoptosis, although the extent to which proteolytic and phosphorylation pathways crosstalk during programmed cell death remains poorly understood. Using a quantitative proteomic platform that integrates phosphorylation sites into the topographical maps of proteins, we identify a cohort of over 500 apoptosis-specific phosphorylation events and show that they are enriched on cleaved proteins and clustered around sites of caspase proteolysis. We find that caspase cleavage can expose new sites for phosphorylation, and, conversely, that phosphorylation at the +3 position of cleavage sites can directly promote substrate proteolysis by caspase-8. This study provides a global portrait of the apoptotic phosphoproteome, revealing heretofore unrecognized forms of functional crosstalk between phosphorylation and caspase proteolytic pathways that lead to enhanced rates of protein cleavage and the unveiling of new sites for phosphorylation.

Dix, Melissa M.; Simon, Gabriel M.; Wang, Chu; Okerberg, Eric; Patricelli, Matthew P.; Cravatt, Benjamin F.

2013-01-01

316

Structure of Prokaryotic Polyamine Deacetylase Reveals Evolutionary Functional Relationships with Eukaryotic Histone Deacetylases  

SciTech Connect

Polyamines are a ubiquitous class of polycationic small molecules that can influence gene expression by binding to nucleic acids. Reversible polyamine acetylation regulates nucleic acid binding and is required for normal cell cycle progression and proliferation. Here, we report the structures of Mycoplana ramosa acetylpolyamine amidohydrolase (APAH) complexed with a transition state analogue and a hydroxamate inhibitor and an inactive mutant complexed with two acetylpolyamine substrates. The structure of APAH is the first of a histone deacetylase-like oligomer and reveals that an 18-residue insert in the L2 loop promotes dimerization and the formation of an 18 {angstrom} long 'L'-shaped active site tunnel at the dimer interface, accessible only to narrow and flexible substrates. The importance of dimerization for polyamine deacetylase function leads to the suggestion that a comparable dimeric or double-domain histone deacetylase could catalyze polyamine deacetylation reactions in eukaryotes.

P Lombardi; H Angell; D Whittington; E Flynn; K Rajashankar; D Christianson

2011-12-31

317

Insight into helicase mechanism and function revealed through single-molecule approaches.  

PubMed

Helicases are a class of nucleic acid (NA) motors that catalyze NTP-dependent unwinding of NA duplexes into single strands, a reaction essential to all areas of NA metabolism. In the last decade, single-molecule (sm) technology has proven to be highly useful in revealing mechanistic insight into helicase activity that is not always detectable via ensemble assays. A combination of methods based on fluorescence, optical and magnetic tweezers, and flow-induced DNA stretching has enabled the study of helicase conformational dynamics, force generation, step size, pausing, reversal and repetitive behaviors during translocation and unwinding by helicases working alone and as part of multiprotein complexes. The contributions of these sm investigations to our understanding of helicase mechanism and function will be discussed. PMID:20682090

Yodh, Jaya G; Schlierf, Michael; Ha, Taekjip

2010-08-04

318

Voluntary selection of task sets revealed by functional magnetic resonance imaging.  

PubMed

In everyday life, we have to selectively adapt our behavior to different situations and tasks. In cognitive psychology, such adaptive behavior can be investigated with the task-switching paradigm. However, in contrast to everyday life, in experiments participants are unequivocally told which task to perform. The present functional magnetic resonance imaging (fMRI) study was set out to investigate processes that are relevant when participants can decide by their own which task to perform. The number of tasks to choose from was varied between a forced condition (no choice) and two voluntary selection conditions (two or three choices). We expected to find prolonged reaction times as well as higher activations within the midcingulate cortex for the choice conditions compared to the no-choice condition. The fMRI results revealed a significant activation difference for the choice conditions versus the no-choice condition. For the choice contrast, activation was found in the rostral cingulate zone (RCZ) as well as the superior parietal lobule and the posterior part of the intraparietal sulcus. These activations revealed no selection-specific difference between three and two choices. Finally, a post hoc analysis showed that the activation in the RCZ is not associated with higher task-dependent response conflict when participants can select a task set. Taken together, these findings indicate that distinct brain areas are involved in the voluntary selection of abstract task set information. PMID:16513004

Forstmann, Birte U; Brass, Marcel; Koch, Iring; von Cramon, D Yves

2006-03-01

319

Modulation of morpho-functional characteristics of astrocytes using chemically-functionalized water-soluble single-walled carbon nanotubes  

NASA Astrophysics Data System (ADS)

In this thesis, I report the use of chemically functionalized water-soluble single-walled carbon nanotubes (ws-SWCNTs) for the modulation of morpho-functional characteristics of astrocytes. When added to the culturing medium, ws-SWCNTs were able to make astrocytes larger and stellate/mature, changes associated with the increase in glial fibrillary acidic protein immunoreactivity. Thus, ws-SWCNTs could have more beneficial effects at the injury site than previously thought; by affecting astrocytes, they could provide for a more comprehensive re-establishment of the brain computational power. Keywords: Carbon nanotubes, graft copolymers, astrocytes, glial fibrillary acidic protein.

Gottipati, Manoj K.

320

Improving the Treatment of Schizophrenia: Role of 5-HT Receptors in Modulating Cognitive and Extrapyramidal Motor Functions.  

PubMed

Patients with schizophrenia exhibit various clinical symptoms including positive and negative symptoms, neurocognitive impairments and mood disturbances. Although a series of second generation antipsychotics (SGAs) (e.g., risperidone, olanzapine and quetiapine) have been developed in the past two decades, clinical reports do not necessarily show advantages over first generation antipsychotics (FGAs) in the treatment of schizophrenia, especially in their efficacy against cognitive impairment and ability to cause extrapyramidal side effects (EPS). Recently, several lines of studies have revealed therapeutic roles of 5-HT receptors in modulating cognitive impairments and extrapyramidal motor disorders. Specifically, inhibition of 5-HT1A, 5-HT3 and 5-HT6 receptors or activation of 5-HT4 receptors alleviates cognitive impairments (e.g., deficits in learning and memory). In addition, stimulation of 5-HT1A receptors or inhibition of 5-HT3 and 5-HT6 receptors as well as 5-HT2A/2C receptors can ameliorate extrapyramidal motor disorders. Thus, controlling the activity of 5-HT1A, 5-HT3 or 5-HT6 receptors seems to provide benefits by both alleviating cognitive impairments and reducing antipsychotic-induced EPS. This article reviews the functional roles and mechanisms of 5-HT receptors in the treatment of schizophrenia, focusing on the serotonergic modulation of cognitive and extrapyramidal motor functions, and illustrates future therapeutic strategies. PMID:23844689

Shimizu, Saki; Mizuguchi, Yuto; Ohno, Yukihiro

2013-09-01

321

Multi-voxel Patterns Reveal Functionally Differentiated Networks Underlying Auditory Feedback Processing of Speech  

PubMed Central

The everyday act of speaking involves the complex processes of speech motor control. An important component of control is monitoring, detection and processing of errors when auditory feedback does not correspond to the intended motor gesture. Here we show, using fMRI and converging operations within a multi-voxel pattern analysis framework, that this sensorimotor process is supported by functionally differentiated brain networks. During scanning, a real-time speech-tracking system was employed to deliver two acoustically different types of distorted auditory feedback or unaltered feedback while human participants were vocalizing monosyllabic words, and to present the same auditory stimuli while participants were passively listening. Whole-brain analysis of neural-pattern similarity revealed three functional networks that were differentially sensitive to distorted auditory feedback during vocalization, compared to during passive listening. One network of regions appears to encode an ‘error signal’ irrespective of acoustic features of the error: this network, including right angular gyrus, right supplementary motor area, and bilateral cerebellum, yielded consistent neural patterns across acoustically different, distorted feedback types, only during articulation (not during passive listening). In contrast, a fronto-temporal network appears sensitive to the speech features of auditory stimuli during passive listening; this preference for speech features was diminished when the same stimuli were presented as auditory concomitants of vocalization. A third network, showing a distinct functional pattern from the other two, appears to capture aspects of both neural response profiles. Taken together, our findings suggest that auditory feedback processing during speech motor control may rely on multiple, interactive, functionally differentiated neural systems.

Zheng, Zane Z.; Vicente-Grabovetsky, Alejandro; MacDonald, Ewen N.; Munhall, Kevin G.; Cusack, Rhodri; Johnsrude, Ingrid S.

2013-01-01

322

Metagenomes from High-Temperature Chemotrophic Systems Reveal Geochemical Controls on Microbial Community Structure and Function  

PubMed Central

The Yellowstone caldera contains the most numerous and diverse geothermal systems on Earth, yielding an extensive array of unique high-temperature environments that host a variety of deeply-rooted and understudied Archaea, Bacteria and Eukarya. The combination of extreme temperature and chemical conditions encountered in geothermal environments often results in considerably less microbial diversity than other terrestrial habitats and offers a tremendous opportunity for studying the structure and function of indigenous microbial communities and for establishing linkages between putative metabolisms and element cycling. Metagenome sequence (14–15,000 Sanger reads per site) was obtained for five high-temperature (>65°C) chemotrophic microbial communities sampled from geothermal springs (or pools) in Yellowstone National Park (YNP) that exhibit a wide range in geochemistry including pH, dissolved sulfide, dissolved oxygen and ferrous iron. Metagenome data revealed significant differences in the predominant phyla associated with each of these geochemical environments. Novel members of the Sulfolobales are dominant in low pH environments, while other Crenarchaeota including distantly-related Thermoproteales and Desulfurococcales populations dominate in suboxic sulfidic sediments. Several novel archaeal groups are well represented in an acidic (pH 3) Fe-oxyhydroxide mat, where a higher O2 influx is accompanied with an increase in archaeal diversity. The presence or absence of genes and pathways important in S oxidation-reduction, H2-oxidation, and aerobic respiration (terminal oxidation) provide insight regarding the metabolic strategies of indigenous organisms present in geothermal systems. Multiple-pathway and protein-specific functional analysis of metagenome sequence data corroborated results from phylogenetic analyses and clearly demonstrate major differences in metabolic potential across sites. The distribution of functional genes involved in electron transport is consistent with the hypothesis that geochemical parameters (e.g., pH, sulfide, Fe, O2) control microbial community structure and function in YNP geothermal springs.

Inskeep, William P.; Rusch, Douglas B.; Jay, Zackary J.; Herrgard, Markus J.; Kozubal, Mark A.; Richardson, Toby H.; Macur, Richard E.; Hamamura, Natsuko; Jennings, Ryan deM.; Fouke, Bruce W.; Reysenbach, Anna-Louise; Roberto, Frank; Young, Mark; Schwartz, Ariel; Boyd, Eric S.; Badger, Jonathan H.; Mathur, Eric J.; Ortmann, Alice C.; Bateson, Mary; Geesey, Gill; Frazier, Marvin

2010-01-01

323

Functional dissection of lysine deacetylases reveals that HDAC1 and p300 regulate AMPK.  

