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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. PMID:18818364

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

Task-related concurrent but opposite modulations of overlapping functional networks as revealed by spatial ICA  

PubMed Central

Animal studies indicate that different functional networks (FNs), each with a unique timecourse, may overlap at common brain regions. For understanding how different FNs overlap in the human brain and how the timecourses of overlapping FNs are modulated by cognitive tasks, we applied spatial independent component analysis (sICA) to functional magnetic resonance imaging (fMRI) data. These data were acquired from healthy participants while they performed a visual task with parametric loads of attention and working memory. SICA identified a total of 14 FNs, and they showed different extents of overlap at a majority of brain regions exhibiting any functional activity. More FNs overlapped at the higher-order association cortex including the anterior and posterior cingulate, precuneus, insula, and lateral and medial frontoparietal cortex (FPC) than at the primary sensorimotor cortex. Furthermore, overlapping FNs exhibited concurrent but different task-related modulations of timecourses. FNs showing task-related up- vs. down-modulation of timecourses overlapped at both the lateral and medial FPC and subcortical structures including the thalamus, striatum, and midbrain ventral tegmental area (VTA). Such task-related, concurrent, but opposite changes in timecourses in the same brain regions may not be detected by current analyses based on General-Linear-Model (GLM). The present findings indicate that multiple cognitive processes may associate with common brain regions and exhibit simultaneous but different modulations in timecourses during cognitive tasks. PMID:23611864

Xu, Jiansong; Zhang, Sheng; Calhoun, Vince D.; Monterosso, John; Li, Chiang-Shan R.; Worhunsky, Patrick D.; Stevens, Michael; Pearlson, Godfrey D.; Potenza, Marc N.

2013-01-01

3

Functional dissection of surfactin synthetase initiation module reveals insights into the mechanism of lipoinitiation.  

PubMed

Although the N-terminally attached fatty acids are key structural elements of nonribosomally assembled lipopeptide antibiotics, little is known about the mechanism of lipid transfer during the initial step of biosynthesis. In this study, we investigated the activity of the dissected initiation module (C-A(Glu)-PCP) of surfactin synthetase SrfAA in vitro to gain further insights into the lipoinitiation reaction. The dissected condensation (C) domain catalyzes the transfer of CoA-activated 3-hydroxy fatty acid with high substrate specificity at its donor site to the peptidyl carrier protein (PCP) bound amino acid glutamate (Glu(1)). Additionally, biochemical studies on four putative acyl CoA ligases in Bacillus subtilis revealed that two of them activate 3-hydroxy fatty acids for surfactin biosynthesis in vitro and that the disruption of corresponding genes has a significant influence on surfactin production. PMID:20797616

Kraas, Femke I; Helmetag, Verena; Wittmann, Melanie; Strieker, Matthias; Marahiel, Mohamed A

2010-08-27

4

Evidence of functional connectivity between auditory cortical areas revealed by amplitude modulation sound processing  

PubMed Central

The human auditory cortex includes several interconnected areas. A better understanding of the mechanisms involved in auditory cortical functions requires a detailed knowledge of neuronal connectivity between functional cortical regions. In human, it is difficult to track in vivo neuronal connectivity. We investigated the inter-area connection in vivo in the auditory cortex using a method of directed coherence (DCOH) applied to depth auditory evoked potentials (AEPs). This paper presents simultaneous AEPs recordings from insular gyrus, primary and secondary cortices (Heschl’s gyrus and planum temporale) and associative areas (BA 22) with multilead intracerebral electrodes in response to sinusoidal modulated white noises in four epileptic patients who underwent invasive monitoring with depth electrodes for epilepsy surgery. DCOH allowed estimation of the causality between two signals recorded from different cortical sites. The results showed: (i) a predominant auditory stream within the primary auditory cortex (PAC) from the most medial region to the most lateral one whatever the modulation frequency (MF), (ii) unidirectional functional connection from the primary to secondary auditory cortex, (iii) a major auditory propagation from the posterior areas to the anterior ones, particularly at 8, 16 and 32 Hz, (iv) a particular role of Heschl’s sulcus (HS), dispatching information to the different auditory areas. These findings suggest that cortical processing of auditory information is performed in serial and parallel streams. Our data showed that the auditory propagation could not be associated to an unidirectional traveling wave but to a constant interaction between these areas, that could reflect the large adaptive and plastic capacities of auditory cortex. The role of the insular gyrus is discussed. PMID:16514106

Gueguin, Marie; Le Bouquin-Jeannes, Regine; Faucon, Gerard; Chauvel, Patrick; Liegeois-Chauvel, Catherine

2007-01-01

5

Visual target modulation of functional connectivity networks revealed by self-organizing group ICA.  

PubMed

We applied a data-driven analysis based on self-organizing group independent component analysis (sogICA) to fMRI data from a three-stimulus visual oddball task. SogICA is particularly suited to the investigation of the underlying functional connectivity and does not rely on a predefined model of the experiment, which overcomes some of the limitations of hypothesis-driven analysis. Unlike most previous applications of ICA in functional imaging, our approach allows the analysis of the data at the group level, which is of particular interest in high order cognitive studies. SogICA is based on the hierarchical clustering of spatially similar independent components, derived from single subject decompositions. We identified four main clusters of components, centered on the posterior cingulate, bilateral insula, bilateral prefrontal cortex, and right posterior parietal and prefrontal cortex, consistently across all participants. Post hoc comparison of time courses revealed that insula, prefrontal cortex and right fronto-parietal components showed higher activity for targets than for distractors. Activation for distractors was higher in the posterior cingulate cortex, where deactivation was observed for targets. While our results conform to previous neuroimaging studies, they also complement conventional results by showing functional connectivity networks with unique contributions to the task that were consistent across subjects. SogICA can thus be used to probe functional networks of active cognitive tasks at the group-level and can provide additional insights to generate new hypotheses for further study. PMID:17990304

van de Ven, Vincent; Bledowski, Christoph; Prvulovic, David; Goebel, Rainer; Formisano, Elia; Di Salle, Francesco; Linden, David E J; Esposito, Fabrizio

2008-12-01

6

Hypoxia Modulates A431 Cellular Pathways Association to Tumor Radioresistance and Enhanced Migration Revealed by Comprehensive Proteomic and Functional Studies*  

PubMed Central

Tumor hypoxia induces cancer cell angiogenesis, invasiveness, treatment resistance, and contributes to poor clinical outcome. However, the molecular mechanism by which tumor hypoxia exerts a coordinated effect on different molecular pathways to enhance tumor growth and survival and lead to poor clinical outcome is not fully understood. In this study, we attempt to elucidate the global protein expression and functional changes in A431 epithelial carcinoma cells induced by hypoxia and reoxygenation using iTRAQ quantitative proteomics and biochemical functional assays. Quantitative proteomics results showed that 4316 proteins were quantified with FDR<1%, in which over 1200 proteins were modulated >1.2 fold, and DNA repair, glycolysis, integrin, glycoprotein turnover, and STAT1 pathways were perturbed by hypoxia and reoxygenation-induced oxidative stress. For the first time, hypoxia was shown to up-regulate the nonhomologous end-joining pathway, which plays a central role in DNA repair of irradiated cells, thereby potentially contributing to the radioresistance of hypoxic A431 cells. The up-regulation of Ku70/Ku80 dimer, a key molecular complex in the nonhomologous end-joining pathway, was confirmed by Western blot and liquid chromatography/tandem mass spectrometry-MRM methods. Functional studies confirmed that up-regulation of glycolysis, integrin, glycoprotein synthesis, and down-regulation of STAT1 pathways during hypoxia enhanced metastastic activity of A431 cells. Migration of A431 cells was dramatically repressed by glycolysis inhibitor (2-Deoxy-d-glucose), glycoprotein synthesis inhibitor (1-Deoxynojirimycin Hydrochloride), and STAT1? overexpression that enhanced the integrin-mediated cell adhesion. These results revealed that hypoxia induced several biological processes involved in tumor migration and radioresistance and provided potential new targets for tumor therapy. PMID:23204318

Ren, Yan; Hao, Piliang; Dutta, Bamaprasad; Cheow, Esther Sok Hwee; Sim, Kae Hwan; Gan, Chee Sian; Lim, Sai Kiang; Sze, Siu Kwan

2013-01-01

7

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

2013-03-01

8

Flubendiamide, a novel Ca2+ channel modulator, reveals evidence for functional cooperation between Ca2+ pumps and Ca2+ release.  

PubMed

Flubendiamide, developed by Nihon Nohyaku Co., Ltd. (Tokyo, Japan), is a novel activator of ryanodine-sensitive calcium release channels (ryanodine receptors; RyRs), and is known to stabilize insect RyRs in an open state in a species-specific manner and to desensitize the calcium dependence of channel activity. In this study, using flubendiamide as an experimental tool, we examined an impact of functional modulation of RyR on Ca2+ pump. Strikingly, flubendiamide induced a 4-fold stimulation of the Ca2+ pump activity (EC50=11 nM) of an insect that resequesters Ca2+ to intracellular stores, a greater increase than with the classical RyR modulators ryanodine and caffeine. This prominent stimulation, which implies tight functional coupling of Ca2+ release with Ca2+ pump, resulted in a marginal net increase in the extravesicular calcium concentration despite robust Ca2+ release from the intracellular stores by flubendiamide. Further analysis suggested that luminal Ca2+ is an important mediator for the functional coordination of RyRs and Ca2+ pumps. However, kinetic factors for Ca2+ pumps, including ATP and cytoplasmic Ca2+, failed to affect the Ca2+ pump stimulation by flubendiamide. We therefore conclude that the stimulation of Ca2+ pump by flubendiamide is mediated by the decrease in luminal calcium, which may induce calcium dissociation from the luminal Ca2+ binding site on the Ca2+ pump. This mechanism should play an essential role in precise control of intracellular Ca2+ homeostasis. PMID:16481391

Masaki, Takao; Yasokawa, Noriaki; Tohnishi, Masanori; Nishimatsu, Tetsuyoshi; Tsubata, Kenji; Inoue, Kazuyoshi; Motoba, Kazuhiko; Hirooka, Takashi

2006-05-01

9

Structural and functional studies of the modulator NS9283 reveal agonist-like mechanism of action at ?4?2 nicotinic acetylcholine receptors.  

PubMed

Modulation of Cys loop receptor ion channels is a proven drug discovery strategy, but many underlying mechanisms of the mode of action are poorly understood. We report the x-ray structure of the acetylcholine-binding protein from Lymnaea stagnalis with NS9283, a stoichiometry selective positive modulator that targets the ?4-?4 interface of ?4?2 nicotinic acetylcholine receptors (nAChRs). Together with homology modeling, mutational data, quantum mechanical calculations, and pharmacological studies on ?4?2 nAChRs, the structure reveals a modulator binding mode that overlaps the ?4-?4 interface agonist (acetylcholine)-binding site. Analysis of contacts to residues known to govern agonist binding and function suggests that modulation occurs by an agonist-like mechanism. Selectivity for ?4-?4 over ?4-?2 interfaces is determined mainly by steric restrictions from Val-136 on the ?2-subunit and favorable interactions between NS9283 and His-142 at the complementary side of ?4. In the concentration ranges where modulation is observed, its selectivity prevents NS9283 from directly activating nAChRs because activation requires coordinated action from more than one interface. However, we demonstrate that in a mutant receptor with one natural and two engineered ?4-?4 interfaces, NS9283 is an agonist. Modulation via extracellular binding sites is well known for benzodiazepines acting at ?-aminobutyric acid type A receptors. Like NS9283, benzodiazepines increase the apparent agonist potency with a minimal effect on efficacy. The shared modulatory profile along with a binding site located in an extracellular subunit interface suggest that modulation via an agonist-like mechanism may be a common mechanism of action that potentially could apply to Cys loop receptors beyond the ?4?2 nAChRs. PMID:24982426

Olsen, Jeppe A; Ahring, Philip K; Kastrup, Jette S; Gajhede, Michael; Balle, Thomas

2014-09-01

10

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. PMID:22090421

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

2011-01-01

11

Role of the N-terminal region in G protein-coupled receptor functions: negative modulation revealed by 5-HT2B receptor polymorphisms.  

PubMed

The putative role of the N-terminal region of rhodopsin-like 7 transmembrane biogenic amine receptors in agonist-induced signaling has not yet been clarified despite recent advances in 7 transmembrane receptor structural biology. Given the existence of N-terminal nonsynonymous polymorphisms (R6G;E42G) within the HTR2B gene in a drug-abusing population, we assessed whether these polymorphisms affect 5-hydroxytryptamine 2B (5-HT2B) receptor in vitro pharmacologic and coupling properties in transfected COS-7 cells. Modification of the 5-HT2B receptor N terminus by the R6G;E42G polymorphisms increases such agonist signaling pathways as inositol phosphate accumulation as assessed by either classic or operational models. The N-terminal R6G;E42G mutations of the 5-HT2B receptor also increase cell proliferation and slow its desensitization kinetics compared with the wild-type receptor, further supporting a role for the N terminus in transduction efficacy. Furthermore, by coexpressing a tethered wild-type 5-HT2B receptor N terminus with a 5-HT2B receptor bearing a N-terminal deletion, we were able to restore original coupling. This reversion to normal activity of a truncated 5-HT2B receptor by coexpression of the membrane-tethered wild-type 5-HT2B receptor N terminus was not observed using a membrane-tethered 5-HT2B receptor R6G;E42G N terminus. These data suggest that the N terminus exerts a negative control over basal as well as agonist-stimulated receptor activity that is lost in the R6G;E42G mutant. Our findings reveal a new and unanticipated role of the 5-HT2B receptor N terminus as a negative modulator, affecting both constitutive and agonist-stimulated activity. Moreover, our data caution against excluding the N terminus and extracellular loops in structural studies of this 7 transmembrane receptor family. PMID:24174497

Belmer, Arnauld; Doly, Stephane; Setola, Vincent; Banas, Sophie M; Moutkine, Imane; Boutourlinsky, Katia; Kenakin, Terry; Maroteaux, Luc

2014-01-01

12

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. PMID:18564421

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

2008-01-01

13

Serotonergic modulation of intrinsic functional connectivity.  

PubMed

Serotonin functions as an essential neuromodulator that serves a multitude of roles, most prominently balancing mood [1]. Serotonergic challenge has been observed to reduce intrinsic functional connectivity in brain regions implicated in mood regulation [2-4]. However, the full scope of serotonergic action on functional connectivity in the human brain has not been explored. Here, we show evidence that a single dose of a serotonin reuptake inhibitor dramatically alters functional connectivity throughout the whole brain in healthy subjects (n = 22). Our network-centrality analysis reveals a widespread decrease in connectivity in most cortical and subcortical areas. In the cerebellum and thalamus, however, we find localized increases. These rapid and brain-encompassing connectivity changes linked to acute serotonin transporter blockade suggest a key role for the serotonin transporter in the modulation of the functional macroscale connectome. PMID:25242032

Schaefer, Alexander; Burmann, Inga; Regenthal, Ralf; Arélin, Katrin; Barth, Claudia; Pampel, André; Villringer, Arno; Margulies, Daniel S; Sacher, Julia

2014-10-01

14

A Reduced-Function Allele Reveals That EARLY FLOWERING3 Repressive Action on the Circadian Clock Is Modulated by Phytochrome Signals in Arabidopsis[C][W  

PubMed Central

Arabidopsis thaliana EARLY FLOWERING3 (ELF3) is essential for the generation of circadian rhythms. ELF3 has been proposed to restrict light signals to the oscillator through phytochrome photoreceptors, but that has not been explicitly shown. Furthermore, the genetic action of ELF3 within the clock had remained elusive. Here, we report a functional characterization of ELF3 through the analysis of the elf3-12 allele, which encodes an amino acid replacement in a conserved domain. Circadian oscillations persisted, and unlike elf3 null alleles, elf3-12 resulted in a short circadian period only under ambient light. The period shortening effect of elf3-12 was enhanced by the overexpression of phytochromes phyA and phyB. We found that elf3-12 was only modestly perturbed in resetting of the oscillator and in gating light-regulated gene expression. Furthermore, elf3-12 essentially displayed wild-type development. We identified targets of ELF3 transcriptional repression in the oscillator, highlighting the action at the morning gene PSEUDO-RESPONSE REGULATOR9. Taken together, we identified two separable roles for ELF3, one affecting the circadian network and the other affecting light input to the oscillator. This is consistent with a dual function of ELF3 as both an integrator of phytochrome signals and a repressor component of the core oscillator. PMID:21908721

Kolmos, Elsebeth; Herrero, Eva; Bujdoso, Nora; Millar, Andrew J.; Toth, Reka; Gyula, Peter; Nagy, Ferenc; Davis, Seth J.

2011-01-01

15

Revealing the Hidden Relationship by Sparse Modules in Complex Networks with a Large-Scale Analysis  

PubMed Central

One of the remarkable features of networks is module that can provide useful insights into not only network organizations but also functional behaviors between their components. Comprehensive efforts have been devoted to investigating cohesive modules in the past decade. However, it is still not clear whether there are important structural characteristics of the nodes that do not belong to any cohesive module. In order to answer this question, we performed a large-scale analysis on 25 complex networks with different types and scales using our recently developed BTS (bintree seeking) algorithm, which is able to detect both cohesive and sparse modules in the network. Our results reveal that the sparse modules composed by the cohesively isolated nodes widely co-exist with the cohesive modules. Detailed analysis shows that both types of modules provide better characterization for the division of a network into functional units than merely cohesive modules, because the sparse modules possibly re-organize the nodes in the so-called cohesive modules, which lack obvious modular significance, into meaningful groups. Compared with cohesive modules, the sizes of sparse ones are generally smaller. Sparse modules are also found to have preferences in social and biological networks than others. PMID:23762457

Jiao, Qing-Ju; Huang, Yan; Liu, Wei; Wang, Xiao-Fan; Chen, Xiao-Shuang; Shen, Hong-Bin

2013-01-01

16

Computer Simulations Reveal Multiple Functions for Aromatic  

E-print Network

Computer Simulations Reveal Multiple Functions for Aromatic Residues in Cellulase Enzymes NREL researchers use high-performance computing to demonstrate fundamental roles of aromatic residues in cellulase enzyme tunnels. National Renewable Energy Laboratory (NREL) computer simulations of a key indus- trial

17

Sensitivity of human auditory cortex to rapid frequency modulation revealed by multivariate representational similarity analysis  

PubMed Central

Functional Magnetic Resonance Imaging (fMRI) was used to investigate the extent, magnitude, and pattern of brain activity in response to rapid frequency-modulated sounds. We examined this by manipulating the direction (rise vs. fall) and the rate (fast vs. slow) of the apparent pitch of iterated rippled noise (IRN) bursts. Acoustic parameters were selected to capture features used in phoneme contrasts, however the stimuli themselves were not perceived as speech per se. Participants were scanned as they passively listened to sounds in an event-related paradigm. Univariate analyses revealed a greater level and extent of activation in bilateral auditory cortex in response to frequency-modulated sweeps compared to steady-state sounds. This effect was stronger in the left hemisphere. However, no regions showed selectivity for either rate or direction of frequency modulation. In contrast, multivoxel pattern analysis (MVPA) revealed feature-specific encoding for direction of modulation in auditory cortex bilaterally. Moreover, this effect was strongest when analyses were restricted to anatomical regions lying outside Heschl's gyrus. We found no support for feature-specific encoding of frequency modulation rate. Differential findings of modulation rate and direction of modulation are discussed with respect to their relevance to phonetic discrimination.

Joanisse, Marc F.; DeSouza, Diedre D.

2014-01-01

18

On function and operator modules  

Microsoft Academic Search

Let $A$ be a unital Banach algebra. We give a characterization of the left\\u000aBanach $A$-modules $X$ for which there exists a commutative unital\\u000a$C^*$-algebra $C(K)$, a linear isometry $i\\\\colon X\\\\to C(K)$, and a contractive\\u000aunital homomorphism $\\\\theta\\\\colon A\\\\to C(K)$ such that $i(a\\\\cdotp x)\\u000a=\\\\theta(a)i(x)$ for any $a\\\\in A, x\\\\in X$. We then deduce a \\

David P. Blecher; Christian Le Merdy

1999-01-01

19

Computational Integration of Homolog and Pathway Gene Module Expression Reveals General Stemness Signatures  

PubMed Central

The stemness hypothesis states that all stem cells use common mechanisms to regulate self-renewal and multi-lineage potential. However, gene expression meta-analyses at the single gene level have failed to identify a significant number of genes selectively expressed by a broad range of stem cell types. We hypothesized that stemness may be regulated by modules of homologs. While the expression of any single gene within a module may vary from one stem cell type to the next, it is possible that the expression of the module as a whole is required so that the expression of different, yet functionally-synonymous, homologs is needed in different stem cells. Thus, we developed a computational method to test for stem cell-specific gene expression patterns from a comprehensive collection of 49 murine datasets covering 12 different stem cell types. We identified 40 individual genes and 224 stemness modules with reproducible and specific up-regulation across multiple stem cell types. The stemness modules included families regulating chromatin remodeling, DNA repair, and Wnt signaling. Strikingly, the majority of modules represent evolutionarily related homologs. Moreover, a score based on the discovered modules could accurately distinguish stem cell-like populations from other cell types in both normal and cancer tissues. This scoring system revealed that both mouse and human metastatic populations exhibit higher stemness indices than non-metastatic populations, providing further evidence for a stem cell-driven component underlying the transformation to metastatic disease. PMID:21559491

Koeva, Martina; Forsberg, E. Camilla; Stuart, Joshua M.

2011-01-01

20

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

21

Working memory modulates attentional control as revealed by sequential effects  

Microsoft Academic Search

Sequential effect refers to the phenomenon that interference in conflict paradigms is smaller after incongruent trials than after congruent trials in tasks for which the stimuli contain irrelevant information. Currently, there are two major groups of interpretations of the sequential effects. One group suggests that enhanced attentional control after perceiving conflict in the preceding trial causes the modulations on attentional

Sufen Chen

2007-01-01

22

EFFERENT MODULATION OF HAIR CELL FUNCTION  

PubMed Central

Purpose of review This review covers papers published between 2010 and early 2011 that presented new findings on inner ear-efferents and their ability to modulate hair cell function. Recent findings Studies published within the review period have increased our understanding of efferent mechanisms on hair cells in the cochlear and vestibular sensory epithelium and provide insights on efferent contributions to the plasticity of bilateral auditory processing. The central nervous system controls the sensitivity of hair cells to physiological stimuli by regulating the gain of hair cell electromechanical amplification and modulating the efficiency of hair cell-8th nerve transmission. A notable advance in the past year has been animal and human studies that have examined the contribution of the olivocochlear efferents to sound localization particularly in a noisy environment. Summary Acoustic activation of olivocochlear fibers provides a clinical test for the integrity of the peripheral auditory system and has provided new understanding about the function and limitations of the cochlear amplifier. While similar tests may be possible in the efferent vestibular system they have not yet been developed. The structural and functional similarities of the sensory epithelia in the inner ear offer hope that testing procedures may be developed that will allow reliable testing of the vestibular hair cell function. PMID:22552698

RABBITT, RICHARD D.; BROWNELL, WILLIAM E.

2012-01-01

23

Modulation transfer function of pyroelectric linear arrays  

NASA Astrophysics Data System (ADS)

Spatial resolution, described by the modulation transfer function (MTF), is very important for multidimensional infrared sensors. The sensor-MTF of a pyroelectric linear array is determined by the geometric, thermal and capacitive MTF. These are calculated in detail by the use of a pyroelectric linear array developed at Dresden University of Technology, Institute for Solid-state Electronics. The linear array has 128 pixels with a centre-to-centre spacing of 100 ?m. Deuterated and L-alanine doped triglycine sulfate (DTGS:L-A) or lithium niobate (LiNbO 3) are used as pyroelectric materials. Finally, the theoretical results are substantiated by measurements.

Budzier, Helmut; Hofmann, Günter; Hess, Norbert

24

Modulation of granulocyte functions by bacterial exotoxin and endotoxins.  

PubMed

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. PMID:2889665

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

1987-11-01

25

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. PMID:2889665

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

1987-01-01

26

Bcl2-associated Athanogene 3 Interactome Analysis Reveals a New Role in Modulating Proteasome Activity*  

PubMed Central

Bcl2-associated athanogene 3 (BAG3), a member of the BAG family of co-chaperones, plays a critical role in regulating apoptosis, development, cell motility, autophagy, and tumor metastasis and in mediating cell adaptive responses to stressful stimuli. BAG3 carries a BAG domain, a WW domain, and a proline-rich repeat (PXXP), all of which mediate binding to different partners. To elucidate BAG3's interaction network at the molecular level, we employed quantitative immunoprecipitation combined with knockdown and human proteome microarrays to comprehensively profile the BAG3 interactome in humans. We identified a total of 382 BAG3-interacting proteins with diverse functions, including transferase activity, nucleic acid binding, transcription factors, proteases, and chaperones, suggesting that BAG3 is a critical regulator of diverse cellular functions. In addition, we characterized interactions between BAG3 and some of its newly identified partners in greater detail. In particular, bioinformatic analysis revealed that the BAG3 interactome is strongly enriched in proteins functioning within the proteasome-ubiquitination process and that compose the proteasome complex itself, suggesting that a critical biological function of BAG3 is associated with the proteasome. Functional studies demonstrated that BAG3 indeed interacts with the proteasome and modulates its activity, sustaining cell survival and underlying resistance to therapy through the down-modulation of apoptosis. Taken as a whole, this study expands our knowledge of the BAG3 interactome, provides a valuable resource for understanding how BAG3 affects different cellular functions, and demonstrates that biologically relevant data can be harvested using this kind of integrated approach. PMID:23824909

Chen, Ying; Yang, Li-Na; Cheng, Li; Tu, Shun; Guo, Shu-Juan; Le, Huang-Ying; Xiong, Qian; Mo, Ran; Li, Chong-Yang; Jeong, Jun-Seop; Jiang, Lizhi; Blackshaw, Seth; Bi, Li-Jun; Zhu, Heng; Tao, Sheng-Ce; Ge, Feng

2013-01-01

27

Acetylcholine-mediated modulation of striatal function.  

PubMed

Striatal spiny neurones serve as a major anatomical locus for the relay of cortical information flow through the basal ganglia. these projection neurones also represent the main synaptic target of cholinergic interneurones, whose physiological role in striatal activity still remains largely enigmatic. The striatal cholinergic system has been implicated in the pathophysiology of movement disorders such as Parkinson's disease, but the cellular mechanisms underlying cholinergic-neurone function are still unknown. On the basis of in vitro electrophysiological evidence, obtained from a rat corticostriatal-slice preparation, we propose that endogenous ACh exerts a complex modulation of striatal synaptic transmission, which produces both short-term and long-term effects. ACh-mediated mechanisms might be of crucial importance in processing the cortical inputs to the striatum. PMID:10675916

Calabresi, P; Centonze, D; Gubellini, P; Pisani, A; Bernardi, G

2000-03-01

28

Heterogeneity in neutrophil microparticles reveals distinct proteome and functional properties.  

PubMed

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. PMID:23660474

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

2013-08-01

29

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. PMID:23660474

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

2013-01-01

30

Viruses as Modulators of Mitochondrial Functions  

PubMed Central

Mitochondria are multifunctional organelles with diverse roles including energy production and distribution, apoptosis, eliciting host immune response, and causing diseases and aging. Mitochondria-mediated immune responses might be an evolutionary adaptation by which mitochondria might have prevented the entry of invading microorganisms thus establishing them as an integral part of the cell. This makes them a target for all the invading pathogens including viruses. Viruses either induce or inhibit various mitochondrial processes in a highly specific manner so that they can replicate and produce progeny. Some viruses encode the Bcl2 homologues to counter the proapoptotic functions of the cellular and mitochondrial proteins. Others modulate the permeability transition pore and either prevent or induce the release of the apoptotic proteins from the mitochondria. Viruses like Herpes simplex virus 1 deplete the host mitochondrial DNA and some, like human immunodeficiency virus, hijack the host mitochondrial proteins to function fully inside the host cell. All these processes involve the participation of cellular proteins, mitochondrial proteins, and virus specific proteins. This review will summarize the strategies employed by viruses to utilize cellular mitochondria for successful multiplication and production of progeny virus. PMID:24260034

Anand, Sanjeev K.; Tikoo, Suresh K.

2013-01-01

31

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  

Microsoft Academic Search

By means of an RT-PCR approach we isolated a specific tyrosine phosphatase (FsPTP1) induced by abscisic acid (ABA) and correlated\\u000a with seed dormancy in Fagus sylvatica seeds. To provide genetic evidence of FsPTP1 function in seed dormancy and ABA signal transduction pathway, we overexpressed\\u000a this gene in Cape Verde Island ecotype of Arabidopsis thaliana, which shows the deepest degree of

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

32

Novel Family of Carbohydrate-Binding Modules Revealed by the Genome Sequence of Spirochaeta thermophila DSM 6192 ? †  

PubMed Central

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

2011-01-01

33

Modulation transfer function measurement using nonspecific views  

NASA Astrophysics Data System (ADS)

The measurement of the Modulation Transfer Function (MTF) to quantify the quality of an imaging system proves to be very important in the context of Earth observation satellites. In particular, this measurement is essential to carry out the focusing of the telescope, or to implement a deconvolution filter whose goal is to enhance the image contrast or to reduce the noise. Its knowledge also allows us to compare the characteristics of different known and unknown satellites. In this paper, we suggest an univariant MTF measurement method using non specific views. First of all, the landscape has to be characterized in order to discriminate ground structure information from MTF information. Once this separation is carried out, landscape structure information can be extracted, allowing a classification between very uniform scenes and more structured ones. Then the MTF, which is described by a bidimensional analytical physical model, can be assessed using an artificial neural network. The principle is to use the artificial neural network to learn the MTF of simulated or perfectly known images, and then to use it to assess the MTF of totally unknown images. One can show that this method is robust even if the noise is taken into account. As a result, maximum MTF assessment errors are less than 10%. This enables us to suggest further developments including a general scheme of criteria assessment of image quality.

Delvit, Jean-Marc; Leger, Dominique; Roques, Sylvie; Valorge, Christophe

2003-03-01

34

Pattern codes for perceived gaze direction revealed by functional MRI  

E-print Network

Pattern codes for perceived gaze direction revealed by functional MRI Johan D. Carlin Hughes Hall University of Cambridge This dissertation is submitted for the degree of Doctor of Philosophy Preface This dissertation is the result of my own work... visit to Caltech and for offering me the opportunity to analyse macaque functional magnetic resonance imaging (fMRI) data. Their generosity and willingness to consider my ideas made a deep impression on me. Finally, I thank the Medical Research Council...

Carlin, Johan D.

2012-06-12

35

Nanoscale periodic modulations on sodium chloride surface revealed by tuning fork atomic force microscopy  

NASA Astrophysics Data System (ADS)

The sodium chloride surface is one of the most common platforms for the study of catalysts, thin film growth, and atmospheric aerosols. Here we report a nanoscale periodic modulation pattern on the surface of a cleaved NaCl single crystal, revealed by non-contact atomic force microscopy with a tuning fork sensor. The surface pattern shows two orthogonal domains, extending over the entire cleavage surface. The spatial modulations exhibit a characteristic period of 5.4 nm, along <110> crystallographic directions of the NaCl. The modulations are robust in vacuum, not affected by the tip-induced electric field or gentle annealing (<300?°C) however, they are eliminated after exposure to water and an atomically flat surface can be recovered by subsequent thermal annealing after water exposure. A strong electrostatic charging is revealed on the cleavage surface which may facilitate the formation of the observed metastable surface reconstruction.

Clark, Kendal W.; Qin, Shengyong; Zhang, X.-G.; Li, An-Ping

2012-05-01

36

Genome-wide analysis reveals mechanisms modulating autophagy in normal brain  

E-print Network

Genome-wide analysis reveals mechanisms modulating autophagy in normal brain aging and in Alzheimer of autophagy, a cellular catabolic mechanism essen- tial for degradation of misfolded proteins, has been implicated in multiple neurodegenerative diseases. However, the mechanisms that lead to the autophagy

37

Modulating noncatalytic function with kinase inhibitors.  

PubMed

In this issue of Chemistry & Biology, Hari and colleagues show that conformation-selective ATP-competitive kinase inhibitors have distinct noncatalytic effects on Erk2, including the ability to modulate protein-protein interactions outside the ATP-binding site. These findings enhance our knowledge about the diverse array of activities in which kinase inhibitors can target signaling pathways. PMID:24856138

Agius, Michael P; Soellner, Matthew B

2014-05-22

38

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. PMID:20100324

2010-01-01

39

Estimating the RAR modulation transfer function directly from SAR ocean wave image spectra  

Microsoft Academic Search

A new method for estimating the phase and amplitude of the real aperture radar (RAR) modulation transfer function (MTF) is proposed. Conventionally, in situ measurements of the seastate have been used in connection with SAR estimation of the RAR MTF. However, investigations using synthetic data reveal that the SAR image spectrum for realistic seastates is shaped by the unknown transfer

K. A. Hogda; S. Jacobsen

1993-01-01

40

Calcium Channel Function Regulated by the SH3-GK Module in ? Subunits  

Microsoft Academic Search

? subunits of voltage-gated calcium channels (VGCCs) regulate channel trafficking and function, thereby shaping the intensity and duration of intracellular changes in calcium. ? subunits share limited sequence homology with the Src homology 3-guanylate kinase (SH3-GK) module of membrane-associated guanylate kinases (MAGUKs). Here, we show biochemical similarities between ? subunits and MAGUKs, revealing important aspects of ? subunit structure and

Aaron W. McGee; Deborah A. Nunziato; Janet M. Maltez; Kenneth E. Prehoda; Geoffrey S. Pitt; David S. Bredt

2004-01-01

41

Identifying protein complexes and functional modules--from static PPI networks to dynamic PPI networks.  

PubMed

Cellular processes are typically carried out by protein complexes and functional modules. Identifying them plays an important role for our attempt to reveal principles of cellular organizations and functions. In this article, we review computational algorithms for identifying protein complexes and/or functional modules from protein-protein interaction (PPI) networks. We first describe issues and pitfalls when interpreting PPI networks. Then based on types of data used and main ideas involved, we briefly describe protein complex and/or functional module identification algorithms in four categories: (i) those based on topological structures of unweighted PPI networks; (ii) those based on characters of weighted PPI networks; (iii) those based on multiple data integrations; and (iv) those based on dynamic PPI networks. The PPI networks are modelled increasingly precise when integrating more types of data, and the study of protein complexes would benefit by shifting from static to dynamic PPI networks. PMID:23780996

Chen, Bolin; Fan, Weiwei; Liu, Juan; Wu, Fang-Xiang

2014-03-01

42

Towards the identification of protein complexes and functional modules by integrating PPI network and gene expression data  

PubMed Central

Background Identification of protein complexes and functional modules from protein-protein interaction (PPI) networks is crucial to understanding the principles of cellular organization and predicting protein functions. In the past few years, many computational methods have been proposed. However, most of them considered the PPI networks as static graphs and overlooked the dynamics inherent within these networks. Moreover, few of them can distinguish between protein complexes and functional modules. Results In this paper, a new framework is proposed to distinguish between protein complexes and functional modules by integrating gene expression data into protein-protein interaction (PPI) data. A series of time-sequenced subnetworks (TSNs) is constructed according to the time that the interactions were activated. The algorithm TSN-PCD was then developed to identify protein complexes from these TSNs. As protein complexes are significantly related to functional modules, a new algorithm DFM-CIN is proposed to discover functional modules based on the identified complexes. The experimental results show that the combination of temporal gene expression data with PPI data contributes to identifying protein complexes more precisely. A quantitative comparison based on f-measure reveals that our algorithm TSN-PCD outperforms the other previous protein complex discovery algorithms. Furthermore, we evaluate the identified functional modules by using “Biological Process” annotated in GO (Gene Ontology). The validation shows that the identified functional modules are statistically significant in terms of “Biological Process”. More importantly, the relationship between protein complexes and functional modules are studied. Conclusions The proposed framework based on the integration of PPI data and gene expression data makes it possible to identify protein complexes and functional modules more effectively. Moveover, the proposed new framework and algorithms can distinguish between protein complexes and functional modules. Our findings suggest that functional modules are closely related to protein complexes and a functional module may consist of one or multiple protein complexes. The program is available at http://netlab.csu.edu.cn/bioinfomatics/limin/DFM-CIN/index.html. PMID:22621308

2012-01-01

43

Muscarinic modulation of striatal function and circuitry.  

PubMed

Striatal cholinergic interneurons are pivotal modulators of the striatal circuitry involved in action selection and decision making. Although nicotinic receptors are important transducers of acetylcholine release in the striatum, muscarinic receptors are more pervasive and have been more thoroughly studied. In this review, the effects of muscarinic receptor signaling on the principal cell types in the striatum and its canonical circuits will be discussed, highlighting new insights into their role in synaptic integration and plasticity. These studies, and those that have identified new circuit elements driven by activation of nicotinic receptors, make it clear that temporally patterned activity in cholinergic interneurons must play an important role in determining the effects on striatal circuitry. These effects could be critical to the response to salient environmental stimuli that serve to direct behavior. PMID:22222701

Goldberg, Joshua A; Ding, Jun B; Surmeier, D James

2012-01-01

44

A systems biology approach using metabolomic data reveals genes and pathways interacting to modulate divergent growth in cattle  

PubMed Central

Background Systems biology enables the identification of gene networks that modulate complex traits. Comprehensive metabolomic analyses provide innovative phenotypes that are intermediate between the initiator of genetic variability, the genome, and raw phenotypes that are influenced by a large number of environmental effects. The present study combines two concepts, systems biology and metabolic analyses, in an approach without prior functional hypothesis in order to dissect genes and molecular pathways that modulate differential growth at the onset of puberty in male cattle. Furthermore, this integrative strategy was applied to specifically explore distinctive gene interactions of non-SMC condensin I complex, subunit G (NCAPG) and myostatin (GDF8), known modulators of pre- and postnatal growth that are only partially understood for their molecular pathways affecting differential body weight. Results Our study successfully established gene networks and interacting partners affecting growth at the onset of puberty in cattle. We demonstrated the biological relevance of the created networks by comparison to randomly created networks. Our data showed that GnRH (Gonadotropin-releasing hormone) signaling is associated with divergent growth at the onset of puberty and revealed two highly connected hubs, BTC and DGKH, within the network. Both genes are known to directly interact with the GnRH signaling pathway. Furthermore, a gene interaction network for NCAPG containing 14 densely connected genes revealed novel information concerning the functional role of NCAPG in divergent growth. Conclusions Merging both concepts, systems biology and metabolomic analyses, successfully yielded new insights into gene networks and interacting partners affecting growth at the onset of puberty in cattle. Genetic modulation in GnRH signaling was identified as key modifier of differential cattle growth at the onset of puberty. In addition, the benefit of our innovative concept without prior functional hypothesis was demonstrated by data suggesting that NCAPG might contribute to vascular smooth muscle contraction by indirect effects on the NO pathway via modulation of arginine metabolism. Our study shows for the first time in cattle that integration of genetic, physiological and metabolomics data in a systems biology approach will enable (or contribute to) an improved understanding of metabolic and gene networks and genotype-phenotype relationships. PMID:24246134

2013-01-01

45

Forced unfolding of the fibronectin type III module reveals a tensile molecular recognition switch.  

PubMed

The 10th type III module of fibronectin possesses a beta-sandwich structure consisting of seven beta-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 beta-strands F and G. Steered molecular dynamics simulations in which tension is applied to the protein's terminal ends reveal that the beta-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 beta-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. PMID:9990027

Krammer, A; Lu, H; Isralewitz, B; Schulten, K; Vogel, V

1999-02-16

46

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

47

Proteomic profiling reveals insights into Triticeae stigma development and function  

PubMed Central

To our knowledge, this study represents the first high-throughput characterization of a stigma proteome in the Triticeae. A total of 2184 triticale mature stigma proteins were identified using three different gel-based approaches combined with mass spectrometry. The great majority of these proteins are described in a Triticeae stigma for the first time. These results revealed many proteins likely to play important roles in stigma development and pollen–stigma interactions, as well as protection against biotic and abiotic stresses. Quantitative comparison of the triticale stigma transcriptome and proteome showed poor correlation, highlighting the importance of having both types of analysis. This work makes a significant contribution towards the elucidation of the Triticeae stigma proteome and provides novel insights into its role in stigma development and function. PMID:25170101

Nazemof, Nazila; Couroux, Philippe; Rampitsch, Christof; Xing, Tim; Robert, Laurian S.

2014-01-01

48

Calmodulin modulates insect odorant receptor function.  

PubMed

Insect odorant receptors (ORs) are heteromeric complexes of an odor-specific receptor protein (OrX) and a ubiquitous co-receptor protein (Orco). The ORs operate as non-selective cation channels, also conducting Ca(2+) ions. The Orco protein contains a conserved putative calmodulin (CaM)-binding motif indicating a role of CaM in its function. Using Ca(2+) imaging to monitor OR activity we investigated the effect of CaM inhibition on the function of OR proteins. Ca(2+) responses elicited in Drosophila olfactory sensory neurons by stimulation with the synthetic OR agonist VUAA1 were reduced and prolonged by CaM inhibition with the potent antagonist W7 but not with the weak antagonist W5. A similar effect was observed for Orco proteins heterologously expressed in CHO cells when CaM was inhibited with W7, trifluoperazine or chlorpromazine, or upon overexpression of CaM-EF-hand mutants. With the Orco CaM mutant bearing a point mutation in the putative CaM site (K339N) the Ca(2+) responses were akin to those obtained for wild type Orco in the presence of W7. There was no uniform effect of W7 on Ca(2+) responses in CHO cells expressing complete ORs (Or22a/Orco, Or47a/Orco, Or33a/Orco, Or56a/Orco). For Or33a and Or47a we observed no significant effect of W7, while it caused a reduced response in cells expressing Or22a and a shortened response for Or56a. PMID:24661599

Mukunda, Latha; Miazzi, Fabio; Kaltofen, Sabine; Hansson, Bill S; Wicher, Dieter

2014-04-01

49

Macrophages modulate cardiac function in lipotoxic cardiomyopathy  

PubMed Central

Diabetes is associated with myocardial lipid accumulation and an increased risk of heart failure. Although cardiac myocyte lipid overload is thought to contribute to the pathogenesis of cardiomyopathy in the setting of diabetes, the mechanism(s) through which this occurs is not well understood. Increasingly, inflammation has been recognized as a key pathogenic feature of lipid excess and diabetes. In this study, we sought to investigate the role of inflammatory activation in the pathogenesis of lipotoxic cardiomyopathy using the ?-myosin heavy chain promoter-driven long-chain acylCoA synthetase 1 (MHC-ACS) transgenic mouse model. We found that several inflammatory cytokines were upregulated in the myocardium of MHC-ACS mice before the onset of cardiac dysfunction, and this was accompanied by macrophage infiltration. Depletion of macrophages with liposomal clodrolip reduced the cardiac inflammatory response and improved cardiac function. Thus, in this model of lipotoxic cardiac injury, early induction of inflammation and macrophage recruitment contribute to adverse cardiac remodeling. These findings have implications for our understanding of heart failure in the setting of obesity and diabetes. PMID:23042950

Schilling, Joel D.; Machkovech, Heather M.; Kim, Alfred H. J.; Schwedwener, Reto

2012-01-01

50

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. PMID:22566962

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

2012-01-01

51

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

52

DNA-scaffolded multivalent ligands to modulate cell function.  

PubMed

We report a simple, versatile, multivalent ligand system that is capable of specifically and efficiently modulating cell-surface receptor clustering and function. The multivalent ligand is made of a polymeric DNA scaffold decorated with biorecognition ligands (i.e., antibodies) to interrogate and modulate cell receptor signaling and function. Using CD20 clustering-mediated apoptosis in B-cell cancer cells as a model system, we demonstrated that our multivalent ligand is significantly more effective at inducing apoptosis of target cancer cells than its monovalent counterpart. This multivalent DNA material approach represents a new chemical biology tool to interrogate cell receptor signaling and functions and to potentially manipulate such functions for the development of therapeutics. PMID:24803415

Zhang, Zhiqing; Eckert, Mark A; Ali, M Monsur; Liu, Linan; Kang, Dong-Ku; Chang, Elizabeth; Pone, Egest J; Sender, Leonard S; Fruman, David A; Zhao, Weian

2014-06-16

53

Development/Plasticity/Repair Functional Requirements for Reward-Modulated  

E-print Network

, animals change their be- havior so as to receive rewards (e.g., juice or food pellets) or avoid aversiveDevelopment/Plasticity/Repair Functional Requirements for Reward-Modulated Spike by neuromodulation. We derive theoretical conditions for successful learning of reward-related behavior for a large

Gerstner, Wulfram

54

17?-Estradiol Modulates hMT1 Melatonin Receptor Function  

Microsoft Academic Search

Estrogen modulates expression and function of G-protein-coupled receptors. The goal of this study was to assess the effect of 17?-estradiol (10 nM) exposure for 1 (E1) or 6 (E6) days on density and function of hMT1 and hMT2 melatonin receptors expressed in Chinese hamster ovary (CHO) cells (CHO-MT1\\/CHO-MT2 cells). This strain of CHO cells expressed both estrogen receptor alpha and

Monica I. Masana; Jose M. Soares Jr.; Margarita L. Dubocovich

2005-01-01

55

Functional connectivity of frontoparietal network predicts cognitive modulation of pain  

PubMed Central

The experience of pain can be significantly influenced by expectancy (predictive cues). This ability to modulate pain has the potential to affect therapeutic analgesia substantially and constitutes a foundation for non-pharmacological pain relief. In this study, we investigated 1) brain regions involved in visual cue modulation of pain during anticipation of pain, pain administration, and pain rating; and 2) the association between pre-test resting-state functional connectivity and the magnitude of cue effects on pain ratings. We found that after cue conditioning, visual cues can significantly modulate subjective pain ratings. fMRI results suggested that brain regions pertaining to the frontoparietal network (prefrontal and parietal cortex) and a pain/emotion modulatory region (rostral anterior cingulate cortex, rACC) are involved in cue modulation during both pain anticipation and administration stage. Most interestingly, we found that pre-test resting state functional connectivity between the frontoparietal network (as identified by independent component analysis) and the rACC/MPFC was positively associated with cue effects on pain rating changes. We believe that these finding will shed new light on our understanding of variable cue/expectancy effects across individuals and how the intrinsic connectivity of the brain may influence expectancy induced modulation of pain. PMID:23352757

Kong, Jian; Jensen, Karin; Loiotile, Rita; Cheetham, Alexandra; Wey, Hsiao-Ying; Tan, Ying; Rosen, Bruce; Smoller, Jordan W.; Kaptchuk, Ted J.; Gollub, Randy L.

2013-01-01

56

Microarray analysis reveals global modulation of endogenous retroelement transcription by microbes  

PubMed Central

Background A substantial proportion of both the mouse and human genomes comprise of endogenous retroelements (REs), which include endogenous retroviruses. Over evolutionary time, REs accumulate inactivating mutations or deletions and thus lose the ability to replicate. Additionally, REs can be transcriptionally repressed by dedicated mechanisms of the host. Nevertheless, many of them still possess and express intact open reading frames, and their transcriptional activity has been associated with many physiological and pathological processes of the host. However, this association remains tenuous due to incomplete understanding of the mechanism by which RE transcription is regulated. Here, we use a bioinformatics tool to examine RE transcriptional activity, measured by microarrays, in murine and human immune cells responding to microbial stimulation. Results Immune cell activation by microbial signals in vitro caused extensive changes in the transcription not only of the host genes involved in the immune response, but also of numerous REs. Modulated REs were frequently found near or embedded within similarly-modulated host genes. Focusing on probes reporting single-integration, intergenic REs, revealed extensive transcriptional responsiveness of these elements to microbial signals. Microbial stimulation modulated RE expression in a cell-intrinsic manner. In line with these results, the transcriptional activity of numerous REs followed characteristics in different tissues according to exposure to environmental microbes and was further heavily altered during viral infection or imbalances with intestinal microbiota, both in mice and humans. Conclusions Together, these results highlight the utility of improved methodologies in assessing RE transcription profiles in both archived and new microarray data sets. More importantly, application of this methodology suggests that immune activation, as a result of infection with pathogens or dysbiosis with commensal microbes, causes global modulation of RE transcription. RE responsiveness to external stimuli should, therefore, be considered in any association between RE transcription and disease. PMID:25063042

2014-01-01

57

Sodium tungstate modulates ATM function upon DNA damage.  

PubMed

Both radiotherapy and most effective chemotherapeutic agents induce different types of DNA damage. Here we show that tungstate modulates cell response to DNA damaging agents. Cells treated with tungstate were more sensitive to etoposide, phleomycin and ionizing radiation (IR), all of which induce DNA double-strand breaks (DSBs). Tungstate also modulated the activation of the central DSB signalling kinase, ATM, in response to these agents. These effects required the functionality of the Mre11-Nbs1-Rad50 (MRN) complex and were mimicked by the inhibition of PP2A phosphatase. Therefore, tungstate may have adjuvant activity when combined with DNA-damaging agents in the treatment of several malignancies. PMID:23587483

Rodriguez-Hernandez, C J; Llorens-Agost, M; Calbó, J; Murguia, J R; Guinovart, J J

2013-05-21

58

Systematic Identification of Functional Plant Modules through the Integration of Complementary Data Sources1[W][OA  

PubMed Central

A major challenge is to unravel how genes interact and are regulated to exert specific biological functions. The integration of genome-wide functional genomics data, followed by the construction of gene networks, provides a powerful approach to identify functional gene modules. Large-scale expression data, functional gene annotations, experimental protein-protein interactions, and transcription factor-target interactions were integrated to delineate modules in Arabidopsis (Arabidopsis thaliana). The different experimental input data sets showed little overlap, demonstrating the advantage of combining multiple data types to study gene function and regulation. In the set of 1,563 modules covering 13,142 genes, most modules displayed strong coexpression, but functional and cis-regulatory coherence was less prevalent. Highly connected hub genes showed a significant enrichment toward embryo lethality and evidence for cross talk between different biological processes. Comparative analysis revealed that 58% of the modules showed conserved coexpression across multiple plants. Using module-based functional predictions, 5,562 genes were annotated, and an evaluation experiment disclosed that, based on 197 recently experimentally characterized genes, 38.1% of these functions could be inferred through the module context. Examples of confirmed genes of unknown function related to cell wall biogenesis, xylem and phloem pattern formation, cell cycle, hormone stimulus, and circadian rhythm highlight the potential to identify new gene functions. The module-based predictions offer new biological hypotheses for functionally unknown genes in Arabidopsis (1,701 genes) and six other plant species (43,621 genes). Furthermore, the inferred modules provide new insights into the conservation of coexpression and coregulation as well as a starting point for comparative functional annotation. PMID:22589469

Heyndrickx, Ken S.; Vandepoele, Klaas

2012-01-01

59

Band gap modulation of functionalized metal-organic frameworks.  

PubMed

Metal-organic frameworks (MOFs) have been envisioned as alternatives to planar metallic catalysts for solar-to-fuel conversion. This is a direct result of their porous structure and the ability to tailor their optical absorption properties. This study investigates the band gap modulation of Zr-UiO-66 MOFs from both the computational and experimental points of view for three linker designs that include benzenedicarboxylate (BDC), BDC-NO2, and BDC-NH2. Emphasis in this study was aimed at understanding the influence of the bonding between the aromatic ring and the functional group. A ground state density functional theory (DFT) calculation was carried out to investigate the projected density of states and the origins of the modulation. A time-dependent density functional theory (TDDFT) calculation of the hydrogen terminated linkers confirmed the modulation and accounted for the electron charge transfer providing comparable optical band gap predictions to experimental results. Computational results confirmed the hybridization of the carbon-nitrogen bond in conjunction with the donor state resulting from the NH2 functionalization. The NO2 functionalization resulted in an acceptor configuration with marginal modification to the valence band maximum. The largest modulation was BDC-NH2 with a band gap of 2.75 eV, followed by BDC-NO2 with a band gap of 2.93 eV and BDC with a band gap of 3.76 eV. The electron effective mass was predicted from the band structure to be 8.9 me for all MOF designs. PMID:25269595

Musho, Terence; Li, Jiangtan; Wu, Nianqiang

2014-11-21

60

Modulation transfer function of a triangular pixel array detector.  

PubMed

The modulation transfer function (MTF) is the main parameter that is used to evaluate image quality in electro-optical systems. Detector sampling MTF in most electro-optical systems determines the cutoff frequency of the system. The MTF of the detector depends on its pixel shape. In this work, we calculated the MTF of a detector with an equilateral triangular pixel shape. Some new results were found in deriving the MTF for the equilateral triangular pixel shape. PMID:25121458

Karimzadeh, Ayatollah

2014-07-01

61

Parametric dependence of ocean wave-radar modulation transfer functions  

NASA Technical Reports Server (NTRS)

Microwave techniques at X and L band were used to determine the dependence of ocean-wave radar modulation transfer functions (MTFs) on various environmental and radar parameters during the Marine Remote Sensing experiment of 1979 (MARSEN 79). These MIF are presented, as are coherence functions between the AM and FM parts of the backscattered microwave signal. It is shown that they both depend on several of these parameters. Besides confirming many of the properties of transfer functions reported by previous authors, indications are found that MTFs decrease with increasing angle between wave propagation and antenna-look directions but are essentially independent of small changes in air-sea temperature difference. However, coherence functions are much smaller when the antennas are pointed perpendicular to long waves. It is found that X band transfer functions measured with horizontally polarized microwave radiation have larger magnitudes than those obtained by using vertical polarization.

Plant, W. J.; Keller, W. C.; Cross, A.

1983-01-01

62

Degree of musical expertise modulates higher order brain functioning.  

PubMed

Using functional magnetic resonance imaging, we show for the first time that levels of musical expertise stepwise modulate higher order brain functioning. This suggests that degree of training intensity drives such cerebral plasticity. Participants (non-musicians, amateurs, and expert musicians) listened to a comprehensive set of specifically composed string quartets with hierarchically manipulated endings. In particular, we implemented 2 irregularities at musical closure that differed in salience but were both within the tonality of the piece (in-key). Behavioral sensitivity scores (d') of both transgressions perfectly separated participants according to their level of musical expertise. By contrasting brain responses to harmonic transgressions against regular endings, functional brain imaging data showed compelling evidence for stepwise modulation of brain responses by both violation strength and expertise level in a fronto-temporal network hosting universal functions of working memory and attention. Additional independent testing evidenced an advantage in visual working memory for the professionals, which could be predicted by musical training intensity. The here introduced findings of brain plasticity demonstrate the progressive impact of musical training on cognitive brain functions that may manifest well beyond the field of music processing. PMID:22832388

Oechslin, Mathias S; Van De Ville, Dimitri; Lazeyras, François; Hauert, Claude-Alain; James, Clara E

2013-09-01

63

The response function of modulated grid Faraday cup plasma instruments  

NASA Technical Reports Server (NTRS)

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

64

Separate modifiability, mental modules, and the use of pure and composite measures to reveal them.  

PubMed

How can we divide a complex mental process into meaningful parts? In this paper, I explore an approach in which processes are divided into parts that are modular in the sense of being separately modifiable. Evidence for separate modifiability is provided by an instance of selective influence: two factors F and G (usually experimental manipulations) such that part A is influenced by F but invariant with respect to G, while part B is influenced by G but invariant with respect to F. Such evidence also indicates that the modules are functionally distinct. If we have pure measures MA and MB, each of which reflects only one of the parts, we need to show that MA is influenced by F but not G, while MB is influenced by G but not F. If we have only a composite measure MAB of the entire process, we usually also need to confirm a combination rule for how the parts contribute to MAB. I present a taxonomy of separate-modifiability methods, discuss their inferential logic, and describe several examples in each category. The three categories involve measures that are derived pure (based on different transformations of the same data; example: separation of sensory and decision processes by signal detection theory), direct pure (based on different data; example: selective effects of adaptation on spatial-frequency thresholds), and composite (examples: the multiplicative-factor method for the analysis of response rate; the additive-factor method for the analysis of reaction time). Six of the examples concern behavioral measures and functional processes, while four concern brain measures and neural processes. They have been chosen for their interest and importance; their diversity of measures, species, and combination rules; their illustration of different ways of thinking about data; the questions they suggest about possibilities and limitations of the separate-modifiability approach; and the case they make for the fruitfulness of searching for mental modules. PMID:11256336

Sternberg, S

2001-01-01

65

Motor Imagery Learning Modulates Functional Connectivity of Multiple Brain Systems in Resting State  

PubMed Central

Background Learning motor skills involves subsequent modulation of resting-state functional connectivity in the sensory-motor system. This idea was mostly derived from the investigations on motor execution learning which mainly recruits the processing of sensory-motor information. Behavioral evidences demonstrated that motor skills in our daily lives could be learned through imagery procedures. However, it remains unclear whether the modulation of resting-state functional connectivity also exists in the sensory-motor system after motor imagery learning. Methodology/Principal Findings We performed a fMRI investigation on motor imagery learning from resting state. Based on previous studies, we identified eight sensory and cognitive resting-state networks (RSNs) corresponding to the brain systems and further explored the functional connectivity of these RSNs through the assessments, connectivity and network strengths before and after the two-week consecutive learning. Two intriguing results were revealed: (1) The sensory RSNs, specifically sensory-motor and lateral visual networks exhibited greater connectivity strengths in precuneus and fusiform gyrus after learning; (2) Decreased network strength induced by learning was proved in the default mode network, a cognitive RSN. Conclusions/Significance These results indicated that resting-state functional connectivity could be modulated by motor imagery learning in multiple brain systems, and such modulation displayed in the sensory-motor, visual and default brain systems may be associated with the establishment of motor schema and the regulation of introspective thought. These findings further revealed the neural substrates underlying motor skill learning and potentially provided new insights into the therapeutic benefits of motor imagery learning. PMID:24465577

Zhang, Hang; Long, Zhiying; Ge, Ruiyang; Xu, Lele; Jin, Zhen; Yao, Li; Liu, Yijun

2014-01-01

66

A Rule-based Detection of Functional Modules in Protein-Protein Interaction Networks  

Microsoft Academic Search

In the protein-protein interaction (PPI) network there are many functional modules, each involving several protein interactions to perform discrete functions. Pathways and protein complexes are the examples of the functional modules. In this paper, we propose a rule-based method for detecting the modules. The rule is expressed in terms of triples and operators between the triples. The former represents conceptual

Jongmin Park; Jaehun Choi; Jaedong Yang; Soo-Jun Park

2006-01-01

67

Modulating executive functioning: Trait motivational reactivity and resting HRV.  

PubMed

This study assessed relationships among individual differences in trait motivational reactivity, executive functioning, and neurovisceral regulation of emotion and attention indexed via resting heart rate variability (rHRV). We derived predictions regarding these relationships according to neurovisceral neural network theory. Because lower rHRV has been suggested as an endophenotype of less adaptive behaviour, low rHRV individuals were predicted to have high aversive and low appetitive trait motivational reactivity, while high rHRV individuals were predicted to have high reactivity in both appetitive and aversive motivational systems. These predictions were supported. Motivational reactivity also was related to executive functioning deficits, although the pattern of results was not in the predicted direction. Results suggest that trait motivational reactivity scores are related to visceral responses proposed in the neurovisceral integration circuit as well as in the modulation of these responses by higher-order cognitive control systems related to executive function. PMID:24606341

Bailey, Rachel L; Potter, Robert F; Lang, Annie; Pisoni, David B

2015-01-01

68

Functional specification of the Performance Measurement (PM) module  

NASA Technical Reports Server (NTRS)

The design of the Performance Measurement Module is described with emphasis on what the PM Module would do, and what it would look like to the user. The PM Module as described could take several man-years to develop. An evolutionary approach to the implementation of the PM Module is presented which would provide an operational baseline PM Module within a few months.

Berliner, J. E.

1980-01-01

69

Thiolactone modulators of quorum sensing revealed through library design and screening.  

PubMed

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. PMID:21798746

McInnis, Christine E; Blackwell, Helen E

2011-08-15

70

Solution structure of the Big domain from Streptococcus pneumoniae reveals a novel Ca2+-binding module  

PubMed Central

Streptococcus pneumoniae is a pathogen causing acute respiratory infection, otitis media and some other severe diseases in human. In this study, the solution structure of a bacterial immunoglobulin-like (Big) domain from a putative S. pneumoniae surface protein SP0498 was determined by NMR spectroscopy. SP0498 Big domain adopts an eight-?-strand barrel-like fold, which is different in some aspects from the two-sheet sandwich-like fold of the canonical Ig-like domains. Intriguingly, we identified that the SP0498 Big domain was a Ca2+ binding domain. The structure of the Big domain is different from those of the well known Ca2+ binding domains, therefore revealing a novel Ca2+-binding module. Furthermore, we identified the critical residues responsible for the binding to Ca2+. We are the first to report the interactions between the Big domain and Ca2+ in terms of structure, suggesting an important role of the Big domain in many essential calcium-dependent cellular processes such as pathogenesis. PMID:23326635

Wang, Tao; Zhang, Jiahai; Zhang, Xuecheng; Xu, Chao; Tu, Xiaoming

2013-01-01

71

Single particle tracking with sterol modulation reveals the cholesterol-mediated diffusion properties of integrin receptors  

NASA Astrophysics Data System (ADS)

A combination of sterol modulation with cyclodextrins plus fluorescence microscopy revealed a biophysical mechanism behind cholesterol’s influence on the diffusion of a ubiquitous class of receptors called integrins. The heterogeneous diffusion of integrins bound to ligand-coated quantum dots was measured using single particle tracking (SPT), and the ensemble changes in integrin diffusion were measured by fluorescence recovery after photobleaching (FRAP). A 25 ± 1% reduction of membrane cholesterol resulted in three significant changes to the diffusion of ligand-bound ?PS2C?PS integrins as measured by SPT. There was a 23% increase in ligand-bound mobile integrins; there was a statistically significant increase in the average diffusion coefficient inside zones of confined diffusion, and histograms of confined integrin trajectories showed an increased frequency in the range of 0.1–1 ?m2 s?1 and a decreased frequency in the 0.001–0.1 ?m2 s?1 range. No statistical change was measured in the duration of confinement nor the size of confined zones. Restoring the cholesterol-depleted cells with exogenous cholesterol or exogenous epicholesterol resulted in similar diffusion properties. Epicholesterol differs from cholesterol in the orientation of a single hydroxyl group. The ability of epicholesterol to substitute for cholesterol suggests a biophysical mechanism for cholesterol’s effect on integrin diffusion. Influences of bilayer thickness, viscosity and organization are discussed as possible explanations for the measured changes in integrin diffusion when the membrane cholesterol concentration is reduced.

Arora, Neha; Syed, Aleem; Sander, Suzanne; Smith, Emily A.

2014-12-01

72

Single particle tracking with sterol modulation reveals the cholesterol-mediated diffusion properties of integrin receptors.  

PubMed

A combination of sterol modulation with cyclodextrins plus fluorescence microscopy revealed a biophysical mechanism behind cholesterol's influence on the diffusion of a ubiquitous class of receptors called integrins. The heterogeneous diffusion of integrins bound to ligand-coated quantum dots was measured using single particle tracking (SPT), and the ensemble changes in integrin diffusion were measured by fluorescence recovery after photobleaching (FRAP). A 25 ± 1% reduction of membrane cholesterol resulted in three significant changes to the diffusion of ligand-bound ?PS2C?PS integrins as measured by SPT. There was a 23% increase in ligand-bound mobile integrins; there was a statistically significant increase in the average diffusion coefficient inside zones of confined diffusion, and histograms of confined integrin trajectories showed an increased frequency in the range of 0.1-1 ?m(2) s(-1) and a decreased frequency in the 0.001-0.1 ?m(2) s(-1) range. No statistical change was measured in the duration of confinement nor the size of confined zones. Restoring the cholesterol-depleted cells with exogenous cholesterol or exogenous epicholesterol resulted in similar diffusion properties. Epicholesterol differs from cholesterol in the orientation of a single hydroxyl group. The ability of epicholesterol to substitute for cholesterol suggests a biophysical mechanism for cholesterol's effect on integrin diffusion. Influences of bilayer thickness, viscosity and organization are discussed as possible explanations for the measured changes in integrin diffusion when the membrane cholesterol concentration is reduced. PMID:25289754

Arora, Neha; Syed, Aleem; Sander, Suzanne; Smith, Emily A

2014-01-01

73

Revealing the dynamic structure of complex solid catalysts using modulated excitation X-ray diffraction.  

PubMed

X-ray diffraction (XRD) is typically silent towards information on low loadings of precious metals on solid catalysts because of their finely dispersed nature. When combined with a concentration modulation approach, time-resolved high-energy XRD is able to provide the detailed redox dynamics of palladium nanoparticles with a diameter of 2?nm in 2?wt?% Pd/CZ (CZ = ceria-zirconia), which is a difficult sample for extended X-ray absorption fine structure (EXAFS) measurements because of the cerium component. The temporal evolution of the Pd(111) and Ce(111) reflections together with surface information from synchronous diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS) measurements reveals that Ce maintains Pd oxidized in the CO pulse, whereas reduction is detected at the beginning of the O2 pulse. Oxygen is likely transferred from Pd to Ce(3+) before the onset of Pd re-oxidation. In this context, adsorbed carbonates appear to be the rate-limiting species for re-oxidation. PMID:24903631

Ferri, Davide; Newton, Mark A; Di Michiel, Marco; Chiarello, Gian Luca; Yoon, Songhak; Lu, Ye; Andrieux, Jérôme

2014-08-18

74

Bessel-like beams modulated by arbitrary radial functions  

PubMed

An approximate method for determining the radial and axial intensity of a Bessel-like beam is presented for the general case in which a radial Bessel distribution of any order is modulated by an arbitrary function. For Bessel-Gauss, generalized Bessel-Gauss, and Bessel-super-Gauss beams, this simple approximation yields results that are very close to the exact values, while they are exact for Bessel beams. A practical beam that can be generated with a combination of simple lenses is also analyzed and illustrated. PMID:10850472

Herman; Wiggins

2000-06-01

75

Functional Imaging Reveals Numerous Fields in the Monkey Auditory Cortex  

PubMed Central

Anatomical studies propose that the primate auditory cortex contains more fields than have actually been functionally confirmed or described. Spatially resolved functional magnetic resonance imaging (fMRI) with carefully designed acoustical stimulation could be ideally suited to extend our understanding of the processing within these fields. However, after numerous experiments in humans, many auditory fields remain poorly characterized. Imaging the macaque monkey is of particular interest as these species have a richer set of anatomical and neurophysiological data to clarify the source of the imaged activity. We functionally mapped the auditory cortex of behaving and of anesthetized macaque monkeys with high resolution fMRI. By optimizing our imaging and stimulation procedures, we obtained robust activity throughout auditory cortex using tonal and band-passed noise sounds. Then, by varying the frequency content of the sounds, spatially specific activity patterns were observed over this region. As a result, the activity patterns could be assigned to many auditory cortical fields, including those whose functional properties were previously undescribed. The results provide an extensive functional tessellation of the macaque auditory cortex and suggest that 11 fields contain neurons tuned for the frequency of sounds. This study provides functional support for a model where three fields in primary auditory cortex are surrounded by eight neighboring “belt” fields in non-primary auditory cortex. The findings can now guide neurophysiological recordings in the monkey to expand our understanding of the processing within these fields. Additionally, this work will improve fMRI investigations of the human auditory cortex. PMID:16774452

Kayser, Christoph; Augath, Mark; Logothetis, Nikos K

2006-01-01

76

Walk the Line: A Module on Linear Functions  

NSDL National Science Digital Library

Prepared with pre-algebra or algebra 1 classes in mind, this module leads students through the process of graphing data and finding a line of best fit while exploring the characteristics of linear equations in algebraic and graphic formats. Then, these topics are connected to real-world experiences in which people use linear functions. During the module, students use these scientific concepts to solve the following hypothetical challenge: You are a new researcher in a lab, and your boss has just given you your first task to analyze a set of data. It being your first assignment, you ask an undergraduate student working in your lab to help you figure it out. She responds that you must determine what the data represents and then find an equation that models the data. You believe that you will be able to determine what the data represents on your own, but you ask for further help modeling the data. In response, she says she is not completely sure how to do it, but gives a list of equations that may fit the data. This module is built around the legacy cycle, a format that incorporates educational research feindings on how people best learn.

Vu Bioengineering Ret Program

77

Walk the Line: A Module on Linear Functions  

NSDL National Science Digital Library

This module was written for a Pre-Algebra or Algebra I class in mind. It will lead students through the process of graphing data and finding a line of best fit while simultaneously exploring the characteristics of linear equations in algebraic and graphic formats. These topics are then tied back into real-world experiences in which people use linear functions. During the module, students utilize these scientific concepts to solve the following problem: You are a new researcher in a lab, and your boss has just given you your first task to analyze a set of data. It being your first assignment, you ask an undergraduate student working in your lab to help you figure it out. She responds that you must determine what the data represents and then find an equation which models the data. You determine that you will be able to determine what the data represents on your own, but you ask for further help modeling the data. In response, she says she is not completely sure how to do it, but gives a list of equations that may fit the data. This module is built around the Legacy Cycle, a format that incorporates findings from educational research on how people best learn.

VU Bioengineering RET Program, School of Engineering,; Mckelvey, Aubrey

2007-01-01

78

Unsuspected functional disparity in Devonian fishes revealed by tooth morphometrics?  

PubMed

The shape of features involved in key biological functions, such as teeth in nutrition, can provide insights into ecological processes even in ancient time, by linking the occupation of the morphological space (disparity) to the occupation of the ecological space. Investigating disparity in radiating groups may provide insights into the ecological diversification underlying evolution of morphological diversity. Actinopterygian fishes initiated their radiation in the Devonian, a period characterized by the diversification of marine ecosystem. Although a former morpho-functional analysis of jaw shape concluded to conservative and poorly diversified morphologies in this early part of their history, fish tooth disparity evidenced here an unsuspected diversity of possible functional significance in the pivotal period of the Late Devonian (Famennian). All teeth being caniniforms, some were stocky and robust, in agreement with expectations for active generalist predators. More surprisingly, elongated teeth also occurred at the beginning of Famennian. Their needle-like shape challenges morpho-functional interpretations by making them fragile in response to bending or torsion. The occurrence of both types of fish teeth during the beginning of the Famennian points to a discrete but real increase in disparity, thus testifying a first burst of feeding specialization despite overall conservative jaw morphology. The disappearance of these needle-like teeth in the Late Famennian might have been related to a relay in dental diversity with abundant co-occurring groups, namely conodonts and chondrichthyans (sharks). PMID:25078254

Gauchey, Samuel; Girard, Catherine; Adnet, Sylvain; Renaud, Sabrina

2014-09-01

79

Systematic Analysis of Experimental Phenotype Data Reveals Gene Functions  

PubMed Central

High-throughput phenotyping projects in model organisms have the potential to improve our understanding of gene functions and their role in living organisms. We have developed a computational, knowledge-based approach to automatically infer gene functions from phenotypic manifestations and applied this approach to yeast (Saccharomyces cerevisiae), nematode worm (Caenorhabditis elegans), zebrafish (Danio rerio), fruitfly (Drosophila melanogaster) and mouse (Mus musculus) phenotypes. Our approach is based on the assumption that, if a mutation in a gene leads to a phenotypic abnormality in a process , then must have been involved in , either directly or indirectly. We systematically analyze recorded phenotypes in animal models using the formal definitions created for phenotype ontologies. We evaluate the validity of the inferred functions manually and by demonstrating a significant improvement in predicting genetic interactions and protein-protein interactions based on functional similarity. Our knowledge-based approach is generally applicable to phenotypes recorded in model organism databases, including phenotypes from large-scale, high throughput community projects whose primary mode of dissemination is direct publication on-line rather than in the literature. PMID:23626672

Hoehndorf, Robert; Hardy, Nigel W.; Osumi-Sutherland, David; Tweedie, Susan; Schofield, Paul N.; Gkoutos, Georgios V.

2013-01-01

80

Unsuspected functional disparity in Devonian fishes revealed by tooth morphometrics?  

NASA Astrophysics Data System (ADS)

The shape of features involved in key biological functions, such as teeth in nutrition, can provide insights into ecological processes even in ancient time, by linking the occupation of the morphological space (disparity) to the occupation of the ecological space. Investigating disparity in radiating groups may provide insights into the ecological diversification underlying evolution of morphological diversity. Actinopterygian fishes initiated their radiation in the Devonian, a period characterized by the diversification of marine ecosystem. Although a former morpho-functional analysis of jaw shape concluded to conservative and poorly diversified morphologies in this early part of their history, fish tooth disparity evidenced here an unsuspected diversity of possible functional significance in the pivotal period of the Late Devonian (Famennian). All teeth being caniniforms, some were stocky and robust, in agreement with expectations for active generalist predators. More surprisingly, elongated teeth also occurred at the beginning of Famennian. Their needle-like shape challenges morpho-functional interpretations by making them fragile in response to bending or torsion. The occurrence of both types of fish teeth during the beginning of the Famennian points to a discrete but real increase in disparity, thus testifying a first burst of feeding specialization despite overall conservative jaw morphology. The disappearance of these needle-like teeth in the Late Famennian might have been related to a relay in dental diversity with abundant co-occurring groups, namely conodonts and chondrichthyans (sharks).

Gauchey, Samuel; Girard, Catherine; Adnet, Sylvain; Renaud, Sabrina

2014-09-01

81

Genome-Wide Association and Functional Follow-Up Reveals New Loci for Kidney Function  

PubMed Central

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

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.

2012-01-01

82

Novel functions of photoreceptor guanylate cyclases revealed by targeted deletion  

Microsoft Academic Search

Targeted deletion of membrane guanylate cyclases (GCs) has yielded new information concerning their function. Here, we summarize\\u000a briefly recent results of laboratory generated non-photoreceptor GC knockouts characterized by complex phenotypes affecting\\u000a the vasculature, heart, brain, kidney, and other tissues. The main emphasis of the review, however, addresses the two GCs\\u000a expressed in retinal photoreceptors, termed GC-E and GC-F. Naturally occurring

Sukanya Karan; Jeanne M. Frederick; Wolfgang Baehr

2010-01-01

83

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. PMID:20053645

Polak, Michal; Rashed, Arash

2010-01-01

84

Yeast studies reveal moonlighting functions of the ancient actin cytoskeleton.  

PubMed

Classic functions of the actin cytoskeleton include control of cell size and shape and the internal organization of cells. These functions are manifest in cellular processes of fundamental importance throughout biology such as the generation of cell polarity, cell migration, cell adhesion, and cell division. However, studies in the unicellular model eukaryote Saccharomyces cerevisiae (Baker's yeast) are giving insights into other functions in which the actin cytoskeleton plays a critical role. These include endocytosis, control of protein translation, and determination of protein 3-dimensional shape (especially conversion of normal cellular proteins into prions). Here, we present a concise overview of these new "moonlighting" roles for the actin cytoskeleton and how some of these roles might lie at the heart of important molecular switches. This is an exciting time for researchers interested in the actin cytoskeleton. We show here how studies of actin are leading us into many new and exciting realms at the interface of genetics, biochemistry, and cell biology. While many of the pioneering studies have been conducted using yeast, the conservation of the actin cytoskeleton and its component proteins throughout eukaryotes suggests that these new roles for the actin cytoskeleton may not be restricted to yeast cells but rather may reflect new roles for the actin cytoskeleton of all eukaryotes. © 2014 IUBMB Life, 66(8):538-545, 2014. PMID:25138357

Sattlegger, Evelyn; Chernova, Tatiana A; Gogoi, Neeku M; Pillai, Indu V; Chernoff, Yury O; Munn, Alan L

2014-08-01

85

Modulation of interhemispheric functional coordination in electroconvulsive therapy for depression  

PubMed Central

Considerable evidence suggests that depression is related to interhemispheric functional coordination deficits. For depression, electroconvulsive therapy (ECT) is the most rapid and effective therapy, but its underlying mechanism remains unknown. The aim of this study was to explore the impact of ECT on the interhemispheric functional coordination in depression patients. We used resting-state functional magnetic resonance imaging to observe the change of interhemispheric functional coordination with the method of voxel-mirrored homotopic connectivity (VMHC) in 11 depressed patients before and after ECT, compared with 15 healthy controls. The results showed that, compared with depression patients before ECT, VMHC was significantly increased in superior frontal gyri (BA 8), middle frontal gyri (two clusters: BA 8/9 and BA 10) and angular gyri (BA 39) in depression patients after ECT. Compared with healthy controls, VMHC in those areas was significantly lower in the middle frontal gyri (BA 8/9) and angular gyri (BA 39) in depression patients before ECT, but no significant difference was observed in the superior frontal gyri (BA 8) and middle frontal gyri (BA 10). There was no significant correlation between the changes of Hamilton Depression Rating Scale scores and changed VMHC values in those four areas in depression patients. The results suggest that ECT selectively modulated interhemispheric functional coordination in depression patients. Such may play an important mechanistic role in the treatment of depression, and may afford a useful avenue for optimizing treatment. PMID:25268257

Wei, Q; Tian, Y; Yu, Y; Zhang, F; Hu, X; Dong, Y; Chen, Y; Hu, P; Hu, X; Wang, K

2014-01-01

86

The modification of the modulation transfer function by sea slicks measured by L-band radar  

NASA Technical Reports Server (NTRS)

Tower-based L-band radar measurements performed on the North Sea covered with an experimental monomolecular oleyl alcohol sea slick revealed that the peak frequency of L-band radar cross section spectra from a "clean" sea area (f subclean = 0.16 Hz; water wave length L = 61 m) is shifted to higher frequencies in the presence of the slick (f subslick = 0.22 Hz; L = 32 m). This effect is explained by a modification of the modulation transfer function by the monomolecular surface film. Independent wind-wave tunnel experiments performed with a wave follower mounted surface potential ionization probe support this interpretation.