PubMed

First identified as histone-modifying proteins, lysine acetyltransferases (KATs) and deacetylases (KDACs) antagonize each other through modification of the side chains of lysine residues in histone proteins. Acetylation of many non-histone proteins involved in chromatin, metabolism or cytoskeleton regulation were further identified in eukaryotic organisms, but the corresponding enzymes and substrate-specific functions of the modifications are unclear. Moreover, mechanisms underlying functional specificity of individual KDACs remain enigmatic, and the substrate spectra of each KDAC lack comprehensive definition. Here we dissect the functional specificity of 12 critical human KDACs using a genome-wide synthetic lethality screen in cultured human cells. The genetic interaction profiles revealed enzyme-substrate relationships between individual KDACs and many important substrates governing a wide array of biological processes including metabolism, development and cell cycle progression. We further confirmed that acetylation and deacetylation of the catalytic subunit of the adenosine monophosphate-activated protein kinase (AMPK), a critical cellular energy-sensing protein kinase complex, is controlled by the opposing catalytic activities of HDAC1 and p300. Deacetylation of AMPK enhances physical interaction with the upstream kinase LKB1, leading to AMPK phosphorylation and activation, and resulting in lipid breakdown in human liver cells. These findings provide new insights into previously underappreciated metabolic regulatory roles of HDAC1 in coordinating nutrient availability and cellular responses upstream of AMPK, and demonstrate the importance of high-throughput genetic interaction profiling to elucidate functional specificity and critical substrates of individual human KDACs potentially valuable for therapeutic applications. PMID:22318606

Lin, Yu-yi; Kiihl, Samara; Suhail, Yasir; Liu, Shang-Yun; Chou, Yi-hsuan; Kuang, Zheng; Lu, Jin-ying; Khor, Chin Ni; Lin, Chi-Long; Bader, Joel S; Irizarry, Rafael; Boeke, Jef D

2012-02-08

324

Comparative Analysis and Functional Mapping of SACS Mutations Reveal Novel Insights into Sacsin Repeated Architecture  

PubMed Central

Autosomal recessive spastic ataxia of Charlevoix–Saguenay (ARSACS) is a neurological disease with mutations in SACS, encoding sacsin, a multidomain protein of 4,579 amino acids. The large size of SACS and its translated protein has hindered biochemical analysis of ARSACS, and how mutant sacsins lead to disease remains largely unknown. Three repeated sequences, called sacsin repeating region (SRR) supradomains, have been recognized, which contribute to sacsin chaperone-like activity. We found that the three SRRs are much larger (?1,100 residues) than previously described, and organized in discrete subrepeats. We named the large repeated regions Sacsin Internal RePeaTs (SIRPT1, SIRPT2, and SIRPT3) and the subrepeats sr1, sr2, sr3, and srX. Comparative analysis of vertebrate sacsins in combination with fine positional mapping of a set of human mutations revealed that sr1, sr2, sr3, and srX are functional. Notably, the position of the pathogenic mutations in sr1, sr2, sr3, and srX appeared to be related to the severity of the clinical phenotype, as assessed by defining a severity scoring system. Our results suggest that the relative position of mutations in subrepeats will variably influence sacsin dysfunction. The characterization of the specific role of each repeated region will help in developing a comprehensive and integrated pathophysiological model of function for sacsin.

Romano, Alessandro; Tessa, Alessandra; Barca, Amilcare; Fattori, Fabiana; Fulvia de Leva, Maria; Terracciano, Alessandra; Storelli, Carlo; Santorelli, Filippo Maria; Verri, Tiziano

2013-01-01

325

Structure and function of Parkin E3 ubiquitin ligase reveals aspects of RING and HECT ligases.  

PubMed

Parkin is a RING-between-RING E3 ligase that functions in the covalent attachment of ubiquitin to specific substrates, and mutations in Parkin are linked to Parkinson's disease, cancer and mycobacterial infection. The RING-between-RING family of E3 ligases are suggested to function with a canonical RING domain and a catalytic cysteine residue usually restricted to HECT E3 ligases, thus termed 'RING/HECT hybrid' enzymes. Here we present the 1.58 Å structure of Parkin-R0RBR, revealing the fold architecture for the four RING domains, and several unpredicted interfaces. Examination of the Parkin active site suggests a catalytic network consisting of C431 and H433. In cells, mutation of C431 eliminates Parkin-catalysed degradation of mitochondria, and capture of an ubiquitin oxyester confirms C431 as Parkin's cellular active site. Our data confirm that Parkin is a RING/HECT hybrid, and provide the first crystal structure of an RING-between-RING E3 ligase at atomic resolution, providing insight into this disease-related protein. PMID:23770887

Riley, B E; Lougheed, J C; Callaway, K; Velasquez, M; Brecht, E; Nguyen, L; Shaler, T; Walker, D; Yang, Y; Regnstrom, K; Diep, L; Zhang, Z; Chiou, S; Bova, M; Artis, D R; Yao, N; Baker, J; Yednock, T; Johnston, J A

2013-01-01

326

Comparative materials differences revealed in engineered bone as a function of cell-specific differentiation  

NASA Astrophysics Data System (ADS)

An important aim of regenerative medicine is to restore tissue function with implantable, laboratory-grown constructs that contain tissue-specific cells that replicate the function of their counterparts in the healthy native tissue. It remains unclear, however, whether cells used in bone regeneration applications produce a material that mimics the structural and compositional complexity of native bone. By applying multivariate analysis techniques to micro-Raman spectra of mineralized nodules formed in vitro, we reveal cell-source-dependent differences in interactions between multiple bone-like mineral environments. Although osteoblasts and adult stem cells exhibited bone-specific biological activities and created a material with many of the hallmarks of native bone, the `bone nodules' formed from embryonic stem cells were an order of magnitude less stiff, and lacked the distinctive nanolevel architecture and complex biomolecular and mineral composition noted in the native tissue. Understanding the biological mechanisms of bone formation in vitro that contribute to cell-source-specific materials differences may facilitate the development of clinically successful engineered bone.

Gentleman, Eileen; Swain, Robin J.; Evans, Nicholas D.; Boonrungsiman, Suwimon; Jell, Gavin; Ball, Michael D.; Shean, Tamaryn A. V.; Oyen, Michelle L.; Porter, Alexandra; Stevens, Molly M.

2009-09-01

327

What do plasma beta-endorphin levels reveal about endogenous opioid analgesic function?  

PubMed

Plasma levels of beta-endorphin (BE), an endogenous opioid analgesic, are often reported as they relate to acute and chronic pain outcomes. However, little is known about what resting plasma BE levels might reveal about functioning of the endogenous opioid antinociceptive system. This study directly examined associations between resting plasma BE and subsequent endogenous opioid analgesic responses to acute pain in 39 healthy controls and 37 individuals with chronic low back pain (LBP). Resting baseline levels of plasma BE were assessed. Next, participants received opioid blockade (8 mg naloxone i.v.) or placebo in a double-blind, randomized, crossover design. Participants then underwent two acute pain stimuli: finger pressure (FP) pain and ischaemic (ISC) forearm pain. Blockade effects (naloxone minus placebo pain ratings) were derived to index endogenous opioid analgesic function. In placebo condition analyses for both pain stimuli, higher resting BE levels were associated with subsequently greater reported pain intensity (p's < 0.05), with this effect occurring primarily in healthy controls (BE × Participant Type interactions, p's < 0.05). In blockade effect analyses across both pain tasks, higher resting plasma BE predicted less subsequent endogenous opioid analgesia (smaller blockade effects; p's < 0.05). For the ISC task, these links were significantly more prominent in LBP participants (BE × Participant Type Interactions, p's < 0.05). Results suggest that elevated resting plasma BE may be a potential biomarker for reduced endogenous opioid analgesic capacity, particularly among individuals with chronic pain. Potential clinical implications are discussed. PMID:22337161

Bruehl, S; Burns, J W; Chung, O Y; Chont, M

2011-12-19

328

Splicing functions and global dependency on fission yeast slu7 reveal diversity in spliceosome assembly.  

PubMed

The multiple short introns in Schizosaccharomyces pombe genes with degenerate cis sequences and atypically positioned polypyrimidine tracts make an interesting model to investigate canonical and alternative roles for conserved splicing factors. Here we report functions and interactions of the S. pombe slu7(+) (spslu7(+)) gene product, known from Saccharomyces cerevisiae and human in vitro reactions to assemble into spliceosomes after the first catalytic reaction and to dictate 3' splice site choice during the second reaction. By using a missense mutant of this essential S. pombe factor, we detected a range of global splicing derangements that were validated in assays for the splicing status of diverse candidate introns. We ascribe widespread, intron-specific SpSlu7 functions and have deduced several features, including the branch nucleotide-to-3' splice site distance, intron length, and the impact of its A/U content at the 5' end on the intron's dependence on SpSlu7. The data imply dynamic substrate-splicing factor relationships in multiintron transcripts. Interestingly, the unexpected early splicing arrest in spslu7-2 revealed a role before catalysis. We detected a salt-stable association with U5 snRNP and observed genetic interactions with spprp1(+), a homolog of human U5-102k factor. These observations together point to an altered recruitment and dependence on SpSlu7, suggesting its role in facilitating transitions that promote catalysis, and highlight the diversity in spliceosome assembly. PMID:23754748

Banerjee, Shataparna; Khandelia, Piyush; Melangath, Geetha; Bashir, Samirul; Nagampalli, Vijaykrishna; Vijayraghavan, Usha

2013-06-10

329

Photostimulation using caged glutamate reveals functional circuitry in living brain slices.  