Huehnerfuss, H.; Lange, P.; Schlude, F.; Garrett, W. D.

1984-01-01

87

Seasonal changes in hepatic gene expression reveal modulation of multiple processes in rainbow smelt (Osmerus mordax).  

PubMed

Rainbow smelt (Osmerus mordax) are freeze-resistant fish that accumulate glycerol and produce an antifreeze protein during winter. Quantitative reverse transcription PCR (qPCR) and subtractive hybridization studies have previously revealed five genes in rainbow smelt liver to be differentially regulated in winter in comparison with the fall when water temperatures are warmer. In order to further define the suite of processes that are regulated seasonally, we undertook a large-scale analysis of gene expression by hybridization of smelt cDNA to the salmonid 16K cGRASP microarray. In total, 69 genes were identified as up-regulated and 14 genes as down-regulated under winter conditions. A subset of these genes was examined for differential regulation by qPCR in the individual cDNA samples that were pooled for microarray analysis. Ten of the 15 genes tested showed significant change in the same direction as microarray results, whereas one showed significant change in the opposite direction. Fructose-bisphosphate aldolase B and the cytosolic NAD-dependent glycerol-3-phosphate dehydrogenase were among the most highly up-regulated genes, a result supporting a metabolic focus on glycerol synthesis during winter. Modulation of other processes, including endoplasmic reticulum stress, lipid metabolism and transport, and protein synthesis, was also suggested by the qPCR analysis of array-identified genes. The 15 genes were subsequently examined by qPCR for seasonal variation in expression over five sampling times between October and March, and ten showed significant variation in expression over the sampling period. Taken together, these results provide new understanding of the biochemical adaptations of vertebrates to an extremely low seasonal temperature. PMID:20107851

Richards, Robert C; Short, Connie E; Driedzic, William R; Ewart, K Vanya

2010-11-01

88

Structural and functional distinctions between auditory centers revealed with MRI in living humans  

E-print Network

From brainstem to cortex, sound is processed in centers that are functionally and structurally distinct. In animals, invasive electrophysiology and histology has revealed these distinctions and, consequently, organizational ...

Sigalovsky, Irina S., 1972-

2005-01-01

89

System identification and model reduction using modulating function techniques  

NASA Technical Reports Server (NTRS)

Weighted least squares (WLS) and adaptive weighted least squares (AWLS) algorithms are initiated for continuous-time system identification using Fourier type modulating function techniques. Two stochastic signal models are examined using the mean square properties of the stochastic calculus: an equation error signal model with white noise residuals, and a more realistic white measurement noise signal model. The covariance matrices in each model are shown to be banded and sparse, and a joint likelihood cost function is developed which links the real and imaginary parts of the modulated quantities. The superior performance of above algorithms is demonstrated by comparing them with the LS/MFT and popular predicting error method (PEM) through 200 Monte Carlo simulations. A model reduction problem is formulated with the AWLS/MFT algorithm, and comparisons are made via six examples with a variety of model reduction techniques, including the well-known balanced realization method. Here the AWLS/MFT algorithm manifests higher accuracy in almost all cases, and exhibits its unique flexibility and versatility. Armed with this model reduction, the AWLS/MFT algorithm is extended into MIMO transfer function system identification problems. The impact due to the discrepancy in bandwidths and gains among subsystem is explored through five examples. Finally, as a comprehensive application, the stability derivatives of the longitudinal and lateral dynamics of an F-18 aircraft are identified using physical flight data provided by NASA. A pole-constrained SIMO and MIMO AWLS/MFT algorithm is devised and analyzed. Monte Carlo simulations illustrate its high-noise rejecting properties. Utilizing the flight data, comparisons among different MFT algorithms are tabulated and the AWLS is found to be strongly favored in almost all facets.

Shen, Yan

1993-01-01

90

The functional modulation of epigenetic regulators by alternative splicing  

PubMed Central

Background Epigenetic regulators (histone acetyltransferases, methyltransferases, chromatin-remodelling enzymes, etc) play a fundamental role in the control of gene expression by modifying the local state of chromatin. However, due to their recent discovery, little is yet known about their own regulation. This paper addresses this point, focusing on alternative splicing regulation, a mechanism already known to play an important role in other protein families, e.g. transcription factors, membrane receptors, etc. Results To this end, we compiled the data available on the presence/absence of alternative splicing for a set of 160 different epigenetic regulators, taking advantage of the relatively large amount of unexplored data on alternative splicing available in public databases. We found that 49 % (70 % in human) of these genes express more than one transcript. We then studied their alternative splicing patterns, focusing on those changes affecting the enzyme's domain composition. In general, we found that these sequence changes correspond to different mechanisms, either repressing the enzyme's function (e.g. by creating dominant-negative inhibitors of the functional isoform) or creating isoforms with new functions. Conclusion We conclude that alternative splicing of epigenetic regulators can be an important tool for the function modulation of these enzymes. Considering that the latter control the transcriptional state of large sets of genes, we propose that epigenetic regulation of gene expression is itself strongly regulated by alternative splicing. PMID:17651478

Lois, Sergio; Blanco, Noemí; Martínez-Balbás, Marian; de la Cruz, Xavier

2007-01-01

91

SUMOylation modulates the transcription repressor function of RIP140.  

PubMed

RIP140/NRIP1 (receptor-interacting protein 140) functions as a corepressor of nuclear receptors. It plays an important role in the transcriptional control of energy metabolism and female fertility. RIP140 contains four distinct repression domains (RD1-RD4), and the repressive activity of RIP140 involves complex mechanisms. The function of both RD1 and RD2 is linked to recruitment of histone deacetylases and C-terminal binding protein, respectively, but the mechanism of repression for RD3 and RD4 has remained elusive. Because covalent modification by small ubiquitin-like modifiers (SUMO-1, -2, and -3; SUMOylation) is often associated with transcriptional repression, we studied whether SUMOylation is involved in the repressive activity of RIP140. We show that two conserved lysines, Lys(756) and Lys(1154), located in RD3 and RD4, respectively, are subject to reversible SUMOylation, with SUMO-1 being more efficiently conjugated than SUMO-2. Interestingly, mutations of the RIP140 SUMOylation sites compromised the transcription repressor function of RIP140 and blunted its capacity to repress estrogen receptor alpha-dependent transcription. Conjugation of SUMO-1 also influenced the subnuclear distribution pattern of RIP140. In sum, our demonstration that the function of RIP140 repression domains 3 and 4 can be modulated by reversible SUMO modification thus adds a novel level to the regulation of RIP140 activity, which may have ramifications in the control of gene networks exerted by RIP140. PMID:18211901

Rytinki, Miia M; Palvimo, Jorma J

2008-04-25

92

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

93

Transcriptome analysis of alternative splicing events regulated by SRSF10 reveals position-dependent splicing modulation  

PubMed Central

Splicing factor SRSF10 is known to function as a sequence-specific splicing activator. Here, we used RNA-seq coupled with bioinformatics analysis to identify the extensive splicing network regulated by SRSF10 in chicken cells. We found that SRSF10 promoted both exon inclusion and exclusion. Motif analysis revealed that SRSF10 binding to cassette exons was associated with exon inclusion, whereas the binding of SRSF10 within downstream constitutive exons was associated with exon exclusion. This positional effect was further demonstrated by the mutagenesis of potential SRSF10 binding motifs in two minigene constructs. Functionally, many of SRSF10-verified alternative exons are linked to pathways of stress and apoptosis. Consistent with this observation, cells depleted of SRSF10 expression were far more susceptible to endoplasmic reticulum stress-induced apoptosis than control cells. Importantly, reconstituted SRSF10 in knockout cells recovered wild-type splicing patterns and considerably rescued the stress-related defects. Together, our results provide mechanistic insight into SRSF10-regulated alternative splicing events in vivo and demonstrate that SRSF10 plays a crucial role in cell survival under stress conditions. PMID:24442672

Zhou, Xuexia; Wu, Wenwu; Li, Huang; Cheng, Yuanming; Wei, Ning; Zong, Jie; Feng, Xiaoyan; Xie, Zhiqin; Chen, Dai; Manley, James L.; Wang, Hui; Feng, Ying

2014-01-01

94

Synucleins Antagonize Endoplasmic Reticulum Function to Modulate Dopamine Transporter Trafficking  

PubMed Central

Synaptic re-uptake of dopamine is dependent on the dopamine transporter (DAT), which is regulated by its distribution to the cell surface. DAT trafficking is modulated by the Parkinson's disease-linked protein alpha-synuclein, but the contribution of synuclein family members beta-synuclein and gamma-synuclein to DAT trafficking is not known. Here we use SH-SY5Y cells as a model of DAT trafficking to demonstrate that all three synucleins negatively regulate cell surface distribution of DAT. Under these conditions the synucleins limit export of DAT from the endoplasmic reticulum (ER) by impairment of the ER-Golgi transition, leading to accumulation of DAT in this compartment. This mechanism for regulating DAT export indirectly through effects on ER and Golgi function represents a previously unappreciated role for the extended synuclein family that is likely applicable to trafficking of the many proteins that rely on the secretory pathway. PMID:23967127

Oaks, Adam W.; Marsh-Armstrong, Nicholas; Jones, Jessica M.; Credle, Joel J.; Sidhu, Anita

2013-01-01

95

Interspecies activity correlations reveal functional correspondence between monkey and human brain areas  

Microsoft Academic Search

Evolution-driven functional changes in the primate brain are typically assessed by aligning monkey and human activation maps using cortical surface expansion models. These models use putative homologous areas as registration landmarks, assuming they are functionally correspondent. For cases in which functional changes have occurred in an area, this assumption prohibits to reveal whether other areas may have assumed lost functions.

Dante Mantini; Uri Hasson; Viviana Betti; Mauro G Perrucci; Gian Luca Romani; Maurizio Corbetta; Guy A Orban; Wim Vanduffel

2012-01-01

96

Phosphoproteome dynamics reveal novel ERK1/2 MAP kinase substrates with broad spectrum of functions  

PubMed Central

The ERK1/2 MAP kinase pathway is an evolutionarily conserved signaling module that controls many fundamental physiological processes. Deregulated activity of ERK1/2 MAP kinases is associated with developmental syndromes and several human diseases. Despite the importance of this pathway, a comprehensive picture of the natural substrate repertoire and biochemical mechanisms regulated by ERK1/2 is still lacking. In this study, we used large-scale quantitative phosphoproteomics and bioinformatics analyses to identify novel candidate ERK1/2 substrates based on their phosphorylation signature and kinetic profiles in epithelial cells. We identified a total of 7936 phosphorylation sites within 1861 proteins, of which 155 classify as candidate ERK1/2 substrates, including 128 new targets. Candidate ERK1/2 substrates are involved in diverse cellular processes including transcriptional regulation, chromatin remodeling, RNA splicing, cytoskeleton dynamics, cellular junctions and cell signaling. Detailed characterization of one newly identified substrate, the transcriptional regulator JunB, revealed that ERK1/2 phosphorylate JunB on a serine adjacent to the DNA-binding domain, resulting in increased DNA-binding affinity and transcriptional activity. Our study expands the spectrum of cellular functions controlled by ERK1/2 kinases. PMID:23712012

Courcelles, Mathieu; Fremin, Christophe; Voisin, Laure; Lemieux, Sebastien; Meloche, Sylvain; Thibault, Pierre

2013-01-01

97

Casein kinase 1 proteomics reveal prohibitin 2 function in molecular clock.  

PubMed

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. PMID:22384121

Kategaya, Lorna S; Hilliard, Aisha; Zhang, Louying; Asara, John M; Ptá?ek, Louis J; Fu, Ying-Hui

2012-01-01

98

CX3CL1-induced modulation at CA1 synapses reveals multiple mechanisms of EPSC modulation involving adenosine receptor subtypes.  

PubMed

We characterized the role of adenosine receptor (AR) subtypes in the modulation of glutamatergic neurotransmission by the chemokine fractalkine (CX3CL1) in mouse hippocampal CA1 neurons. CX(3)CL1 causes a reversible depression of excitatory postsynaptic current (EPSC), which is abolished by the A(3)R antagonist MRS1523, but not by A(1)R (DPCPX) or A(2A)R (SCH58261) antagonists. Consistently, CX3CL1-induced EPSC depression is absent in slices from A(3)R(-/-) but not A(1)R(-/-) or A(2A)R(-/-) mice. Further, A(3)R stimulation causes similar EPSC depression. In cultured neurons, CX3CL1-induced depression of AMPA current shows A(1)R-A(3)R pharmacology. We conclude that glutamatergic depression induced by released adenosine requires the stimulation of different ARs. PMID:20570369

Piccinin, S; Di Angelantonio, S; Piccioni, A; Volpini, R; Cristalli, G; Fredholm, B B; Limatola, C; Eusebi, F; Ragozzino, D

2010-07-27

99

Modulation of Conjunctival Goblet Cell Function by Inflammatory Cytokines  

PubMed Central

Ocular surface inflammation associated with Sjögren's syndrome is characterized by a loss of secretory function and alteration in numbers of mucin secreting goblet cells. Such changes are a prominent feature of ocular surface inflammatory diseases and are attributed to inflammation; however, the exact effect of the inflammatory cytokines on conjunctival goblet cell function remains largely unknown. In this study, we developed a primary culture of mouse goblet cells from conjunctival tissue and evaluated the effects on their function by inflammatory cytokines detected in the conjunctiva of mouse model of Sjögren's syndrome (Thrombospondin-1 deficient mice). We found that apoptosis of goblet cells was primarily induced by TNF-? and IFN-?. These two cytokines also inhibited mucin secretion by goblet cells in response to cholinergic stimulation, whereas IL-6 enhanced such secretion. No changes in secretory response were detected in the presence of IL-13 or IL-17. Goblet cells proliferated to varying degrees in response to all the tested cytokines with the greatest response to IL-13 followed by IL-6. Our results therefore reveal that inflammatory cytokines expressed in the conjunctiva during an ocular surface disease directly disrupt conjunctival goblet cell functions, compromising the protective function of tears, thereby contributing to ocular surface damage. PMID:24453426

Contreras-Ruiz, L.; Ghosh-Mitra, A.; Shatos, M. A.; Dartt, D. A.; Masli, S.

2013-01-01

100

Functional Protein Network Activation Mapping Reveals New Potential Molecular Drug Targets for Poor Prognosis Pediatric BCP-ALL  

PubMed Central

Background In spite of leukemia therapy improvements obtained over the last decades, therapy is not yet effective in all cases. Current approaches in Acute Lymphoblastic Leukemia (ALL) research focus on identifying new molecular targets to improve outcome for patients with a dismal prognosis. In this light phosphoproteomics seems to hold great promise for the identification of proteins suitable for targeted therapy. Methodology/Principal Findings We employed Reverse Phase Protein Microarrays to identify aberrantly activated proteins in 118 pediatric B-cell precursor (BCP)-ALL patients. Signal transduction pathways were assayed for activation/expression status of 92 key signalling proteins. We observed an increased activation/expression of several pathways involved in cell proliferation in poor clinical prognosis patients. MLL-rearranged tumours revealed BCL-2 hyperphosphorylation through AMPK activation, which indicates that AMPK could provide a functional role in inhibiting apoptosis in MLL-rearranged patients, and could be considered as a new potential therapeutic target. Second, in patients with poor clinical response to prednisone we observed the up-modulation of LCK activity with respect to patients with good response. This tyrosine-kinase can be down-modulated with clinically used inhibitors, thus modulating LCK activity could be considered for further studies as a new additional therapy for prednisone-resistant patients. Further we also found an association between high levels of CYCLIN E and relapse incidence. Moreover, CYCLIN E is more expressed in early relapsed patients, who usually show an unfavourable prognosis. Conclusions/Significance We conclude that functional protein pathway activation mapping revealed specific deranged signalling networks in BCP-ALL that could be potentially modulated to produce a better clinical outcome for patients resistant to standard-of-care therapies. PMID:21042412

Accordi, Benedetta; Espina, Virginia; Giordan, Marco; VanMeter, Amy; Milani, Gloria; Galla, Luisa; Ruzzene, Maria; Sciro, Manuela; Trentin, Luca; De Maria, Ruggero; te Kronnie, Geertruy; Petricoin, Emanuel; Liotta, Lance; Basso, Giuseppe

2010-01-01

101

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

PubMed Central

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 in human and mouse. The motif most strongly associated with aging was that of the transcription factor NF-?B. Inducible genetic blockade of NF-?B for 2 wk in the epidermis of chronologically aged mice reverted the tissue characteristics and global gene expression programs to those of young mice. Age-specific NF-?B blockade and orthogonal cell cycle interventions revealed that NF-?B controls cell cycle exit and gene expression signature of aging in parallel but not sequential pathways. These results identify a conserved network of regulatory pathways underlying mammalian aging and show that NF-?B is continually required to enforce many features of aging in a tissue-specific manner. PMID:18055696

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

2007-01-01

102

Modeling Single-Trial ERP Reveals Modulation of Bottom-Up Face Visual Processing by Top-Down Task Constraints (in Some Subjects)  

PubMed Central

We studied how task constraints modulate the relationship between single-trial event-related potentials (ERPs) and image noise. Thirteen subjects performed two interleaved tasks: on different blocks, they saw the same stimuli, but they discriminated either between two faces or between two colors. Stimuli were two pictures of red or green faces that contained from 10 to 80% of phase noise, with 10% increments. Behavioral accuracy followed a noise dependent sigmoid in the identity task but was high and independent of noise level in the color task. EEG data recorded concurrently were analyzed using a single-trial ANCOVA: we assessed how changes in task constraints modulated ERP noise sensitivity while regressing out the main ERP differences due to identity, color, and task. Single-trial ERP sensitivity to image phase noise started at about 95–110?ms post-stimulus onset. Group analyses showed a significant reduction in noise sensitivity in the color task compared to the identity task from about 140?ms to 300?ms post-stimulus onset. However, statistical analyses in every subject revealed different results: significant task modulation occurred in 8/13 subjects, one showing an increase and seven showing a decrease in noise sensitivity in the color task. Onsets and durations of effects also differed between group and single-trial analyses: at any time point only a maximum of four subjects (31%) showed results consistent with group analyses. We provide detailed results for all 13 subjects, including a shift function analysis that revealed asymmetric task modulations of single-trial ERP distributions. We conclude that, during face processing, bottom-up sensitivity to phase noise can be modulated by top-down task constraints, in a broad window around the P2, at least in some subjects. PMID:21886627

Rousselet, Guillaume A.; Gaspar, Carl M.; Wieczorek, Kacper P.; Pernet, Cyril R.

2011-01-01

103

The small GTPase Arf1 modulates mitochondrial morphology and function.  

PubMed

The small GTPase Arf1 plays critical roles in membrane traffic by initiating the recruitment of coat proteins and by modulating the activity of lipid-modifying enzymes. Here, we report an unexpected but evolutionarily conserved role for Arf1 and the ArfGEF GBF1 at mitochondria. Loss of function of ARF-1 or GBF-1 impaired mitochondrial morphology and activity in Caenorhabditis elegans. Similarly, mitochondrial defects were observed in mammalian and yeast cells. In Saccharomyces cerevisiae, aberrant clusters of the mitofusin Fzo1 accumulated in arf1-11 mutants and were resolved by overexpression of Cdc48, an AAA-ATPase involved in ER and mitochondria-associated degradation processes. Yeast Arf1 co-fractionated with ER and mitochondrial membranes and interacted genetically with the contact site component Gem1. Furthermore, similar mitochondrial abnormalities resulted from knockdown of either GBF-1 or contact site components in worms, suggesting that the role of Arf1 in mitochondrial functioning is linked to ER-mitochondrial contacts. Thus, Arf1 is involved in mitochondrial homeostasis and dynamics, independent of its role in vesicular traffic. PMID:25190516

Ackema, Karin B; Hench, Jürgen; Böckler, Stefan; Wang, Shyi Chyi; Sauder, Ursula; Mergentaler, Heidi; Westermann, Benedikt; Bard, Frédéric; Frank, Stephan; Spang, Anne

2014-11-18

104

Probiotic modulation of dendritic cell function is influenced by ageing.  

PubMed

Dendritic cells (DCs) are critical for the generation of T-cell responses. DC function may be modulated by probiotics, which confer health benefits in immunocompromised individuals, such as the elderly. This study investigated the effects of four probiotics, Bifidobacterium longum bv. infantis CCUG 52486, B. longum SP 07/3, Lactobacillus rhamnosus GG (L.GG) and L. casei Shirota (LcS), on DC function in an allogeneic mixed leucocyte reaction (MLR) model, using DCs and T-cells from young and older donors in different combinations. All four probiotics enhanced expression of CD40, CD80 and CCR7 on both young and older DCs, but enhanced cytokine production (TGF-?, TNF-?) by old DCs only. LcS induced IL-12 and IFN? production by DC to a greater degree than other strains, while B. longum bv. infantis CCUG 52486 favoured IL-10 production. Stimulation of young T cells in an allogeneic MLR with DC was enhanced by probiotic pretreatment of old DCs, which demonstrated greater activation (CD25) than untreated controls. However, pretreatment of young or old DCs with LPS or probiotics failed to enhance the proliferation of T-cells derived from older donors. In conclusion, this study demonstrates that ageing increases the responsiveness of DCs to probiotics, but this is not sufficient to overcome the impact of immunosenescence in the MLR. PMID:24094416

You, Jialu; Dong, Honglin; Mann, Elizabeth R; Knight, Stella C; Yaqoob, Parveen

2014-02-01

105

Probiotic modulation of dendritic cell function is influenced by ageing  

PubMed Central

Dendritic cells (DCs) are critical for the generation of T-cell responses. DC function may be modulated by probiotics, which confer health benefits in immunocompromised individuals, such as the elderly. This study investigated the effects of four probiotics, Bifidobacterium longum bv. infantis CCUG 52486, B. longum SP 07/3, Lactobacillus rhamnosus GG (L.GG) and L. casei Shirota (LcS), on DC function in an allogeneic mixed leucocyte reaction (MLR) model, using DCs and T-cells from young and older donors in different combinations. All four probiotics enhanced expression of CD40, CD80 and CCR7 on both young and older DCs, but enhanced cytokine production (TGF-?, TNF-?) by old DCs only. LcS induced IL-12 and IFN? production by DC to a greater degree than other strains, while B. longum bv. infantis CCUG 52486 favoured IL-10 production. Stimulation of young T cells in an allogeneic MLR with DC was enhanced by probiotic pretreatment of old DCs, which demonstrated greater activation (CD25) than untreated controls. However, pretreatment of young or old DCs with LPS or probiotics failed to enhance the proliferation of T-cells derived from older donors. In conclusion, this study demonstrates that ageing increases the responsiveness of DCs to probiotics, but this is not sufficient to overcome the impact of immunosenescence in the MLR. PMID:24094416

You, Jialu; Dong, Honglin; Mann, Elizabeth R.; Knight, Stella C.; Yaqoob, Parveen

2014-01-01

106

Identification of Arabidopsis Meiotic Cyclins Reveals Functional Diversification among Plant Cyclin Genes  

PubMed Central

Meiosis is a modified cell division in which a single S-phase is followed by two rounds of chromosome segregation resulting in the production of haploid gametes. The meiotic mode of chromosome segregation requires extensive remodeling of the basic cell cycle machinery and employment of unique regulatory mechanisms. Cyclin-dependent kinases (CDKs) and cyclins represent an ancient molecular module that drives and regulates cell cycle progression. The cyclin gene family has undergone a massive expansion in angiosperm plants, but only a few cyclins were thoroughly characterized. In this study we performed a systematic immunolocalization screen to identify Arabidopsis thaliana A- and B-type cyclins expressed in meiosis. Many of these cyclins exhibit cell-type-specific expression in vegetative tissues and distinct subcellular localization. We found six A-type cyclins and a single B-type cyclin (CYCB3;1) to be expressed in male meiosis. Mutant analysis revealed that these cyclins contribute to distinct meiosis-related processes. While A2 cyclins are important for chromosome segregation, CYCB3;1 prevents ectopic cell wall formation. We further show that cyclin SDS does not contain a D-box and is constitutively expressed throughout meiosis. Analysis of plants carrying cyclin SDS with an introduced D-box motif determined that, in addition to its function in recombination, SDS acts together with CYCB3;1 in suppressing unscheduled cell wall synthesis. Our phenotypic and expression data provide extensive evidence that multiplication of cyclins is in plants accompanied by functional diversification. PMID:23671425

Bulankova, Petra; Akimcheva, Svetlana; Fellner, Nicole; Riha, Karel

2013-01-01

107

Cued Spatial Attention Drives Functionally Relevant Modulation of the Mu Rhythm in Primary Somatosensory Cortex  

E-print Network

Cued spatial attention modulates functionally relevant alpha rhythms in visual cortices in humans. Here, we present evidence for analogous phenomena in primary somatosensory neocortex (SI). Using magnetoencephalography, ...

Jones, Stephanie R.

108

Quetiapine modulates functional connectivity in brain aggression networks.  

PubMed

Aggressive behavior is associated with dysfunctions in an affective regulation network encompassing amygdala and prefrontal areas such as orbitofrontal (OFC), anterior cingulate (ACC), and dorsolateral prefrontal cortex (DLPFC). In particular, prefrontal regions have been postulated to control amygdala activity by inhibitory projections, and this process may be disrupted in aggressive individuals. The atypical antipsychotic quetiapine successfully attenuates aggressive behavior in various disorders; the underlying neural processes, however, are unknown. A strengthened functional coupling in the prefrontal-amygdala system may account for these anti-aggressive effects. An inhibition of this network has been reported for virtual aggression in violent video games as well. However, there have been so far no in-vivo observations of pharmacological influences on corticolimbic projections during human aggressive behavior. In a double-blind, placebo-controlled study, quetiapine and placebo were administered for three successive days prior to an fMRI experiment. In this experiment, functional brain connectivity was assessed during virtual aggressive behavior in a violent video game and an aggression-free control task in a non-violent modification. Quetiapine increased the functional connectivity of ACC and DLPFC with the amygdala during virtual aggression, whereas OFC-amygdala coupling was attenuated. These effects were observed neither for placebo nor for the non-violent control. These results demonstrate for the first time a pharmacological modification of aggression-related human brain networks in a naturalistic setting. The violence-specific modulation of prefrontal-amygdala networks appears to control aggressive behavior and provides a neurobiological model for the anti-aggressive effects of quetiapine. PMID:23501053

Klasen, Martin; Zvyagintsev, Mikhail; Schwenzer, Michael; Mathiak, Krystyna A; Sarkheil, Pegah; Weber, René; Mathiak, Klaus

2013-07-15

109

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

110

Acupuncture Modulates the Functional Connectivity of the Default Mode Network in Stroke Patients  

PubMed Central

Abundant evidence from previous fMRI studies on acupuncture has revealed significant modulatory effects at widespread brain regions. However, few reports on the modulation to the default mode network (DMN) of stroke patients have been investigated in the field of acupuncture. To study the modulatory effects of acupuncture on the DMN of stroke patients, eight right hemispheric infarction and stable ischemic stroke patients and ten healthy subjects were recruited to undergo resting state fMRI scanning before and after acupuncture stimulation. Functional connectivity analysis was applied with the bilateral posterior cingulate cortices chosen as the seed regions. The main finding demonstrated that the interregional interactions between the ACC and PCC especially enhanced after acupuncture at GB34 in stroke patients, compared with healthy controls. The results indicated that the possible mechanisms of the modulatory effects of acupuncture on the DMN of stroke patients could be interpreted in terms of cognitive ability and motor function recovery. PMID:24734113

Zhang, Yong; Li, Kuangshi; Ren, Yi; Cui, Fangyuan; Xie, Zijing; Shin, Jae-Young; Tan, Zhongjian; Tang, Lixin; Bai, Lijun; Zou, Yihuai

2014-01-01

111

Mfn2 modulates the UPR and mitochondrial function via repression of PERK  

PubMed Central

Mitofusin 2 (Mfn2) is a key protein in mitochondrial fusion and it participates in the bridging of mitochondria to the endoplasmic reticulum (ER). Recent data indicate that Mfn2 ablation leads to ER stress. Here we report on the mechanisms by which Mfn2 modulates cellular responses to ER stress. Induction of ER stress in Mfn2-deficient cells caused massive ER expansion and excessive activation of all three Unfolded Protein Response (UPR) branches (PERK, XBP-1, and ATF6). In spite of an enhanced UPR, these cells showed reduced activation of apoptosis and autophagy during ER stress. Silencing of PERK increased the apoptosis of Mfn2-ablated cells in response to ER stress. XBP-1 loss-of-function ameliorated autophagic activity of these cells upon ER stress. Mfn2 physically interacts with PERK, and Mfn2-ablated cells showed sustained activation of this protein kinase under basal conditions. Unexpectedly, PERK silencing in these cells reduced ROS production, normalized mitochondrial calcium, and improved mitochondrial morphology. In summary, our data indicate that Mfn2 is an upstream modulator of PERK. Furthermore, Mfn2 loss-of-function reveals that PERK is a key regulator of mitochondrial morphology and function. PMID:23921556

Munoz, Juan Pablo; Ivanova, Saska; Sanchez-Wandelmer, Jana; Martinez-Cristobal, Paula; Noguera, Eduard; Sancho, Ana; Diaz-Ramos, Angels; Hernandez-Alvarez, Maria Isabel; Sebastian, David; Mauvezin, Caroline; Palacin, Manuel; Zorzano, Antonio

2013-01-01

112

Functional Chromatography Reveals Three Natural Products that Target the Same Protein with Distinct Mechanisms of Action.  

PubMed

Access to lead compounds with defined molecular targets continues to be a barrier to the translation of natural product resources. As a solution, we developed a system that uses discrete, recombinant proteins as the vehicles for natural product isolation. Here, we describe the use of this functional chromatographic method to identify natural products that bind to the AAA+ chaperone, p97, a promising cancer target. Application of this method to a panel of fungal and plant extracts identified rheoemodin, 1-hydroxydehydroherbarin, and phomapyrrolidone A as distinct p97 modulators. Excitingly, each of these molecules displayed a unique mechanism of p97 modulation. This discovery provides strong support for the application of functional chromatography to the discovery of protein modulators that would likely escape traditional high-throughput or phenotypic screening platforms. PMID:25125376

Kang, Min Jin; Wu, Tongde; Wijeratne, E M Kithsiri; Lau, Eric C; Mason, Damian J; Mesa, Celestina; Tillotson, Joseph; Zhang, Donna D; Gunatilaka, A A Leslie; La Clair, James J; Chapman, Eli

2014-09-22

113

Adipocyte-derived lipids modulate CD4+ T-cell function.  

PubMed

Adipose tissue contains several immune cells whose number and phenotype vary depending on the adiposity. In the present study, we show that IFN-?(+) CD4(+) T cells are enriched in human adipose tissue compared with in blood. To gain insight into the underlying mechanisms, we investigated the possibility that human adipocytes modulate CD4(+) T-cell cytokine production and proliferation and show that CD4(+) T cells produced increased levels of IFN-? when activated in the presence of adipocytes. This effect was mediated by soluble mediators, as shown in transwell and adipocyte-conditioned medium (ACM) transfer experiments. Additionally, ACM induced increased proliferation of CD4(+) T cells upon activation. Intriguingly, the proliferation-enhancing effect resided mainly in the lipid fraction of ACM, as shown upon separation of the protein and lipid fraction. Further separation of these lipids based on polarity revealed that the modulatory effect is confined to fractions containing free fatty acids. All identified fatty acids were able to individually enhance T-cell proliferation. These data indicate that adipocytes can modulate CD4(+) T-cell function through the release of lipids. Remarkably, free fatty acids were the most prominent modulators of T-cell proliferation, possibly leading to an accumulation of these cells in adipose tissue. PMID:23504601

Ioan-Facsinay, Andreea; Kwekkeboom, Joanneke C; Westhoff, Sanne; Giera, Martin; Rombouts, Yoann; van Harmelen, Vanessa; Huizinga, Tom W J; Deelder, André; Kloppenburg, Margreet; Toes, René E M

2013-06-01

114

Epigenetic modulation of neuronal apoptosis and cognitive functions in sepsis-associated encephalopathy.  

PubMed

Sepsis-associated encephalopathy (SAE), which associates with neuronal apoptosis and cognitive disorders, is a common complication of systemic sepsis. However, the mechanism involving its modulation remains to be elucidated. Recent studies showed that histone deacetylases (HDACs) were implicated in neurodegeneration and cognitive functions. The current study was designed to investigate whether septic brain is epigenetically modulated by HDACs, using cecal ligation and peroration (CLP) rats and primary hippocampal neuronal cultures. We found that hippocampal acetylated histone 3 (AcH3), acetylated histone 4 (AcH4), cytoplasmic HDAC4 and Bcl-XL were inhibited in septic brain. Hippocampal Bax and nuclear HDAC4 expressions were enhanced in CLP rats. Administration of HDACs inhibitor, trichostatin A (TSA) or suberoylanilide hydroxamic acid (SAHA) rescued the changes of Bcl-XL and Bax in vivo, and decreased apoptotic cells in vitro. In addition, HDAC4 shRNA transfection significantly enhanced AcH3, AcH4 and Bcl-XL, but suppressed Bax. Neuronal apoptosis was also reduced by transfection of HDAC4 shRNA. Furthermore, CLP rats exhibited significant spatial learning and memory deficits, which could be ameliorated by application of TSA or SAHA without influence on locomotive activity. These results reveal that epigenetic modulation is involved in septic brain, and the inhibition of HDACs may serve as a potential therapeutic approach for SAE treatment. PMID:23925573

Fang, Jun; Lian, Yanhong; Xie, Kangjie; Cai, Shunv; Wen, Penglu

2014-02-01

115

Functional proteomic analysis reveals the involvement of KIAA1199 in breast cancer growth, motility and invasiveness  

PubMed Central

Background KIAA1199 is a recently identified novel gene that is up-regulated in human cancer with poor survival. Our proteomic study on signaling polarity in chemotactic cells revealed KIAA1199 as a novel protein target that may be involved in cellular chemotaxis and motility. In the present study, we examined the functional significance of KIAA1199 expression in breast cancer growth, motility and invasiveness. Methods We validated the previous microarray observation by tissue microarray immunohistochemistry using a TMA slide containing 12 breast tumor tissue cores and 12 corresponding normal tissues. We performed the shRNA-mediated knockdown of KIAA1199 in MDA-MB-231 and HS578T cells to study the role of this protein in cell proliferation, migration and apoptosis in vitro. We studied the effects of KIAA1199 knockdown in vivo in two groups of mice (n?=?5). We carried out the SILAC LC-MS/MS based proteomic studies on the involvement of KIAA1199 in breast cancer. Results KIAA1199 mRNA and protein was significantly overexpressed in breast tumor specimens and cell lines as compared with non-neoplastic breast tissues from large-scale microarray and studies of breast cancer cell lines and tumors. To gain deeper insights into the novel role of KIAA1199 in breast cancer, we modulated KIAA1199 expression using shRNA-mediated knockdown in two breast cancer cell lines (MDA-MB-231 and HS578T), expressing higher levels of KIAA1199. The KIAA1199 knockdown cells showed reduced motility and cell proliferation in vitro. Moreover, when the knockdown cells were injected into the mammary fat pads of female athymic nude mice, there was a significant decrease in tumor incidence and growth. In addition, quantitative proteomic analysis revealed that knockdown of KIAA1199 in breast cancer (MDA-MB-231) cells affected a broad range of cellular functions including apoptosis, metabolism and cell motility. Conclusions Our findings indicate that KIAA1199 may play an important role in breast tumor growth and invasiveness, and that it may represent a novel target for biomarker development and a novel therapeutic target for breast cancer. PMID:24628760

2014-01-01

116

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. PMID:21607142

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

2010-01-01

117

A Product of Heme Catabolism Modulates Bacterial Function and Survival  

PubMed Central

Bilirubin is the terminal metabolite in heme catabolism in mammals. After deposition into bile, bilirubin is released in large quantities into the mammalian gastrointestinal (GI) tract. We hypothesized that intestinal bilirubin may modulate the function of enteric bacteria. To test this hypothesis, we investigated the effect of bilirubin on two enteric pathogens; enterohemorrhagic E. coli (EHEC), a Gram-negative that causes life-threatening intestinal infections, and E. faecalis, a Gram-positive human commensal bacterium known to be an opportunistic pathogen with broad-spectrum antibiotic resistance. We demonstrate that bilirubin can protect EHEC from exogenous and host-generated reactive oxygen species (ROS) through the absorption of free radicals. In contrast, E. faecalis was highly susceptible to bilirubin, which causes significant membrane disruption and uncoupling of respiratory metabolism in this bacterium. Interestingly, similar results were observed for other Gram-positive bacteria, including B. cereus and S. aureus. A model is proposed whereby bilirubin places distinct selective pressure on enteric bacteria, with Gram-negative bacteria being protected from ROS (positive outcome) and Gram-positive bacteria being susceptible to membrane disruption (negative outcome). This work suggests bilirubin has differential but biologically relevant effects on bacteria and justifies additional efforts to determine the role of this neglected waste catabolite in disease processes, including animal models. PMID:23935485

Nobles, Christopher L.; Green, Sabrina I.; Maresso, Anthony W.

2013-01-01

118

Serotonin targets inhibitory synapses to induce modulation of network functions  

PubMed Central

The cellular effects of serotonin (5-HT), a neuromodulator with widespread influences in the central nervous system, have been investigated. Despite detailed knowledge about the molecular biology of cellular signalling, it is not possible to anticipate the responses of neuronal networks to a global action of 5-HT. Heterogeneous expression of various subtypes of serotonin receptors (5-HTR) in a variety of neurons differently equipped with cell-specific transmitter receptors and ion channel assemblies can provoke diverse cellular reactions resulting in various forms of network adjustment and, hence, motor behaviour. Using the respiratory network as a model for reciprocal synaptic inhibition, we demonstrate that 5-HT1AR modulation primarily affects inhibition through glycinergic synapses. Potentiation of glycinergic inhibition of both excitatory and inhibitory neurons induces a functional reorganization of the network leading to a characteristic change of motor output. The changes in network operation are robust and help to overcome opiate-induced respiratory depression. Hence, 5-HT1AR activation stabilizes the rhythmicity of breathing during opiate medication of pain. PMID:19651659

Manzke, Till; Dutschmann, Mathias; Schlaf, Gerald; Morschel, Michael; Koch, Uwe R.; Ponimaskin, Evgeni; Bidon, Olivier; Lalley, Peter M.; Richter, Diethelm W.

2009-01-01

119

Role of sex hormones in the modulation of cholangiocyte function.  

PubMed

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. PMID:21607142

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

2010-06-15

120

Modulation of EEG Functional Connectivity Networks in Subjects Undergoing Repetitive Transcranial Magnetic Stimulation  

PubMed Central

Transcranial magnetic stimulation (TMS) is a noninvasive brain stimulation technique that utilizes magnetic fluxes to alter cortical activity. Continuous theta-burst repetitive TMS (cTBS) results in long-lasting decreases in indices of cortical excitability, and alterations in performance of behavioral tasks. We investigated the effects of cTBS on cortical function via functional connectivity and graph theoretical analysis of EEG data. Thirty-one channel resting-state EEG recordings were obtained before and after 40 s of cTBS stimulation to the left primary motor cortex. Functional connectivity between nodes was assessed in multiple frequency bands using lagged max-covariance, and subsequently thresholded to construct undirected graphs. After cTBS, we find widespread decreases in functional connectivity in the alpha band. There are also simultaneous increases in functional connectivity in the high-beta bands, especially amongst anterior and interhemispheric connections. The analysis of the undirected graphs reveals that interhemispheric and interregional connections are more likely to be modulated after cTBS than local connections. There is also a shift in the topology of network connectivity, with an increase in the clustering coefficient after cTBS in the beta bands, and a decrease in clustering and increase in path length in the alpha band, with the alpha-band connectivity primarily decreased near the site of stimulation. cTBS produces widespread alterations in cortical functional connectivity, with resulting shifts in cortical network topology. PMID:23471637

Shafi, Mouhsin M.; Westover, M. Brandon; Oberman, Lindsay; Cash, Sydney S.; Pascual-Leone, Alvaro

2014-01-01

121

ForPeerReview Resting-state functional connectivity MRI reveals active  

E-print Network

, Laboratory of Brain and Cognition, Department of Human Development, Cornell University; nathan Spreng, Nathan; Cornell University, Human Development Keywords: Neuroimaging, Default network, Knowledge-state functional connectivity MRI reveals active processes central to cognition Full name and affiliation; email

Spreng, R. Nathan

122

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

123

Injection laser with a functionally integrated frequency modulator based on spatially shifted quantum wells  

NASA Astrophysics Data System (ADS)

A method for designing injection lasers with functionally integrated optical-radiation frequency modulators based on spatially shifted quantum wells in conduction and valence bands is proposed. The structure and variants of band diagrams of functionally integrated laser modulators are considered. It is shown that, in the proposed nanoheterostructures, maximum modulation frequencies are determined by the time of controlled relocation of charge-carrier density maxima in quantum domains and correspond to the terahertz range.

Konoplev, B. G.; Ryndin, E. A.; Denisenko, M. A.

2013-11-01

124

Relative sideband amplitudes versus modulation index for common functions using frequency and phase modulation. [for design and testing of communication system  

NASA Technical Reports Server (NTRS)

The equations defining the amplitude of sidebands resulting from either frequency modulation or phase modulation by either square wave, sine wave, sawtooth or triangular modulating functions are presented. Spectral photographs and computer generated tables of modulation index vs. relative sideband amplitudes are also included.

Stocklin, F.

1973-01-01

125

The FASEB Journal Research Communication T-cadherin modulates hepatocyte functions in vitro  

E-print Network

The FASEB Journal · Research Communication T-cadherin modulates hepatocyte functions in vitro of Medicine, Brigham & Women's Hospital, Boston, Massachusetts, USA ABSTRACT Primary hepatocytes from several functions in primary hepatocytes in vitro; however, the molecular mediators underlying this "coculture

Bhatia, Sangeeta

126

Calculations on the Optical Modulation Transfer Function of the Human Eye for White Light  

Microsoft Academic Search

Modulation transfer functions of the dioptrics of the human eye for white (equal energy distribution) light were calculated for different pupil sizes from experimental data on the aberrations. The largest aberration is the chromatic difference of focus. Since this aberration is well known quantitatively and is subject to small individual differences only, the calculated modulation transfer functions can be considered

A. van Meeteren

1974-01-01

127

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. PMID:21559274

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

2011-01-01

128

Title of Module: Models of Higher Brain Functions  

E-print Network

) as well as numerical simulations & programming exercises (Program- ming Tutorial). Working in small groups completing the module, participants should understand strengths and limitations of the different modeling, motor system, psychology and neuroscience of attention, memory systems, executive control, decision

Wichmann, Felix

129

Genomic analysis of COP9 signalosome function in Drosophila melanogaster reveals a role in temporal  

E-print Network

Genomic analysis of COP9 signalosome function in Drosophila melanogaster reveals a role in temporal are using Drosophila as a model system to elucidate the function of this important complex. Transcriptome during development of Drosophila, resulting in achronic gene expression in the csn mutants. `Time shift

Tuller, Tamir

130

Nitric oxide as an endogenous peripheral modulator of visceral sensory neuronal function.  

PubMed

Nitric oxide (NO) plays important roles in CNS and smooth muscle function. Here we reveal an additional function in peripheral sensory transmission. We hypothesized that endogenous NO modulates the function of gastrointestinal vagal afferent endings. The nonselective NO synthase (NOS) inhibitor N(G)-nitro-L-arginine methyl ester hydrochloride increased responses to tactile mechanical stimuli of mucosal afferent endings in two species, in some cases severalfold. This was mimicked by a neuronal NOS inhibitor but not an endothelial NOS inhibitor. NOS inhibitors did not affect the responsiveness of smooth muscle afferent endings, suggesting that the endogenous source of NO is exclusively accessible to mucosal receptors. The role of the NO-soluble guanylyl cyclase (sGC)-cGMP pathway was confirmed using the sGC inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one and the cGMP phosphodiesterase 5' inhibitor sildenafil. The first enhanced and the second inhibited mechanosensory function. Exogenous NO, from the donor S-nitroso-N-acetylpenicillamine, significantly reduced mechanosensitivity of both types of ending. Up to one-third of stomach-projecting afferent neurons in the nodose ganglia expressed neuronal NOS (nNOS). However, anterograde-traced vagal endings were nNOS negative, indicating NOS is not transported peripherally and there are alternative sources of NO for afferent modulation. A subpopulation of enteroendocrine cells in the gut mucosa were nNOS positive, which were found anatomically in close apposition with mucosal vagal afferent endings. These results indicate an inhibitory neuromodulatory role of epithelial NO, which targets a select population of vagal afferents. This interaction is likely to play a role in generation of symptoms and behaviors from the upper gastrointestinal system. PMID:19494147

Page, Amanda J; O'Donnell, Tracey A; Cooper, Nicole J; Young, Richard L; Blackshaw, L Ashley

2009-06-01

131

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

132

The Structure of a Streptomyces avermitilis ?-l-Rhamnosidase Reveals a Novel Carbohydrate-binding Module CBM67 within the Six-domain Arrangement*  

PubMed Central

?-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. Glu636 is predicted to donate protons to the glycosidic oxygen, and Glu895 is the likely catalytic general base, activating the nucleophilic water, indicating that the enzyme operates through an inverting mechanism. Replacement of Glu636 and Glu895 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

2013-01-01

133

Energetic Changes Caused by Antigenic Module Insertion in a Virus-Like Particle Revealed by Experiment and Molecular Dynamics Simulations  

PubMed Central

The success of recombinant virus-like particles (VLPs) for human papillomavirus and hepatitis B demonstrates the potential of VLPs as safe and efficacious vaccines. With new modular designs emerging, the effects of antigen module insertion on the self-assembly and structural integrity of VLPs should be clarified so as to better enabling improved design. Previous work has revealed insights into the molecular energetics of a VLP subunit, capsomere, comparing energetics within various solution conditions known to drive or inhibit self-assembly. In the present study, molecular dynamics (MD) simulations coupled with the molecular mechanics-Poisson-Boltzmann surface area (MM-PBSA) method were performed to examine the molecular interactions and energetics in a modular capsomere of a murine polyomavirus (MPV) VLP designed to protect against influenza. Insertion of an influenza antigenic module is found to lower the binding energy within the capsomere, and a more active state is observed in Assembly Buffer as compared with that in Stabilization Buffer, which has been experimentally validated through measurements using differential scanning calorimetry. Further in-depth analysis based on free-energy decomposition indicates that destabilized binding can be attributed to electrostatic interaction induced by the chosen antigen module. These results provide molecular insights into the conformational stability of capsomeres and their abilities to be exploited for antigen presentation, and are expected to be beneficial for the biomolecular engineering of VLP vaccines. PMID:25215874

Zhang, Lin; Tang, Ronghong; Bai, Shu; Connors, Natalie K.; Lua, Linda H. L.; Chuan, Yap P.; Middelberg, Anton P. J.; Sun, Yan

2014-01-01

134

Temporal Modulation Transfer Functions Measured From Auditory-Nerve Responses Following Sensorineural Hearing Loss  

PubMed Central

The ability of auditory-nerve (AN) fibers to encode modulation frequencies, as characterized by temporal modulation transfer functions (TMTFs), generally shows a low-pass shape with a cut-off frequency that increases with fiber characteristic frequency (CF). Because AN-fiber bandwidth increases with CF, this result has been interpreted to suggest that peripheral filtering has a significant effect on limiting the encoding of higher modulation frequencies. Sensorineural hearing loss (SNHL), which is typically associated with broadened tuning, is thus predicted to increase the range of modulation frequencies encoded; however, perceptual studies have generally not supported this prediction. The present study sought to determine whether the range of modulation frequencies encoded by AN fibers is affected by SNHL, and whether the effects of SNHL on envelope coding are similar at all modulation frequencies within the TMTF passband. Modulation response gain for sinusoidally amplitude modulated (SAM) tones was measured as a function of modulation frequency, with the carrier frequency placed at fiber CF. TMTFs were compared between normal-hearing chinchillas and chinchillas with a noise-induced hearing loss for which AN fibers had significantly broadened tuning. Synchrony and phase responses for individual SAM-tone components were quantified to explore a variety of factors that can influence modulation coding. Modulation gain was found to be higher than normal in noise-exposed fibers across the entire range of modulation frequencies encoded by AN fibers. The range of modulation frequencies encoded by noise-exposed AN fibers was not affected by SNHL, as quantified by TMTF 3- and 10-dB cut-off frequencies. These results suggest that physiological factors other than peripheral filtering may have a significant role in determining the range of modulation frequencies encoded in AN fibers. Furthermore, these neural data may help to explain the lack of a consistent association between perceptual measures of temporal resolution and degraded frequency selectivity. PMID:22366500

Kale, Sushrut; Heinz, Michael G.

2012-01-01

135

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

2007-04-17

136

Modulation of molecular interactions and function by rhodopsin palmitylation†  

PubMed Central

Rhodopsin is palmitylated at two cysteine residues in its carboxyl terminal region. We have looked at the effects of palmitylation on the molecular interactions formed by rhodopsin using single-molecule force spectroscopy and the function of rhodopsin using both in vitro and in vivo approaches. A knockin mouse model expressing palmitate-deficient rhodopsin was used for live animal in vivo studies and to obtain native tissue samples for in vitro assays. We specifically looked at the effects palmitylation has on the chromophore-binding pocket, interactions of rhodopsin with transducin, and molecular interactions stabilizing the receptor structure. The structure of rhodopsin is largely unperturbed by the absence of palmitate linkage. The binding pocket for the chromophore 11-cis-retinal is minimally altered as palmitate-deficient rhodopsin exhibited the same absorbance spectrum as wild-type rhodopsin. Similarly, the rate of release of all-trans-retinal after light activation was the same both in the presence and absence of palmitylation. Significant differences were observed in the rate of transducin activation by rhodopsin and in the force required to unfold the last stable structural segment in rhodopsin at its carboxyl terminal region. A 1.3-fold reduction in the rate of transducin activation by rhodopsin was observed in the absence of palmitylation. Single-molecule force spectroscopy revealed a 2.1-fold reduction in normalized force required to unfold the carboxyl terminal end of rhodopsin. The absence of palmitylation in rhodopsin therefore destabilizes the molecular interactions formed in the carboxyl terminal end of the receptor, which appears to hinder the activation of transducin by light-activated rhodopsin. PMID:19348429

Park, Paul S.-H.; Sapra, K. Tanuj; Jastrzebska, Beata; Maeda, Tadao; Maeda, Akiko; Pulawski, Wojciech; Kono, Masahiro; Lem, Janis; Crouch, Rosalie K.; Filipek, Slawomir; Muller, Daniel J.; Palczewski, Krzysztof

2009-01-01

137

Integrative analysis using module-guided random forests reveals correlated genetic factors related to mouse weight.  

PubMed

Complex traits such as obesity are manifestations of intricate interactions of multiple genetic factors. However, such relationships are difficult to identify. Thanks to the recent advance in high-throughput technology, a large amount of data has been collected for various complex traits, including obesity. These data often measure different biological aspects of the traits of interest, including genotypic variations at the DNA level and gene expression alterations at the RNA level. Integration of such heterogeneous data provides promising opportunities to understand the genetic components and possibly genetic architecture of complex traits. In this paper, we propose a machine learning based method, module-guided Random Forests (mgRF), to integrate genotypic and gene expression data to investigate genetic factors and molecular mechanism underlying complex traits. mgRF is an augmented Random Forests method enhanced by a network analysis for identifying multiple correlated variables of different types. We applied mgRF to genetic markers and gene expression data from a cohort of F2 female mouse intercross. mgRF outperformed several existing methods in our extensive comparison. Our new approach has an improved performance when combining both genotypic and gene expression data compared to using either one of the two types of data alone. The resulting predictive variables identified by mgRF provide information of perturbed pathways that are related to body weight. More importantly, the results uncovered intricate interactions among genetic markers and genes that have been overlooked if only one type of data was examined. Our results shed light on genetic mechanisms of obesity and our approach provides a promising complementary framework to the "genetics of gene expression" analysis for integrating genotypic and gene expression information for analyzing complex traits. PMID:23505362

Chen, Zheng; Zhang, Weixiong

2013-01-01

138

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

2013-01-01

139

Comparative Systems Biology Reveals Allelic Variation Modulating Tocochromanol Profiles in Barley (Hordeum vulgare L.)  

PubMed Central

Tocochromanols are recognized for nutritional content, plant stress response, and seed longevity. Here we present a systems biological approach to characterize and develop predictive assays for genes affecting tocochromanol variation in barley. Major QTL, detected in three regions of a SNP linkage map, affected multiple tocochromanol forms. Candidate genes were identified through barley/rice orthology and sequenced in genotypes with disparate tocochromanol profiles. Gene-specific markers, designed based on observed polymorphism, mapped to the originating QTL, increasing R2 values at the respective loci. Polymorphism within promoter regions corresponded to motifs known to influence gene expression. Quantitative PCR analysis revealed a trend of increased expression in tissues grown at cold temperatures. These results demonstrate utility of a novel method for rapid gene identification and characterization, and provide a resource for efficient development of barley lines with improved tocochromanol profiles. PMID:24820172

Oliver, Rebekah E.; Islamovic, Emir; Obert, Donald E.; Wise, Mitchell L.; Herrin, Lauri L.; Hang, An; Harrison, Stephen A.; Ibrahim, Amir; Marshall, Juliet M.; Miclaus, Kelci J.; Lazo, Gerard R.; Hu, Gongshe; Jackson, Eric W.

2014-01-01

140

Cholesterol Levels Modulate EGF Receptor-Mediated Signaling by Altering Receptor Function and Trafficking  

E-print Network

Cholesterol Levels Modulate EGF Receptor-Mediated Signaling by Altering Receptor Function to be affected by changes in cellular cholesterol content. However, no information is available regarding the locus (or loci) in the pathways that are susceptible to modulation by cholesterol. We report here

Pike, Linda J.

141

Fast algorithms for detecting overlapping functional modules in protein-protein interaction networks  

Microsoft Academic Search

Accumulating evidence suggests that biological systems are composed of interacting, separable, functional modules which is that groups of vertices within which connections are dense but between which they are sparse. Identifying these modules is likely to capture the biologically meaningful interactions. In recent years, many algorithms have been developed for detecting such structures. These algorithms however are computationally demanding, which

Peng-Gang Sun; Lin Gao

2009-01-01

142

Bio-mimicking of Proline-Rich Motif Applied to Carbon Nanotube Reveals Unexpected Subtleties Underlying Nanoparticle Functionalization.  

PubMed

Here, we report computational studies of the SH3 protein domain interacting with various single-walled carbon nanotubes (SWCNT) either bare or functionalized by mimicking the proline-rich motif (PRM) ligand (PPPVPPRR) and compare it to the SH3-PRM complex binding. With prolines or a single arginine attached, the SWCNT gained slightly on specificity when compared with the bare control, whereas with multi-arginine systems the specificity dropped dramatically to our surprise. Although the electrostatic interaction provided by arginines is crucial in the recognition between PRM and SH3 domain, our results suggest that attaching multiple arginines to the SWCNT has a detrimental effect on the binding affinity. Detailed analysis of the MD trajectories found two main factors that modulate the specificity of the binding: the existence of competing acidic patches at the surface of SH3 that leads to "trapping and clamping" by the arginines, and the rigidity of the SWCNT introducing entropic penalties in the proper binding. Further investigation revealed that the same "clamping" phenomenon exits in the PRM-SH3 system, which has not been reported in previous literature. The competing effects between nanoparticle and its functionalization components revealed by our model system should be of value to current and future nanomedicine designs. PMID:25427563

Zhang, Yuanzhao; Jimenez-Cruz, Camilo A; Wang, Jian; Zhou, Bo; Yang, Zaixing; Zhou, Ruhong

2014-01-01

143

Prediction of functional modules based on comparative genome analysis and Gene Ontology application  

PubMed Central

We present a computational method for the prediction of functional modules encoded in microbial genomes. In this work, we have also developed a formal measure to quantify the degree of consistency between the predicted and the known modules, and have carried out statistical significance analysis of consistency measures. We first evaluate the functional relationship between two genes from three different perspectives—phylogenetic profile analysis, gene neighborhood analysis and Gene Ontology assignments. We then combine the three different sources of information in the framework of Bayesian inference, and we use the combined information to measure the strength of gene functional relationship. Finally, we apply a threshold-based method to predict functional modules. By applying this method to Escherichia coli K12, we have predicted 185 functional modules. Our predictions are highly consistent with the previously known functional modules in E.coli. The application results have demonstrated that our approach is highly promising for the prediction of functional modules encoded in a microbial genome. PMID:15901854

Wu, Hongwei; Su, Zhengchang; Mao, Fenglou; Olman, Victor; Xu, Ying

2005-01-01

144

Modulation of Functional Connectivity During the Resting State and the Motor Task  

E-print Network

.g., attention modulation of visual cortex [Friston and Buchel, 2000], plastic changes of brain regions relating; Xiong et al., 1999; ]. In function- ally related regions of the brain, these fluctuations are syn

Jiang,Tianzi

145

The Neural Consequences of Repeated Cocaine Exposure Revealed by Functional MRI in Awake Rats  

E-print Network

The Neural Consequences of Repeated Cocaine Exposure Revealed by Functional MRI in Awake Rats models of cocaine addiction is an invaluable tool for investigating the neuroadaptations that lead circuits affected by repeated cocaine administration. Rats were given an injection of cocaine (15 mg/kg, i

Duong, Timothy Q.

146

Pupillometry reveals changes in cognitive control dynamics as a function of motivational incentives.  

E-print Network

Pupillometry reveals changes in cognitive control dynamics as a function of motivational, Washington University in St. Louis Behavioural and neural evidence suggests that motivational incentives of mental effort). Changes in task performance were consistent with the idea that incentive is associated

147

Nonlinear analysis of EEG during NREM sleep reveals changes in functional connectivity due to natural aging  

E-print Network

). This assistance has been observed in brain imaging studies of sleep deprived young adults, suggesting that similarNonlinear analysis of EEG during NREM sleep reveals changes in functional connectivity due organization of nonlinear interactions between different brain re- gions during the first NREM sleep stage

148

Deep small RNA sequencing from the nematode Ascaris reveals conservation, functional diversification,  

E-print Network

Research Deep small RNA sequencing from the nematode Ascaris reveals conservation, functional on small RNA pathways in nematodes, we identified and characterized known and novel small RNA classes through gametogenesis and embryo development in the parasitic nematode Ascaris suum and compared them

Davis, Richard E.

149

Soil Science Society of America Journal Revealing Soil Structure and Functional Macroporosity  

E-print Network

Soil Science Society of America Journal Revealing Soil Structure and Functional Macroporosity along a Clay Gradient Using X-ray Computed Tomography T he preservation and restoration of a beneficial soil of soil structure has also been recognized for environmental and groundwater protection because it governs

Wildenschild, Dorthe

150

Structural and functional MRI reveals multiple retinal layers Thul, Darin E. Olson, and Timothy Q. Duong  

E-print Network

. Duong Haiying Cheng, Govind Nair, Tiffany A. Walker, Moon K. Kim, Machelle T. Pardue, Peter M. doi:10 Cheng , Govind Nair , Tiffany A. Walker , Moon K. Kim , Machelle T. Pardue§ , Peter M. Thule´¶ , Darin E and the vitreous. Similarly, blood-oxygen-level- dependent (BOLD) functional MRI revealed layer-specific responses

Duong, Timothy Q.

151

Parametric Dependence of Ocean Wave-Radar Modulation Transfer Functions  

Microsoft Academic Search

much smaller when the antennas are pointed perpendicular to long waves, however. X band transfer functions measured with horizontally polarized microwave radiation are found to have larger magnitudes than those obtained by using vertical polarization. Under conditions encountered in this experiment, transfer functions are independent of long-wave amplitude when waves and antennas are aligned. Coherence functions, however, depend strongly on

W. J. Plant; W. C. Keller; A. Cross

1983-01-01

152

Engineered TAL Effector modulators for the large-scale gain-of-function screening  

PubMed Central

Recent effective use of TAL Effectors (TALEs) has provided an important approach to the design and synthesis of sequence-specific DNA-binding proteins. However, it is still a challenging task to design and manufacture effective TALE modulators because of the limited knowledge of TALE–DNA interactions. Here we synthesized more than 200 TALE modulators and identified two determining factors of transcription activity in vivo: chromatin accessibility and the distance from the transcription start site. The implementation of these modulators in a gain-of-function screen was successfully demonstrated for four cell lines in migration/invasion assays and thus has broad relevance in this field. Furthermore, a novel TALE–TALE modulator was developed to transcriptionally inhibit target genes. Together, these findings underscore the huge potential of these TALE modulators in the study of gene function, reprogramming of cellular behaviors, and even clinical investigation. PMID:24939900

Zhang, Hanshuo; Li, Juan; Hou, Sha; Wang, Gancheng; Jiang, Mingjun; Sun, Changhong; Hu, Xiongbing; Zhuang, Fengfeng; Dai, Zhifei; Dai, Junbiao; Xi, Jianzhong Jeff

2014-01-01

153

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. PMID:23388107

2013-01-01

154

Perk Gene Dosage Regulates Glucose Homeostasis by Modulating Pancreatic ?-Cell Functions  

PubMed Central

Background Insulin synthesis and cell proliferation are under tight regulation in pancreatic ?-cells to maintain glucose homeostasis. Dysfunction in either aspect leads to development of diabetes. PERK (EIF2AK3) loss of function mutations in humans and mice exhibit permanent neonatal diabetes that is characterized by insufficient ?-cell mass and reduced proinsulin trafficking and insulin secretion. Unexpectedly, we found that Perk heterozygous mice displayed lower blood glucose levels. Methodology Longitudinal studies were conducted to assess serum glucose and insulin, intracellular insulin synthesis and storage, insulin secretion, and ?-cell proliferation in Perk heterozygous mice. In addition, modulation of Perk dosage specifically in ?-cells showed that the glucose homeostasis phenotype of Perk heterozygous mice is determined by reduced expression of PERK in the ?-cells. Principal Findings We found that Perk heterozygous mice first exhibited enhanced insulin synthesis and secretion during neonatal and juvenile development followed by enhanced ?-cell proliferation and a substantial increase in ?-cell mass at the adult stage. These differences are not likely to entail the well-known function of PERK to regulate the ER stress response in cultured cells as several markers for ER stress were not differentially expressed in Perk heterozygous mice. Conclusions In addition to the essential functions of PERK in ?-cells as revealed by severely diabetic phenotype in humans and mice completely deficient for PERK, reducing Perk gene expression by half showed that intermediate levels of PERK have a profound impact on ?-cell functions and glucose homeostasis. These results suggest that an optimal level of PERK expression is necessary to balance several parameters of ?-cell function and growth in order to achieve normoglycemia. PMID:24915520

Wang, Rong; Munoz, Elyse E.; Zhu, Siying; McGrath, Barbara C.; Cavener, Douglas R.

2014-01-01

155

A Functional Screen Reveals an Extensive Layer of Transcriptional and Splicing Control Underlying RAS/MAPK Signaling in Drosophila  

PubMed Central

The small GTPase RAS is among the most prevalent oncogenes. The evolutionarily conserved RAF-MEK-MAPK module that lies downstream of RAS is one of the main conduits through which RAS transmits proliferative signals in normal and cancer cells. Genetic and biochemical studies conducted over the last two decades uncovered a small set of factors regulating RAS/MAPK signaling. Interestingly, most of these were found to control RAF activation, thus suggesting a central regulatory role for this event. Whether additional factors are required at this level or further downstream remains an open question. To obtain a comprehensive view of the elements functionally linked to the RAS/MAPK cascade, we used a quantitative assay in Drosophila S2 cells to conduct a genome-wide RNAi screen for factors impacting RAS-mediated MAPK activation. The screen led to the identification of 101 validated hits, including most of the previously known factors associated to this pathway. Epistasis experiments were then carried out on individual candidates to determine their position relative to core pathway components. While this revealed several new factors acting at different steps along the pathway—including a new protein complex modulating RAF activation—we found that most hits unexpectedly work downstream of MEK and specifically influence MAPK expression. These hits mainly consist of constitutive splicing factors and thereby suggest that splicing plays a specific role in establishing MAPK levels. We further characterized two representative members of this group and surprisingly found that they act by regulating mapk alternative splicing. This study provides an unprecedented assessment of the factors modulating RAS/MAPK signaling in Drosophila. In addition, it suggests that pathway output does not solely rely on classical signaling events, such as those controlling RAF activation, but also on the regulation of MAPK levels. Finally, it indicates that core splicing components can also specifically impact alternative splicing. PMID:24643257

Ashton-Beaucage, Dariel; Udell, Christian M.; Gendron, Patrick; Sahmi, Malha; Lefrancois, Martin; Baril, Caroline; Guenier, Anne-Sophie; Duchaine, Jean; Lamarre, Daniel; Lemieux, Sebastien; Therrien, Marc

2014-01-01

156

Metagenomic analysis reveals significant changes of microbial compositions and protective functions during drinking water treatment.  

PubMed

The metagenomic approach was applied to characterize variations of microbial structure and functions in raw (RW) and treated water (TW) in a drinking water treatment plant (DWTP) at Pearl River Delta, China. Microbial structure was significantly influenced by the treatment processes, shifting from Gammaproteobacteria and Betaproteobacteria in RW to Alphaproteobacteria in TW. Further functional analysis indicated the basic metabolic functions of microorganisms in TW did not vary considerably. However, protective functions, i.e. glutathione synthesis genes in 'oxidative stress' and 'detoxification' subsystems, significantly increased, revealing the surviving bacteria may have higher chlorine resistance. Similar results were also found in glutathione metabolism pathway, which identified the major reaction for glutathione synthesis and supported more genes for glutathione metabolism existed in TW. This metagenomic study largely enhanced our knowledge about the influences of treatment processes, especially chlorination, on bacterial community structure and protective functions (e.g. glutathione metabolism) in ecosystems of DWTPs. PMID:24352003

Chao, Yuanqing; Ma, Liping; Yang, Ying; Ju, Feng; Zhang, Xu-Xiang; Wu, Wei-Min; Zhang, Tong

2013-01-01

157

Metagenomic analysis reveals significant changes of microbial compositions and protective functions during drinking water treatment  

NASA Astrophysics Data System (ADS)

The metagenomic approach was applied to characterize variations of microbial structure and functions in raw (RW) and treated water (TW) in a drinking water treatment plant (DWTP) at Pearl River Delta, China. Microbial structure was significantly influenced by the treatment processes, shifting from Gammaproteobacteria and Betaproteobacteria in RW to Alphaproteobacteria in TW. Further functional analysis indicated the basic metabolic functions of microorganisms in TW did not vary considerably. However, protective functions, i.e. glutathione synthesis genes in `oxidative stress' and `detoxification' subsystems, significantly increased, revealing the surviving bacteria may have higher chlorine resistance. Similar results were also found in glutathione metabolism pathway, which identified the major reaction for glutathione synthesis and supported more genes for glutathione metabolism existed in TW. This metagenomic study largely enhanced our knowledge about the influences of treatment processes, especially chlorination, on bacterial community structure and protective functions (e.g. glutathione metabolism) in ecosystems of DWTPs.

Chao, Yuanqing; Ma, Liping; Yang, Ying; Ju, Feng; Zhang, Xu-Xiang; Wu, Wei-Min; Zhang, Tong

2013-12-01

158

A nanobody modulates the p53 transcriptional program without perturbing its functional architecture.  

PubMed

The p53 transcription factor plays an important role in genome integrity. To perform this task, p53 regulates the transcription of genes promoting various cellular outcomes including cell cycle arrest, apoptosis or senescence. The precise regulation of this activity remains elusive as numerous mechanisms, e.g. posttranslational modifications of p53 and (non-)covalent p53 binding partners, influence the p53 transcriptional program. We developed a novel, non-invasive tool to manipulate endogenous p53. Nanobodies (Nb), raised against the DNA-binding domain of p53, allow us to distinctively target both wild type and mutant p53 with great specificity. Nb3 preferentially binds 'structural' mutant p53, i.e. R175H and R282W, while a second but distinct nanobody, Nb139, binds both mutant and wild type p53. The co-crystal structure of the p53 DNA-binding domain in complex with Nb139 (1.9 Å resolution) reveals that Nb139 binds opposite the DNA-binding surface. Furthermore, we demonstrate that Nb139 does not disturb the functional architecture of the p53 DNA-binding domain using conformation-specific p53 antibody immunoprecipitations, glutaraldehyde crosslinking assays and chromatin immunoprecipitation. Functionally, the binding of Nb139 to p53 allows us to perturb the transactivation of p53 target genes. We propose that reduced recruitment of transcriptional co-activators or modulation of selected post-transcriptional modifications account for these observations. PMID:25324313

Bethuyne, Jonas; De Gieter, Steven; Zwaenepoel, Olivier; Garcia-Pino, Abel; Durinck, Kaat; Verhelle, Adriaan; Hassanzadeh-Ghassabeh, Gholamreza; Speleman, Frank; Loris, Remy; Gettemans, Jan

2014-11-10

159

Modulation of Neutrophil Function by a Secreted Mucinase of Escherichia coli O157:H7  

PubMed Central

Escherichia coli O157?H7 is a human enteric pathogen that causes hemorrhagic colitis which can progress to hemolytic uremic syndrome, a severe kidney disease with immune involvement. During infection, E. coli O157?H7 secretes StcE, a metalloprotease that promotes the formation of attaching and effacing lesions and inhibits the complement cascade via cleavage of mucin-type glycoproteins. We found that StcE cleaved the mucin-like, immune cell-restricted glycoproteins CD43 and CD45 on the neutrophil surface and altered neutrophil function. Treatment of human neutrophils with StcE led to increased respiratory burst production and increased cell adhesion. StcE-treated neutrophils exhibited an elongated morphology with defective rear detachment and impaired migration, suggesting that removal of the anti-adhesive capability of CD43 by StcE impairs rear release. Use of zebrafish embryos to model neutrophil migration revealed that StcE induced neutrophil retention in the fin after tissue wounding, suggesting that StcE modulates neutrophil-mediated inflammation in vivo. Neutrophils are crucial innate effectors of the antibacterial immune response and can contribute to severe complications caused by infection with E. coli O157?H7. Our data suggest that the StcE mucinase can play an immunomodulatory role by directly altering neutrophil function during infection. StcE may contribute to inflammation and tissue destruction by mediating inappropriate neutrophil adhesion and activation. PMID:19247439

Szabady, Rose L.; Lokuta, Mary A.; Walters, Kevin B.; Huttenlocher, Anna; Welch, Rodney A.

2009-01-01

160

A nanobody modulates the p53 transcriptional program without perturbing its functional architecture  

PubMed Central

The p53 transcription factor plays an important role in genome integrity. To perform this task, p53 regulates the transcription of genes promoting various cellular outcomes including cell cycle arrest, apoptosis or senescence. The precise regulation of this activity remains elusive as numerous mechanisms, e.g. posttranslational modifications of p53 and (non-)covalent p53 binding partners, influence the p53 transcriptional program. We developed a novel, non-invasive tool to manipulate endogenous p53. Nanobodies (Nb), raised against the DNA-binding domain of p53, allow us to distinctively target both wild type and mutant p53 with great specificity. Nb3 preferentially binds ‘structural’ mutant p53, i.e. R175H and R282W, while a second but distinct nanobody, Nb139, binds both mutant and wild type p53. The co-crystal structure of the p53 DNA-binding domain in complex with Nb139 (1.9 Å resolution) reveals that Nb139 binds opposite the DNA-binding surface. Furthermore, we demonstrate that Nb139 does not disturb the functional architecture of the p53 DNA-binding domain using conformation-specific p53 antibody immunoprecipitations, glutaraldehyde crosslinking assays and chromatin immunoprecipitation. Functionally, the binding of Nb139 to p53 allows us to perturb the transactivation of p53 target genes. We propose that reduced recruitment of transcriptional co-activators or modulation of selected post-transcriptional modifications account for these observations. PMID:25324313

Bethuyne, Jonas; De Gieter, Steven; Zwaenepoel, Olivier; Garcia-Pino, Abel; Durinck, Kaat; Verhelle, Adriaan; Hassanzadeh-Ghassabeh, Gholamreza; Speleman, Frank; Loris, Remy; Gettemans, Jan

2014-01-01

161

Functional analysis of rice HOMEOBOX4 (Oshox4) gene reveals a negative function in gibberellin responses.  

PubMed

The homeodomain-leucine zipper (HD-Zip) putative transcription factor genes are divided into 4 families. In this work, we studied the function of a rice HD-Zip I gene, H OME O BO X4 (Oshox4). Oshox4 transcripts were detected in leaf and floral organ primordia but excluded from the shoot apical meristem and the protein was nuclear localized. Over-expression of Oshox4 in rice induced a semi-dwarf phenotype that could not be complemented by applied GA3. The over-expression plants accumulated elevated levels of bioactive GA, while the GA catabolic gene GA2ox3 was upregulated in the transgenic plants. In addition, over-expression of Oshox4 blocked GA-dependent alpha-amylase production. However, down-regulation of Oshox4 in RNAi transgenic plants induced no phenotypic alteration. Interestingly, the expression of YAB1 that is involved in the negative feedback regulation of the GA biosynthesis was upregulated in the Oshox4 over-expressing plants. One-hybrid assays showed that Oshox4 could interact with YAB1 promoter in yeast. In addition, Oshox4 expression was upregulated by GA. These data together suggest that Oshox4 may be involved in the negative regulation of GA signalling and may play a role to fine tune GA responses in rice. PMID:18049796

Dai, Mingqiu; Hu, Yongfeng; Ma, Qian; Zhao, Yu; Zhou, Dao-Xiu

2008-02-01

162

Age-related differences in the temporal modulation transfer function with pure-tone carriers  

PubMed Central

Detection of amplitude modulation (AM) in 500 and 4000 Hz tonal carriers was measured as a function of modulation frequency from younger and older adults with normal hearing through 4000 Hz. The modulation frequency above which sensitivity to AM increased (“transition frequency”) was similar for both groups. Temporal modulation transfer function shapes showed significant age-related differences. For younger subjects, AM detection thresholds were generally constant for low modulation frequencies. For a higher carrier frequency, AM detection thresholds then increased as modulation frequency further increased until the transition frequency. In contrast, AM detection for older subjects continuously increased with increasing modulation frequency, indicating an age-related decline in temporal resolution for faster envelope fluctuations. Significant age-related differences were observed whenever AM detection was dependent on temporal cues. For modulation frequencies above the transition frequency, age-related differences were larger for the lower frequency carrier (where both temporal and spectral cues were available) than for the higher frequency carrier (where AM detection was primarily dependent on spectral cues). These results are consistent with a general age-related decline in the synchronization of neural responses to both the carrier waveform and envelope fluctuation. PMID:19206810

He, Ning-ji; Mills, John H.; Ahlstrom, Jayne B.; Dubno, Judy R.