PubMed Central

An approach for high-spatial-resolution mapping of functional circuitry in living mammalian brain slices has been developed. The locations of neurons making functional synaptic connections to a single neuron are revealed by photostimulation of highly restricted areas of the slice (50-100 microns in diameter) while maintaining a whole-cell recording of the neuron of interest. Photostimulation is achieved by bathing brain slices in a molecularly caged form of the neurotransmitter glutamate [L-glutamic acid alpha-(4,5-dimethoxy-2-nitrobenzyl) ester], which is then converted to the active form by brief pulses (< 1 ms in duration) of ultraviolet irradiation. Direct activation of receptors on recorded neurons in rat hippocampus and ferret visual cortex demonstrates that photostimulation is reliable and reproducible and can be repeated at the same site at least 30 times without obvious decrement in neuronal responsiveness. Photostimulation of presynaptic neurons at sites distant to the recorded neuron evoked synaptic responses in hippocampal and cortical cells at distances of up to several millimeters from the recorded neuron. Stimulation of 25-100 distinct presynaptic sites while recording from a single postsynaptic neuron was easily achieved. Caged glutamate-based photostimulation eliminates artifacts and limitations inherent in conventional stimulation methods, including stimulation of axons of passage, desensitization, and poor temporal resolution of "puffer" pipettes, and current artifacts of iontophoretic application. This approach allows detailed physiological investigation and manipulation of the complex intrinsic circuitry of the mammalian brain. Images Fig. 2 Fig. 4

Callaway, E M; Katz, L C

1993-01-01

330

A Drosophila model of the neurodegenerative disease SCA17 reveals a role of RBP-J/Su(H) in modulating the pathological outcome  

PubMed Central

Expanded polyglutamine (polyQ) tract in the human TATA-box-binding protein (hTBP) causes the neurodegenerative disease spinocerebellar ataxia 17 (SCA17). To investigate the pathological effects of polyQ expansion, we established a SCA17 model in Drosophila. Similar to SCA17 patients, transgenic flies expressing a mutant hTBP protein with an expanded polyQ tract (hTBP80Q) exhibit progressive neurodegeneration, late-onset locomotor impairment and shortened lifespan. Microarray analysis reveals that hTBP80Q causes widespread and time-dependent transcriptional dysregulation in Drosophila. In a candidate screen for genetic modifiers, we identified RBP-J/Su(H), a transcription factor that contains Q/N-rich domains and participates in Notch signaling. Knockdown of Su(H) by RNAi further enhances hTBP80Q-induced eye defects, whereas overexpression of Su(H) suppresses such defects. While the Su(H) transcript level is not significantly altered in hTBP80Q-expressing flies, genes that contain Su(H)-binding sites are among those that are dysregulated. We further show that hTBP80Q interacts more efficiently with Su(H) than wild-type hTBP, suggesting that a reduction in the fraction of Su(H) available for its normal cellular functions contributes to hTBP80Q-induced phenotypes. While the Notch signaling pathway has been implicated in several neurological disorders, our study suggests a possibility that the activity of its nuclear component RBP-J/Su(H) may modulate the pathological progression in SCA17 patients.

Ren, Jie; Jegga, Anil G.; Zhang, Minlu; Deng, Jingyuan; Liu, Junbo; Gordon, Christopher B.; Aronow, Bruce J.; Lu, Long J.; Zhang, Bo; Ma, Jun

2011-01-01

331

A Drosophila model of the neurodegenerative disease SCA17 reveals a role of RBP-J/Su(H) in modulating the pathological outcome.  

PubMed

Expanded polyglutamine (polyQ) tract in the human TATA-box-binding protein (hTBP) causes the neurodegenerative disease spinocerebellar ataxia 17 (SCA17). To investigate the pathological effects of polyQ expansion, we established a SCA17 model in Drosophila. Similar to SCA17 patients, transgenic flies expressing a mutant hTBP protein with an expanded polyQ tract (hTBP80Q) exhibit progressive neurodegeneration, late-onset locomotor impairment and shortened lifespan. Microarray analysis reveals that hTBP80Q causes widespread and time-dependent transcriptional dysregulation in Drosophila. In a candidate screen for genetic modifiers, we identified RBP-J/Su(H), a transcription factor that contains Q/N-rich domains and participates in Notch signaling. Knockdown of Su(H) by RNAi further enhances hTBP80Q-induced eye defects, whereas overexpression of Su(H) suppresses such defects. While the Su(H) transcript level is not significantly altered in hTBP80Q-expressing flies, genes that contain Su(H)-binding sites are among those that are dysregulated. We further show that hTBP80Q interacts more efficiently with Su(H) than wild-type hTBP, suggesting that a reduction in the fraction of Su(H) available for its normal cellular functions contributes to hTBP80Q-induced phenotypes. While the Notch signaling pathway has been implicated in several neurological disorders, our study suggests a possibility that the activity of its nuclear component RBP-J/Su(H) may modulate the pathological progression in SCA17 patients. PMID:21653638

Ren, Jie; Jegga, Anil G; Zhang, Minlu; Deng, Jingyuan; Liu, Junbo; Gordon, Christopher B; Aronow, Bruce J; Lu, Long J; Zhang, Bo; Ma, Jun

2011-06-08

332

Functional magnetic resonance adaptation reveals the involvement of the dorsomedial stream in hand orientation for grasping.  

PubMed

Reach-to-grasp actions require coordination of different segments of the upper limbs. Previous studies have examined the neural substrates of arm transport and hand grip components of such actions; however, a third component has been largely neglected: the orientation of the wrist and hand appropriately for the object. Here we used functional magnetic resonance imaging adaptation (fMRA) to investigate human brain areas involved in processing hand orientation during grasping movements. Participants used the dominant right hand to grasp a rod with the four fingers opposing the thumb or to reach and touch the rod with the knuckles without visual feedback. In a control condition, participants passively viewed the rod. Trials in a slow event-related design consisted of two sequential stimuli in which the rod orientation changed (requiring a change in wrist posture while grasping but not reaching or looking) or remained the same. We found reduced activation, that is, adaptation, in superior parieto-occipital cortex (SPOC) when the object was repeatedly grasped with the same orientation. In contrast, there was no adaptation when reaching or looking at an object in the same orientation, suggesting that hand orientation, rather than object orientation, was the critical factor. These results agree with recent neurophysiological research showing that a parieto-occipital area of macaque (V6A) is modulated by hand orientation during reach-to-grasp movements. We suggest that the human dorsomedial stream, like that in the macaque, plays a key role in processing hand orientation in reach-to-grasp movements. PMID:21795615

Monaco, Simona; Cavina-Pratesi, Cristiana; Sedda, Anna; Fattori, Patrizia; Galletti, Claudio; Culham, Jody C

2011-07-27

333

Cortical hubs revealed by intrinsic functional connectivity: mapping, assessment of stability, and relation to Alzheimer's disease.  

PubMed

Recent evidence suggests that some brain areas act as hubs interconnecting distinct, functionally specialized systems. These nexuses are intriguing because of their potential role in integration and also because they may augment metabolic cascades relevant to brain disease. To identify regions of high connectivity in the human cerebral cortex, we applied a computationally efficient approach to map the degree of intrinsic functional connectivity across the brain. Analysis of two separate functional magnetic resonance imaging datasets (each n = 24) demonstrated hubs throughout heteromodal areas of association cortex. Prominent hubs were located within posterior cingulate, lateral temporal, lateral parietal, and medial/lateral prefrontal cortices. Network analysis revealed that many, but not all, hubs were located within regions previously implicated as components of the default network. A third dataset (n = 12) demonstrated that the locations of hubs were present across passive and active task states, suggesting that they reflect a stable property of cortical network architecture. To obtain an accurate reference map, data were combined across 127 participants to yield a consensus estimate of cortical hubs. Using this consensus estimate, we explored whether the topography of hubs could explain the pattern of vulnerability in Alzheimer's disease (AD) because some models suggest that regions of high activity and metabolism accelerate pathology. Positron emission tomography amyloid imaging in AD (n = 10) compared with older controls (n = 29) showed high amyloid-beta deposition in the locations of cortical hubs consistent with the possibility that hubs, while acting as critical way stations for information processing, may also augment the underlying pathological cascade in AD. PMID:19211893

Buckner, Randy L; Sepulcre, Jorge; Talukdar, Tanveer; Krienen, Fenna M; Liu, Hesheng; Hedden, Trey; Andrews-Hanna, Jessica R; Sperling, Reisa A; Johnson, Keith A

2009-02-11

334

Revealing the Functional Neuroanatomy of Intrinsic Alertness Using fMRI: Methodological Peculiarities  

PubMed Central

Clinical observations and neuroimaging data revealed a right-hemisphere fronto-parietal-thalamic-brainstem network for intrinsic alertness, and additional left fronto-parietal activity during phasic alertness. The primary objective of this fMRI study was to map the functional neuroanatomy of intrinsic alertness as precisely as possible in healthy participants, using a novel assessment paradigm already employed in clinical settings. Both the paradigm and the experimental design were optimized to specifically assess intrinsic alertness, while at the same time controlling for sensory-motor processing. The present results suggest that the processing of intrinsic alertness is accompanied by increased activity within the brainstem, thalamus, anterior cingulate gyrus, right insula, and right parietal cortex. Additionally, we found increased activation in the left hemisphere around the middle frontal gyrus (BA 9), the insula, the supplementary motor area, and the cerebellum. Our results further suggest that rather minute aspects of the experimental design may induce aspects of phasic alertness, which in turn might lead to additional brain activation in left-frontal areas not normally involved in intrinsic alertness. Accordingly, left BA 9 activation may be related to co-activation of the phasic alertness network due to the switch between rest and task conditions functioning as an external warning cue triggering the phasic alertness network. Furthermore, activation of the intrinsic alertness network during fixation blocks due to enhanced expectancy shortly before the switch to the task block might, when subtracted from the task block, lead to diminished activation in the typical right hemisphere intrinsic alertness network. Thus, we cautiously suggest that – as a methodological artifact – left frontal activations might show up due to phasic alertness involvement and intrinsic alertness activations might be weakened due to contrasting with fixation blocks, when assessing the functional neuroanatomy of intrinsic alertness with a block design in fMRI studies.

Clemens, Benjamin; Zvyagintsev, Mikhail; Sack, Alexander; Heinecke, Armin; Willmes, Klaus; Sturm, Walter

2011-01-01

335

Elucidation of the mechanism of the regulatory function of the Ig1 module of the fibroblast growth factor receptor 1  

PubMed Central

The extracellular part of the fibroblast growth factor (FGF) receptor (FGFR) consists of up to three Ig modules (Ig1–Ig3), in which the Ig2 and Ig3 modules determine affinity and specificity for FGF and heparin. The FGFR isoforms lacking the Ig1 module have higher affinity for FGF and heparin than the triple Ig-module isoforms, suggesting that the Ig1 module is involved in the regulation of the FGFR–ligand interaction. We show here by surface plasmon resonance and NMR analyses that the Ig1 module binds to the Ig2 module, and identify by NMR the binding sites involved in the Ig1–Ig2 interaction. The identified binding site in the Ig2 module was found to be in the area of the FGF–Ig2 and Ig2–heparin contact sites, thus providing direct structural evidence that the Ig1 module functions as a competitive autoinhibitor of the FGFR–ligand interaction. Furthermore, the Ig1 binding site of the Ig2 module overlaps the Ig2–Ig2 contact site. This suggests that the function of the Ig1 module is not only regulation of the FGFR–ligand binding affinity but also prevention of spontaneous FGFR dimerization (through a direct Ig2–Ig2 interaction) in the absence of FGF.