2008-01-01

163

Functional Modulation of Cardiac Form through Regionally Confined Cell Shape  

Microsoft Academic Search

Developing organs acquire a specific three-dimensional form that ensures their normal function. Cardiac function, for example, depends upon properly shaped chambers that emerge from a primitive heart tube. The cellular mechanisms that control chamber shape are not yet understood. Here, we demonstrate that chamber morphology develops via changes in cell morphology, and we determine key regulatory influences on this process.

Heidi J. Auman; Hope Coleman; Heather E. Riley; Felix Olale; Huai-Jen Tsai; Deborah Yelon

164

Band gap modulation of bilayer graphene by single and dual molecular doping: A van der Waals density-functional study  

NASA Astrophysics Data System (ADS)

Density functional calculations including long-range dispersion effects demonstrate that non-covalent doping with an electron donor acceptor couple of molecules can open an energy gap in a bilayer graphene. The band gap modulation can be controlled not only by the choice of adsorbed molecules (n-dopant versus p-dopant) but also by their concentration. A deep analysis of the charge transfer reveals that charge redistribution in bilayer graphene is the key issue for gap opening, due to the induced inversion symmetry breaking. The dual molecular non-covalent doping mode can achieve the opening of a gap up to 138 meV.

Hu, Tao; Gerber, Iann C.

2014-11-01

165

Functionally integrated reconfigurable optical add/drop module  

NASA Astrophysics Data System (ADS)

Reconfigurable Add/drop Multiplexer (ROADM) is a broad definition of a functionally reconfigurable filtering device for dynamic networking. We focus on a class of ROADM architecture that allows scalability of wavelength channels, add/drop port counts as well as functional capability of integrating variable attenuation and monitoring elements. We demonstrate the proposed concepts of integrating a ROADM with a variable optical attenuator and a performance monitor array.

Li, Yao; He, Chun; Wang, Daoyi; Wang, Xinzhong; Wu, Frank; Tsay, Wei-Shin

2004-05-01

166

Probing astroglia with carbon nanotubes: modulation of form and function.  

PubMed

Carbon nanotubes (CNTs) have shown much promise in neurobiology and biomedicine. Their structural stability and ease of chemical modification make them compatible for biological applications. In this review, we discuss the effects that chemically functionalized CNTs, applied as colloidal solutes or used as strata, have on the morpho-functional properties of astrocytes, the most abundant cells present in the brain, with an insight into the potential use of CNTs in neural prostheses. PMID:25225092

Gottipati, Manoj K; Verkhratsky, Alexei; Parpura, Vladimir

2014-10-19

167

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

168

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. PMID:23049741

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

2012-01-01

169

Antigenic and Mutational Analyses of Herpes Simplex Virus Glycoprotein B Reveal Four Functional Regions  

Microsoft Academic Search

Glycoprotein B (gB), along with gD, gH, and gL, is essential for herpes simplex virus (HSV) entry. The crystal structure of the gB ectodomain revealed it to be an elongated multidomain trimer. We generated and characterized a panel of 67 monoclonal antibodies (MAbs). Eleven of the MAbs had virus-neutralizing activity. To organize gB into functional regions within these domains, we

Florent C. Bender; Minu Samanta; Ekaterina E. Heldwein; Manuel Ponce de Leon; Elina Bilman; Huan Lou; J. Charles Whitbeck; Roselyn J. Eisenberg; Gary H. Cohen

2007-01-01

170

Inducible knock-down of GNOM during root formation reveals tissue-specific response to auxin transport and its modulation of local auxin biosynthesis  

PubMed Central

In plants, active transport of auxin plays an essential role in root development. Localization of the PIN1 auxin transporters to the basal membrane of cells directs auxin flow and depends on the trafficking mediator GNOM. GNOM-dependent auxin transport is vital for root development and thus offers a useful tool for the investigation of a possible tissue-specific response to dynamic auxin transport. To avoid pleiotropic effects, DEX-inducible expression of GNOM antisense RNA was used to disrupt GNOM expression transiently or persistently during embryonic root development. It was found that the elongation zone and the pericycle layer are the most sensitive to GNOM-dependent auxin transport variations, which is shown by the phenotypes in cell elongation and the initiation of lateral root primordia, respectively. This suggests that auxin dynamics is critical to cell differentiation and cell fate transition, but not to cell division. The results also reveal that GNOM-dependent auxin transport could affect local auxin biosynthesis. This suggests that local auxin biosynthesis may also contribute to the establishment of GNOM-dependent auxin gradients in specific tissues, and that auxin transport and local auxin biosynthesis may function together in the regulatory network for initiation and development of lateral root primordia. Thus, the data reveal a tissue-specific response to auxin transport and modulation of local auxin biosynthesis by auxin transport. PMID:24453227

Sun, Meng-Xiang

2014-01-01

171

Reducing the diffraction artifacts while implementing a phase function on a spatial light modulator.  

PubMed

Spatial light modulators are often used to implement phase modulation. Since they are pixelated, the phase function is usually approximated by a regularly sampled piecewise constant function, and the periodicity of the pixel sampling generates annoying diffraction peaks. We theoretically investigate two pixelation techniques: the isophase method and a new nonperiodic method derived from the Voronoi tessellation technique. We show that, for a suitable choice of parameters, the diffraction peaks disappear and are replaced by a smoothly varying halo. We illustrate the potential of these two techniques for implementing a lens function and wavefront correction. PMID:21283242

Benoît-Pasanau, Céline; Goudail, François; Chavel, Pierre; Cano, Jean-Paul; Ballet, Jérôme

2011-02-01

172

Supplemental Information for "T-cadherin Modulates Hepatocyte Functions In Vitro" by Khetani et al.  

E-print Network

1 Supplemental Information for "T-cadherin Modulates Hepatocyte Functions In Vitro" by Khetani et al. Supplemental Figure 1. Long-term induction of hepatocyte functions upon co-cultivation with T-specific differentiation and protein synthesis) by primary rat hepatocytes was induced upon co-cultivation with CHO cells

Bhatia, Sangeeta

173

Serotonin modulates muscle function in the medicinal leech Hirudo verbana  

PubMed Central

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.

2011-01-01

174

HIV induces modulation of functionally important cellular antigens.  

PubMed Central

Infection of T lymphoblastoid CEM cells with the IIIB isolate of HIV-1 results in modulation of the expression of several cellular antigens in addition to the CD4 molecule. The intercellular adhesion receptor LFA-1 (CD11a/CD18) and HLA-DR are markedly induced in the cytoplasm and at the cell surface, and the CD7 antigen is down-regulated, being virtually undetectable by sensitive immunocytochemical techniques in the infected cell population. These modulatory effects are to some degree dependent on the virus isolate examined, as the CBL-1 British isolate did not induce comparable phenotypic changes in the CEM cell line. Furthermore, these effects are not reproduced by recombinant gp120 (IIIB isolate) or p24 added exogenously to uninfected CEM cells. The CD7 molecule appears to play a regulatory role in T cell proliferation, and the LFA-1 integrin molecule is involved in a wide range of immunologically important cell-cell interactions, as well as HIV-induced syncytium formation. The possible contributions of such effects to the pathogenesis of HIV infection are considered. PMID:1712685

Wrightham, M; Schimpf, A; Pennington, T H; Walker, F; Sewell, H F

1991-01-01

175

Revealing Molecular Mechanisms by Integrating High-Dimensional Functional Screens with Protein Interaction Data  

PubMed Central

Functional genomics screens using multi-parametric assays are powerful approaches for identifying genes involved in particular cellular processes. However, they suffer from problems like noise, and often provide little insight into molecular mechanisms. A bottleneck for addressing these issues is the lack of computational methods for the systematic integration of multi-parametric phenotypic datasets with molecular interactions. Here, we present Integrative Multi Profile Analysis of Cellular Traits (IMPACT). The main goal of IMPACT is to identify the most consistent phenotypic profile among interacting genes. This approach utilizes two types of external information: sets of related genes (IMPACT-sets) and network information (IMPACT-modules). Based on the notion that interacting genes are more likely to be involved in similar functions than non-interacting genes, this data is used as a prior to inform the filtering of phenotypic profiles that are similar among interacting genes. IMPACT-sets selects the most frequent profile among a set of related genes. IMPACT-modules identifies sub-networks containing genes with similar phenotype profiles. The statistical significance of these selections is subsequently quantified via permutations of the data. IMPACT (1) handles multiple profiles per gene, (2) rescues genes with weak phenotypes and (3) accounts for multiple biases e.g. caused by the network topology. Application to a genome-wide RNAi screen on endocytosis showed that IMPACT improved the recovery of known endocytosis-related genes, decreased off-target effects, and detected consistent phenotypes. Those findings were confirmed by rescreening 468 genes. Additionally we validated an unexpected influence of the IGF-receptor on EGF-endocytosis. IMPACT facilitates the selection of high-quality phenotypic profiles using different types of independent information, thereby supporting the molecular interpretation of functional screens. PMID:25188415

Collinet, Claudio; Galvez, Thierry; Kalaidzidis, Yannis; Zerial, Marino; Beyer, Andreas

2014-01-01

176

Essential role of the 58-kDa microspherule protein in the modulation of Daxx-dependent transcriptional repression as revealed by nucleolar sequestration.  

PubMed

Daxx has been reported to mediate the Fas/JNK-dependent signals in the cytoplasm. However, several lines of evidence have suggested that Daxx is located mainly in the nucleus and functions as a transcriptional regulator. Recent studies have further indicated that Daxx-elicited transcriptional repression can be inhibited by the nuclear body-associated promyelocytic leukemia protein and apoptosis signal-regulating kinase 1 by sequestering Daxx to the nuclear bodies and the cytoplasm, respectively. Here, we further investigated the coordinated molecular mechanism by which Daxx function is regulated through protein-protein interaction. Using yeast two-hybrid screens to identify Daxx-interacting protein(s), three independent clones encoding the 58-kDa microspherule protein (MSP58) fragments were identified. Furthermore, we have demonstrated that Daxx interacts in vitro and in vivo with MSP58 via its NH(2)-terminal segment, which is distinct from the binding region of Fas, apoptosis signal-regulating kinase 1, and promyelocytic leukemia protein, suggesting a unique modulatory role of MSP58 on Daxx function. Transient transfection experiments revealed that MSP58 relieves the repressor activity of Daxx in a dose-dependent manner in COS-1 and 293 cells but not in HeLa cells, implicating cell type-specific modulation of Daxx function by MSP58. Moreover, immunofluorescence analysis unequivocally demonstrated that MSP58 overexpression results in a translocation of Daxx to the enlarged nucleoli in COS-1 or 293 cells, whereas Daxx exhibited a diffuse nuclear pattern in HeLa cells. Taken together, these findings delineate a network of regulatory signaling pathways that converges on MSP58/Daxx interaction, causally associating Daxx nucleolus targeting with its transcriptional activation function. PMID:11948183

Lin, Ding-Yen; Shih, Hsiu-Ming

2002-07-12

177

How to modulate chemical structure of polyoxazolines by appropriate functionalization  

E-print Network

-oxazolines) are anticipated to be suitable to build antimicrobial materials, when associated with quaternary, caused by the polymer itself or by side products which are toxic. Unexpected pharmacokinetic behavior can-opening polymerization (CROP) of cyclic 2-R-2-oxazolines and various properties are obtained as a function of the nature

Paris-Sud XI, Université de

178

Heteromeric MT1/MT2 Melatonin Receptors Modulate Photoreceptor Function  

PubMed Central

The formation of G protein-coupled receptor (GPCR) heteromers elicits signaling diversification and holds great promise for improved drug selectivity. Most studies have been conducted in heterologous expression systems; however, in vivo validation is missing from most cases thus questioning the physiological significance of GPCR heteromerization. Melatonin MT1 and MT2 receptors have been shown to exist as homo- and heteromers in vitro. We show here that the effect of melatonin on rod photoreceptor light sensitivity is mediated by melatonin MT1/MT2 receptor heteromers. This effect involves activation of the heteromer-specific PLC/PKC pathway and is abolished in MT1?/? and MT2?/? mice as well as in mice overexpressing a non-functional MT2 receptor mutant that competes with the formation of functional MT1/MT2 heteromers in photoreceptor cells. This study establishes the essential role of melatonin receptor heteromers in retinal function and supports the physiological importance of GPCR heteromerization. Finally, our work may have important therapeutic implications, as the heteromer complex may provide a unique pharmacological target to improve photoreceptor functioning and to extend the viability of photoreceptors during aging. PMID:24106342

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

2013-01-01

179

Protein kinase CK2 phosphorylates Hsp105 alpha at Ser509 and modulates its function.  

PubMed Central

The 105 kDa heat-shock protein (Hsp) Hsp105 alpha is a mammalian stress protein that belongs to the HSP105/HSP110 family. We have shown previously that Hsp105 alpha exists as non-phosphorylated and phosphorylated forms in vivo, and is phosphorylated by protein kinase CK2 (CK2) in vitro. In this study, to elucidate the role of phosphorylation of Hsp105 alpha, we first analysed the site of phosphorylation of Hsp105 alpha by CK2. Peptide mapping analysis of Hsp105 alpha phosphorylated by CK2 and in vitro phosphorylation experiments using various deletion and substitution mutants of Hsp105 alpha revealed that Hsp105 alpha is phosphorylated at Ser(509) in the beta-sheet domain. Furthermore, Ser(509) in Hsp105 alpha was also phosphorylated in mammalian COS-7 cells, although other sites were phosphorylated as well. Next, we examined the effects of phosphorylation of Hsp105 alpha on its functions using CK2-phosphorylated Hsp105 alpha. Interestingly, Hsp105 alpha suppressed 70 kDa heat-shock cognate protein (Hsc70)-mediated protein folding, whereas the phosphorylation of Hsp105 alpha at Ser(509) abolished the inhibitory activity of Hsp105 alpha in vitro. In accordance with these findings, wild-type Hsp105 alpha, which was thought to be phosphorylated in vivo, had no effect on Hsp70-mediated refolding of heat-denatured luciferase, whereas a non-phosphorylatable mutant of Hsp105 alpha suppressed the Hsp70-mediated refolding of heat-denatured luciferase in mammalian cells. Thus it was suggested that CK2 phosphorylates Hsp105 alpha at Ser(509) and modulates the function of Hsp105 alpha. The regulation of Hsp105 alpha function by phosphorylation may play an important role in a variety of cellular events. PMID:12558502

Ishihara, Keiichi; Yamagishi, Nobuyuki; Hatayama, Takumi

2003-01-01

180

Meta-analytic connectivity modeling reveals differential functional connectivity of the medial and lateral orbitofrontal cortex.  

PubMed

The orbitofrontal cortex (OFC) is implicated in a broad range of behaviors and neuropsychiatric disorders. Anatomical tracing studies in nonhuman primates reveal differences in connectivity across subregions of the OFC, but data on the connectivity of the human OFC remain limited. We applied meta-analytic connectivity modeling in order to examine which brain regions are most frequently coactivated with the medial and lateral portions of the OFC in published functional neuroimaging studies. The analysis revealed a clear divergence in the pattern of connectivity for the medial OFC (mOFC) and lateral OFC (lOFC) regions. The lOFC showed coactivations with a network of prefrontal regions and areas involved in cognitive functions including language and memory. In contrast, the mOFC showed connectivity with default mode, autonomic, and limbic regions. Convergent patterns of coactivations were observed in the amygdala, hippocampus, striatum, and thalamus. A small number of regions showed connectivity specific to the anterior or posterior sectors of the OFC. Task domains involving memory, semantic processing, face processing, and reward were additionally analyzed in order to identify the different patterns of OFC functional connectivity associated with specific cognitive and affective processes. These data provide a framework for understanding the human OFC's position within widespread functional networks. PMID:23042731

Zald, David H; McHugo, Maureen; Ray, Kimberly L; Glahn, David C; Eickhoff, Simon B; Laird, Angela R

2014-01-01

181

Core microbial functional activities in ocean environments revealed by global metagenomic profiling analyses.  

PubMed

Metagenomics-based functional profiling analysis is an effective means of gaining deeper insight into the composition of marine microbial populations and developing a better understanding of the interplay between the functional genome content of microbial communities and abiotic factors. Here we present a comprehensive analysis of 24 datasets covering surface and depth-related environments at 11 sites around the world's oceans. The complete datasets comprises approximately 12 million sequences, totaling 5,358 Mb. Based on profiling patterns of Clusters of Orthologous Groups (COGs) of proteins, a core set of reference photic and aphotic depth-related COGs, and a collection of COGs that are associated with extreme oxygen limitation were defined. Their inferred functions were utilized as indicators to characterize the distribution of light- and oxygen-related biological activities in marine environments. The results reveal that, while light level in the water column is a major determinant of phenotypic adaptation in marine microorganisms, oxygen concentration in the aphotic zone has a significant impact only in extremely hypoxic waters. Phylogenetic profiling of the reference photic/aphotic gene sets revealed a greater variety of source organisms in the aphotic zone, although the majority of individual photic and aphotic depth-related COGs are assigned to the same taxa across the different sites. This increase in phylogenetic and functional diversity of the core aphotic related COGs most probably reflects selection for the utilization of a broad range of alternate energy sources in the absence of light. PMID:24921648

Ferreira, Ari J S; Siam, Rania; Setubal, João C; Moustafa, Ahmed; Sayed, Ahmed; Chambergo, Felipe S; Dawe, Adam S; Ghazy, Mohamed A; Sharaf, Hazem; Ouf, Amged; Alam, Intikhab; Abdel-Haleem, Alyaa M; Lehvaslaiho, Heikki; Ramadan, Eman; Antunes, André; Stingl, Ulrich; Archer, John A C; Jankovic, Boris R; Sogin, Mitchell; Bajic, Vladimir B; El-Dorry, Hamza

2014-01-01

182

Nestin Modulates Glucocorticoid Receptor Function by Cytoplasmic Anchoring  

PubMed Central

Nestin is the characteristic intermediate filament (IF) protein of rapidly proliferating progenitor cells and regenerating tissue. Nestin copolymerizes with class III IF-proteins, mostly vimentin, into heteromeric filaments. Its expression is downregulated with differentiation. Here we show that a strong nestin expression in mouse embryo tissue coincides with a strong accumulation of the glucocorticoid receptor (GR), a key regulator of growth and differentiation in embryonic development. Microscopic studies on cultured cells show an association of GR with IFs composed of vimentin and nestin. Cells lacking nestin, but expressing vimentin, or cells expressing vimentin, but lacking nestin accumulate GR in the nucleus. Completing these networks with an exogenous nestin, respectively an exogenous vimentin restores cytoplasmic anchoring of GR to the IF system. Thus, heteromeric filaments provide the basis for anchoring of GR. The reaction pattern with phospho-GR specific antibodies and the presence of the chaperone HSC70 suggest that specifically the unliganded receptor is anchored to the IF system. Ligand addition releases GR from IFs and shifts the receptor into the nucleus. Suppression of nestin by specific shRNA abolishes anchoring of GR, induces its accumulation in the nucleus and provokes an irreversible G1/S cell cycle arrest. Suppression of GR prior to that of nestin prevents entry into the arrest. The data give evidence that nestin/vimentin specific anchoring modulates growth suppression by GR. We hypothesize that expression of nestin is a major determinant in suppression of anti-proliferative activity of GR in undifferentiated tissue and facilitates activation of this growth control in a precise tissue and differentiation dependent manner. PMID:19562035

Szalay, Beata; Hagel, Christian; Hohenberg, Heinrich; Deppert, Wolfgang; Bohn, Wolfgang

2009-01-01

183

Kinetics of Salicylate-Mediated Suppression of Jasmonate Signaling Reveal a Role for Redox Modulation1[OA  

PubMed Central

Cross talk between salicylic acid (SA) and jasmonic acid (JA) signaling pathways plays an important role in the regulation and fine tuning of induced defenses that are activated upon pathogen or insect attack. Pharmacological experiments revealed that transcription of JA-responsive marker genes, such as PDF1.2 and VSP2, is highly sensitive to suppression by SA. This antagonistic effect of SA on JA signaling was also observed when the JA pathway was biologically activated by necrotrophic pathogens or insect herbivores, and when the SA pathway was triggered by a biotrophic pathogen. Furthermore, all 18 Arabidopsis (Arabidopsis thaliana) accessions tested displayed SA-mediated suppression of JA-responsive gene expression, highlighting the potential significance of this phenomenon in induced plant defenses in nature. During plant-attacker interactions, the kinetics of SA and JA signaling are highly dynamic. Mimicking this dynamic response by applying SA and methyl jasmonate (MeJA) at different concentrations and time intervals revealed that PDF1.2 transcription is readily suppressed when the SA response was activated at or after the onset of the JA response, and that this SA-JA antagonism is long lasting. However, when SA was applied more than 30 h prior to the onset of the JA response, the suppressive effect of SA was completely absent. The window of opportunity of SA to suppress MeJA-induced PDF1.2 transcription coincided with a transient increase in glutathione levels. The glutathione biosynthesis inhibitor l-buthionine-sulfoximine strongly reduced PDF1.2 suppression by SA, suggesting that SA-mediated redox modulation plays an important role in the SA-mediated attenuation of the JA signaling pathway. PMID:18539774

Koornneef, Annemart; Leon-Reyes, Antonio; Ritsema, Tita; Verhage, Adriaan; Den Otter, Floor C.; Van Loon, L.C.; Pieterse, Corne M.J.

2008-01-01

184

Phosphatidic acid modulation of Kv channel voltage sensor function.  

PubMed

Membrane phospholipids can function as potent regulators of ion channel function. This study uncovers and investigates the effect of phosphatidic acid on Kv channel gating. Using the method of reconstitution into planar lipid bilayers, in which protein and lipid components are defined and controlled, we characterize two effects of phosphatidic acid. The first is a non-specific electrostatic influence on activation mediated by electric charge density on the extracellular and intracellular membrane surfaces. The second is specific to the presence of a primary phosphate group, acts only through the intracellular membrane leaflet and depends on the presence of a particular arginine residue in the voltage sensor. Intracellular phosphatidic acid accounts for a nearly 50 mV shift in the midpoint of the activation curve in a direction consistent with stabilization of the voltage sensor's closed conformation. These findings support a novel mechanism of voltage sensor regulation by the signaling lipid phosphatidic acid. PMID:25285449

Hite, Richard K; Butterwick, Joel A; MacKinnon, Roderick

2014-01-01

185

Simplifying complexity: genetically resculpting glycosphingolipid synthesis pathways in mice to reveal function.  

PubMed

Glycosphingolipids (GSLs) are a group of plasma-membrane lipids notable for their extremely diverse glycan head groups. The metabolic pathways for GSLs, including the identity of the biosynthetic enzymes needed for synthesis of their glycans, are now well understood. Many of their cellular functions, which include plasma-membrane organization, regulation of cell signaling, endocytosis, and serving as binding sites for pathogens and endogenous receptors, have also been established. However, an understanding of their functions in vivo had been lagging. Studies employing genetic manipulations of the GSL synthesis pathways in mice have been used to systematically reduce the large numbers and complexity of GSL glycan structures, allowing the in vivo functions of GSLs to be revealed from analysis of the resulting phenotypes. Findings from these studies have produced a clearer picture of the role of GSLs in mammalian physiology, which is the topic of this review. PMID:25351657

Allende, Maria Laura; Proia, Richard L

2014-12-01

186

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

187

Pentoxifylline-induced modulation of human leukocyte function in vitro.  

PubMed Central

We previously demonstrated that pentoxifylline stimulated leukocyte migration in vitro and leukocyte accumulation in vivo and protects neonatal mice from experimentally induced Staphylococcus aureus infections. In the present studies we have investigated pentoxifylline's effect on human leukocyte function in vitro. In these studies we demonstrate that pentoxifylline at low concentrations (ie, 0.01 and 0.1 mg/ml) stimulates both leukocyte migration and microbicidal activity in vitro. Alternatively, low concentrations (0.001 to 0.1 mg/ml) of pentoxifylline had no significant effect on the binding uptake of S. aureus by leukocytes, nor did it enhance phagocytic degranulation. At extremely low concentrations (0.001 mg/ml), pentoxifylline enhanced oxygen metabolism by human leukocytes, as reflected by increased H2O2 production and chemiluminescence (CL). At higher concentrations (ie, 0.1 to 1 mg/ml), pentoxifylline consistently suppressed these leukocyte functions in vitro. Thus, this study supports the following hypothesis: 1) the in vivo effects of pentoxifylline may involve a direct effect on both leukocyte mobilization and microbicidal activity, and 2) the enhanced microbicidal activity induced by pentoxifylline may be a result of enhanced leukocyte oxygen metabolism. In summary, pentoxifylline appears to be an interesting immunomodulator (ie, immunoenhancement and immunosuppression) of leukocyte function in vitro, but additional studies will be required before the efficacy of pentoxifylline in man can be determined. PMID:2316627

Josaki, K.; Contrino, J.; Kristie, J.; Krause, P.; Kreutzer, D. L.

1990-01-01

188

Virtual screening on an ?-helix to ?-strand switchable region of the FGFR2 extracellular domain revealed positive and negative modulators.  

PubMed

The secondary structure of some protein segments may vary between ?-helix and ?-strand. To predict these switchable segments, we have developed an algorithm, Switch-P, based solely on the protein sequence. This algorithm was used on the extracellular parts of FGF receptors. For FGFR2, it predicted that ?4 and ?5 strands of the third Ig-like domain were highly switchable. These two strands possess a high number of somatic mutations associated with cancer. Analysis of PDB structures of FGF receptors confirmed the switchability prediction for ?5. We thus evaluated if compound-driven ?-helix/?-strand switching of ?5 could modulate FGFR2 signaling. We performed the virtual screening of a library containing 1.4 million of chemical compounds with two models of the third Ig-like domain of FGFR2 showing different secondary structures for ?5, and we selected 32 compounds. Experimental testing using proliferation assays with FGF7-stimulated SNU-16 cells and a FGFR2-dependent Erk1/2 phosphorylation assay with FGFR2-transfected L6 cells, revealed activators and inhibitors of FGFR2. Our method for the identification of switchable proteinic regions, associated with our virtual screening approach, provides an opportunity to discover new generation of drugs with under-explored mechanism of action. Proteins 2014; 82:2982-2997. © 2014 Wiley Periodicals, Inc. PMID:25082719

Diaz, Constantino; Corentin, Herbert; Thierry, Vermat; Chantal, Alcouffe; Tanguy, Bozec; David, Sibrac; Jean-Marc, Herbert; Pascual, Ferrara; Françoise, Bono; Edgardo, Ferran

2014-11-01

189

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

2009-09-01

190

Modulation of synaptic function through the ?-neurexin-specific ligand neurexophilin-1.  

PubMed

Neurotransmission at different synapses is highly variable, and cell-adhesion molecules like ?-neurexins (?-Nrxn) and their extracellular binding partners determine synapse function. Although ?-Nrxn affect transmission at excitatory and inhibitory synapses, the contribution of neurexophilin-1 (Nxph1), an ?-Nrxn ligand with restricted expression in subpopulations of inhibitory neurons, is unclear. To reveal its role, we investigated mice that either lack or overexpress Nxph1. We found that genetic deletion of Nxph1 impaired GABAB receptor (GABA(B)R)-dependent short-term depression of inhibitory synapses in the nucleus reticularis thalami, a region where Nxph1 is normally expressed at high levels. To test the conclusion that Nxph1 supports presynaptic GABA(B)R, we expressed Nxph1 ectopically at excitatory terminals in the neocortex, which normally do not contain this molecule but can be modulated by GABA(B)R. We generated Nxph1-GFP transgenic mice under control of the Thy1.2 promoter and observed a reduced short-term facilitation at these excitatory synapses, representing an inverse phenotype to the knockout. Consistently, the diminished facilitation could be reversed by pharmacologically blocking GABA(B)R with CGP-55845. Moreover, a complete rescue was achieved by additional blocking of postsynaptic GABA(A)R with intracellular picrotoxin or gabazine, suggesting that Nxph1 is able to recruit or stabilize both presynaptic GABA(B)R and postsynaptic GABA(A)R. In support, immunoelectron microscopy validated the localization of ectopic Nxph1 at the synaptic cleft of excitatory synapses in transgenic mice and revealed an enrichment of GABA(A)R and GABA(B)R subunits compared with wild-type animals. Thus, our data propose that Nxph1 plays an instructive role in synaptic short-term plasticity and the configuration with GABA receptors. PMID:24639499

Born, Gesche; Breuer, Dorothee; Wang, Shaopeng; Rohlmann, Astrid; Coulon, Philippe; Vakili, Puja; Reissner, Carsten; Kiefer, Friedemann; Heine, Martin; Pape, Hans-Christian; Missler, Markus

2014-04-01

191

Modulation of synaptic function through the ?-neurexin-specific ligand neurexophilin-1  

PubMed Central

Neurotransmission at different synapses is highly variable, and cell-adhesion molecules like ?-neurexins (?-Nrxn) and their extracellular binding partners determine synapse function. Although ?-Nrxn affect transmission at excitatory and inhibitory synapses, the contribution of neurexophilin-1 (Nxph1), an ?-Nrxn ligand with restricted expression in subpopulations of inhibitory neurons, is unclear. To reveal its role, we investigated mice that either lack or overexpress Nxph1. We found that genetic deletion of Nxph1 impaired GABAB receptor (GABABR)-dependent short-term depression of inhibitory synapses in the nucleus reticularis thalami, a region where Nxph1 is normally expressed at high levels. To test the conclusion that Nxph1 supports presynaptic GABABR, we expressed Nxph1 ectopically at excitatory terminals in the neocortex, which normally do not contain this molecule but can be modulated by GABABR. We generated Nxph1-GFP transgenic mice under control of the Thy1.2 promoter and observed a reduced short-term facilitation at these excitatory synapses, representing an inverse phenotype to the knockout. Consistently, the diminished facilitation could be reversed by pharmacologically blocking GABABR with CGP-55845. Moreover, a complete rescue was achieved by additional blocking of postsynaptic GABAAR with intracellular picrotoxin or gabazine, suggesting that Nxph1 is able to recruit or stabilize both presynaptic GABABR and postsynaptic GABAAR. In support, immunoelectron microscopy validated the localization of ectopic Nxph1 at the synaptic cleft of excitatory synapses in transgenic mice and revealed an enrichment of GABAAR and GABABR subunits compared with wild-type animals. Thus, our data propose that Nxph1 plays an instructive role in synaptic short-term plasticity and the configuration with GABA receptors. PMID:24639499

Born, Gesche; Breuer, Dorothee; Wang, Shaopeng; Rohlmann, Astrid; Coulon, Philippe; Vakili, Puja; Reissner, Carsten; Kiefer, Friedemann; Heine, Martin; Pape, Hans-Christian; Missler, Markus

2014-01-01

192

Remote Synchronization Reveals Network Symmetries and Functional Modules Vincenzo Nicosia,1  

E-print Network

in nature [1]. Remarkable examples include phase locking in laser arrays, rhythms of flashing fireflies,26], even if there exist polynomial-time algorithms for graphs with bounded maximum degree [27]. Recent

Diaz-Guilera, Albert

193

Modulating endothelial barrier function by targeting vimentin phosphorylation.  

PubMed

Vimentin is a major intermediate filament protein in vascular endothelial cells which might be involved in their function as a barrier tissue. It is proposed to dynamically maintain integrity of the endothelium as a tightly regulated permeability barrier that is subjected to a variety of shear and contractile forces. The results described in this report demonstrate that vimentin plays that role through mechanisms that are dependent on its phosphorylation state. Withaferin A (WFA), a vimentin targeting drug is shown to disrupt endothelial barrier function through its effects on vimentin filament distribution and physical properties. These effects are related to WFA's ability to increase vimentin phosphorylation. Through overexpressing a non-phosphorylatable vimentin mutant we can block the effects of WFA on vimentin distribution and barrier permeability. The barrier augmentation effect appears to extend to endothelial cells that do not express detectable mutant vimentin which might suggest transmissible effects across cells. Blocking vimentin phosphorylation also protects the endothelial barrier against LPS endotoxin, implicating it as a target for drug development against pulmonary edema and acute respiratory distress syndrome (ARDS). PMID:24648251

Liu, Tiegang; Ghamloush, Maher M; Aldawood, Ali; Warburton, Rod; Toksoz, Deniz; Hill, Nicholas S; Tang, Dale D; Kayyali, Usamah S

2014-10-01

194

Dynamic functional connectivity analysis reveals transient states of dysconnectivity in schizophrenia  

PubMed Central

Schizophrenia is a psychotic disorder characterized by functional dysconnectivity or abnormal integration between distant brain regions. Recent functional imaging studies have implicated large-scale thalamo-cortical connectivity as being disrupted in patients. However, observed connectivity differences in schizophrenia have been inconsistent between studies, with reports of hyperconnectivity and hypoconnectivity between the same brain regions. Using resting state eyes-closed functional imaging and independent component analysis on a multi-site data that included 151 schizophrenia patients and 163 age- and gender matched healthy controls, we decomposed the functional brain data into 100 components and identified 47 as functionally relevant intrinsic connectivity networks. We subsequently evaluated group differences in functional network connectivity, both in a static sense, computed as the pairwise Pearson correlations between the full network time courses (5.4 minutes in length), and a dynamic sense, computed using sliding windows (44 s in length) and k-means clustering to characterize five discrete functional connectivity states. Static connectivity analysis revealed that compared to healthy controls, patients show significantly stronger connectivity, i.e., hyperconnectivity, between the thalamus and sensory networks (auditory, motor and visual), as well as reduced connectivity (hypoconnectivity) between sensory networks from all modalities. Dynamic analysis suggests that (1), on average, schizophrenia patients spend much less time than healthy controls in states typified by strong, large-scale connectivity, and (2), that abnormal connectivity patterns are more pronounced during these connectivity states. In particular, states exhibiting cortical–subcortical antagonism (anti-correlations) and strong positive connectivity between sensory networks are those that show the group differences of thalamic hyperconnectivity and sensory hypoconnectivity. Group differences are weak or absent during other connectivity states. Dynamic analysis also revealed hypoconnectivity between the putamen and sensory networks during the same states of thalamic hyperconnectivity; notably, this finding cannot be observed in the static connectivity analysis. Finally, in post-hoc analyses we observed that the relationships between sub-cortical low frequency power and connectivity with sensory networks is altered in patients, suggesting different functional interactions between sub-cortical nuclei and sensorimotor cortex during specific connectivity states. While important differences between patients with schizophrenia and healthy controls have been identified, one should interpret the results with caution given the history of medication in patients. Taken together, our results support and expand current knowledge regarding dysconnectivity in schizophrenia, and strongly advocate the use of dynamic analyses to better account for and understand functional connectivity differences. PMID:25161896

Damaraju, E.; Allen, E.A.; Belger, A.; Ford, J.M.; McEwen, S.; Mathalon, D.H.; Mueller, B.A.; Pearlson, G.D.; Potkin, S.G.; Preda, A.; Turner, J.A.; Vaidya, J.G.; van Erp, T.G.; Calhoun, V.D.

2014-01-01

195

Construction of multi-functional open modulized Matlab simulation toolbox for imaging ladar system  

NASA Astrophysics Data System (ADS)

Ladar system simulation is to simulate the ladar models using computer simulation technology in order to predict the performance of the ladar system. This paper presents the developments of laser imaging radar simulation for domestic and overseas studies and the studies of computer simulation on ladar system with different application requests. The LadarSim and FOI-LadarSIM simulation facilities of Utah State University and Swedish Defence Research Agency are introduced in details. This paper presents the low level of simulation scale, un-unified design and applications of domestic researches in imaging ladar system simulation, which are mostly to achieve simple function simulation based on ranging equations for ladar systems. Design of laser imaging radar simulation with open and modularized structure is proposed to design unified modules for ladar system, laser emitter, atmosphere models, target models, signal receiver, parameters setting and system controller. Unified Matlab toolbox and standard control modules have been built with regulated input and output of the functions, and the communication protocols between hardware modules. A simulation based on ICCD gain-modulated imaging ladar system for a space shuttle is made based on the toolbox. The simulation result shows that the models and parameter settings of the Matlab toolbox are able to simulate the actual detection process precisely. The unified control module and pre-defined parameter settings simplify the simulation of imaging ladar detection. Its open structures enable the toolbox to be modified for specialized requests. The modulization gives simulations flexibility.

Wu, Long; Zhao, Yuan; Tang, Meng; He, Jiang; Zhang, Yong

2011-06-01

196

Fixed Points and Quartic Functional Equations in ? -Banach Modules  

Microsoft Academic Search

Let M = { 1, 2, . . . , n } and let $${\\\\mathcal {V}=\\\\{\\\\,I \\\\subseteq M: 1 \\\\in I\\\\,\\\\}}$$ , where n is an integer greater than 1. Denote $${M{\\\\setminus}{I}}$$ by I\\u000a \\u000a c\\u000a for $${I \\\\in \\\\mathcal {V}.}$$ We investigate the solution of the following generalized quartic functional equation\\u000a \\u000a \\u000a \\u000a $$\\\\begin{array}{ll} \\\\sum\\\\limits_{I \\\\in\\\\mathcal {V}}f\\\\, \\\\left({\\\\sum\\\\limits_{i \\\\in I}}a_ix_i-\\\\sum\\\\limits_{i \\\\in I^c}a_ix_i\\\\right) \\\\, = \\\\,2^{n-2} \\\\sum\\\\limits_{1\\\\leq

M. Eshaghi Gordji; H. Khodaei; A. Najati

197

Bursicon functions within the Drosophila CNS to modulate wing expansion behavior, hormone secretion, and cell death.  

PubMed

Hormones are often responsible for synchronizing somatic physiological changes with changes in behavior. Ecdysis (i.e., the shedding of the exoskeleton) in insects has served as a useful model for elucidating the molecular and cellular mechanisms of this synchronization, and has provided numerous insights into the hormonal coordination of body and behavior. An example in which the mechanisms have remained enigmatic is the neurohormone bursicon, which, after the final molt, coordinates the plasticization and tanning of the initially folded wings with behaviors that drive wing expansion. The somatic effects of the hormone are governed by bursicon that is released into the blood from neurons in the abdominal ganglion (the B(AG)), which die after wing expansion. How bursicon induces the behavioral programs required for wing expansion, however, has remained unknown. Here we show by targeted suppression of excitability that a pair of bursicon-immunoreactive neurons distinct from the B(AG) and located within the subesophageal ganglion in Drosophila (the B(SEG)) is involved in controlling wing expansion behaviors. Unlike the B(AG), the B(SEG) arborize widely in the nervous system, including within the abdominal neuromeres, suggesting that, in addition to governing behavior, they also may modulate the B(AG.) Indeed, we show that animals lacking bursicon receptor function have deficits both in the humoral release of bursicon and in posteclosion apoptosis of the B(AG). Our results reveal novel neuromodulatory functions for bursicon and support the hypothesis that the B(SEG) are essential for orchestrating both the behavioral and somatic processes underlying wing expansion. PMID:19118171

Peabody, Nathan C; Diao, Fengqiu; Luan, Haojiang; Wang, Howard; Dewey, Elizabeth M; Honegger, Hans-Willi; White, Benjamin H

2008-12-31

198

Coherent Functional Modules Improve Transcription Factor Target Identification, Cooperativity Prediction, and Disease Association  

PubMed Central

Transcription factors (TFs) are fundamental controllers of cellular regulation that function in a complex and combinatorial manner. Accurate identification of a transcription factor's targets is essential to understanding the role that factors play in disease biology. However, due to a high false positive rate, identifying coherent functional target sets is difficult. We have created an improved mapping of targets by integrating ChIP-Seq data with 423 functional modules derived from 9,395 human expression experiments. We identified 5,002 TF-module relationships, significantly improved TF target prediction, and found 30 high-confidence TF-TF associations, of which 14 are known. Importantly, we also connected TFs to diseases through these functional modules and identified 3,859 significant TF-disease relationships. As an example, we found a link between MEF2A and Crohn's disease, which we validated in an independent expression dataset. These results show the power of combining expression data and ChIP-Seq data to remove noise and better extract the associations between TFs, functional modules, and disease. PMID:24516403

Karczewski, Konrad J.; Snyder, Michael; Altman, Russ B.; Tatonetti, Nicholas P.

2014-01-01

199

Structure and Dynamics of the First Archaeal Parvulin Reveal a New Functionally Important Loop in Parvulin-type Prolyl Isomerases*  

PubMed Central

Parvulins are a group of peptidyl-prolyl isomerases (PPIases) responsible for important biological processes in all kingdoms of life. The PinA protein from the psychrophilic archaeon Cenarchaeum symbiosum is a parvulin-like PPIase. Due to its striking similarity to the human parvulins Pin1 and Par14, PinA constitutes an interesting subject for structural and functional studies. Here, we present the first high resolution NMR structure of an archaeal parvulin, PinA, based on 1798 conformational restraints. Structure calculation yields an ensemble of 20 convergent low energy structures with a backbone r.m.s.d. value of 0.6 ? within the secondary structure elements. The overall fold of PinA comprises the ?-?3-?-?-?2 fold typical for all parvulin structures known so far, but with helix III being a short 310-helix. A detailed comparison of this high resolution structure of the first archaeal PinA protein with bacterial and eukaryotic parvulin PPIase structures reveals an atypically large catalytic binding site. This feature provides an explanation for cold-adapted protein function. Moreover, the residues in and around 310-helix III exhibit strong intramolecular dynamics on a microsecond to millisecond timescale and display structural heterogeneity within the NMR ensemble. A putative peptide ligand was found for PinA by phage display and was used for 1H-15N-HSQC titrations. Again, the flexible region around 310-helix III as well as residues of the peptide binding pocket showed the strongest chemical shift perturbations upon peptide binding. The local flexibility of this region also was modulated by ligand binding. A glycine and two positively charged residues are conserved in most parvulin proteins in this flexible loop region, which may be of general functional importance for parvulin-type PPIases. PMID:21138844

Jaremko, Lukasz; Jaremko, Mariusz; Elfaki, Imadeldin; Mueller, Jonathan W.; Ejchart, Andrzej; Bayer, Peter; Zhukov, Igor

2011-01-01

200

Acupuncture Modulates Resting State Hippocampal Functional Connectivity in Alzheimer Disease  

PubMed Central

Our objective is to clarify the effects of acupuncture on hippocampal connectivity in patients with Alzheimer disease (AD) using functional magnetic resonance imaging (fMRI). Twenty-eight right-handed subjects (14 AD patients and 14 healthy elders) participated in this study. Clinical and neuropsychological examinations were performed on all subjects. MRI was performed using a SIEMENS verio 3-Tesla scanner. The fMRI study used a single block experimental design. We first acquired baseline resting state data during the initial 3 minutes and then performed acupuncture stimulation on the Tai chong and He gu acupoints for 3 minutes. Last, we acquired fMRI data for another 10 minutes after the needle was withdrawn. The preprocessing and data analysis were performed using statistical parametric mapping (SPM5) software. Two-sample t-tests were performed using data from the two groups in different states. We found that during the resting state, several frontal and temporal regions showed decreased hippocampal connectivity in AD patients relative to control subjects. During the resting state following acupuncture, AD patients showed increased connectivity in most of these hippocampus related regions compared to the first resting state. In conclusion, we investigated the effect of acupuncture on AD patients by combing fMRI and traditional acupuncture. Our fMRI study confirmed that acupuncture at Tai chong and He gu can enhance the hippocampal connectivity in AD patients. PMID:24603951

Wang, Zhiqun; Liang, Peipeng; Zhao, Zhilian; Han, Ying; Song, Haiqing; Xu, Jianyang; Lu, Jie; Li, Kuncheng

2014-01-01

201

Quantitative protein localization signatures reveal an association between spatial and functional divergences of proteins.  

PubMed

Protein subcellular localization is a major determinant of protein function. However, this important protein feature is often described in terms of discrete and qualitative categories of subcellular compartments, and therefore it has limited applications in quantitative protein function analyses. Here, we present Protein Localization Analysis and Search Tools (PLAST), an automated analysis framework for constructing and comparing quantitative signatures of protein subcellular localization patterns based on microscopy images. PLAST produces human-interpretable protein localization maps that quantitatively describe the similarities in the localization patterns of proteins and major subcellular compartments, without requiring manual assignment or supervised learning of these compartments. Using the budding yeast Saccharomyces cerevisiae as a model system, we show that PLAST is more accurate than existing, qualitative protein localization annotations in identifying known co-localized proteins. Furthermore, we demonstrate that PLAST can reveal protein localization-function relationships that are not obvious from these annotations. First, we identified proteins that have similar localization patterns and participate in closely-related biological processes, but do not necessarily form stable complexes with each other or localize at the same organelles. Second, we found an association between spatial and functional divergences of proteins during evolution. Surprisingly, as proteins with common ancestors evolve, they tend to develop more diverged subcellular localization patterns, but still occupy similar numbers of compartments. This suggests that divergence of protein localization might be more frequently due to the development of more specific localization patterns over ancestral compartments than the occupation of new compartments. PLAST enables systematic and quantitative analyses of protein localization-function relationships, and will be useful to elucidate protein functions and how these functions were acquired in cells from different organisms or species. A public web interface of PLAST is available at http://plast.bii.a-star.edu.sg. PMID:24603469

Loo, Lit-Hsin; Laksameethanasan, Danai; Tung, Yi-Ling

2014-03-01

202

Quantitative Protein Localization Signatures Reveal an Association between Spatial and Functional Divergences of Proteins  

PubMed Central

Protein subcellular localization is a major determinant of protein function. However, this important protein feature is often described in terms of discrete and qualitative categories of subcellular compartments, and therefore it has limited applications in quantitative protein function analyses. Here, we present Protein Localization Analysis and Search Tools (PLAST), an automated analysis framework for constructing and comparing quantitative signatures of protein subcellular localization patterns based on microscopy images. PLAST produces human-interpretable protein localization maps that quantitatively describe the similarities in the localization patterns of proteins and major subcellular compartments, without requiring manual assignment or supervised learning of these compartments. Using the budding yeast Saccharomyces cerevisiae as a model system, we show that PLAST is more accurate than existing, qualitative protein localization annotations in identifying known co-localized proteins. Furthermore, we demonstrate that PLAST can reveal protein localization-function relationships that are not obvious from these annotations. First, we identified proteins that have similar localization patterns and participate in closely-related biological processes, but do not necessarily form stable complexes with each other or localize at the same organelles. Second, we found an association between spatial and functional divergences of proteins during evolution. Surprisingly, as proteins with common ancestors evolve, they tend to develop more diverged subcellular localization patterns, but still occupy similar numbers of compartments. This suggests that divergence of protein localization might be more frequently due to the development of more specific localization patterns over ancestral compartments than the occupation of new compartments. PLAST enables systematic and quantitative analyses of protein localization-function relationships, and will be useful to elucidate protein functions and how these functions were acquired in cells from different organisms or species. A public web interface of PLAST is available at http://plast.bii.a-star.edu.sg. PMID:24603469

Loo, Lit-Hsin; Laksameethanasan, Danai; Tung, Yi-Ling

2014-01-01

203

Single-cell analysis reveals functionally distinct classes within the planarian stem cell compartment.  

PubMed

Planarians are flatworms capable of regenerating any missing body region. This capacity is mediated by neoblasts, a proliferative cell population that contains pluripotent stem cells. Although population-based studies have revealed many neoblast characteristics, whether functionally distinct classes exist within this population is unclear. Here, we used high-dimensional single-cell transcriptional profiling from over a thousand individual neoblasts to directly compare gene expression fingerprints during homeostasis and regeneration. We identified two prominent neoblast classes that we named ? (zeta) and ? (sigma). Zeta-neoblasts encompass specified cells that give rise to an abundant postmitotic lineage, including epidermal cells, and are not required for regeneration. By contrast, sigma-neoblasts proliferate in response to injury, possess broad lineage capacity, and can give rise to zeta-neoblasts. These findings indicate that planarian neoblasts comprise two major and functionally distinct cellular compartments. PMID:25017721

van Wolfswinkel, Josien C; Wagner, Daniel E; Reddien, Peter W

2014-09-01

204

Axonal and dendritic synaptotagmin isoforms revealed by a pHluorin-syt functional screen  

PubMed Central

The synaptotagmins (syts) are a family of molecules that regulate membrane fusion. There are 17 mammalian syt isoforms, most of which are expressed in the brain. However, little is known regarding the subcellular location and function of the majority of these syts in neurons, largely due to a lack of isoform-specific antibodies. Here we generated pHluorin-syt constructs harboring a luminal domain pH sensor, which reports localization, pH of organelles to which syts are targeted, and the kinetics and sites of exocytosis and endocytosis. Of interest, only syt-1 and 2 are targeted to synaptic vesicles, whereas other isoforms selectively recycle in dendrites (syt-3 and 11), axons (syt-5, 7, 10, and 17), or both axons and dendrites (syt-4, 6, 9, and 12), where they undergo exocytosis and endocytosis with distinctive kinetics. Hence most syt isoforms localize to distinct secretory organelles in both axons and dendrites and may regulate neuropeptide/neurotrophin release to modulate neuronal function. PMID:22398727

Dean, Camin; Dunning, F. Mark; Liu, Huisheng; Bomba-Warczak, Ewa; Martens, Henrik; Bharat, Vinita; Ahmed, Saheeb; Chapman, Edwin R.

2012-01-01

205

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. PMID:21911745

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

206

Impact of shear rate modulation on vascular function in humans.  

PubMed

Shear stress is an important stimulus to arterial adaptation in response to exercise and training in humans. We recently observed significant reverse arterial flow and shear during exercise and different antegrade/retrograde patterns of shear and flow in response to different types of exercise. The purpose of this study was to simultaneously examine flow-mediated dilation, a largely NO-mediated vasodilator response, in both brachial arteries of healthy young men before and after 30-minute interventions consisting of bilateral forearm heating, recumbent leg cycling, and bilateral handgrip exercise. During each intervention, a cuff inflated to 60 mm Hg was placed on 1 arm to unilaterally manipulate the shear rate stimulus. In the noncuffed arm, antegrade flow and shear increased similarly in response to each intervention (ANOVA; P<0.001, no interaction between interventions; P=0.71). Baseline flow-mediated dilation (4.6%, 6.9%, and 6.7%) increased similarly in response to heating, handgrip, and cycling (8.1%, 10.4%, and 8.9%, ANOVA; P<0.001, no interaction; P=0.89). In contrast, cuffed arm antegrade shear rate was lower than in the noncuffed arm for all of the conditions (P<0.05), and the increase in flow-mediated dilation was abolished in this arm (4.7%, 6.7%, and 6.1%; 2-way ANOVA: all conditions interacted P<0.05). These results suggest that differences in the magnitude of antegrade shear rate transduce differences in endothelial vasodilator function in humans, a finding that may have relevance for the impact of different exercise interventions on vascular adaptation in humans. PMID:19546374

Tinken, Toni M; Thijssen, Dick H J; Hopkins, Nicola; Black, Mark A; Dawson, Ellen A; Minson, Christopher T; Newcomer, Sean C; Laughlin, M Harold; Cable, N Timothy; Green, Daniel J

2009-08-01

207

Frequency-specific functional connectivity in the brain during resting state revealed by NIRS.  

PubMed

Analyses of spontaneous hemodynamic fluctuations observed on functional magnetic resonance imaging (fMRI) have revealed the existence of temporal correlations in signal changes between widely separated brain regions during the resting state, termed "resting state functional connectivity." Recent studies have demonstrated that these correlations are also present in the hemodynamic signals measured by near infrared spectroscopy (NIRS). However, it is still uncertain whether frequency-specific characteristics exist in these signals. In the present study, we used multichannel NIRS to investigate the frequency dependency of functional connectivity between diverse regions in the cerebral cortex by decomposing fluctuations of oxygenated hemoglobin (oxy-Hb) and deoxygenated hemoglobin (deoxy-Hb) signals into various frequency bands. First, within a wide frequency range (0.009-0.1Hz), we observed that both oxy-Hb and deoxy-Hb signals showed functional connectivity within local regions and between contralateral hemispheric regions of the cortex. Next, by decomposing measured fluctuations into narrower frequency components, we determined that only oxy-Hb signals showed frequency-specific functional connectivity between the frontal and occipital regions, emerging in a narrow frequency range (0.04-0.1Hz). To clarify the coherency of functional connectivity, we calculated the average coherence values between selected channel pairs. This approach demonstrated that functional connectivity based on the oxy-Hb signals between homologous cortical regions of the contralateral hemisphere (homologous connectivity) showed high coherence over a wide frequency range (0.009-0.1Hz), whereas connectivity between the prefrontal and occipital regions (fronto-posterior connectivity) showed high coherence only within a specific narrow frequency range (0.04-0.1Hz). Our findings suggest that homologous connectivity may reflect synchronization of neural activation over a wide frequency range through direct neuroanatomical connections, whereas fronto-posterior connectivity as revealed by high coherence only within a specific narrow frequency range corresponding to the time scale of typical hemodynamic response to a single event may reflect synchronization of transient neural activation among distant cortical regions. The present study demonstrated that NIRS provides a powerful tool to elucidate network properties of the cortex during resting state. PMID:21211570

Sasai, Shuntaro; Homae, Fumitaka; Watanabe, Hama; Taga, Gentaro

2011-05-01

208

Proteomic analysis reveals a FANCA-modulated neddylation pathway involved in CXCR5 membrane targeting and cell mobility.  

PubMed

The aim of this study was to identify novel substrates of the FANCcore complex, the inactivation of which leads to the genetic disorder Fanconi anemia, which is associated with bone marrow failure, developmental abnormalities and a predisposition to cancer. Eight FANC proteins participate in the nuclear FANCcore complex, which functions as an E3 ubiquitin-ligase that monoubiquitylates FANCD2 and FANCI in response to replicative stress. Here, we use mass spectrometry to compare proteins from FANCcore-complex-deficient cells to those of rescued control cells after treatment with hydroxyurea, an inducer of FANCD2 monoubiquitylation. FANCD2 and FANCI appear to be the only targets of the FANCcore complex. We identify other proteins that are post-translationally modified in a FANCA- or FANCC-dependent manner. The majority of these potential targets localize to the cell membrane. Finally, we demonstrate that (a) the chemokine receptor CXCR5 is neddylated; (b) FANCA but not FANCC appears to modulate CXCR5 neddylation through an unknown mechanism; (c) CXCR5 neddylation is involved in targeting the receptor to the cell membrane; and (d) CXCR5 neddylation stimulates cell migration and motility. Our work has uncovered a pathway involving FANCA in neddylation and cell motility. PMID:25015289

Renaudin, Xavier; Guervilly, Jean-Hugues; Aoufouchi, Said; Rosselli, Filippo

2014-08-15

209

KCNQ modulators reveal a key role for KCNQ potassium channels in regulating the tone of rat pulmonary artery smooth muscle.  

PubMed

Potassium channels are central to the regulation of pulmonary vascular tone. The smooth muscle cells of pulmonary artery display a background K(+) conductance with biophysical properties resembling those of KCNQ (K(V)7) potassium channels. Therefore, we investigated the expression and functional role of KCNQ channels in pulmonary artery. The effects of selective KCNQ channel modulators were investigated on K(+) current and membrane potential in isolated pulmonary artery smooth muscle cells (PASMCs), on the tension developed by intact pulmonary arteries, and on pulmonary arterial pressure in isolated perfused lungs and in vivo. The KCNQ channel blockers, linopirdine and XE991 [10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone], inhibited the noninactivating background K(+) conductance in PASMCs and caused depolarization, vasoconstriction, and raised pulmonary arterial pressure without constricting several systemic arteries or raising systemic pressure. The KCNQ channel openers, retigabine and flupirtine, had the opposite effects. PASMCs were found to express KCNQ4 mRNA, at higher levels than mesenteric artery, along with smaller amounts of KCNQ1 and 5. It is concluded that KCNQ channels, most probably KCNQ4, make an important contribution to the regulation of pulmonary vascular tone, with a greater contribution in pulmonary compared with systemic vessels. The pulmonary vasoconstrictor effect of KCNQ blockers is a potentially serious side effect, but the pulmonary vasodilator effect of the openers may be useful in the treatment of pulmonary hypertension. PMID:19151245

Joshi, Shreena; Sedivy, Vojtech; Hodyc, Daniel; Herget, Jan; Gurney, Alison M

2009-04-01

210

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. PMID:23922774

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

2013-01-01

211

Opposite Modulation of Brain Functional Networks Implicated at Low vs. High Demand of Attention and Working Memory  

PubMed Central

Background Functional magnetic resonance imaging (fMRI) studies indicate that the brain organizes its activity into multiple functional networks (FNs) during either resting condition or task-performance. However, the functions of these FNs are not fully understood yet. Methodology/Principal Findings To investigate the operation of these FNs, spatial independent component analysis (sICA) was used to extract FNs from fMRI data acquired from healthy participants performing a visual task with two levels of attention and working memory load. The task-related modulations of extracted FNs were assessed. A group of FNs showed increased activity at low-load conditions and reduced activity at high-load conditions. These FNs together involve the left lateral frontoparietal cortex, insula, and ventromedial prefrontal cortex. A second group of FNs showed increased activity at high-load conditions and reduced activity at low-load conditions. These FNs together involve the intraparietal sulcus, frontal eye field, lateral frontoparietal cortex, insula, and dorsal anterior cingulate, bilaterally. Though the two groups of FNs showed opposite task-related modulations, they overlapped extensively at both the lateral and medial frontoparietal cortex and insula. Such an overlap of FNs would not likely be revealed using standard general-linear-model-based analyses. Conclusions By assessing task-related modulations, this study differentiated the functional roles of overlapping FNs. Several FNs including the left frontoparietal network are implicated in task conditions of low attentional load, while another set of FNs including the dorsal attentional network is implicated in task conditions involving high attentional demands. PMID:24498021

Xu, Jiansong; Calhoun, Vince D.; Pearlson, Godfrey D.; Potenza, Marc N.

2014-01-01

212

Protease proteomics: revealing protease in vivo functions using systems biology approaches.  

PubMed

Proteases irreversibly modify proteins by cleaving their amide bonds and are implicated in virtually every important biological process such as immunity, development and tissue repair. Accordingly, it is easy to see that deregulated proteolysis is a pathognomic feature of many diseases. Most of the current information available on proteases was acquired using in vitro methods, which reveals molecular structure, enzyme kinetics and active-site specificity. However, considerably less is known about the relevant biological functions and combined roles of proteases in moulding the proteome. Although models using genetically modified animals are powerful, they are slow to develop, they can be difficult to interpret, and while useful, they remain only models of human disease. Therefore, to understand how proteases accomplish their tasks in organisms and how they participate in pathology, we need to elucidate the protease degradome-the repertoire of proteases expressed by a cell, a tissue or an organism at a particular time-their expression level, activation state, their biological substrates, also known as the substrate degradome-the repertoire of substrates for each protease-and the effect of the activity of each protease on the pathways of the system under study. Achieving this goal is challenging because several proteases might cleave the same protein, and proteases also form pathways and interact to form the protease web [Overall, C.M., Kleifeld, O., 2006. Tumour microenvironment - opinion: validating matrix metalloproteinases as drug targets and anti-targets for cancer therapy. Nat. Rev. Cancer 6 (3), 227-239]. Hence, the net proteolytic potential of the degradome at a particular time on a substrate and pathway must also be understood. Proteomics offers one of the few routes to the understanding of proteolysis in complex in vivo systems and especially in man where genetic manipulations are impossible. The aim of this chapter is to review methods and tools that allow researchers to study protease biological functions using proteomics and mass spectrometry. We describe methods to assess protease expression at the messenger RNA level using DNA microarrays and at the protein level using mass spectrometry-based proteomics. We also review methods to reveal and quantify the activity state of proteases and to identify their biological substrates. The information acquired using these high throughput, high content techniques can then be interpreted with different bioinformatics approaches to reveal the effects of proteolysis on the system under study. Systems biology of the protease web-degradomics in the broadest sense-promises to reveal the functions of proteases in homeostasis and in disease states. This will indicate which proteases participate in defined pathologies and will help targeting specific proteases for disease treatments. PMID:18571712

Doucet, Alain; Overall, Christopher M

2008-10-01

213

High-throughput mutagenesis reveals functional determinants for DNA targeting by activation-induced deaminase  

PubMed Central

Antibody maturation is a critical immune process governed by the enzyme activation-induced deaminase (AID), a member of the AID/APOBEC DNA deaminase family. AID/APOBEC deaminases preferentially target cytosine within distinct preferred sequence motifs in DNA, with specificity largely conferred by a small 9–11 residue protein loop that differs among family members. Here, we aimed to determine the key functional characteristics of this protein loop in AID and to thereby inform our understanding of the mode of DNA engagement. To this end, we developed a methodology (Sat-Sel-Seq) that couples saturation mutagenesis at each position across the targeting loop, with iterative functional selection and next-generation sequencing. This high-throughput mutational analysis revealed dominant characteristics for residues within the loop and additionally yielded enzymatic variants that enhance deaminase activity. To rationalize these functional requirements, we performed molecular dynamics simulations that suggest that AID and its hyperactive variants can engage DNA in multiple specific modes. These findings align with AID's competing requirements for specificity and flexibility to efficiently drive antibody maturation. Beyond insights into the AID-DNA interface, our Sat-Sel-Seq approach also serves to further expand the repertoire of techniques for deep positional scanning and may find general utility for high-throughput analysis of protein function. PMID:25064858

Gajula, Kiran S.; Huwe, Peter J.; Mo, Charlie Y.; Crawford, Daniel J.; Stivers, James T.; Radhakrishnan, Ravi; Kohli, Rahul M.

2014-01-01

214

Evolutionary, structural and functional relationships revealed by comparative analysis of syntenic genes in Rhizobiales  

PubMed Central

Background Comparative genomics has provided valuable insights into the nature of gene sequence variation and chromosomal organization of closely related bacterial species. However, questions about the biological significance of gene order conservation, or synteny, remain open. Moreover, few comprehensive studies have been reported for rhizobial genomes. Results We analyzed the genomic sequences of four fast growing Rhizobiales (Sinorhizobium meliloti, Agrobacterium tumefaciens, Mesorhizobium loti and Brucella melitensis). We made a comprehensive gene classification to define chromosomal orthologs, genes with homologs in other replicons such as plasmids, and those which were species-specific. About two thousand genes were predicted to be orthologs in each chromosome and about 80% of these were syntenic. A striking gene colinearity was found in pairs of organisms and a large fraction of the microsyntenic regions and operons were similar. Syntenic products showed higher identity levels than non-syntenic ones, suggesting a resistance to sequence variation due to functional constraints; also, an unusually high fraction of syntenic products contained membranal segments. Syntenic genes encode a high proportion of essential cell functions, presented a high level of functional relationships and a very low horizontal gene transfer rate. The sequence variability of the proteins can be considered the species signature in response to specific niche adaptation. Comparatively, an analysis with genomes of Enterobacteriales showed a different gene organization but gave similar results in the synteny conservation, essential role of syntenic genes and higher functional linkage among the genes of the microsyntenic regions. Conclusion Syntenic bacterial genes represent a commonly evolved group. They not only reveal the core chromosomal segments present in the last common ancestor and determine the metabolic characteristics shared by these microorganisms, but also show resistance to sequence variation and rearrangement, possibly due to their essential character. In Rhizobiales and Enterobacteriales, syntenic genes encode a high proportion of essential cell functions and presented a high level of functional relationships. PMID:16229745

Guerrero, Gabriela; Peralta, Humberto; Aguilar, Alejandro; Diaz, Rafael; Villalobos, Miguel Angel; Medrano-Soto, Arturo; Mora, Jaime

2005-01-01

215

T-cell factor 4 functions as a tumor suppressor whose disruption modulates colon cell proliferation  

E-print Network

T-cell factor 4 functions as a tumor suppressor whose disruption modulates colon cell proliferation via T-cell factor/Lymphoid enhancer-binding factor (Tcf/Lef) DNA binding factors. Misregula- tion of the colonic epithelium and that disruption of Tcf4 activity increases prolifera- tion, leading to colon

Capecchi, Mario R.

216

Investigation of the large-scale functional brain networks modulated by acupuncture  

E-print Network

Investigation of the large-scale functional brain networks modulated by acupuncture Yuanyuan Fenga effects of acupuncture. Considering that acupuncture can induce long-lasting effects, several researchers have begun to pay attention to the sustained effects of acupuncture on the resting brain. Most

Tian, Jie

217

Radiation Monitoring System in Service Module of International Space Station. Eight Years of Functioning  

Microsoft Academic Search

Radiation monitoring system (RMS) installed on board the Russian module (RM) of the In-ternational Space Station (ISS) is an important part of radiation safety system of a spacecraft. RMS function practically continuously beginning from 1 August 2001 year. Integration the RMS with other systems of RM permits to transmit measured values to the Earth by the telemetry and to reflect

Victor Benghin; Vladislav Petrov; Mikhail Panasyuk; Aleksey Volkov; Igor Nikolaev; Oleg Nechaev; Andrey Lishnevskii; Mikhail Tel

2010-01-01

218

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

219

Cysteine regulation of protein function – as exemplified by NMDA-receptor modulation  

Microsoft Academic Search

Until recently cysteine residues, especially those located extracellularly, were thought to be important for metal coordination, catalysis and protein structure by forming disulfide bonds – but they were not thought to regulate protein function. However, this is not the case. Crucial cysteine residues can be involved in modulation of protein activity and signaling events via other reactions of their thiol

Stuart A. Lipton; Yun-Beom Choi; Hiroto Takahashi; Dongxian Zhang; Weizhong Li; Adam Godzik; Laurie A. Bankston

2002-01-01

220

Compensating Printer Modulation Transfer Function in Spatial and Color Adaptive Rendering Workflows  

Microsoft Academic Search

Experiments have shown that the quality of printed images depends on the capacity of the printing system to accurately re- produce details. We propose to improve the quality by compensat- ing for the Modulation Transfer Function (MTF) of the printing system. The MTF of the printing system is measured using a mod- ified version of the method proposed by Jang

Nicolas Bonnier; Albrecht Lindner; Christophe Leynadier; Francis Schmitt

221

Modulation transfer function for a large-area amorphous silicon image receptor  

Microsoft Academic Search

The modulation transfer function (MTF) of an amorphous silicon (aSi) sensor array was measured using proper sampling techniques to determine the edge spread function (ESF). The detector under study was a area detector (EG&G Heimann, RTM128) consisting of aSi photodiodes arranged in a square array. Two independent methods for calculating the presampling MTF were implemented, based on finely sampling the

Jonathan R. D. Earnhart; Edward L. Chaney

1997-01-01

222

Molecular Mechanisms of COMPLEXIN Fusion Clamp Function in Synaptic Exocytosis Revealed in a New Drosophila Mutant  

PubMed Central

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, cpx1257, revealing spatially defined and separable pools of CPX which make distinct contributions to the activation and clamping functions. In cpx1257, 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 cpx1257 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 cpx1257 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, cpx1257 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

2013-01-01

223

LINCing complex functions at the nuclear envelope: what the molecular architecture of the LINC complex can reveal about its function.  

PubMed

Linker of nucleoskeleton and cytoskeleton (LINC) complexes span the double membrane of the nuclear envelope (NE) and physically connect nuclear structures to cytoskeletal elements. LINC complexes are envisioned as force transducers in the NE, which facilitate processes like nuclear anchorage and migration, or chromosome movements. The complexes are built from members of two evolutionary conserved families of transmembrane (TM) proteins, the SUN (Sad1/UNC-84) domain proteins in the inner nuclear membrane (INM) and the KASH (Klarsicht/ANC-1/SYNE homology) domain proteins in the outer nuclear membrane (ONM). In the lumen of the NE, the SUN and KASH domains engage in an intimate assembly to jointly form a NE bridge. Detailed insights into the molecular architecture and atomic structure of LINC complexes have recently revealed the molecular basis of nucleo-cytoskeletal coupling. They bear important implications for LINC complex function and suggest new potential and as yet unexplored roles, which the complexes may play in the cell. PMID:23324460

Rothballer, Andrea; Schwartz, Thomas U; Kutay, Ulrike

2013-01-01

224

Dual-functionalized PAMAM dendrimers with improved P-glycoprotein inhibition and tight junction modulating effect.  

PubMed

This study aims to surface modify poly(amido amine) or PAMAM dendrimers by sequentially grafting poly(ethylene glycol) or PEG and 4-thiobutylamidine (TBA) so as to reduce PAMAM cytotoxicity while improving the ability of PAMAM to modulate P-glycoprotein (P-gp) efflux and tight junction integrity. Conjugation of functional groups was determined by NMR spectroscopy, FT-IR, thiol group quantification and molecular weight estimation. The yield of the dual-functionalized dendrimers was >80%. The dual-functionalized dendrimer could significantly reduce PAMAM cytotoxicity to <15% as reflected by LDH release in Caco-2 and MDCK/MDR1 cells after 72 h of exposure. Thiolated dendrimers could increase cellular accumulation and permeation of the P-gp substrate R-123, and such effect could be affected by the extent of PEGylation of the dendrimer. Surface-modified PAMAM dendrimers, either by single or dual functionalization, could better modulate tight junction integrity in comparison with unmodified PAMAM, as demonstrated through immunostaining of the tight junction marker ZO-1, permeation of the model compound Lucifer Yellow (LY) and transepithelial electrical resistance (TEER). Of importance, reversible tight junction modulating effect was only observed in the dual-functionalized dendrimers. Collectively, dual functionalization with PEG and TBA represented a promising approach in altering PAMAM dendrimer surface for potential application in oral drug delivery. PMID:24219381

Liu, Yuanjie; Chiu, Gigi N C

2013-12-01

225

Exchangeable Chaperone Modules Contribute to Specification of Type I and Type II Hsp40 Cellular Function  

PubMed Central

Hsp40 family members regulate Hsp70s ability to bind nonnative polypeptides and thereby play an essential role in cell physiology. Type I and type II Hsp40s, such as yeast Ydj1 and Sis1, form chaperone pairs with cytosolic Hsp70 Ssa1 that fold proteins with different efficiencies and carry out specific cellular functions. The mechanism by which Ydj1 and Sis1 specify Hsp70 functions is not clear. Ydj1 and Sis1 share a high degree of sequence identity in their amino and carboxyl terminal ends, but each contains a structurally unique and centrally located protein module that is implicated in chaperone function. To test whether the chaperone modules of Ydj1 and Sis1 function in the specification of Hsp70 action, we constructed a set of chimeric Hsp40s in which the chaperone domains of Ydj1 and Sis1 were swapped to form YSY and SYS. Purified SYS and YSY exhibited protein-folding activity and substrate specificity that mimicked that of Ydj1 and Sis1, respectively. In in vivo studies, YSY exhibited a gain of function and, unlike Ydj1, could complement the lethal phenotype of sis1? and facilitate maintenance of the prion [RNQ+]. Ydj1 and Sis1 contain exchangeable chaperone modules that assist in specification of Hsp70 function. PMID:14657253

Fan, Chun-Yang; Lee, Soojin; Ren, Hong-Yu; Cyr, Douglas M.

2004-01-01

226

The age-related posterior-anterior shift as revealed by voxelwise analysis of functional brain networks  

PubMed Central

The posterior-anterior shift in aging (PASA) is a commonly observed phenomenon in functional neuroimaging studies of aging, characterized by age-related reductions in occipital activity alongside increases in frontal activity. In this work we have investigated the hypothesis as to whether the PASA is also manifested in functional brain network measures such as degree, clustering coefficient, path length and local efficiency. We have performed statistical analysis upon functional networks derived from a fMRI dataset containing data from healthy young, healthy aged, and aged individuals with very mild to mild Alzheimer's disease (AD). Analysis of both task based and resting state functional network properties has indicated that the PASA can also be characterized in terms of modulation of functional network properties, and that the onset of AD appears to accentuate this modulation. We also explore the effect of spatial normalization upon the results of our analysis.

McCarthy, Paul; Benuskova, Lubica; Franz, Elizabeth A.

2014-01-01

227

Comparative expression profiling reveals gene functions in female meiosis and gametophyte development in Arabidopsis.  

PubMed

Megasporogenesis is essential for female fertility, and requires the accomplishment of meiosis and the formation of functional megaspores. The inaccessibility and low abundance of female meiocytes make it particularly difficult to elucidate the molecular basis underlying megasporogenesis. We used high-throughput tag-sequencing analysis to identify genes expressed in female meiocytes (FMs) by comparing gene expression profiles from wild-type ovules undergoing megasporogenesis with those from the spl mutant ovules, which lack megasporogenesis. A total of 862 genes were identified as FMs, with levels that are consistently reduced in spl ovules in two biological replicates. Fluorescence-assisted cell sorting followed by RNA-seq analysis of DMC1:GFP-labeled female meiocytes confirmed that 90% of the FMs are indeed detected in the female meiocyte protoplast profiling. We performed reverse genetic analysis of 120 candidate genes and identified four FM genes with a function in female meiosis progression in Arabidopsis. We further revealed that KLU, a putative cytochrome P450 monooxygenase, is involved in chromosome pairing during female meiosis, most likely by affecting the normal expression pattern of DMC1 in ovules during female meiosis. Our studies provide valuable information for functional genomic analyses of plant germline development as well as insights into meiosis. PMID:25182975

Zhao, Lihua; He, Jiangman; Cai, Hanyang; Lin, Haiyan; Li, Yanqiang; Liu, Renyi; Yang, Zhenbiao; Qin, Yuan

2014-11-01

228

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. PMID:23115289

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

2013-01-01

229

Spatial clustering of binding motifs and charges reveals conserved functional features in disordered nucleoporin sequences  

NASA Astrophysics Data System (ADS)

The Nuclear Pore Complex (NPC) gates the only channel through which cells exchange material between the nucleus and cytoplasm. Traffic is regulated by transport receptors bound to cargo which interact with numerous of disordered phenylalanine glycine (FG) repeat containing proteins (FG nups) that line this channel. The precise physical mechanism of transport regulation has remained elusive primarily due to the difficulty in understanding the structure and dynamics of such a large assembly of interacting disordered proteins. Here we have performed a comprehensive bioinformatic analysis, specifically tailored towards disordered proteins, on thousands of nuclear pore proteins from a variety of species revealing a set of highly conserved features in the sequence structure among FG nups. Contrary to the general perception that these proteins are functionally equivalent to homogeneous polymers, we show that biophysically important features within individual nups like the separation, spatial localization and ordering along the chain of FG and charge domains are highly conserved. Our current understanding of NPC structure and function should therefore be revised to account for these common features that are functionally relevant for the underlying physical mechanism of NPC gating.

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

2013-03-01

230

Diurnal Changes in Mitochondrial Function Reveal Daily Optimization of Light and Dark Respiratory Metabolism in Arabidopsis*  

PubMed Central

Biomass production by plants is often negatively correlated with respiratory rate, but the value of this rate changes dramatically during diurnal cycles, and hence, biomass is the cumulative result of complex environment-dependent metabolic processes. Mitochondria in photosynthetic plant tissues undertake substantially different metabolic roles during light and dark periods that are dictated by substrate availability and the functional capacity of mitochondria defined by their protein composition. We surveyed the heterogeneity of the mitochondrial proteome and its function during a typical night and day cycle in Arabidopsis shoots. This used a staged, quantitative analysis of the proteome across 10 time points covering 24 h of the life of 3-week-old Arabidopsis shoots grown under 12-h dark and 12-h light conditions. Detailed analysis of enzyme capacities and substrate-dependent respiratory processes of isolated mitochondria were also undertaken during the same time course. Together these data reveal a range of dynamic changes in mitochondrial capacity and uncover day- and night-enhanced protein components. Clear diurnal changes were evident in mitochondrial capacities to drive the TCA cycle and to undertake functions associated with nitrogen and sulfur metabolism, redox poise, and mitochondrial antioxidant defense. These data quantify the nature and nuances of a daily rhythm in Arabidopsis mitochondrial respiratory capacity. PMID:20601493

Lee, Chun Pong; Eubel, Holger; Millar, A. Harvey

2010-01-01

231

High-resolution chemical dissection of a model eukaryote reveals targets, pathways and gene functions.  