Kiselyov, Vladislav V.; Kochoyan, Arthur; Poulsen, Flemming M.; Bock, Elisabeth; Berezin, Vladimir

2006-01-01

336

The Small Molecule Wnt Signaling Modulator ICG-001 Improves Contractile Function in Chronically Infarcted Rat Myocardium.  

PubMed

The adult mammalian heart has limited capability for self-repair after myocardial infarction. Therefore, therapeutic strategies that improve post-infarct cardiac function are critically needed. The small molecule ICG-001 modulates Wnt signaling and increased the expression of genes beneficial for cardiac regeneration in epicardial cells. Lineage tracing experiments, demonstrated the importance of ?-catenin/p300 mediated transcription for epicardial progenitor contribution to the myocardium. Female rats given ICG-001 for 10 days post-occlusion significantly improved ejection fraction by 8.4%, compared to controls (P<0.05). Taken together, Wnt modulation via ?-catenin/CBP inhibition offers a promising therapeutic strategy towards restoration of myocardial tissues and an enhancement of cardiac functions following infarction. PMID:24069374

Sasaki, Tomoyo; Hwang, Hyosook; Nguyen, Cu; Kloner, Robert A; Kahn, Michael

2013-09-12

337

The Small Molecule Wnt Signaling Modulator ICG-001 Improves Contractile Function in Chronically Infarcted Rat Myocardium  

PubMed Central

The adult mammalian heart has limited capability for self-repair after myocardial infarction. Therefore, therapeutic strategies that improve post-infarct cardiac function are critically needed. The small molecule ICG-001 modulates Wnt signaling and increased the expression of genes beneficial for cardiac regeneration in epicardial cells. Lineage tracing experiments, demonstrated the importance of ?-catenin/p300 mediated transcription for epicardial progenitor contribution to the myocardium. Female rats given ICG-001 for 10 days post-occlusion significantly improved ejection fraction by 8.4%, compared to controls (P<0.05). Taken together, Wnt modulation via ?-catenin/CBP inhibition offers a promising therapeutic strategy towards restoration of myocardial tissues and an enhancement of cardiac functions following infarction.

Nguyen, Cu; Kloner, Robert A.; Kahn, Michael

2013-01-01

338

Dual-functional polymeric waveguide with optical amplification and electro-optic modulation  

NASA Astrophysics Data System (ADS)

Optical amplification and electro-optic modulation have been observed simultaneously in one polymeric material photo-lime gel which has been used as a volume holographic material to produce dichromated gelatin (DCG) films. In this paper, the dual functions were achieved by doping neodymium chloride hexahydrate (NdCl3(DOT)6H2O) and chlorophenol red (C19H12Cl2O5S). The optimized doping concentrations of Nd+3 and chlorophenol red were 6.7 X 1019/cm3 and 23% respectively. We observed a gain of 3.8 dB at 1.04 micrometers and an electro-optic coefficient of 30 pm/V at 633 nm. The experimental results confirms that the co-doping process does not degrade the respective functions of Nd+3 for optical amplification and chlorophenol red for electro-optic modulation.

An, Dechang; Yue, Zuzhou; Chen, Ray T.

1997-12-01

339

Instrumentation system for determination and compensation of electro-optic modulator transfer function drift  

NASA Astrophysics Data System (ADS)

This paper presents an instrumentation system developed to improve the operation of an electro-optic modulator (EOM). During their operating time, EOM are subject to a drift of the optical transfer function; therefore the initial tuning of the bias point no longer corresponds to the best characteristics of the device. Because of this drift the EOM no longer behaves linearly and there is degradation during time of the performances of the system in which the EOM is included. To determine the drift, a low frequency modulation signal (at 500 Hz) is applied to the EOM and the second harmonic component at 1 kHz is detected. A new criterion is introduced for estimating the nonlinearity and for compensating the drift of the transfer function, keeping the optical bias point at the quadrature position. Temperature changes significantly influence the EOM characteristics. Thus, the instrumentation system has to be simultaneously developed with temperature control and drift compensation of the optical transfer function. The design is based on PSOC microcontrollers for tuning the different parameters, for data acquisition and regulation process. By setting the temperature to some specific values, it is possible to test the behaviour of the modulator. Finally, by using both temperature and bias point control, a significant reduction of the nonlinearity can be obtained during 2 h of experiment: the biasing point at the quadrature point of the transfer function which corresponds to the most linear behaviour can be stabilized within ±0.22% of the half-wave voltage. All the works presented here were carried out with a Mach-Zehnder intensity modulator made of lithium niobate, but it is also possible to apply this method to other kinds of material, for example polymer material.

Thanh Bui, Dang; Thanh Nguyen, Chi; Ledoux-Rak, Isabelle; Zyss, Joseph; Journet, Bernard

2011-12-01

340

The cyclooxygenase-2 product prostaglandin E 2 modulates cardiac contractile function in adult rat ventricular cardiomyocytes  

Microsoft Academic Search

Prostaglandin E2 (PGE2), a product of the cyclooxygenase-2 pathway, has been shown to increase cardiac output and modulate cardiac contractile function. However, whether the cardiac contractile response of PGE2 is due to its action on single ventricular myocytes has not been elucidated. To assess the mechanical effect of PGE2 at the cellular level, adult rat ventricular myocytes were isolated and

Aaron L. Klein; Loren E. Wold; Jun Ren

2004-01-01

341

Cardiac responses of Pacific oyster Crassostrea gigas to agents modulating cholinergic function  

Microsoft Academic Search

To examine the functional effects of cholinergic modulation compounds in oyster hearts and to explore their possible use in monitoring intoxication with acetylcholine-esterase (AChE) inhibitors such as organophosphates, tests were performed with in situ oyster heart preparations. The endogenous cholinergic agonist acetylcholine (ACh), AChE-resistant synthetic agonist carbachol, and the reversible carbamate type of AChE inhibitor physostigmine, all potently depressed spontaneous

Kwan Ha Park; Young-Suk Kim; Ee-Yung Chung; Sun-Nam Choe; Jong-Jae Choo

2004-01-01

342

On-orbit modulation transfer function characterization of terra MODIS using the moon  

Microsoft Academic Search

The on-orbit Modulation Transfer Function (MTF) of MODIS instrument can be accurately measured by its on-board SpectroRadiometirc Calibration Assembly (SRCA). For other Earth observing instruments without calibrators similar to SRCA, the sharp edge of moon provides a reasonable high-contrast target for their on-orbit MTF characterization. In this paper, we propose a procedure to measure MODIS on-orbit MTF from the moon

Zhipeng Wang; Taeyoung Choi; Xiaoxiong Xiong

2011-01-01

343

Polypeptides and methods for modulating D1-D2 dopamine receptor interaction and function  

US Patent & Trademark Office Database

The present invention provides for prevention and/or treatment of neurological or neuropsychiatric disorders involving abnormal D1-D2 dopamine receptor coupling and/or activation. Methods and agents are provided for modulating dopamine receptor function arising from D1-D2 coupling and/or activation. Agents of the present invention include fragments of D2 receptor or D1 receptor that can disrupt D1-D2 coupling.

2013-04-16

344

Modulation of lymphocyte function in low frequency electric and magnetic environments  

Microsoft Academic Search

Quiescent human lymphocytes require an activation step followed by a proliferative step requiring growth factors that lead to differentiation into effector function. The authors examined the effect of low frequency magnetic field (MF) on the modulation of human T and B-lymphocytes and the generation of LAK-cell activities in the presence of rIL-2. A 15 Hz, 1 G vertically oriented field

M. Lefebvre; M. Wiesendanger; D. Blackinton; S. Mehta; D. Cherlin; C. Polk

1992-01-01

345

Reconstruction of an integrated genome-scale co-expression network reveals key modules involved in lung adenocarcinoma.  

PubMed

Our goal of this study was to reconstruct a "genome-scale co-expression network" and find important modules in lung adenocarcinoma so that we could identify the genes involved in lung adenocarcinoma. We integrated gene mutation, GWAS, CGH, array-CGH and SNP array data in order to identify important genes and loci in genome-scale. Afterwards, on the basis of the identified genes a co-expression network was reconstructed from the co-expression data. The reconstructed network was named "genome-scale co-expression network". As the next step, 23 key modules were disclosed through clustering. In this study a number of genes have been identified for the first time to be implicated in lung adenocarcinoma by analyzing the modules. The genes EGFR, PIK3CA, TAF15, XIAP, VAPB, Appl1, Rab5a, ARF4, CLPTM1L, SP4, ZNF124, LPP, FOXP1, SOX18, MSX2, NFE2L2, SMARCC1, TRA2B, CBX3, PRPF6, ATP6V1C1, MYBBP1A, MACF1, GRM2, TBXA2R, PRKAR2A, PTK2, PGF and MYO10 are among the genes that belong to modules 1 and 22. All these genes, being implicated in at least one of the phenomena, namely cell survival, proliferation and metastasis, have an over-expression pattern similar to that of EGFR. In few modules, the genes such as CCNA2 (Cyclin A2), CCNB2 (Cyclin B2), CDK1, CDK5, CDC27, CDCA5, CDCA8, ASPM, BUB1, KIF15, KIF2C, NEK2, NUSAP1, PRC1, SMC4, SYCE2, TFDP1, CDC42 and ARHGEF9 are present that play a crucial role in cell cycle progression. In addition to the mentioned genes, there are some other genes (i.e. DLGAP5, BIRC5, PSMD2, Src, TTK, SENP2, PSMD2, DOK2, FUS and etc.) in the modules. PMID:23874428

Bidkhori, Gholamreza; Narimani, Zahra; Hosseini Ashtiani, Saman; Moeini, Ali; Nowzari-Dalini, Abbas; Masoudi-Nejad, Ali

2013-07-11

346

REVEALING PROBABLE UNIVERSAL FEATURES IN THE LOWER RED GIANT BRANCH LUMINOSITY FUNCTIONS OF GALACTIC GLOBULAR CLUSTERS  

SciTech Connect

This paper aims at demonstrating, for the first time, very probable universal peculiarities of the evolution of stars in the lower red giant branch (RGB) of Galactic globular clusters (GCs), reflected in two corresponding dips in the luminosity functions (LFs). By relying on the database of Hubble Space Telescope photometry of GCs, we analyze the lower RGB LFs of a sample of 18 GCs in a wide metallicity range, {delta}[Fe/H] {approx} 1.9 dex. We first show that in the F555W-(F439W-F555W) color-magnitude diagrams (CMDs), the lower RGB of GCs, except for the most metal-poor of them, frequently shows an apparent 'knee'. It reveals itself as a fairly abrupt change of the RGB slope. At the same luminosity level, the RGB LFs show a feature in the form of a more or less pronounced dip. We find that the magnitude difference between the RGB base and the given feature is, on average, around {delta} F555W{sup dip} {sub base}{approx} 1.4 mag. It shows a marginal variation with metallicity, if any, comparable to the error. At the same time, the magnitude difference between the dip and the RGB bump, {delta} F555W{sup bump} {sub dip}, decreases with increasing metallicity and falls within the range 0.8 {approx}< {delta} F555W{sup bump} {sub dip} {approx}< 1.7 mag. Generalized LFs (GLFs) have been obtained for three subsamples of GCs within limited metallicity ranges and with different horizontal branch (HB) morphology. They reproduce the 'knee-related' dip that is statistically significant in two of the GLFs. This feature turns out to be more pronounced in the GLFs of GCs with either the blue or red HB morphology than with the intermediate one. The same GLFs also reveal an additional probable universal dip. It shows up below the RGB bump at {delta} F555W slightly increasing from {approx}0.3 to {approx}0.5 mag with increasing metallicity. Also, the statistical significance of this 'prebump' dip increases, on average, toward higher metallicity. Except for the well known RGB bump, no other universal features corresponding to those found here were so far empirically revealed or theoretically predicted in the lower RGB of GCs.

Kravtsov, V. V. [Instituto de AstronomIa, Universidad Catolica del Norte, Avenida Angamos 0610, Casilla 1280, Antofagasta (Chile)], E-mail: vkravtsov@ucn.cl

2009-06-15

347

Launch and Functional Considerations Guiding the Scaling and Design of Rigid Inflatable Habitat Modules  

NASA Astrophysics Data System (ADS)

The Sasakawa International Center for Space Architecture (SICSA) has a long history of projects that involve design of space structures, including habitats for low-Earth orbit (LEO) and planetary applications. Most of these facilities and component systems are planned to comply with size, geometry and mass restrictions imposed by the Space Shuttle Orbiter's payload and lift/landing abort restrictions. These constraints limit launch elements to approximately 15 ft. diameter, 40 ft. long cylindrical dimensions weighing no more than approximately 25 metric tons. It is clear that future success of commercial space programs such as tourism will hinge upon the availability of bigger and more efficient Earth to LEO launch vehicles which can greatly reduce transportation and operational costs. This will enable development and utilization of larger habitat modules and other infrastructure elements which can be deployed with fewer launches and on-orbit assembly procedures. The sizing of these new heavy lift launchers should be scaled to optimize habitat functionality and efficiency, just as the habitat designs must consider optimization of launch vehicle economy. SICSA's planning studies address these vehicle and habitat optimization priorities as parallel and interdependent considerations. The allowable diameter of habitat modules established by launch vehicle capacity dictates functionally acceptable internal configuration options. Analyses of these options relative to practical dimensions for Earth-to-orbit launch vehicle scaling were conducted for two general schemes. The "bologna slice" configuration stacks the floors within a predominately cylindrical or spherical envelope, producing circular areas. The "banana split" approach divides a cylindrical module longitudinally, creating floors that are generally rectangular in shape. The assessments established minimum sizes for reasonable utility and efficiency. The bologna slice option. This configuration is only acceptable for modules with diameters of approximately 45 ft. or more. Smaller dimensions will severely limit maximum sight lines, creating claustrophobic conditions. Equipment racks and other elements typically located around internal parameters will further reduce open areas, and vertical circulation access ways between floor levels will diminish usable space even more. However this scheme can work very well for larger diameter habitats, particularly for surface applications where a relatively wide-based/low height module is to be landed vertically. The banana split option. A longitudinal floor orientation can serve very satisfactorily for modules with diameters of 15 ft. or more. Unlike the bologna slice's circular floors, the rectangular spaces offer considerable versatility to accommodate diverse equipment and functional arrangements. Modules smaller than 15 ft. in diameter (the International Space Station standard) will be incompatible with efficient equipment rack design and layouts due to tight-radius wall curvatures. Beyond the 15 ft. diameters, it is logical to scale the modules at dimensional increments based upon the number of desired floors, allowing approximately 8-9 ft. of height/level. Current SICSA Mars mission planning advocates development of new launchers with payload accommodations for 45 ft. diameter, 200 metric ton cargo elements. This large booster will offer launch economies along with habitat scaling advantages. Launch system design efficiencies are influenced by the amount of functional drag that results as the vehicle passes through the Earth's atmosphere. These drag losses are subject to a "cubed-squared law". As the launchcraft's external dimensions increase, its surface area increases with the square of the dimension, while the volume increases with the cube. Since drag is a function of surface, not volume, increasing the vehicle size will reduce proportional drag losses. For this reason, the huge Saturn V Moon rocket experienced relatively low drag. Module pressure envelope geometries also influence internal l

Bell, L.

2002-01-01

348

Conditional Expression in Corticothalamic Efferents Reveals a Developmental Role for Nicotinic Acetylcholine Receptors in Modulation of Passive Avoidance Behavior  

Microsoft Academic Search

Prenatal nicotine exposure has been linked to attention deficit hyperactivity disorder and cognitive impairment, but the sites of action for these effects of nicotine are still under investigation. High-affinity nicotinic acetylcholine receptors (nAChRs) contain the2 subunit and modulate passive avoidance (PA) learning in mice. Using an inducible, tetracycline-regulated transgenic system, we generated lines of mice with expression of high-affinity nicotinic

Sarah L. King; Michael J. Marks; Sharon R. Grady; Barbara J. Caldarone; Andrei O. Koren; Alexey G. Mukhin; Allan C. Collins; Marina R. Picciotto

2003-01-01

349

Mutations of the GABA-A receptor ?1 subunit M1 domain reveal unexpected complexity for modulation by neuroactive steroids  

PubMed Central

Neuroactive steroids are among the most efficacious modulators of the mammalian GABA-A receptor. Previous work has proposed that receptor potentiation is mediated by steroid interactions with a site defined by the residues ?1N407/Y410 in the M4 transmembrane domain, and residue ?1Q241 in the M1 domain. We examined the role of residues in the ?1 subunit M1 domain in the modulation of the rat ?1?2?2L GABA-A receptor by neuroactive steroids. The data demonstrate that the region is critical to the actions of potentiating neuroactive steroids. Receptors containing the ?1Q241W or ?1Q241L mutations were insensitive to (3?,5?)-3-hydroxypregnan-20-one (3?5?P), albeit with different underlying mechanisms. The ?1Q241S mutant was potentiated by 3?5?P but the kinetic mode of potentiation was altered by the mutation. Interestingly, the ?1Q241L mutation was without effect on channel potentiation by (3?,5?)-3-hydroxymethylpregnan-20-one, but mutation of the neighboring residue, ?1S240, prevented channel modulation. A steroid lacking a H-bonding group on C3 (5?-pregnan-20-one) potentiated the wild-type receptor but not the ?1Q241L mutant. The findings are consistent with a model where the ?1S240 and ?1Q241 residues shape the surface to which steroid molecules bind.

Akk, Gustav; Li, Ping; Bracamontes, John; Reichert, David E.; Covey, Douglas F.; Steinbach, Joe Henry

2009-01-01

350

Transcriptomic analysis of toxoplasma development reveals many novel functions and structures specific to sporozoites and oocysts.  

PubMed

Sexual reproduction of Toxoplasma gondii occurs exclusively within enterocytes of the definitive felid host. The resulting immature oocysts are excreted into the environment during defecation, where in the days following, they undergo a complex developmental process. Within each oocyst, this culminates in the generation of two sporocysts, each containing 4 sporozoites. A single felid host is capable of shedding millions of oocysts, which can survive for years in the environment, are resistant to most methods of microbial inactivation during water-treatment and are capable of producing infection in warm-blooded hosts at doses as low as 1-10 ingested oocysts. Despite its extremely interesting developmental biology and crucial role in initiating an infection, almost nothing is known about the oocyst stage beyond morphological descriptions. Here, we present a complete transcriptomic analysis of the oocyst from beginning to end of its development. In addition, and to identify genes whose expression is unique to this developmental form, we compared the transcriptomes of developing oocysts with those of in vitro-derived tachyzoites and in vivo-derived bradyzoites. Our results reveal many genes whose expression is specifically up- or down-regulated in different developmental stages, including many genes that are likely critical to oocyst development, wall formation, resistance to environmental destruction and sporozoite infectivity. Of special note is the up-regulation of genes that appear "off" in tachyzoites and bradyzoites but that encode homologues of proteins known to serve key functions in those asexual stages, including a novel pairing of sporozoite-specific paralogues of AMA1 and RON2, two proteins that have recently been shown to form a crucial bridge during tachyzoite invasion of host cells. This work provides the first in-depth insight into the development and functioning of one of the most important but least studied stages in the Toxoplasma life cycle. PMID:22347997

Fritz, Heather M; Buchholz, Kerry R; Chen, Xiucui; Durbin-Johnson, Blythe; Rocke, David M; Conrad, Patricia A; Boothroyd, John C

2012-02-13

351

Proteomic analysis of chromoplasts from six crop species reveals insights into chromoplast function and development.  

PubMed

Chromoplasts are unique plastids that accumulate massive amounts of carotenoids. To gain a general and comparative characterization of chromoplast proteins, this study performed proteomic analysis of chromoplasts from six carotenoid-rich crops: watermelon, tomato, carrot, orange cauliflower, red papaya, and red bell pepper. Stromal and membrane proteins of chromoplasts were separated by 1D gel electrophoresis and analysed using nLC-MS/MS. A total of 953-2262 proteins from chromoplasts of different crop species were identified. Approximately 60% of the identified proteins were predicted to be plastid localized. Functional classification using MapMan bins revealed large numbers of proteins involved in protein metabolism, transport, amino acid metabolism, lipid metabolism, and redox in chromoplasts from all six species. Seventeen core carotenoid metabolic enzymes were identified. Phytoene synthase, phytoene desaturase, ?-carotene desaturase, 9-cis-epoxycarotenoid dioxygenase, and carotenoid cleavage dioxygenase 1 were found in almost all crops, suggesting relative abundance of them among the carotenoid pathway enzymes. Chromoplasts from different crops contained abundant amounts of ATP synthase and adenine nucleotide translocator, which indicates an important role of ATP production and transport in chromoplast development. Distinctive abundant proteins were observed in chromoplast from different crops, including capsanthin/capsorubin synthase and fibrillins in pepper, superoxide dismutase in watermelon, carrot, and cauliflower, and glutathione-S-transferease in papaya. The comparative analysis of chromoplast proteins among six crop species offers new insights into the general metabolism and function of chromoplasts as well as the uniqueness of chromoplasts in specific crop species. This work provides reference datasets for future experimental study of chromoplast biogenesis, development, and regulation in plants. PMID:23314817

Wang, Yong-Qiang; Yang, Yong; Fei, Zhangjun; Yuan, Hui; Fish, Tara; Thannhauser, Theodore W; Mazourek, Michael; Kochian, Leon V; Wang, Xiaowu; Li, Li

2013-01-10

352

Integration of genomic and functional approaches reveals enhancers at LMX1A and LMX1B.  