PubMed

Due to evolutionary conservation of biology, experimental knowledge captured from genetic studies in eukaryotic model organisms provides insight into human cellular pathways and ultimately physiology. Yeast chemogenomic profiling is a powerful approach for annotating cellular responses to small molecules. Using an optimized platform, we provide the relative sensitivities of the heterozygous and homozygous deletion collections for nearly 1800 biologically active compounds. The data quality enables unique insights into pathways that are sensitive and resistant to a given perturbation, as demonstrated with both known and novel compounds. We present examples of novel compounds that inhibit the therapeutically relevant fatty acid synthase and desaturase (Fas1p and Ole1p), and demonstrate how the individual profiles facilitate hypothesis-driven experiments to delineate compound mechanism of action. Importantly, the scale and diversity of tested compounds yields a dataset where the number of modulated pathways approaches saturation. This resource can be used to map novel biological connections, and also identify functions for unannotated genes. We validated hypotheses generated by global two-way hierarchical clustering of profiles for (i) novel compounds with a similar mechanism of action acting upon microtubules or vacuolar ATPases, and (ii) an un-annotated ORF, YIL060w, that plays a role in respiration in the mitochondria. Finally, we identify and characterize background mutations in the widely used yeast deletion collection which should improve the interpretation of past and future screens throughout the community. This comprehensive resource of cellular responses enables the expansion of our understanding of eukaryotic pathway biology. PMID:24360837

Hoepfner, Dominic; Helliwell, Stephen B; Sadlish, Heather; Schuierer, Sven; Filipuzzi, Ireos; Brachat, Sophie; Bhullar, Bhupinder; Plikat, Uwe; Abraham, Yann; Altorfer, Marc; Aust, Thomas; Baeriswyl, Lukas; Cerino, Raffaele; Chang, Lena; Estoppey, David; Eichenberger, Juerg; Frederiksen, Mathias; Hartmann, Nicole; Hohendahl, Annika; Knapp, Britta; Krastel, Philipp; Melin, Nicolas; Nigsch, Florian; Oakeley, Edward J; Petitjean, Virginie; Petersen, Frank; Riedl, Ralph; Schmitt, Esther K; Staedtler, Frank; Studer, Christian; Tallarico, John A; Wetzel, Stefan; Fishman, Mark C; Porter, Jeffrey A; Movva, N Rao

2014-01-01

232

A multi-functional chimeric chaperone serves as a novel immune modulator inducing therapeutic antitumor immunity  

PubMed Central

Converting the immunosuppressive tumor environment into one that is favorable to induction of antitumor immunity is indispensable for effective cancer immunotherapy. Here we strategically incorporate a pathogen (i.e., Flagellin)-derived, NF-?B-stimulating `danger' signal into the large stress protein or chaperone Grp170 (HYOU1/ORP150) that was previously shown to facilitate antigen cross-presentation. This engineered chimeric molecule (i.e., Flagrp170) is capable of transporting tumor antigens and concurrently inducing functional activation of dendritic cells. Intratumoral administration of adenoviruses expressing Flagrp170 induces a superior antitumor response against B16 melanoma and its distant lung metastasis compared to unmodified Grp170 and Flagellin. The enhanced tumor destruction is accompanied with significantly increased tumor infiltration by CD8+ cells as well as elevation of IFN-? and IL-12 levels in the tumor sites. In situ Ad.Flagrp170 therapy provokes systemic activation of CTLs that recognize several antigens naturally expressing in melanoma (e.g., gp100/PMEL and TRP2/DCT). The mechanistic studies using CD11c-DTR transgenic mice and Batf3-deficient mice reveal that CD8?+ DCs are required for the improved T cell cross-priming. Antibody neutralization assays show that IL-12 and IFN-? are essential for the Flagrp170-elicited antitumor response, which also involves CD8+ T cells and NK cells. The therapeutic efficacy of Flagrp170 and its immune stimulating activity are also confirmed in mouse prostate cancer and colon carcinoma. Together, targeting the tumor microenvironment with this chimeric chaperone is highly effective in mobilizing or restoring antitumor immunity, supporting the potential therapeutic use of this novel immune modulator in the treatment of metastatic diseases. PMID:23333935

Yu, Xiaofei; Guo, Chunqing; Yi, Huanfa; Qian, Jie; Fisher, Paul B.; Subjeck, John R.; Wang, Xiang-Yang

2013-01-01

233

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. PMID:23349812

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

2013-01-01

234

A functional genomic approach reveals the transcriptional role of EDD in the expression and function of angiogenesis regulator ACVRL1.  

PubMed

EDD (E3 isolated by differential display) was initially isolated as a progestin-regulated gene in breast cancer cells, and represents the human ortholog of the Drosophila melanogaster hyperplastic discs gene (hyd). It encodes a highly conserved and predominantly nuclear ubiquitin E3 ligase of the HECT family, with potential multifunctional roles in development and tumorigenesis. In this study, we further examined the largely uncharacterized role of EDD in transcriptional regulation by uncovering the spectrum of its direct target genes at a genome-wide level. Use of a systematic approach that integrates gene expression and chromatin binding profiling identified several candidate EDD-target genes, one of which is ACVRL1, a TGF-? receptor with functional implications in blood vessel development. Further characterization revealed a negative regulation of ACVRL1 gene expression by EDD that is exerted at the promoter. Consistent with the aberrant upregulation of ACVRL1 and downstream Smad signaling, abrogation of EDD led to deregulated vessel development and endothelial cell motility. Collectively, these results extended the known cellular roles of EDD to critical functions in transcriptional regulation as well as angiogenesis, and may provide mechanistic explanations for EDD's tumorigenic and developmental roles. PMID:24189493

Chen, Hui-Wen; Yang, Chang-Ching; Hsieh, Chia-Ling; Liu, Hsuan; Lee, Sheng-Chung; Tan, Bertrand Chin-Ming

2013-12-01

235

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. PMID:22174789

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

236

Attention-dependent modulation of cortical taste circuits revealed by Granger causality with signal-dependent noise.  

PubMed

We show, for the first time, that in cortical areas, for example the insular, orbitofrontal, and lateral prefrontal cortex, there is signal-dependent noise in the fMRI blood-oxygen level dependent (BOLD) time series, with the variance of the noise increasing approximately linearly with the square of the signal. Classical Granger causal models are based on autoregressive models with time invariant covariance structure, and thus do not take this signal-dependent noise into account. To address this limitation, here we describe a Granger causal model with signal-dependent noise, and a novel, likelihood ratio test for causal inferences. We apply this approach to the data from an fMRI study to investigate the source of the top-down attentional control of taste intensity and taste pleasantness processing. The Granger causality with signal-dependent noise analysis reveals effects not identified by classical Granger causal analysis. In particular, there is a top-down effect from the posterior lateral prefrontal cortex to the insular taste cortex during attention to intensity but not to pleasantness, and there is a top-down effect from the anterior and posterior lateral prefrontal cortex to the orbitofrontal cortex during attention to pleasantness but not to intensity. In addition, there is stronger forward effective connectivity from the insular taste cortex to the orbitofrontal cortex during attention to pleasantness than during attention to intensity. These findings indicate the importance of explicitly modeling signal-dependent noise in functional neuroimaging, and reveal some of the processes involved in a biased activation theory of selective attention. PMID:24204221

Luo, Qiang; Ge, Tian; Grabenhorst, Fabian; Feng, Jianfeng; Rolls, Edmund T

2013-10-01

237

Salivary Gland Proteome Analysis Reveals Modulation of Anopheline Unique Proteins in Insensitive Acetylcholinesterase Resistant Anopheles gambiae Mosquitoes  

PubMed Central

Insensitive acetylcholinesterase resistance due to a mutation in the acetylcholinesterase (ace) encoding ace-1 gene confers cross-resistance to organophosphate and carbamate insecticides in Anopheles gambiae populations from Central and West Africa. This mutation is associated with a strong genetic cost revealed through alterations of some life history traits but little is known about the physiological and behavioural changes in insects bearing the ace-1R allele. Comparative analysis of the salivary gland contents between An. gambiae susceptible and ace-1R resistant strains was carried out to charaterize factors that could be involved in modifications of blood meal process, trophic behaviour or pathogen interaction in the insecticide-resistant mosquitoes. Differential analysis of the salivary gland protein profiles revealed differences in abundance for several proteins, two of them showing major differences between the two strains. These two proteins identified as saglin and TRIO are salivary gland-1 related proteins, a family unique to anopheline mosquitoes, one of them playing a crucial role in salivary gland invasion by Plasmodium falciparum sporozoites. Differential expression of two other proteins previously identified in the Anopheles sialome was also observed. The differentially regulated proteins are involved in pathogen invasion, blood feeding process, and protection against oxidation, relevant steps in the outcome of malaria infection. Further functional studies and insect behaviour experiments would confirm the impact of the modification of the sialome composition on blood feeding and pathogen transmission abilities of the resistant mosquitoes. The data supports the hypothesis of alterations linked to insecticide resistance in the biology of the primary vector of human malaria in Africa. PMID:25102176

Cornelie, Sylvie; Rossignol, Marie; Seveno, Martial; Demettre, Edith; Mouchet, Francois; Djegbe, Innocent; Marin, Philippe; Chandre, Fabrice; Corbel, Vincent; Remoue, Franck; Mathieu-Daude, Francoise

2014-01-01

238

Attention-Dependent Modulation of Cortical Taste Circuits Revealed by Granger Causality with Signal-Dependent Noise  

PubMed Central

We show, for the first time, that in cortical areas, for example the insular, orbitofrontal, and lateral prefrontal cortex, there is signal-dependent noise in the fMRI blood-oxygen level dependent (BOLD) time series, with the variance of the noise increasing approximately linearly with the square of the signal. Classical Granger causal models are based on autoregressive models with time invariant covariance structure, and thus do not take this signal-dependent noise into account. To address this limitation, here we describe a Granger causal model with signal-dependent noise, and a novel, likelihood ratio test for causal inferences. We apply this approach to the data from an fMRI study to investigate the source of the top-down attentional control of taste intensity and taste pleasantness processing. The Granger causality with signal-dependent noise analysis reveals effects not identified by classical Granger causal analysis. In particular, there is a top-down effect from the posterior lateral prefrontal cortex to the insular taste cortex during attention to intensity but not to pleasantness, and there is a top-down effect from the anterior and posterior lateral prefrontal cortex to the orbitofrontal cortex during attention to pleasantness but not to intensity. In addition, there is stronger forward effective connectivity from the insular taste cortex to the orbitofrontal cortex during attention to pleasantness than during attention to intensity. These findings indicate the importance of explicitly modeling signal-dependent noise in functional neuroimaging, and reveal some of the processes involved in a biased activation theory of selective attention. PMID:24204221

Luo, Qiang; Ge, Tian; Grabenhorst, Fabian; Feng, Jianfeng; Rolls, Edmund T.

2013-01-01

239

Lipidomic profiling reveals protective function of fatty acid oxidation in cocaine-induced hepatotoxicity[S  

PubMed Central

During cocaine-induced hepatotoxicity, lipid accumulation occurs prior to necrotic cell death in the liver. However, the exact influences of cocaine on the homeostasis of lipid metabolism remain largely unknown. In this study, the progression of subacute hepatotoxicity, including centrilobular necrosis in the liver and elevation of transaminase activity in serum, was observed in a three-day cocaine treatment, accompanying the disruption of triacylglycerol (TAG) turnover. Serum TAG level increased on day 1 of cocaine treatment but remained unchanged afterwards. In contrast, hepatic TAG level was elevated continuously during three days of cocaine treatment and was better correlated with the development of hepatotoxicity. Lipidomic analyses of serum and liver samples revealed time-dependent separation of the control and cocaine-treated mice in multivariate models, which was due to the accumulation of long-chain acylcarnitines together with the disturbances of many bioactive phospholipid species in the cocaine-treated mice. An in vitro function assay confirmed the progressive inhibition of mitochondrial fatty acid oxidation after the cocaine treatment. Cotreatment of fenofibrate significantly increased the expression of peroxisome proliferator-activated receptor ? (PPAR?)-targeted genes and the mitochondrial fatty acid oxidation activity in the cocaine-treated mice, resulting in the inhibition of cocaine-induced acylcarnitine accumulation and other hepatotoxic effects. Overall, the results from this lipidomics-guided study revealed that the inhibition of fatty acid oxidation plays an important role in cocaine-induced liver injury. PMID:22904346

Shi, Xiaolei; Yao, Dan; Gosnell, Blake A.; Chen, Chi

2012-01-01

240

Global functional map of the p23 molecular chaperone reveals an extensive cellular network.  

PubMed

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 and 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. PMID:21777812

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

2011-07-22

241

Evidence for a frontoparietal control system revealed by intrinsic functional connectivity.  

PubMed

Two functionally distinct, and potentially competing, brain networks have been recently identified that can be broadly distinguished by their contrasting roles in attention to the external world versus internally directed mentation involving long-term memory. At the core of these two networks are the dorsal attention system and the hippocampal-cortical memory system, a component of the brain's default network. Here spontaneous blood-oxygenation-level-dependent (BOLD) signal correlations were used in three separate functional magnetic resonance imaging data sets (n = 105) to define a third system, the frontoparietal control system, which is spatially interposed between these two previously defined systems. The frontoparietal control system includes many regions identified as supporting cognitive control and decision-making processes including lateral prefrontal cortex, anterior cingulate cortex, and inferior parietal lobule. Detailed analysis of frontal and parietal cortex, including use of high-resolution data, revealed clear evidence for contiguous but distinct regions: in general, the regions associated with the frontoparietal control system are situated between components of the dorsal attention and hippocampal-cortical memory systems. The frontoparietal control system is therefore anatomically positioned to integrate information from these two opposing brain systems. PMID:18799601

Vincent, Justin L; Kahn, Itamar; Snyder, Abraham Z; Raichle, Marcus E; Buckner, Randy L

2008-12-01

242

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. PMID:23280630

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

2013-01-01

243

Metagenomics Reveals Microbial Community Composition And Function With Depth In Arctic Permafrost Cores  

NASA Astrophysics Data System (ADS)

The Arctic is one of the most climatically sensitive regions on Earth and current surveys show that permafrost degradation is widespread in arctic soils. Biogeochemical feedbacks of permafrost thaw are expected to be dominated by the release of currently stored carbon back into the atmosphere as CO2 and CH4. Understanding the dynamics of C release from permafrost requires assessment of microbial functions from different soil compartments. To this end, as part of the Next Generation Ecosystem Experiment in the Arctic, we collected two replicate permafrost cores (1m and 3m deep) from a transitional polygon near Barrow, AK. At this location, permafrost starts from 0.5m in depth and is characterized by variable ice content and higher pH than surface soils. Prior to sectioning, the cores were CT-scanned to determine the physical heterogeneity throughout the cores. In addition to detailed geochemical characterization, we used Illumina MiSeq technology to sequence 16SrRNA genes throughout the depths of the cores at 1 cm intervals. Selected depths were also chosen for metagenome sequencing of total DNA (including phylogenetic and functional genes) using the Illumina HiSeq platform. The 16S rRNA gene sequence data revealed that the microbial community composition and diversity changed dramatically with depth. The microbial diversity decreased sharply below the first few centimeters of the permafrost and then gradually increased in deeper layers. Based on the metagenome sequence data, the permafrost microbial communities were found to contain members with a large metabolic potential for carbon processing, including pathways for fermentation and methanogenesis. The surface active layers had more representatives of Verrucomicrobia (potential methane oxidizers) whereas the deep permafrost layers were dominated by several different species of Actinobacteria. The latter are known to have a diverse metabolic capability and are able to adapt to stress by entering a dormant yet viable state. In addition, several isolates were obtained from different depths throughout the cores, including methanogens from some of the deeper layers. Together these data present a new view of potential geochemical cycles carried out by microorganisms in permafrost and reveal how community members and functions are distributed with depth.

Jansson, J.; Tas, N.; Wu, Y.; Ulrich, C.; Kneafsey, T. J.; Torn, M. S.; Hubbard, S. S.; Chakraborty, R.; Graham, D. E.; Wullschleger, S. D.

2013-12-01

244

The modulation of brain functional connectivity with manual acupuncture in healthy subjects: An electroencephalograph case study  

NASA Astrophysics Data System (ADS)

Manual acupuncture is widely used for pain relief and stress control. Previous studies on acupuncture have shown its modulatory effects on the functional connectivity associated with one or a few preselected brain regions. To investigate how manual acupuncture modulates the organization of functional networks at a whole-brain level, we acupuncture at ST36 of a right leg to obtain electroencephalograph (EEG) signals. By coherence estimation, we determine the synchronizations between all pairwise combinations of EEG channels in three acupuncture states. The resulting synchronization matrices are converted into functional networks by applying a threshold, and the clustering coefficients and path lengths are computed as a function of threshold. The results show that acupuncture can increase functional connections and synchronizations between different brain areas. For a wide range of thresholds, the clustering coefficient during acupuncture and post-acupuncture period is higher than that during the pre-acupuncture control period, whereas the characteristic path length is shorter. We provide further support for the presence of “small-world" network characteristics in functional networks by using acupuncture. These preliminary results highlight the beneficial modulations of functional connectivity by manual acupuncture, which could contribute to the understanding of the effects of acupuncture on the entire brain, as well as the neurophysiological mechanisms underlying acupuncture. Moreover, the proposed method may be a useful approach to the further investigation of the complexity of patterns of interrelations between EEG channels.

Yi, Guo-Sheng; Wang, Jiang; Han, Chun-Xiao; Deng, Bin; Wei, Xi-Le; Li, Nuo

2013-02-01

245

Microwave influence on the isolated heart function. 1: Effect of modulation  

SciTech Connect

Dependence of the microwave effect on modulation parameters (pulse width, duty ratio, and peak intensity) was studied in an isolated frog auricle preparation. The rate and amplitude of spontaneous auricle twitches were measured during and after a 2 min exposure to 915 or 885 MHz microwaves and were compared to preexposure values. The studied ranges of modulation parameters were: pulse width, 10{sup {minus}6}--10{sup {minus}2} s; duty ratio, 7:100000, and peak specific absorption rate, 100--3,000 W/kg. Combinations of the parameters were chosen by chance, and about 400 various exposure regimes were tested. The experiments established that no regime was effective unless the average microwave power was high enough to induce preparation heating (0.1--0.4 C). The twitch rate instantly increased, and the amplitude decreased, as the temperature rose; similar changes could be induced by equivalent conventional heating. the data provide evidence that the effect of short-term microwave exposure on the isolated heart pacemaker and contractile functions depends on pulse modulation just as much as modulation determines the average absorbed power. These functions demonstrated no specific dependence on exposure parameters such as frequency or power windows.

Pakhomov, A.G.; Dubovick, B.V.; Degtyariov, I.G.; Pronkevich, A.N. [Russian Academy of Medical Sciences, Obninsk (Russian Federation). Medical Radiology Research Center

1995-09-01

246

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

2011-11-01

247

Endogenous Urotensin II Selectively Modulates Erectile Function through eNOS  

PubMed Central

Background Urotensin II (U-II) is a cyclic peptide originally isolated from the neurosecretory system of the teleost fish and subsequently found in other species, including man. U-II was identified as the natural ligand of a G-protein coupled receptor, namely UT receptor. U-II and UT receptor are expressed in a variety of peripheral organs and especially in cardiovascular tissue. Recent evidence indicates the involvement of U-II/UT pathway in penile function in human, but the molecular mechanism is still unclear. On these bases the aim of this study is to investigate the mechanism(s) of U-II-induced relaxation in human corpus cavernosum and its relationship with L-arginine/Nitric oxide (NO) pathway. Methodology/Principal Findings Human corpus cavernosum tissue was obtained following in male-to-female transsexuals undergoing surgical procedure for sex reassignment. Quantitative RT-PCR clearly demonstrated the U-II expression in human corpus cavernosum. U-II (0.1 nM–10 µM) challenge in human corpus cavernosum induced a significant increase in NO production as revealed by fluorometric analysis. NO generation was coupled to a marked increase in the ratio eNOS phosphorilated/eNOS as determined by western blot analysis. A functional study in human corpus cavernosum strips was performed to asses eNOS involvement in U-II-induced relaxation by using a pharmacological modulation. Pre-treatment with both wortmannin or geldanamycinin (inhibitors of eNOS phosphorylation and heath shock protein 90 recruitment, respectively) significantly reduced U-II-induced relaxation (0.1 nM–10 µM) in human corpus cavernosum strips. Finally, a co-immunoprecipitation study demonstrated that UT receptor and eNOS co-immunoprecipitate following U-II challenge of human corpus cavernosum tissue. Conclusion/Significance U-II is endogenously synthesized and locally released in human corpus cavernosum. U-II elicited penile erection through eNOS activation. Thus, U-II/UT pathway may represent a novel therapeutical target in erectile dysfunction. PMID:22319601

d'Emmanuele di Villa Bianca, Roberta; Mitidieri, Emma; Fusco, Ferdinando; D'Aiuto, Elena; Grieco, Paolo; Novellino, Ettore; Imbimbo, Ciro; Mirone, Vincenzo; Cirino, Giuseppe; Sorrentino, Raffaella

2012-01-01

248

A large scale survey reveals that chromosomal copy-number alterations significantly affect gene modules involved in cancer initiation and progression  

Microsoft Academic Search

Background  Recent observations point towards the existence of a large number of neighborhoods composed of functionally-related gene modules\\u000a that lie together in the genome. This local component in the distribution of the functionality across chromosomes is probably\\u000a affecting the own chromosomal architecture by limiting the possibilities in which genes can be arranged and distributed across\\u000a the genome. As a direct consequence

Eva Alloza; Fátima Al-Shahrour; Juan C Cigudosa; Joaquín Dopazo

2011-01-01

249

Emotional regulatory function of receptor interacting protein 140 revealed in the ventromedial hypothalamus.  

PubMed

Receptor-interacting protein (RIP140) is a transcription co-regulator highly expressed in macrophages to regulate inflammatory and metabolic processes. However, its implication in neurological, cognitive and emotional conditions, and the cellular systems relevant to its biological activity within the central nervous system are currently less clear. A transgenic mouse line with macrophage-specific knockdown of RIP140 was generated (M?RIPKD mice) and brain-region specific RIP140 knockdown efficiency evaluated. Mice were subjected to a battery of tests, designed to evaluate multiple behavioral domains at naïve or following site-specific RIP140 re-expression. Gene expression analysis assessed TNF-?, IL-1?, TGF-1?, IL1-RA and neuropeptide Y (NPY) expression, and in vitro studies examined the effects of macrophage's RIP140 on astrocytes' NPY production. We found that RIP140 expression was dramatically reduced in macrophages within the ventromedial hypothalamus (VMH) and the cingulate cortex of M?RIPKD mice. These animals exhibited increased anxiety- and depressive-like behaviors. VMH-targeted RIP140 re-expression in M?RIPKD mice reversed its depressive- but not its anxiety-like phenotype. Analysis of specific neurochemical changes revealed reduced astrocytic-NPY expression within the hypothalamus of M?RIPKD mice, and in vitro analysis confirmed that conditioned medium of RIP140-silnenced macrophage culture could no longer stimulate NPY production from astrocytes. The current study revealed an emotional regulatory function of macrophage-derived RIP140 in the VMH, and secondary dysregulation of NPY within hypothalamic astrocyte population, which might be associated with the observed behavioral phenotype of M?RIPKD mice. This study highlights RIP140 as a novel target for the development of potential therapeutic and intervention strategies for emotional regulation disorders. PMID:24726835

Flaisher-Grinberg, S; Tsai, H C; Feng, X; Wei, L N

2014-08-01

250

Functional Genomics Analysis of the Saccharomyces cerevisiae Iron Responsive Transcription Factor Aft1 Reveals Iron-Independent Functions  

PubMed Central

The Saccharomyces cerevisiae transcription factor Aft1 is activated in iron-deficient cells to induce the expression of iron regulon genes, which coordinate the increase of iron uptake and remodel cellular metabolism to survive low-iron conditions. In addition, Aft1 has been implicated in numerous cellular processes including cell-cycle progression and chromosome stability; however, it is unclear if all cellular effects of Aft1 are mediated through iron homeostasis. To further investigate the cellular processes affected by Aft1, we identified >70 deletion mutants that are sensitive to perturbations in AFT1 levels using genome-wide synthetic lethal and synthetic dosage lethal screens. Our genetic network reveals that Aft1 affects a diverse range of cellular processes, including the RIM101 pH pathway, cell-wall stability, DNA damage, protein transport, chromosome stability, and mitochondrial function. Surprisingly, only a subset of mutants identified are sensitive to extracellular iron fluctuations or display genetic interactions with mutants of iron regulon genes AFT2 or FET3. We demonstrate that Aft1 works in parallel with the RIM101 pH pathway and the role of Aft1 in DNA damage repair is mediated by iron. In contrast, through both directed studies and microarray transcriptional profiling, we show that the role of Aft1 in chromosome maintenance and benomyl resistance is independent of its iron regulatory role, potentially through a nontranscriptional mechanism. PMID:20439772

Berthelet, Sharon; Usher, Jane; Shulist, Kristian; Hamza, Akil; Maltez, Nancy; Johnston, Anne; Fong, Ying; Harris, Linda J.; Baetz, Kristin

2010-01-01

251

Modulation of hypothalamic-pituitary-interrenal axis function by social status in rainbow trout.  

PubMed

Juvenile rainbow trout (Oncorhynchus mykiss) form stable dominance hierarchies when confined in pairs. These hierarchies are driven by aggressive competition over limited resources and result in one fish becoming dominant over the other. An important indicator of low social status is sustained elevation of circulating cortisol levels as a result of chronic activation of the hypothalamic-pituitary-interrenal (HPI) axis. In the present study it was hypothesized that social status modulates the expression of key proteins involved in the functioning of the HPI axis. Cortisol treatment and fasting were used to assess whether these characteristics seen in subordinate fish also affected HPI axis function. Social status modulated plasma adrenocorticotropic hormone (ACTH) levels, cortisol synthesis, and liver glucocorticoid receptor (GR) expression. Plasma ACTH levels were lower by approximately 2-fold in subordinate and cortisol-treated fish, consistent with a negative feedback role for cortisol in modulating HPI axis function. Although cortisol-treated fish exhibited differences in corticotropin-releasing factor (CRF) and CRF-binding protein (CRF-BP) mRNA relative abundances in the preoptic area and telencephalon, respectively, no effect of social status on CRF or CRF-BP was detected. Head kidney melanocortin 2 receptor (MC2R) mRNA relative levels were unaffected by social status, while mRNA relative abundances of steroidogenic acute regulatory protein (StAR) and cytochrome P450 side chain cleavage (P450scc) enzyme were elevated in dominant fish. Liver GR2 mRNA and total GR protein levels in subordinate fish were lower than control values by approximately 2-fold. In conclusion, social status modulated the functioning of the HPI axis in rainbow trout. Our results suggest altered cortisol dynamics and reduced target tissue response to this steroid in subordinate fish, while the higher transcript levels for steroid biosynthesis in dominant fish leads us to propose an adaptive role for responding to subsequent stressors. PMID:22326353

Jeffrey, Jennifer D; Esbaugh, Andrew J; Vijayan, Mathilakath M; Gilmour, Kathleen M

2012-04-01

252

Identifying Functional Modules Using MST-Based Weighted Gene CoExpression Networks  

Microsoft Academic Search

This paper proposes an effective method for identifying functional modules of the weighted gene co-expression network using a minimum spanning tree (MST) approach coupled with network neighborhood connectivity. The MST-based gene co-expression network was reconstructed to serve as the backbone of gene co-expression network. Highly connected hub genes were identified based on the connectivity of the backbone network. All sub-networks

Atthawut Chanthaphan; Santitham Prom-on; Asawin Meechai; Jonathan Hoyin Chan

2009-01-01

253

Serotonin transporter genotype modulates cognitive reappraisal of negative emotions: a functional magnetic resonance imaging study  

PubMed Central

A functional polymorphism within the serotonin transporter gene (5-HTTLPR) has been reported to modulate emotionality and risk for affective disorders. The short (S) allele has less functional efficacy than the long (L) allele and has been associated with enhanced emotional reactivity. One possible contributing factor to the high emotionality in S carriers may be inefficient use of cognitive strategies such as reappraisal to regulate emotional responses. The aim of the present study was to test whether the 5-HTTLPR genotype modulates the neural correlates of emotion regulation. To determine neural differences between S and L allele carriers during reappraisal of negative emotions, 15 homozygous S (S?/S?) and 15 homozygous L (L?/L?) carriers underwent functional magnetic resonance imaging (fMRI), while performing an instructed emotion regulation task including downregulation, upregulation and passive viewing of negative emotional pictures. Compared to L?/L? allele carriers, subjects who carry the S?/S? allele responded with lower posterior insula and prefrontal brain activation during passive perception of negative emotional information but showed greater prefrontal activation and anterior insula activation during down- and upregulation of negative emotional responses. The current results support and extend previous findings of enhanced emotionality in S carriers by providing additional evidence of 5-HTTLPR modulation of volitional emotion regulation. PMID:22345383

Siep, Nicolette; Markus, C. Rob

2013-01-01

254

Serotonin transporter genotype modulates cognitive reappraisal of negative emotions: a functional magnetic resonance imaging study.  

PubMed

A functional polymorphism within the serotonin transporter gene (5-HTTLPR) has been reported to modulate emotionality and risk for affective disorders. The short (S) allele has less functional efficacy than the long (L) allele and has been associated with enhanced emotional reactivity. One possible contributing factor to the high emotionality in S carriers may be inefficient use of cognitive strategies such as reappraisal to regulate emotional responses. The aim of the present study was to test whether the 5-HTTLPR genotype modulates the neural correlates of emotion regulation. To determine neural differences between S and L allele carriers during reappraisal of negative emotions, 15 homozygous S (S'/S') and 15 homozygous L (L'/L') carriers underwent functional magnetic resonance imaging (fMRI), while performing an instructed emotion regulation task including downregulation, upregulation and passive viewing of negative emotional pictures. Compared to L'/L' allele carriers, subjects who carry the S'/S' allele responded with lower posterior insula and prefrontal brain activation during passive perception of negative emotional information but showed greater prefrontal activation and anterior insula activation during down- and upregulation of negative emotional responses. The current results support and extend previous findings of enhanced emotionality in S carriers by providing additional evidence of 5-HTTLPR modulation of volitional emotion regulation. PMID:22345383

Firk, Christine; Siep, Nicolette; Markus, C Rob

2013-03-01

255

Transcriptome Analysis of Tomato Flower Pedicel Tissues Reveals Abscission Zone-Specific Modulation of Key Meristem Activity Genes  

PubMed Central

Tomato flower abscises at the anatomically distinct abscission zone that separates the pedicel into basal and apical portions. During abscission, cell separation occurs only at the abscission zone indicating distinctive molecular regulation in its cells. We conducted a transcriptome analysis of tomato pedicel tissues during ethylene promoted abscission. We found that the abscission zone was the most active site with the largest set of differentially expressed genes when compared with basal and apical portions. Gene Ontology analyses revealed enriched transcription regulation and hydrolase activities in the abscission zone. We also demonstrate coordinated responses of hormone and cell wall related genes. Besides, a number of ESTs representing homologs of key Arabidopsis shoot apical meristem activity genes were found to be preferentially expressed in the abscission zone, including WUSCHEL (WUS), KNAT6, LATERAL ORGAN BOUNDARIES DOMAIN PROTEIN 1(LBD1), and BELL-like homeodomain protein 1 (BLH1), as well as tomato axillary meristem genes BLIND (Bl) and LATERAL SUPPRESSOR (Ls). More interestingly, the homologs of WUS and the potential functional partner OVATE FAMILIY PROTEIN (OFP) were subsequently down regulated during abscission while Bl and AGL12 were continuously and specifically induced in the abscission zone. The expression patterns of meristem activity genes corroborate the idea that cells of the abscission zone confer meristem-like nature and coincide with the course of abscission and post-abscission cell differentiation. Our data therefore propose a possible regulatory scheme in tomato involving meristem genes that may be required not only for the abscission zone development, but also for abscission. PMID:23390523

Sun, Xiuli; Zhang, Rongzhi; Wu, Liang; Liang, Yanchun; Mao, Long

2013-01-01

256

Evolution of TNF-induced apoptosis reveals 550 My of functional conservation.  

PubMed

The Precambrian explosion led to the rapid appearance of most major animal phyla alive today. It has been argued that the complexity of life has steadily increased since that event. Here we challenge this hypothesis through the characterization of apoptosis in reef-building corals, representatives of some of the earliest animals. Bioinformatic analysis reveals that all of the major components of the death receptor pathway are present in coral with high-predicted structural conservation with Homo sapiens. The TNF receptor-ligand superfamilies (TNFRSF/TNFSF) are central mediators of the death receptor pathway, and the predicted proteome of Acropora digitifera contains more putative coral TNFRSF members than any organism described thus far, including humans. This high abundance of TNFRSF members, as well as the predicted structural conservation of other death receptor signaling proteins, led us to wonder what would happen if corals were exposed to a member of the human TNFSF (HuTNF?). HuTNF? was found to bind directly to coral cells, increase caspase activity, cause apoptotic blebbing and cell death, and finally induce coral bleaching. Next, immortalized human T cells (Jurkats) expressing a functional death receptor pathway (WT) and a corresponding Fas-associated death domain protein (FADD) KO cell line were exposed to a coral TNFSF member (AdTNF1) identified and purified here. AdTNF1 treatment resulted in significantly higher cell death (P < 0.0001) in WT Jurkats compared with the corresponding FADD KO, demonstrating that coral AdTNF1 activates the H. sapiens death receptor pathway. Taken together, these data show remarkable conservation of the TNF-induced apoptotic response representing 550 My of functional conservation. PMID:24927546

Quistad, Steven D; Stotland, Aleksandr; Barott, Katie L; Smurthwaite, Cameron A; Hilton, Brett Jameson; Grasis, Juris A; Wolkowicz, Roland; Rohwer, Forest L

2014-07-01

257

Evolution of TNF-induced apoptosis reveals 550 My of functional conservation  

PubMed Central

The Precambrian explosion led to the rapid appearance of most major animal phyla alive today. It has been argued that the complexity of life has steadily increased since that event. Here we challenge this hypothesis through the characterization of apoptosis in reef-building corals, representatives of some of the earliest animals. Bioinformatic analysis reveals that all of the major components of the death receptor pathway are present in coral with high-predicted structural conservation with Homo sapiens. The TNF receptor-ligand superfamilies (TNFRSF/TNFSF) are central mediators of the death receptor pathway, and the predicted proteome of Acropora digitifera contains more putative coral TNFRSF members than any organism described thus far, including humans. This high abundance of TNFRSF members, as well as the predicted structural conservation of other death receptor signaling proteins, led us to wonder what would happen if corals were exposed to a member of the human TNFSF (HuTNF?). HuTNF? was found to bind directly to coral cells, increase caspase activity, cause apoptotic blebbing and cell death, and finally induce coral bleaching. Next, immortalized human T cells (Jurkats) expressing a functional death receptor pathway (WT) and a corresponding Fas-associated death domain protein (FADD) KO cell line were exposed to a coral TNFSF member (AdTNF1) identified and purified here. AdTNF1 treatment resulted in significantly higher cell death (P < 0.0001) in WT Jurkats compared with the corresponding FADD KO, demonstrating that coral AdTNF1 activates the H. sapiens death receptor pathway. Taken together, these data show remarkable conservation of the TNF-induced apoptotic response representing 550 My of functional conservation. PMID:24927546

Quistad, Steven D.; Stotland, Aleksandr; Barott, Katie L.; Smurthwaite, Cameron A.; Hilton, Brett Jameson; Grasis, Juris A.; Wolkowicz, Roland; Rohwer, Forest L.

2014-01-01

258

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

259

Proteomics profiling reveals novel proteins and functions of the plant stigma exudate.  

PubMed

Proteomic analysis of the stigmatic exudate of Lilium longiflorum and Olea europaea led to the identification of 51 and 57 proteins, respectively, most of which are described for the first time in this secreted fluid. These results indicate that the stigmatic exudate is an extracellular environment metabolically active, participating in at least 80 different biological processes and 97 molecular functions. The stigma exudate showed a markedly catabolic profile and appeared to possess the enzyme machinery necessary to degrade large polysaccharides and lipids secreted by papillae to smaller units, allowing their incorporation into the pollen tube during pollination. It may also regulate pollen-tube growth in the pistil through the selective degradation of tube-wall components. Furthermore, some secreted proteins were involved in pollen-tube adhesion and orientation, as well as in programmed cell death of the papillae cells in response to either compatible pollination or incompatible pollen rejection. Finally, the results also revealed a putative cross-talk between genetic programmes regulating stress/defence and pollination responses in the stigma. PMID:24151302

Rejón, Juan David; Delalande, François; Schaeffer-Reiss, Christine; Carapito, Christine; Zienkiewicz, Krzysztof; de Dios Alché, Juan; Rodríguez-García, María Isabel; Van Dorsselaer, Alain; Castro, Antonio Jesús

2013-12-01

260

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

261

Opsin switch reveals function of the ultraviolet cone in fish foraging  

PubMed Central

Although several studies have shown that ultraviolet (UV) wavelengths are important in naturally occurring, visually guided behaviours of vertebrates, the function of the UV cone in such behaviours is unknown. Here, I used thyroid hormone to transform the UV cones of young rainbow trout into blue cones, a phenomenon that occurs naturally as the animal grows, to test whether the resulting loss of UV sensitivity affected the animal's foraging performance on Daphnia magna, a prey zooplankton. The distances and angles at which prey were located (variables that are known indicators of foraging performance) were significantly reduced for UV knock-out fish compared with controls. Optical measurements and photon-catch calculations revealed that the contrast of Daphnia was greater when perceived by the visual system of control versus that of thyroid-hormone-treated fish, demonstrating that the UV cone enhanced the foraging performance of young rainbow trout. Because most juvenile fishes have UV cones and feed on zooplankton, this finding has wide implications for understanding the visual ecology of fishes. The enhanced target contrast provided by UV cones could be used by other vertebrates in various behaviours, including foraging, mate selection and communication. PMID:23222448

Novales Flamarique, Inigo

2013-01-01

262

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 PMID:8016087

Tribe, R M; Borin, M L; Blaustein, M P

1994-01-01

263

The roles of evolutionarily conserved functional modules in cilia-related trafficking  

PubMed Central

Cilia are present across most eukaryotic phyla and have diverse sensory and motility roles in animal physiology, cell signalling and development. Their biogenesis and maintenance depend on vesicular and intraciliary (intraflagellar) trafficking pathways that share conserved structural and functional modules. The functional units of the interconnected pathways, which include proteins involved in membrane coating as well as small GTPases and their accessory factors, were first experimentally associated with canonical vesicular trafficking. These components are, however, ancient, having been co-opted by the ancestral eukaryote to establish the ciliary organelle, and their study can inform us about ciliary biology in higher organisms. PMID:24296415

Sung, Ching-Hwa; Leroux, Michel R.