PubMed

LMX1A and LMX1B encode two closely related members of the LIM homeobox family of transcription factors. These genes play significant, and frequently overlapping, roles in the development of many structures in the nervous system, including the cerebellum, hindbrain, spinal cord roof plate, sensory systems and dopaminergic midbrain neurons. Little is known about the cis-acting regulatory elements (REs) that dictate their temporal and spatial expression or about the regulatory landscape surrounding them. The availability of comparative sequence data and the advent of genomic technologies such as ChIP-seq have revolutionized our capacity to identify regulatory sequences like enhancers. Despite this wealth of data, the vast majority of loci lack any significant in vivo functional exploration of their non-coding regions. We have completed a significant functional screen of conserved non-coding sequences (putative REs) scattered across these critical human loci, assaying the temporal and spatial control using zebrafish transgenesis. We first identify and describe the LMX1A paralogs lmx1a and lmx1a-like, comparing their expression during embryogenesis with that in mammals, along with lmx1ba and lmx1bb genes. Consistent with their prominent neuronal expression, 47/71 sequences selected within and flanking LMX1A and LMX1B exert spatial control of reporter expression in the central nervous system (CNS) of mosaic zebrafish embryos. Upon germline transmission, we identify CNS reporter expression in multiple independent founders for 22 constructs (LMX1A, n = 17; LMX1B, n = 5). The identified enhancers display significant overlap in their spatial control and represent only a fraction of the conserved non-coding sequences at these critical genes. Our data reveal the abundance of regulatory instruction located near these developmentally important genes. PMID:23942840

Burzynski, Grzegorz M; Reed, Xylena; Maragh, Samantha; Matsui, Takeshi; McCallion, Andrew S

2013-08-13

353

What do plasma beta-endorphin levels reveal about endogenous opioid analgesic function?  

PubMed Central

Plasma levels of beta-endorphin (BE), an endogenous opioid analgesic, are often reported as they relate to acute and chronic pain outcomes. However, little is known about what resting plasma BE levels might reveal about functioning of the endogenous opioid antinociceptive system. This study directly examined associations between resting plasma BE and subsequent endogenous opioid analgesic responses to acute pain in 39 healthy controls and 37 individuals with chronic low back pain (LBP). Resting baseline levels of plasma BE were assessed. Next, participants received opioid blockade (8 mg naloxone i.v.) or placebo in a double-blind, randomized, crossover design. Participants then underwent two acute pain stimuli: finger pressure (FP) pain and ischaemic (ISC) forearm pain. Blockade effects (naloxone minus placebo pain ratings) were derived to index endogenous opioid analgesic function. In placebo condition analyses for both pain stimuli, higher resting BE levels were associated with subsequently greater reported pain intensity (p’s < 0.05), with this effect occurring primarily in healthy controls (BE × Participant Type interactions, p’s < 0.05). In blockade effect analyses across both pain tasks, higher resting plasma BE predicted less subsequent endogenous opioid analgesia (smaller blockade effects; p’s < 0.05). For the ISC task, these links were significantly more prominent in LBP participants (BE × Participant Type Interactions, p’s < 0.05). Results suggest that elevated resting plasma BE may be a potential biomarker for reduced endogenous opioid analgesic capacity, particularly among individuals with chronic pain. Potential clinical implications are discussed.

Bruehl, S.; Burns, J.W.; Chung, O.Y.; Chont, M.

2013-01-01

354

MicroRNA expression profiling reveals the potential function of microRNA-31 in chordomas.  

PubMed

Chordomas are rare bone tumors arising from remnants of the notochord. Molecular studies to determine the pathways involved in their pathogenesis and develop better treatments are limited. Alterations in microRNAs (miRNAs) play important roles in cancer. miRNAs are small RNA sequences that affect transcriptional and post-transcriptional regulation of gene expression in most eukaryotic organisms. Studies show that miRNA dysregulation is important for tumor initiation and progression. We compared the expression profile of miRNAs in chordomas to that of healthy nucleus pulposus samples to gain insight into the molecular pathogenesis of chordomas. Results of functional studies on one of the altered miRNAs, miR-31, are presented. The comparison between the miRNA profile of chordoma samples and the profile of normal nucleus pulposus samples suggests dysregulation of 53 miRNAs. Thirty miRNAs were upregulated in our tumor samples, while 23 were downregulated. Notably, hsa-miR-140-3p and hsa-miR-148a were upregulated in most chordomas relative to levels in nucleus pulposus cells. Two other miRNAs, hsa-miR-31 and hsa-miR-222, were downregulated in chordomas compared with the control group. Quantification with real-time polymerase chain reaction confirmed up or downregulation of these miRNAs among all samples. Functional analyses showed that hsa-miR-31 has an apoptotic effect on chordoma cells and downregulates the expression of c-MET and radixin. miRNA profiling showed that hsa-miR-31, hsa-miR-222, hsa-miR-140-3p and hsa-miR-148a are differentially expressed in chordomas compared with healthy nucleus pulposus. Our profiling may be the first step toward delineating the differential regulation of cancer-related genes in chordomas, helping to reveal the mechanisms of initiation and progression. PMID:23912551

Bayrak, Omer Faruk; Gulluoglu, Sukru; Aydemir, Esra; Ture, Ugur; Acar, Hasan; Atalay, Basar; Demir, Zeynel; Sevli, Serhat; Creighton, Chad J; Ittmann, Michael; Sahin, Fikrettin; Ozen, Mustafa

2013-08-03

355

Dual function electroabsorption waveguide modulator/detector for photonic rf signal processing  

NASA Astrophysics Data System (ADS)

A Franz-Keldysh effect InGaAsP electroabsorption waveguide device is utilized as the high-frequency, high-linear dynamic range modulator and photodetector. The dual-function modulator/photodetector can be useful in compact transmit/receive front end antenna architectures. Adjusting the electrical bias to the reverse-biased p-i-n diode, either efficient optical modulation or detection is demonstrated. As an electroabsorption modulator, a fiber optic link with a minus 17.4 dB rf loss and a 124 dB-Hz4/5 sub-octave spurious-free dynamic range is obtained with electrical biases in the 2 to 3 V range. As a waveguide photodetector, a 0.47 A/W fiber coupled responsivity, photocurrents up to 20 mA, and an output second-order intercept of plus 34.5 dBm are achieved at 7 V electrical bias. Supporting measurements on additional test devices show a trend toward larger intercept point with longer device lengths.

Welstand, Robert B.; Pappert, Stephen A.; Sun, C. K.; Jiang, Hao; Li, G. L.; Chen, W. X.; Zhu, J. T.; Liu, Yet-Zen; Yu, Paul K.

1997-07-01

356

Histone-DNA contacts in structure/function relationships of nucleosomes as revealed by crosslinking  

SciTech Connect

The magnitude of the problem of understanding the structure/function relationships of eukaryotic chromosomes can be appreciated from the fact that the human diploid genome contains more than 2 meters of DNA packaged into 46 chromosomes, each at metaphase being several microns in length. Each chromatid of a chromosome contains a single DNA molecule several centimeters in length. In addition to the DNA, chromosomes contain an equal weight of histones and an equal weight of non-histone chromosomal proteins. These histones are the major chromosomal structural proteins. The non-histone chromosomal proteins are involved in the DNA processes of transcription and replication, in chromosome organization and in nuclear architecture. Polytene chromosomes with their bands and interbands and puffs of active genetic loci provide visual evidence for long range order as do the bands and interbands of mammalian metaphase chromosomes. The gentle removal of histones and all but the most tightly bound 2--3% of non-histone proteins from metaphase chromosomes revealed by electron microscopy a residual protein scaffold constraining a halo of DNA loops extending out from the scaffold.

Usachenko, S.I. [Univ. of California, Davis, CA (United States); Bradbury, E.M. [Los Alamos National Lab., NM (United States). Life Science Div.]|[Univ. of California, Davis, CA (United States)

1998-12-31

357

Functional plant cell wall design revealed by the Raman imaging approach.  

PubMed

Using the Raman imaging approach, the optimization of the plant cell wall design was investigated on the micron level within different tissue types at different positions of a Phormium tenax leaf. Pectin and lignin distribution were visualized and the cellulose microfibril angle (MFA) of the cell walls was determined. A detailed analysis of the Raman spectra extracted from the selected regions, allowed a semi-quantitative comparison of the chemical composition of the investigated tissue types on the micron level. The cell corners of the parenchyma revealed almost pure pectin and the cell wall an amount of 38-49% thereof. Slight lignification was observed in the parenchyma and collenchyma in the top of the leaf and a high variability (7-44%) in the sclerenchyma. In the cell corners and in the cell wall of the sclerenchymatic fibres surrounding the vascular tissue, the highest lignification was observed, which can act as a barrier and protection of the vascular tissue. In the sclerenchyma high variable MFA (4°-40°) was detected, which was related with lignin variability. In the primary cell walls a constant high MFA (57°-58°) was found together with pectin. The different plant cell wall designs on the tissue and microlevel involve changes in chemical composition as well as cellulose microfibril alignment and are discussed and related according to the development and function. PMID:21197544

Richter, Stephan; Müssig, Jörg; Gierlinger, Notburga

2011-01-01

358

Distinct cortical anatomy linked to subregions of the medial temporal lobe revealed by intrinsic functional connectivity.  

PubMed

The hippocampus and adjacent cortical structures in the medial temporal lobe (MTL) contribute to memory through interactions with distributed brain areas. Studies of monkey and rodent anatomy suggest that parallel pathways converge on distinct subregions of the MTL. To explore the cortical areas linked to subregions of the MTL in humans, we examined cortico-cortical and hippocampal-cortical correlations using high-resolution, functional connectivity analysis in 100 individuals. MTL seed regions extended along the anterior to posterior axis and included hippocampus and adjacent structures. Results revealed two separate brain pathways that correlated with distinct subregions within the MTL. The body of the hippocampus and posterior parahippocampal cortex correlated with lateral parietal cortex, regions along the posterior midline including posterior cingulate and retrosplenial cortex, and ventral medial prefrontal cortex. By contrast, anterior hippocampus and the perirhinal/entorhinal cortices correlated with distinct regions in the lateral temporal cortex extending into the temporal pole. The present results are largely consistent with known connectivity in the monkey and provide a novel task-independent dissociation of the parallel pathways supporting the MTL memory system in humans. The cortical pathways include regions that have undergone considerable areal expansion in humans, providing insight into how the MTL memory system has evolved to support a diverse array of cognitive domains. PMID:18385483

Kahn, Itamar; Andrews-Hanna, Jessica R; Vincent, Justin L; Snyder, Abraham Z; Buckner, Randy L

2008-04-02

359

Functionally and spatially distinct Ca2+ stores are revealed in cultured vascular smooth muscle cells.  

PubMed Central

Sarcoplasmic reticulum Ca2+ in vascular smooth muscle may be separated into at least two types of Ca2+ stores, one releasable by inositol 1,4,5-trisphosphate and the other releasable by caffeine and ryanodine. We employed digital imaging with fura-2 to study the effects of thapsigargin (which blocks Ca2+ sequestration in the inositol trisphosphate-sensitive store) and caffeine on the cytosolic free Ca2+ concentration ([Ca2+]cyt) in cultured arterial myocytes. These agents increased [Ca2+]cyt by depleting different Ca2+ stores in the absence of extracellular Ca2+. Moreover, Ca2+ could be transferred between the two stores, as prior application of caffeine, which alone evoked little or no rise in [Ca2+]cyt, significantly augmented the response to thapsigargin. Conversely, a substantial caffeine-induced rise in [Ca2+]cyt was observed only after the ability of the thapsigargin-sensitive Ca2+ store to sequester Ca2+ was inhibited. This suggests that the caffeine-sensitive store may have a thapsigargin-insensitive Ca(2+)-sequestration mechanism. To complement these fura-2 experiments, chlortetracycline was used to visualize the Ca2+ stores directly. The latter studies revealed spatial differences in the location of the thapsigargin-sensitive and caffeine-sensitive Ca2+ stores (measured as thapsigargin-sensitive and caffeine-sensitive chlortetracycline fluorescence). Thus, these two types of stores appear to be both functionally and spatially distinct. Images

Tribe, R M; Borin, M L; Blaustein, M P

1994-01-01

360

Quantitative proteomics reveals oxygen-dependent changes in neuronal mitochondria affecting function and sensitivity to rotenone.  

PubMed

Mitochondria are implicated in a variety of degenerative disorders and aging. Mitochondria are responsive to the oxygen in their environment, yet tissue culture is performed at atmospheric (21%) oxygen and not at physiological (1-11%) oxygen levels found in tissues. We employed imaging of mitochondrial probes, mass spectrometry, Western blots, and ATP assays of the human neuroblastoma cell-line SH-SY5Y and imaging of mitochondrial probes in human primary neurons under standard nonphysiological oxygen conditions (atmospheric) and under physiological oxygen levels in the nervous system to assess the impact of oxygen on mitochondrial function. SH-SY5Y cells cultured in physiological 5% oxygen exhibited the lowest reactive oxygen species (ROS) production, indicating that culture at 5% oxygen is favored; these results were mimicked in primary human cells. Mass spectrometric analysis revealed extensive mitochondrial proteomic alterations in SH-SY5Y cells based on oxygen culture condition. Among these, the rotenone-sensitive subunit of complex I NDUFV3 was increased in cells cultured at 5% oxygen. Rotenone is a Parkinson's disease-linked toxin, and correspondingly SH-SY5Y cells cultured at 5% oxygen also exhibited over 10 times greater sensitivity to rotenone than those cultured in atmospheric, 21%, oxygen. Our results indicate that neuronal mitochondria are responsive to oxygen levels and produce differential responses under different oxygen levels. PMID:23971408

Villeneuve, Lance; Tiede, Leann M; Morsey, Brenda; Fox, Howard S

2013-09-10

361

Modulation of the effective work function of TiN metal gate for PMOS application  

NASA Astrophysics Data System (ADS)

It is important to find a way to modulate the work function of TiN metal gate towards the valence band edge of Si, which can meet the lower threshold voltage requirement of p-type metal—oxide—semiconductor (MOS) transistor. In this work, effects of TiN thickness, post-deposition annealing (PDA), oxygen incorporation and N concentration variation on the work function of TiN metal gate in MOS structures are systematically investigated. It can be found that the work function positively shifts at the initial stage as the thickness of the TiN layer increases and stabilizes at such a thickness. PDA at N2 ambience with a trace of O2 can also cause a positive shift in the work function of TiN metal gate. The same tendency can be observed when oxygen is incorporated into TiN. Finally, increasing the N concentration in TiN can also positively shift the work function. All these measures are effective in modulating the TiN metal gate so that it is more suitable for PMOS application.

Kai, Han; Xueli, Ma; Hong, Yang; Wenwu, Wang

2013-08-01

362

Chemically functionalized single-walled carbon nanotube films modulate the morpho-functional and proliferative characteristics of astrocytes.  

PubMed

We used single-walled carbon nanotube (CNT) films to modulate the morpho-functional and proliferative characteristics of astrocytes. When plated on the CNT films of various thicknesses, astrocytes grow bigger and rounder in shape with a decrease in the immunoreactivity of glial fibrillary acidic protein along with an increase in their proliferation, changes associated with the dedifferentiation of astrocytes in culture. Thus, CNT films, as a coating material for electrodes used in brain machine interface, could reduce astrogliosis around the site of implantation. PMID:23937522

Gottipati, Manoj K; Samuelson, Josheua J; Kalinina, Irina; Bekyarova, Elena; Haddon, Robert C; Parpura, Vladimir

2013-08-19

363

Distinct Modulated Pupil Function System for Real-Time Imaging of Living Cells  

PubMed Central

Optical microscopy is one of the most contributive tools for cell biology in the past decades. Many microscopic techniques with various functions have been developed to date, i.e., phase contrast microscopy, differential interference contrast (DIC) microscopy, confocal microscopy, two photon microscopy, superresolution microscopy, etc. However, person who is in charge of an experiment has to select one of the several microscopic techniques to achieve an experimental goal, which makes the biological assay time-consuming and expensive. To solve this problem, we have developed a microscopic system with various functions in one instrument based on the optical Fourier transformation with a lens system for detection while focusing on applicability and user-friendliness for biology. The present instrument can arbitrarily modulate the pupil function with a micro mirror array on the Fourier plane of the optical pathway for detection. We named the present instrument DiMPS (Distinct optical Modulated Pupil function System). The DiMPS is compatible with conventional fluorescent probes and illumination equipment, and gives us a Fourier-filtered image, a pseudo-relief image, and a deep focus depth. Furthermore, DiMPS achieved a resolution enhancement (pseudo-superresolution) of 110 nm through the subtraction of two images whose pupil functions are independently modulated. In maximum, the spatial and temporal resolution was improved to 120 nm and 2 ms, respectively. Since the DiMPS is based on relay optics, it can be easily combined with another microscopic instrument such as confocal microscope, and provides a method for multi-color pseudo-superresolution. Thus, the DiMPS shows great promise as a flexible optical microscopy technique in biological research fields.

Watanabe, Tomonobu M.; Tsukasaki, Yoshikazu; Fujita, Hideaki; Ichimura, Taro; Saitoh, Tatsuya; Akira, Shizuo; Yanagida, Toshio

2012-01-01

364

Connectivity–behavior analysis reveals that functional connectivity between left BA39 and Broca's area varies with reading ability  

Microsoft Academic Search

Correlations between temporal fluctuations in MRI signals may reveal functional connectivity between brain regions within individual subjects. Such correlations would be especially useful indices of functional connectivity if they covary with behavioral performance or other subject variables. This study investigated whether such a relationship could be demonstrated in the context of the reading circuit in the brain. The method proved

Michelle Hampson; Fuyuze Tokoglu; Zhongdong Sun; Robin J. Schafer; Pawel Skudlarski; John C. Gore; R. Todd Constable

2006-01-01

365

A histidine-rich motif mediates mitochondrial localization of ZnT2 to modulate mitochondrial function  

PubMed Central

Female reproductive tissues such as mammary glands, ovaries, uterus, and placenta are phenotypically dynamic, requiring tight integration of bioenergetic and apoptotic mechanisms. Mitochondrial zinc (Zn) pools have emerged as a central player in regulating bioenergetics and apoptosis. Zn must first be imported into mitochondria to modulate mitochondrion-specific functions; however, mitochondrial Zn import mechanisms have not been identified. Here we documented that the Zn transporter ZnT2 is associated with the inner mitochondrial membrane and acts as an auxiliary Zn importer into mitochondria in mammary cells. We found that attenuation of ZnT2 expression significantly reduced mitochondrial Zn uptake and total mitochondrial Zn pools. Moreover, expression of a ZnT2-hemagglutinin (HA) fusion protein was localized to mitochondria and significantly increased Zn uptake and mitochondrial Zn pools, directly implicating ZnT2 in Zn import into mitochondria. Confocal microscopy of truncated and point mutants of ZnT2-green fluorescent protein (GFP) fusion proteins revealed a histidine-rich motif (51HHXH54) in the NH2 terminus that is important for mitochondrial targeting of ZnT2. More importantly, the expansion of mitochondrial Zn pools by ZnT2 overexpression significantly reduced ATP biogenesis and mitochondrial oxidation concurrent with increased apoptosis, suggesting a functional role for ZnT2-mediated Zn import into mitochondria. These results identify the first Zn transporter directly associated with mitochondria and suggest that unique secretory tissues such as the mammary gland require novel mechanisms to modulate mitochondrion-specific functions.

Seo, Young Ah; Lopez, Veronica

2011-01-01

366

Identification of functional modules using network topology and high-throughput data  

PubMed Central

Background With the advent of systems biology, biological knowledge is often represented today by networks. These include regulatory and metabolic networks, protein-protein interaction networks, and many others. At the same time, high-throughput genomics and proteomics techniques generate very large data sets, which require sophisticated computational analysis. Usually, separate and different analysis methodologies are applied to each of the two data types. An integrated investigation of network and high-throughput information together can improve the quality of the analysis by accounting simultaneously for topological network properties alongside intrinsic features of the high-throughput data. Results We describe a novel algorithmic framework for this challenge. We first transform the high-throughput data into similarity values, (e.g., by computing pairwise similarity of gene expression patterns from microarray data). Then, given a network of genes or proteins and similarity values between some of them, we seek connected sub-networks (or modules) that manifest high similarity. We develop algorithms for this problem and evaluate their performance on the osmotic shock response network in S. cerevisiae and on the human cell cycle network. We demonstrate that focused, biologically meaningful and relevant functional modules are obtained. In comparison with extant algorithms, our approach has higher sensitivity and higher specificity. Conclusion We have demonstrated that our method can accurately identify functional modules. Hence, it carries the promise to be highly useful in analysis of high throughput data.

Ulitsky, Igor; Shamir, Ron

2007-01-01

367

Modulating cortico-striatal and thalamo-cortical functional connectivity with transcranial direct current stimulation.  

PubMed

Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technique that has been shown to alter cortical excitability and activity via application of weak direct currents. Beyond intracortical effects, functional imaging as well as behavioral studies are suggesting additional tDCS-driven alterations of subcortical areas, however, direct evidence for such effects is scarce. We aimed to investigate the impact of tDCS on cortico-subcortical functional networks by seed functional connectivity analysis of different striatal and thalamic regions to prove tDCS-induced alterations of the cortico-striato-thalamic circuit. fMRI resting state data sets were acquired immediately before and after 10 min of bipolar tDCS during rest, with the anode/cathode placed over the left primary motor cortex (M1) and the cathode/anode over the contralateral frontopolar cortex. To control for possible placebo effects, an additional sham stimulation session was carried out. Functional coupling between the left thalamus and the ipsilateral primary motor cortex (M1) significantly increased following anodal stimulation over M1. Additionally, functional connectivity between the left caudate nucleus and parietal association cortices was significantly strengthened. In contrast, cathodal tDCS over M1 decreased functional coupling between left M1 and contralateral putamen. In summary, in this study, we show for the first time that tDCS modulates functional connectivity of cortico-striatal and thalamo-cortical circuits. Here we highlight that anodal tDCS over M1 is capable of modulating elements of the cortico-striato-thalamo-cortical functional motor circuit. PMID:21922602

Polanía, Rafael; Paulus, Walter; Nitsche, Michael A

2011-09-16

368

Modulation of Immune Function by Polyphenols: Possible Contribution of Epigenetic Factors  

PubMed Central

Several biological activities have been described for polyphenolic compounds, including a modulator effect on the immune system. The effects of these biologically active compounds on the immune system are associated to processes as differentiation and activation of immune cells. Among the mechanisms associated to immune regulation are epigenetic modifications as DNA methylation of regulatory sequences, histone modifications and posttranscriptional repression by microRNAs that influences the gene expression of key players involved in the immune response. Considering that polyphenols are able to regulate the immune function and has been also demonstrated an effect on epigenetic mechanisms, it is possible to hypothesize that there exists a mediator role of epigenetic mechanisms in the modulation of the immune response by polyphenols.

Cuevas, Alejandro; Saavedra, Nicolas; Salazar, Luis A.; Abdalla, Dulcineia S. P.

2013-01-01

369

DMD-based infrared scene projection: comparison of MWIR and LWIR modulation transfer function  

NASA Astrophysics Data System (ADS)

We compare modulation-transfer-function (MTF) measurements for both mid-wave (MWIR) and long-wave IR (LWIR) bands for an IR-laser scene projector based on the digital micro-mirror device (DMD). We evaluate MTF for both IR-CO2 (10.6 micron) and IR-HeNe (3.39 micron) laser systems. This gives a quantitative image-quality criterion for verifying system performance using identical configurations of the DMD, lens, and screen. Different angles of illumination for the MWIR and LWIR were used, to give an output beam always perpendicular to the DMD. For this experiment a set of bar-target images was used to measure the residual modulation depth at the fundamental spatial frequency of the bars. As expected, the MWIR projector system has better MTF than the LWIR system because of diffraction effects occurring at the 17-micron pixels of the DMD.

Folks, William R.; Mullally, Daniel; Zummo, Guy; Weeks, Arthur R.; Boreman, Glenn D.

2004-08-01

370

Identifying Cellular Pathways Modulated by Drosophila Palmitoyl-protein Thioesterase 1 Function  

PubMed Central

Infantile-onset Neuronal Ceroid Lipofuscinosis (INCL) is a severe pediatric neurodegenerative disorder produced by mutations in the gene encoding palmitoyl-protein thioesterase 1 (Ppt1). This enzyme is responsible for the removal of a palmitate post-translational modification from an unknown set of substrate proteins. To better understand the function of Ppt1 in neurons, we performed an unbiased dominant loss-of-function genetic modifier screen in Drosophila using a previously characterized Ppt1 gain-of-function system. The enhancers and suppressors identified in our screen make novel connections between Ppt1 and genes involved in cellular trafficking and the modulation of synaptic growth. We further support the relevance of our screen by demonstrating that Garland cells from Ppt1 loss-of-function mutants have defects in endocytic trafficking. Endocytic tracer uptake and ultrastructural analysis of these non-neuronal cells points to Ppt1 playing a role in modulating the early stages of vesicle formation. This work lays the groundwork for further experimental exploration of these processes to better understand their contributions to the INCL disease process.

Saja, Stephanie; Buff, Haley; Smith, Alexis C.; Williams, Tiffany S.; Korey, Christopher A.

2010-01-01

371

Docosahexaenoic acid modulates inflammatory and antineurogenic functions of activated microglial cells.  

PubMed

The complex process of microglial activation encompasses several functional activation states associated either with neurotoxic/antineurogenic or with neurotrophic/proneurogenic properties, depending mainly on the extent of activation and the nature of the activating stimuli. Several studies have demonstrated that acute exposure to the prototypical activating agent lipopolysaccharide (LPS) confers antineurogenic properties upon microglial cells. Acutely activated microglia ortheir conditioned media (CM) reduce neural stem progenitor cell (NPC) survival and prevent NPC differentiation into neurons. The present study tested the hypothesis that docosahexaenoic acid (DHA), a long-chain polyunsatured fatty acid (L-PUFA) with potent immunomodulatory properties, could dampen microglial proinflammatory functions and modulate their antineurogenic effect. We demonstrate that DHA dose dependently inhibits the synthesis of inflammatory products in activated microglia without inducing an alternative antiinflammatory phenotype. Among the possible DHA mechanisms of action, we propose the inhibition of p38 MAPK phosphorylation and the activation of the nuclear receptor peroxisome proliferator activated receptor (PPAR)-?. The attenuation of M1 proinflammatory phenotype has relevant consequences for the survival and differentiation of NPC, because DHA reverses the antineurogenic activities of conditioned media from LPS-activated microglia. Our study identifies new relevant potentially protective and proneurogenic functions of DHA, exerted through the modulation of microglial functions, that could be exploited to sustain or promote neuroregenerative processes in damaged/aged brain. PMID:22057807

Antonietta Ajmone-Cat, Maria; Lavinia Salvatori, Maria; De Simone, Roberta; Mancini, Melissa; Biagioni, Stefano; Bernardo, Antonietta; Cacci, Emanuele; Minghetti, Luisa

2011-11-04

372

NMR studies reveal the role of biomembranes in modulating ligand binding and release by intracellular bile acid binding proteins.  

PubMed

Bile acid molecules are transferred vectorially between basolateral and apical membranes of hepatocytes and enterocytes in the context of the enterohepatic circulation, a process regulating whole body lipid homeostasis. This work addresses the role of the cytosolic lipid binding proteins in the intracellular transfer of bile acids between different membrane compartments. We present nuclear magnetic resonance (NMR) data describing the ternary system composed of the bile acid binding protein, bile acids, and membrane mimetic systems, such as anionic liposomes. This work provides evidence that the investigated liver bile acid binding protein undergoes association with the anionic membrane and binding-induced partial unfolding. The addition of the physiological ligand to the protein-liposome mixture is capable of modulating this interaction, shifting the equilibrium towards the free folded holo protein. An ensemble of NMR titration experiments, based on nitrogen-15 protein and ligand observation, confirm that the membrane and the ligand establish competing binding equilibria, modulating the cytoplasmic permeability of bile acids. These results support a mechanism of ligand binding and release controlled by the onset of a bile salt concentration gradient within the polarized cell. The location of a specific protein region interacting with liposomes is highlighted. PMID:19836400

Pedò, Massimo; Löhr, Frank; D'Onofrio, Mariapina; Assfalg, Michael; Dötsch, Volker; Molinari, Henriette

2009-10-22

373

Functional interactions between prefrontal and visual association cortex contribute to top-down modulation of visual processing.  

PubMed

Attention-dependent modulation of neural activity in visual association cortex (VAC) is thought to depend on top-down modulatory control signals emanating from the prefrontal cortex (PFC). In a previous functional magnetic resonance imaging study utilizing a working memory task, we demonstrated that activity levels in scene-selective VAC (ssVAC) regions can be enhanced above or suppressed below a passive viewing baseline level depending on whether scene stimuli were attended or ignored (Gazzaley, Cooney, McEvoy, et al. 2005). Here, we use functional connectivity analysis to identify possible sources of these modulatory influences by examining how network interactions with VAC are influenced by attentional goals at the time of encoding. Our findings reveal a network of regions that exhibit strong positive correlations with a ssVAC seed during all task conditions, including foci in the left middle frontal gyrus (MFG). This PFC region is more correlated with the VAC seed when scenes were remembered and less correlated when scenes were ignored, relative to passive viewing. Moreover, the strength of MFG-VAC coupling correlates with the magnitude of attentional enhancement and suppression of VAC activity. Although our correlation analyses do not permit assessment of directionality, these findings suggest that PFC biases activity levels in VAC by adjusting the strength of functional coupling in accordance with stimulus relevance. PMID:17725995

Gazzaley, Adam; Rissman, Jesse; Cooney, Jeffrey; Rutman, Aaron; Seibert, Tyler; Clapp, Wesley; D'Esposito, Mark

2007-09-01

374

Epileptic Networks in Focal Cortical Dysplasia Revealed Using Electroencephalography-Functional Magnetic Resonance Imaging  

PubMed Central

Objective Surgical treatment of focal epilepsy in patients with focal cortical dysplasia (FCD) is most successful if all epileptogenic tissue is resected. This may not be evident on structural magnetic resonance imaging (MRI), so intracranial electroencephalography (icEEG) is needed to delineate the seizure onset zone (SOZ). EEG-functional MRI (fMRI) can reveal interictal discharge (IED)-related hemodynamic changes in the irritative zone (IZ). We assessed the value of EEG-fMRI in patients with FCD-associated focal epilepsy by examining the relationship between IED-related hemodynamic changes, icEEG findings, and postoperative outcome. Methods Twenty-three patients with FCD-associated focal epilepsy undergoing presurgical evaluation including icEEG underwent simultaneous EEG-fMRI at 3T. IED-related hemodynamic changes were modeled, and results were overlaid on coregistered T1-weighted MRI scans fused with computed tomography scans showing the intracranial electrodes. IED-related hemodynamic changes were compared with the SOZ on icEEG and postoperative outcome at 1 year. Results Twelve of 23 patients had IEDs during recording, and 11 of 12 had significant IED-related hemodynamic changes. The fMRI results were concordant with the SOZ in 5 of 11 patients, all of whom had a solitary SOZ on icEEG. Four of 5 had >50% reduction in seizure frequency following resective surgery. The remaining 6 of 11 patients had widespread or discordant regions of IED-related fMRI sign