2014-01-01

264

A method for evaluating dynamic functional network connectivity and task-modulation: application to schizophrenia  

Microsoft Academic Search

Objective  In this paper, we develop a dynamic functional network connectivity (FNC) analysis approach using correlations between windowed\\u000a time-courses of different brain networks (components) estimated via spatial independent component analysis (sICA). We apply\\u000a the developed method to fMRI data to evaluate it and to study task-modulation of functional connections.\\u000a \\u000a \\u000a \\u000a \\u000a Materials and methods  We study the theoretical basis of the approach, perform a

Ünal Sako?lu; Godfrey D. Pearlson; Kent A. Kiehl; Y. Michelle Wang; Andrew M. Michael; Vince D. Calhoun

2010-01-01

265

Modified slanted-edge method and multidirectional modulation transfer function estimation.  

PubMed

The slanted-edge method specified in ISO Standard 12233, which measures the modulation transfer function (MTF) by analyzing an image of a slightly slanted knife-edge target, is not robust against noise because it takes the derivative of each data line in the edge-angle estimation. We propose here a modified method that estimates the edge angle by fitting a two-dimensional function to the image data. The method has a higher accuracy, precision, and robustness against noise than the ISO 12233 method and is applicable to any arbitrary pixel array, enabling a multidirectional MTF estimate in a single measurement of a starburst image. PMID:24663939

Masaoka, Kenichiro; Yamashita, Takayuki; Nishida, Yukihiro; Sugawara, Masayuki

2014-03-10

266

MyD88-deficient Hydra reveal an ancient function of TLR signaling in sensing bacterial colonizers  

E-print Network

MyD88-deficient Hydra reveal an ancient function of TLR signaling in sensing bacterial colonizers metazoans such as the cnidarians Hydra magnipapillata and Nematostella vectensis, all components loss- of-function approach in Hydra to demonstrate that recognition of bacteria is an ancestral

267

Reconfigurable optical interleaver modules with tunable wavelength transfer matrix function using polymer photonics lightwave circuits.  

PubMed

A transparent reconfigurable optical interleaver module composed of cascaded AWGs-based wavelength-channel-selector/interleaver monolithically integrated with multimode interference (MMI) variable optical attenuators (VOAs) and Mach-Zehnder interferometer (MZI) switch arrays was designed and fabricated using polymer photonic lightwave circuits. Highly fluorinated photopolymer and grafting modified organic-inorganic hybrid material were synthesized as the waveguide core and caldding, respectively. Thermo-optic (TO) tunable wavelength transfer matrix (WTM) function of the module can be achieved for optical routing network. The one-chip transmission loss is ~6dB and crosstalk is less than ~25 dB for transverse-magnetic (TM) mode. The crosstalk and extinction ratio of the MMI VOAs were measured as -15.2 dB and 17.5 dB with driving current 8 mA, respectively. The modulation depth of the TO switches is obtained as ~18.2 dB with 2.2 V bias. Proposed novel interleaver module could be well suited for DWDM optical communication systems. PMID:25321200

Chen, Changming; Niu, Xiaoyan; Han, Chao; Shi, Zuosen; Wang, Xinbin; Sun, Xiaoqiang; Wang, Fei; Cui, Zhanchen; Zhang, Daming

2014-08-25

268

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

2013-01-01

269

Distinct modulated pupil function system for real-time imaging of living cells.  

PubMed

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. PMID:22962597

Watanabe, Tomonobu M; Tsukasaki, Yoshikazu; Fujita, Hideaki; Ichimura, Taro; Saitoh, Tatsuya; Akira, Shizuo; Yanagida, Toshio

2012-01-01

270

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. PMID:22962597

Watanabe, Tomonobu M.; Tsukasaki, Yoshikazu; Fujita, Hideaki; Ichimura, Taro; Saitoh, Tatsuya; Akira, Shizuo; Yanagida, Toshio

2012-01-01

271

Analysis of Candida albicans Mutants Defective in the Cdk8 Module of Mediator Reveal Links between Metabolism and Biofilm Formation.  

PubMed

Candida albicans biofilm formation is a key virulence trait that involves hyphal growth and adhesin expression. Pyocyanin (PYO), a phenazine secreted by Pseudomonas aeruginosa, inhibits both C. albicans biofilm formation and development of wrinkled colonies. Using a genetic screen, we identified two mutants, ssn3?/? and ssn8?/?, which continued to wrinkle in the presence of PYO. Ssn8 is a cyclin-like protein and Ssn3 is similar to cyclin-dependent kinases; both proteins are part of the heterotetrameric Cdk8 module that forms a complex with the transcriptional co-regulator, Mediator. Ssn3 kinase activity was also required for PYO sensitivity as a kinase dead mutant maintained a wrinkled colony morphology in the presence of PYO. Furthermore, similar phenotypes were observed in mutants lacking the other two components of the Cdk8 module-Srb8 and Srb9. Through metabolomics analyses and biochemical assays, we showed that a compromised Cdk8 module led to increases in glucose consumption, glycolysis-related transcripts, oxidative metabolism and ATP levels even in the presence of PYO. In the mutant, inhibition of respiration to levels comparable to the PYO-treated wild type inhibited wrinkled colony development. Several lines of evidence suggest that PYO does not act through Cdk8. Lastly, the ssn3 mutant was a hyperbiofilm former, and maintained higher biofilm formation in the presence of PYO than the wild type. Together these data provide novel insights into the role of the Cdk8 module of Mediator in regulation of C. albicans physiology and the links between respiratory activity and both wrinkled colony and biofilm development. PMID:25275466

Lindsay, Allia K; Morales, Diana K; Liu, Zhongle; Grahl, Nora; Zhang, Anda; Willger, Sven D; Myers, Lawrence C; Hogan, Deborah A

2014-10-01

272

Analysis of Candida albicans Mutants Defective in the Cdk8 Module of Mediator Reveal Links between Metabolism and Biofilm Formation  

PubMed Central

Candida albicans biofilm formation is a key virulence trait that involves hyphal growth and adhesin expression. Pyocyanin (PYO), a phenazine secreted by Pseudomonas aeruginosa, inhibits both C. albicans biofilm formation and development of wrinkled colonies. Using a genetic screen, we identified two mutants, ssn3?/? and ssn8?/?, which continued to wrinkle in the presence of PYO. Ssn8 is a cyclin-like protein and Ssn3 is similar to cyclin-dependent kinases; both proteins are part of the heterotetrameric Cdk8 module that forms a complex with the transcriptional co-regulator, Mediator. Ssn3 kinase activity was also required for PYO sensitivity as a kinase dead mutant maintained a wrinkled colony morphology in the presence of PYO. Furthermore, similar phenotypes were observed in mutants lacking the other two components of the Cdk8 module—Srb8 and Srb9. Through metabolomics analyses and biochemical assays, we showed that a compromised Cdk8 module led to increases in glucose consumption, glycolysis-related transcripts, oxidative metabolism and ATP levels even in the presence of PYO. In the mutant, inhibition of respiration to levels comparable to the PYO-treated wild type inhibited wrinkled colony development. Several lines of evidence suggest that PYO does not act through Cdk8. Lastly, the ssn3 mutant was a hyperbiofilm former, and maintained higher biofilm formation in the presence of PYO than the wild type. Together these data provide novel insights into the role of the Cdk8 module of Mediator in regulation of C. albicans physiology and the links between respiratory activity and both wrinkled colony and biofilm development. PMID:25275466

Lindsay, Allia K.; Morales, Diana K.; Liu, Zhongle; Grahl, Nora; Zhang, Anda; Willger, Sven D.; Myers, Lawrence C.; Hogan, Deborah A.

2014-01-01

273

Presence and Function of Dopamine Transporter (DAT) in Stallion Sperm: Dopamine Modulates Sperm Motility and Acrosomal Integrity  

PubMed Central

Dopamine is a catecholamine with multiple physiological functions, playing a key role in nervous system; however its participation in reproductive processes and sperm physiology is controversial. High dopamine concentrations have been reported in different portions of the feminine and masculine reproductive tract, although the role fulfilled by this catecholamine in reproductive physiology is as yet unknown. We have previously shown that dopamine type 2 receptor is functional in boar sperm, suggesting that dopamine acts as a physiological modulator of sperm viability, capacitation and motility. In the present study, using immunodetection methods, we revealed the presence of several proteins important for the dopamine uptake and signalling in mammalian sperm, specifically monoamine transporters as dopamine (DAT), serotonin (SERT) and norepinephrine (NET) transporters in equine sperm. We also demonstrated for the first time in equine sperm a functional dopamine transporter using 4-[4-(Dimethylamino)styryl]-N-methylpyridinium iodide (ASP+), as substrate. In addition, we also showed that dopamine (1 mM) treatment in vitro, does not affect sperm viability but decreases total and progressive sperm motility. This effect is reversed by blocking the dopamine transporter with the selective inhibitor vanoxerine (GBR12909) and non-selective inhibitors of dopamine reuptake such as nomifensine and bupropion. The effect of dopamine in sperm physiology was evaluated and we demonstrated that acrosome integrity and thyrosine phosphorylation in equine sperm is significantly reduced at high concentrations of this catecholamine. In summary, our results revealed the presence of monoamine transporter DAT, NET and SERT in equine sperm, and that the dopamine uptake by DAT can regulate sperm function, specifically acrosomal integrity and sperm motility. PMID:25402186

Covarrubias, Alejandra A.; Rodríguez-Gil, Joan Enric; Ramírez-Reveco, Alfredo; Concha, Ilona I.

2014-01-01

274

Electrical synapses between AII amacrine cells in the retina: Function and modulation.  

PubMed

Adaptation enables the visual system to operate across a large range of background light intensities. There is evidence that one component of this adaptation is mediated by modulation of gap junctions functioning as electrical synapses, thereby tuning and functionally optimizing specific retinal microcircuits and pathways. The AII amacrine cell is an interneuron found in most mammalian retinas and plays a crucial role for processing visual signals in starlight, twilight and daylight. AII amacrine cells are connected to each other by gap junctions, potentially serving as a substrate for signal averaging and noise reduction, and there is evidence that the strength of electrical coupling is modulated by the level of background light. Whereas there is extensive knowledge concerning the retinal microcircuits that involve the AII amacrine cell, it is less clear which signaling pathways and intracellular transduction mechanisms are involved in modulating the junctional conductance between electrically coupled AII amacrine cells. Here we review the current state of knowledge, with a focus on the recent evidence that suggests that the modulatory control involves activity-dependent changes in the phosphorylation of the gap junction channels between AII amacrine cells, potentially linked to their intracellular Ca(2+) dynamics. This article is part of a Special Issue entitled Electrical Synapses. PMID:22776293

Hartveit, Espen; Veruki, Margaret Lin

2012-12-01

275

Functional insights into modulation of BKCa channel activity to alter myometrial contractility  

PubMed Central

The large-conductance voltage- and Ca2+-activated K+ channel (BKCa) is an important regulator of membrane excitability in a wide variety of cells and tissues. In myometrial smooth muscle, activation of BKCa plays essential roles in buffering contractility to maintain uterine quiescence during pregnancy and in the transition to a more contractile state at the onset of labor. Multiple mechanisms of modulation have been described to alter BKCa channel activity, expression, and cellular localization. In the myometrium, BKCa is regulated by alternative splicing, protein targeting to the plasma membrane, compartmentation in membrane microdomains, and posttranslational modifications. In addition, interaction with auxiliary proteins (i.e., ?1- and ?2-subunits), association with G-protein coupled receptor signaling pathways, such as those activated by adrenergic and oxytocin receptors, and hormonal regulation provide further mechanisms of variable modulation of BKCa channel function in myometrial smooth muscle. Here, we provide an overview of these mechanisms of BKCa channel modulation and provide a context for them in relation to myometrial function. PMID:25132821

Lorca, Ramon A.; Prabagaran, Monali; England, Sarah K.

2014-01-01

276

Identification of a Functionally Relevant Cannabinoid Receptor on Mouse Spleen Cells that Is Involved in Cannabinoid-Mediated Immune Modulation  

PubMed Central

SUMMARY Extensive behavioral and biochemical characterization of cannabinoid-mediated effects on the central nervous system has revealed at least three lines of evidence supporting the role of a putative guanine nucleotide-binding protein-coupled cannabinoid receptor for cannabimimetic effects, (i) stereoselectivity, (ii) inhibition of the adenylate cyclase/cAMP second messenger system, and (iii) radioligand-binding studies with the synthetic cannabinoid [3H]CP-55,940 indicating a high degree of specific binding to brain tissue preparations. Based on recent findings from our laboratory demonstrating that ?9-tetrahydrocannabinol markedly inhibited forskolin-stimulated cAMP accumulation in mouse spleen cells, the presence of a guanine nucleotide-binding protein-coupled cannabinoid receptor associated with mouse spleen cells and its functional role in immune modulation were investigated. In the present studies, stereoselective immune modulation was observed with the synthetic bicyclic cannabinoid (?)-CP-55,940 versus (+) CP-56,667 and with 11-OH-?8-tetrahydrocannabinol-dimethylheptyl, (?)-HU-210 versus (+)-HU-211. In both cases, the (?)-enantiomer demonstrated greater immunoinhibitory potency than the (+)-isomer, as measured by the in vitro sheep red blood cell antibody-forming cell response. Radioligand binding studies produced a saturation isotherm exhibiting approximately 45–65% specific binding to mouse spleen cells. Scatchard analysis demonstrated a single binding site on spleen cells, possessing a Kd of 910 pm and a Bmax of approximately 1000 receptors/spleen cell. RNA polymerase chain reaction of isolated splenic RNA using specific primers for the cannabinoid receptor resulted in the amplification of a 854-kilobase predicted product that hybridized with cannabinoid receptor cDNA, demonstrating the presence of cannabinoid receptor mRNA in mouse spleen. Together, these findings strongly support the role of a cannabinoid receptor in immune modulation by cannabimimetic agents. PMID:1279376

Kaminski, Norbert E.; Abood, Mary E.; Kessler, Fay K.; Martin, Billy R.; Schatz, Anthony R.

2013-01-01

277

Modulation of the input-output function by GABAA receptor-mediated currents in rat oculomotor nucleus motoneurons.  

PubMed

The neuronal input-output function depends on recruitment threshold and gain of the firing frequency-current (f-I) relationship. These two parameters are positively correlated in ocular motoneurons (MNs) recorded in alert preparation and inhibitory inputs could contribute to this correlation. Phasic inhibition mediated by ?-amino butyric acid (GABA) occurs when a high concentration of GABA at the synaptic cleft activates postsynaptic GABAA receptors, allowing neuronal information transfer. In some neuronal populations, low concentrations of GABA activate non-synaptic GABAA receptors and generate a tonic inhibition, which modulates cell excitability. This study determined how ambient GABA concentrations modulate the input-output relationship of rat oculomotor nucleus MNs. Superfusion of brain slices with GABA (100 ?m) produced a GABAA receptor-mediated current that reduced the input resistance, increased the recruitment threshold and shifted the f-I relationship rightward without any change in gain. These modifications did not depend on MN size. In absence of exogenous GABA, gabazine (20 ?m; antagonist of GABAA receptors) abolished spontaneous inhibitory postsynaptic currents and revealed a tonic current in MNs. Gabazine increased input resistance and decreased recruitment threshold mainly in larger MNs. The f-I relationship shifted to the left, without any change in gain. Gabazine effects were chiefly due to MN tonic inhibition because tonic current amplitude was five-fold greater than phasic. This study demonstrates a tonic inhibition in ocular MNs that modulates cell excitability depending on cell size. We suggest that GABAA tonic inhibition acting concurrently with glutamate receptors activation could reproduce the positive covariation between threshold and gain reported in alert preparation. PMID:25194049

Torres-Torrelo, Julio; Torres, Blas; Carrascal, Livia

2014-11-15

278

Azores Deep Structure as Revealed by P and S Receiver Functions  

NASA Astrophysics Data System (ADS)

Seismic recordings of IRIS/IDA/GSN station CMLA and of several temporary stations in the Azores archipelago are processed with P and S receiver function (PRF and SRF) techniques. Contrary to regional seismic tomography these methods provide estimates of the absolute velocities and of the Vp/Vs ratio up to a depth of ~300 km. Joint inversion of PRFs and SRFs for a few data sets consistently reveals a division of the subsurface medium into four zones with a distinctly different Vp/Vs ratio: the crust ~20km thick with a ratio of ~1.9 in the lower crust, the high-Vs mantle lid with a strongly reduced Vp/Vs velocity ratio relative to the standard 1.8, the low-velocity zone (LVZ) with a velocity ratio of ~2.0, and the underlying upper-mantle layer with a standard velocity ratio. The base of the high-Vs lid (the Gutenberg discontinuity) is at a depth of ~80 km. The LVZ with a reduction of S velocity of ~15% relative to the standard (IASP91) model is terminated at a depth of ~200 km. The average thickness of the mantle transition zone (TZ) is evaluated from the time difference between the S410p and SKS660p, seismic phases that are robustly detected in the S and SKS receiver functions. This thickness is practically similar to the standard IASP91 value of 250 km, and is characteristic of a large region of the North Atlantic outside the Azores plateau. Our data are indicative of a reduction of the S-wave velocity of several percent relative to the standard velocity in a depth interval from 460 to 500 km. This reduction is found in the nearest vicinities of the Azores, in the region sampled by the PRFs, but, as evidenced by SRFs, it is missing at a distance of a few hundred kilometers from the islands. We speculate that this anomaly may correspond to the source of a plume which generated the Azores hotspot. Previously, a low S velocity in this depth range was found with SRF techniques beneath a few other hotspots.

Vinnik, L.; Stutzmann, E.; Silveira, M. M.; Kiselev, S.; Farra, V.; Morais, I.

2010-12-01

279

Functional Coding Variation in Recombinant Inbred Mouse Lines Reveals Novel Serotonin Transporter-Associated Phenotypes  

SciTech Connect

The human serotonin (5-hydroxytryptamine, 5-HT) transporter (hSERT, SLC6A4) figures prominently in the etiology or treatment of many prevalent neurobehavioral disorders including anxiety, alcoholism, depression, autism and obsessive-compulsive disorder (OCD). Here we utilize naturally occurring polymorphisms in recombinant inbred (RI) lines to identify novel phenotypes associated with altered SERT function. The widely used mouse strain C57BL/6J, harbors a SERT haplotype defined by two nonsynonymous coding variants (Gly39 and Lys152 (GK)). At these positions, many other mouse lines, including DBA/2J, encode Glu39 and Arg152 (ER haplotype), assignments found also in hSERT. Synaptosomal 5-HT transport studies revealed reduced uptake associated with the GK variant. Heterologous expression studies confirmed a reduced SERT turnover rate for the GK variant. Experimental and in silico approaches using RI lines (C57Bl/6J X DBA/2J=BXD) identifies multiple anatomical, biochemical and behavioral phenotypes specifically impacted by GK/ER variation. Among our findings are multiple traits associated with anxiety and alcohol consumption, as well as of the control of dopamine (DA) signaling. Further bioinformatic analysis of BXD phenotypes, combined with biochemical evaluation of SERT knockout mice, nominates SERT-dependent 5-HT signaling as a major determinant of midbrain iron homeostasis that, in turn, dictates ironregulated DA phenotypes. Our studies provide a novel example of the power of coordinated in vitro, in vivo and in silico approaches using murine RI lines to elucidate and quantify the system-level impact of gene variation.

Carneiro, Ana [Vanderbilt University; Airey, David [University of Tennessee Health Science Center, Memphis; Thompson, Brent [Vanderbilt University; Zhu, C [Vanderbilt University; Rinchik, Eugene M [ORNL; Lu, Lu [University of Tennessee Health Science Center, Memphis; Chesler, Elissa J [ORNL; Erikson, Keith [University of North Carolina; Blakely, Randy [Vanderbilt University

2009-01-01

280

Selected phenolic compounds in cultivated plants: ecologic functions, health implications, and modulation by pesticides.  

PubMed Central

Phenolic compounds are widely distributed in the plant kingdom. Plant tissues may contain up to several grams per kilogram. External stimuli such as microbial infections, ultraviolet radiation, and chemical stressors induce their synthesis. The phenolic compounds resveratrol, flavonoids, and furanocoumarins have many ecologic functions and affect human health. Ecologic functions include defense against microbial pathogens and herbivorous animals. Phenolic compounds may have both beneficial and toxic effects on human health. Effects on low-density lipoproteins and aggregation of platelets are beneficial because they reduce the risk of coronary heart disease. Mutagenic, cancerogenic, and phototoxic effects are risk factors of human health. The synthesis of phenolic compounds in plants can be modulated by the application of herbicides and, to a lesser extent, insecticides and fungicides. The effects on ecosystem functioning and human health are complex and cannot be predicted with great certainty. The consequences of the combined natural and pesticide-induced modulating effects for ecologic functions and human health should be further evaluated. PMID:10229712

Daniel, O; Meier, M S; Schlatter, J; Frischknecht, P

1999-01-01

281

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. PMID:23812304

Cuevas, Alejandro; Saavedra, Nicolas; Salazar, Luis A.; Abdalla, Dulcineia S. P.

2013-01-01

282

The endocannabinoid system: an emotional buffer in the modulation of memory function.  

PubMed

Extensive evidence indicates that endocannabinoids modulate cognitive processes in animal models and human subjects. However, the results of endocannabinoid system manipulations on cognition have been contradictory. As for anxiety behavior, a duality has indeed emerged with regard to cannabinoid effects on memory for emotional experiences. Here we summarize findings describing cannabinoid effects on memory acquisition, consolidation, retrieval and extinction. Additionally, we review findings showing how the endocannabinoid system modulates memory function differentially, depending on the level of stress and arousal associated with the experimental context. Based on the evidence reviewed here, we propose that the endocannabinoid system is an emotional buffer that moderates the effects of environmental context and stress on cognitive processes. PMID:24382324

Morena, Maria; Campolongo, Patrizia

2014-07-01

283

Crystallographic and biochemical studies revealing the structural basis for antizyme inhibitor function  

E-print Network

Crystallographic and biochemical studies revealing the structural basis for antizyme inhibitor. In addition, the absence of residues and interactions required for pyridoxal 59-phosphate (PLP) binding suggests that AzI does not bind PLP. Biochemical studies confirmed the lack of PLP binding and revealed

Kahana, Chaim

284

NbIT - A New Information Theory-Based Analysis of Allosteric Mechanisms Reveals Residues that Underlie Function in the Leucine Transporter LeuT  

PubMed Central

Complex networks of interacting residues and microdomains in the structures of biomolecular systems underlie the reliable propagation of information from an input signal, such as the concentration of a ligand, to sites that generate the appropriate output signal, such as enzymatic activity. This information transduction often carries the signal across relatively large distances at the molecular scale in a form of allostery that is essential for the physiological functions performed by biomolecules. While allosteric behaviors have been documented from experiments and computation, the mechanism of this form of allostery proved difficult to identify at the molecular level. Here, we introduce a novel analysis framework, called N-body Information Theory (NbIT) analysis, which is based on information theory and uses measures of configurational entropy in a biomolecular system to identify microdomains and individual residues that act as (i)-channels for long-distance information sharing between functional sites, and (ii)-coordinators that organize dynamics within functional sites. Application of the new method to molecular dynamics (MD) trajectories of the occluded state of the bacterial leucine transporter LeuT identifies a channel of allosteric coupling between the functionally important intracellular gate and the substrate binding sites known to modulate it. NbIT analysis is shown also to differentiate residues involved primarily in stabilizing the functional sites, from those that contribute to allosteric couplings between sites. NbIT analysis of MD data thus reveals rigorous mechanistic elements of allostery underlying the dynamics of biomolecular systems. PMID:24785005

LeVine, Michael V.; Weinstein, Harel

2014-01-01

285

Dengue Virus Type 2 Modulates Endothelial Barrier Function through CD73  

PubMed Central

Dengue hemorrhagic fever is characterized by a unique vascular leakage syndrome. The mechanisms of endothelial barrier dysfunction in dengue hemorrhagic fever are not well understood. We examined the modulation of endothelial barrier function in dengue virus type 2 (DENV2) infections using primary human umbilical vein endothelial cells. We demonstrated that the increase in endothelial barrier function within 72 hours after DENV2 infection is mediated by type I interferon–dependent CD73 up-regulation. After 72 hours, DENV2 slowed the recovery of endothelial barrier function in response to tumor necrosis factor-? or vascular endothelial growth factor. This phenomenon was likely caused by type I interferon receptor signaling inhibition and lower CD73 levels in DENV2-infected endothelial cells. Our findings suggest that during DENV2 infection, endothelial barrier homeostasis is maintained by a balance between pro-inflammatory and pro-angiogenic cytokines, and type I interferon–dependent CD73 expression and activity. PMID:23149581

Patkar, Chinmay; Giaya, Kris; Libraty, Daniel H.

2013-01-01

286

Age-Related Decline in Brain Resources Modulates Genetic Effects on Cognitive Functioning  

PubMed Central

Individual differences in cognitive performance increase from early to late adulthood, likely reflecting influences of a multitude of factors. We hypothesize that losses in neurochemical and anatomical brain resources in normal aging modulate the effects of common genetic variations on cognitive functioning. Our hypothesis is based on the assumption that the function relating brain resources to cognition is nonlinear, so that genetic differences exert increasingly large effects on cognition as resources recede from high to medium levels in the course of aging. Direct empirical support for this hypothesis comes from a study by Nagel et al. (2008), who reported that the effects of the Catechol-O-Methyltransferase (COMT) gene on cognitive performance are magnified in old age and interacted with the Brain-Derived Neurotrophic Factor (BDNF) gene. We conclude that common genetic polymorphisms contribute to the increasing heterogeneity of cognitive functioning in old age. Extensions of the hypothesis to other polymorphisms are discussed. (150 of 150 words) PMID:19225597

Lindenberger, Ulman; Nagel, Irene E.; Chicherio, Christian; Li, Shu-Chen; Heekeren, Hauke R.; Backman, Lars

2008-01-01

287

A ryanodine fluorescent derivative reveals the presence of high-affinity ryanodine binding sites in the Golgi complex of rat sympathetic neurons, with possible functional roles in intracellular Ca 2+ signaling  

Microsoft Academic Search

The plant alkaloid ryanodine (Ry) is a high-affinity modulator of ryanodine receptor (RyR) Ca2+ release channels. Although these channels are present in a variety of cell types, their functional role in nerve cells is still puzzling. Here, a monosubstituted fluorescent Ry analogue, B-FL-X Ry, was used to reveal the distribution of RyRs in cultured rat sympathetic neurons. B-FL-X Ry competitively

Fredy Cifuentes; Carlos E González; Tatiana Fiordelisio; Georgina Guerrero; F. Anthony Lai; Arturo Hernández-Cruz

2001-01-01

288

Nanosecond pulsed electric fields modulate cell function through intracellular signal transduction mechanisms.  

PubMed

These studies describe the effects of nanosecond (10-300 ns) pulsed electric fields (nsPEF) on mammalian cell structure and function. As the pulse durations decrease, effects on the plasma membrane (PM) decrease and effects on intracellular signal transduction mechanisms increase. When nsPEF-induced PM electroporation effects occur, they are distinct from classical PM electroporation effects, suggesting unique, nsPEF-induced PM modulations. In HL-60 cells, nsPEF that are well below the threshold for PM electroporation and apoptosis induction induce effects that are similar to purinergic agonistmediated calcium release from intracellular stores, which secondarily initiate capacitive calcium influx through store-operated calcium channels in the PM. NsPEF with durations and electric field intensities that do or do not cause PM electroporation, induce apoptosis in mammalian cells with a well-characterized phenotype typified by externalization of phosphatidylserine on the outer PM and activation of caspase proteases. Treatment of mouse fibrosarcoma tumors with nsPEF also results in apoptosis induction. When Jurkat cells were transfected by electroporation and then treated with nsPEF, green fluorescent protein expression was enhanced compared to electroporation alone. The results indicate that nsPEF activate intracellular mechanisms that can determine cell function and fate, providing an important new tool for probing signal transduction mechanisms that modulate cell structure and function and for potential therapeutic applications for cancer and gene therapy. PMID:15382843

Beebe, Stephen J; Blackmore, Peter F; White, Jody; Joshi, Ravindra P; Schoenbach, Karl H

2004-08-01

289

Modulations of functional connectivity in the healthy and schizophrenia groups during task and rest  

PubMed Central

Connectivity analysis using functional magnetic resonance imaging (fMRI) data is an important area, useful for the identification of biomarkers for various mental disorders, including schizophrenia. Most studies to date have focused on resting data, while the study of functional connectivity during task and the differences between task and rest are of great interest as well. In this work, we examine the graph-theoretical properties of the connectivity maps constructed using spatial components derived from independent component analysis (ICA) for healthy controls and patients with schizophrenia during an auditory oddball task (AOD) and at extended rest. We estimate functional connectivity using the higher-order statistical dependence, i.e., mutual information among the ICA spatial components, instead of the typically used temporal correlation. We also define three novel topological metrics based on the modules of brain networks obtained using a clustering approach. Our experimental results show that although the schizophrenia patients preserve the small-world property, they present a significantly lower small-worldness during both AOD task and rest when compared to the healthy controls, indicating a consistent tendency towards a more random organization of brain networks. In addition, the task-induced modulations to topological measures of several components involving motor, cerebellum and parietal regions are altered in patients relative to controls, providing further evidence for the aberrant connectivity in schizophrenia. PMID:22634855

Ma, Sai; Calhoun, Vince D.; Eichele, Tom; Du, Wei; Adali, Tülay

2012-01-01

290

Disgust trait modulates frontal-posterior coupling as a function of disgust domain  

PubMed Central

Following the two-stage model of disgust, ‘core disgust’ (e.g. elicited by rotten food) is extended to stimuli that remind us of our animal nature ‘AR disgust’ (e.g. mutilations, animalistic instincts). There is ample evidence that core and AR represent distinct domains of disgust elicitors. Moreover, people show large differences in their tendency to respond with disgust to potential disgust elicitors (propensity), as well as in their appraisal of experiencing disgust (sensitivity). Thus these traits may be important moderators of people's response patterns. Here, we aimed to find brain mechanisms associated with these distinct disgust domains and traits, as well as the interaction between them. The right ventrolateral occipitotemporal cortex, which preferentially responded to visual AR, was functionally coupled to the middle cingulate cortex (MCC), thalamus and prefrontal cortex (medial, dorsolateral), as a function of disgust domain. Coupling with the anterior part of MCC was modulated by disgust ‘propensity’, which was strongest during AR. Coupling with anterior insula and ventral premotor cortex was weaker, but relied fully on this domain–trait interaction. Disgust ‘sensitivity’ modulated left anterior insula activity irrespective of domain, and did not affect functional connectivity. Thus a frontal-posterior network that interacts with disgust ‘propensity’ dissects AR and core disgust. PMID:22258801

de Jong, Peter J.; Renken, Remco J.; Georgiadis, Janniko R.

2013-01-01

291

Modulation of immune function by a modified bovine whey protein concentrate.  

PubMed

The commercial preparation of dairy foodstuffs generates large volumes of by-products, many of which have as yet undocumented effects on mammalian immune function. In the present report, a modified whey protein concentrate (mWPC), derived as a by-product from the commercial manufacture of cheese, was tested for its ability to modulate murine immune function in vitro. The mWPC suppressed T and B lymphocyte proliferative responses to mitogens in a dose-dependent fashion. The mWPC also suppressed alloantigen-induced lymphocyte proliferation during a mixed leucocyte reaction, but showed no suppressive effect against IL-2-sustained proliferation of mitogen-activated T cell blasts. Other indices of lymphocyte activation, such as cytokine secretion and the formation of activated (CD25+) T cell blasts, were suppressed by the mWPC, suggesting that the mode of suppression may be to inhibit the lymphocyte activation process. Enzymatic digestion by pepsin and pancreatin, under physiologically realistic conditions in vitro, ablated the immunomodulatory function of the mWPC. These results are discussed in relation to the potential development of complex-mixture dairy products into health-modulating products. PMID:10457202

Cross, M L; Gill, H S

1999-08-01

292

A Hydrodynamic Analysis of APOBEC3G Reveals a Monomer-Dimer-Tetramer Self-Association that has Implications for Anti-HIV Function  

PubMed Central

The innate antiviral factor APOBEC3G (A3G) possesses RNA binding activity and deaminates HIV-1 DNA. High-molecular-mass forms of A3G can be isolated from a variety of cell types, but exhibit limited deaminase activity relative to low-molecular-mass species prepared under RNA-depleted conditions. To investigate the fundamental oligomeric state and shape of A3G, we conducted sedimentation velocity analyses of the pure enzyme under RNA-deficient conditions. The results reveal a predominant dimer in equilibrium with minor monomeric and tetrameric species. Hydrodynamic modeling of the dimer supports an extended cylindrical shape that assembles into an elongated tetramer. Overall, the results provide physical restraints for the A3G quaternary structure that have implications for modulating antiviral function. PMID:19839647

Salter, Jason D.; Krucinska, Jolanta; Raina, Jay; Smith, Harold C.; Wedekind, Joseph E.

2009-01-01

293

Dynamic changes in the air–tear film interface modulation transfer function  

Microsoft Academic Search

Purpose  To determine objectively the changes in the optical quality of the air–tear film interface by measuring the modulation transfer\\u000a function (MTF) of the anterior surface of the film.\\u000a \\u000a \\u000a \\u000a Methods  Air–tear film interface MTF was determined from the wavefront aberration obtained from corneal elevation maps and custom software.\\u000a MTF and Strehl ratio were derived for 3 (photopic) and 7 (mesopic) mm pupils,

Teresa Ferrer-Blasco; Santiago García-Lázaro; Robert Montés-Micó; Alejandro Cerviño; Jose M. González-Méijome

2010-01-01

294

Particle distribution functions in modulation theory. [for cosmic rays in solar wind  

NASA Technical Reports Server (NTRS)

Development of a simple formulation of the cosmic ray modulation problem which involves the use of the omnidirectional part of the distribution function in phase space, and the magnitude of the momentum or the rigidity. It is shown that, by employing the proposed formulation, the Compton-Getting factor is greatly simplified, and the well-known force-field equation is reduced to a one-dimensional Vlasov equation. In addition, another Vlasov equation can be written for the very low energy galactic particles which are convected by the solar wind.

Forman, M. A.; Fisk, L. A.; Axford, W. I.

1974-01-01

295

Equal modulation of endothelial cell function by four distinct tissue-specific mesenchymal stem cells  

PubMed Central

Mesenchymal stem cells (MSCs) can generate multiple end-stage mesenchymal cell types and constitute a promising population of cells for regenerative therapies. Additionally, there is increasing evidence supporting other trophic activities of MSCs, including the ability to enable formation of vasculature in vivo. Although MSCs were originally isolated from the bone marrow, the presence of these cells in the stromal vascular fraction of multiple adult tissues has been recently recognized. However, it is unknown whether the capacity to modulate vasculogenesis is ubiquitous to all MSCs regardless of their tissue of origin. Here, we demonstrated that tissue-resident MSCs isolated from four distinct tissues have equal capacity to modulate endothelial cell function, including formation of vascular networks in vivo. MSCs were isolated from four murine tissues, including bone marrow, white adipose tissue, skeletal muscle, and myocardium. In culture, all four MSC populations secreted a plethora of pro-angiogenic factors that unequivocally induced proliferation, migration, and tube formation of endothelial colony-forming cells (ECFCs). In vivo, co-implantation of MSCs with ECFCs into mice generated an extensive network of blood vessels with ECFCs specifically lining the lumens and MSCs occupying perivascular positions. Importantly, there were no differences among all four MSCs evaluated. Our studies suggest that the capacity to modulate the formation of vasculature is a ubiquitous property of all MSCs, irrespective of their original anatomical location. These results validate multiple tissues as potential sources of MSCs for future cell-based vascular therapies. PMID:22527199

Lin, Ruei-Zeng; Moreno-Luna, Rafael; Zhou, Bin; Pu, William T.

2012-01-01

296

Superspace extrapolation reveals inductive biases in function learning Christopher G. Lucas  

E-print Network

on the basis of a single training example (Fig- ure 1b). We focus on the corresponding problem in two functions, polynomial functions, and others (Carroll, 1963; Brehmer, 1974; Koh & Meyer, 1991; Koh, 1993

Kemp, Charles

297

GABAB1 Knockout Mice Reveal Alterations in Prolactin Levels, Gonadotropic Axis, and Reproductive Function  

Microsoft Academic Search

?-Aminobutyric acid (GABA) has been implicated in the control of hypophyseal functions. We evaluated whether the constitutive loss of functional GABAB receptors in GABAB1 knockout (GABAB1–\\/–) mice alters hormonal levels, under basal and stimulated conditions, and reproductive function. The serum hormone levels were measured by radioimmunoassay, the estrous cyclicity was evaluated by vaginal lavages, and the mating behavior was determined

Paolo N. Catalano; María Marta Bonaventura; Patricia Silveyra; Bernhard Bettler; Carlos Libertun; Victoria A. Lux-Lantos

2005-01-01

298

Glucocorticoid Modulation of Mitochondrial Function in Hepatoma Cells Requires the Mitochondrial Fission Protein Drp1  

PubMed Central

Abstract Aims: Glucocorticoids, such as dexamethasone, enhance hepatic energy metabolism and gluconeogenesis partly through changes in mitochondrial function. Mitochondrial function is influenced by the balance between mitochondrial fusion and fission events. However, whether glucocorticoids modulate mitochondrial function through the regulation of mitochondrial dynamics is currently unknown. Results: Here, we report that the effects of dexamethasone on mitochondrial function and gluconeogenesis in hepatoma cells are dependent on the mitochondrial fission protein dynamin-related protein 1 (Drp1). Dexamethasone increased routine oxygen consumption, maximal respiratory capacity, superoxide anion, proton leak, and gluconeogenesis in hepatoma cells. Under these conditions, dexamethasone altered mitochondrial morphology, which was paralleled by a large increase in Drp1 expression, and reduced mitofusin 1 (Mfn1) and Mfn2. In vivo dexamethasone treatment also enhanced Drp1 expression in mouse liver. On the basis of these observations, we analyzed the dependence on the Drp1 function of dexamethasone effects on mitochondrial respiration and gluconeogenesis. We show that the increase in mitochondrial respiration and gluconeogenesis induced by dexamethasone are hampered by the inhibition of Drp1 function. Innovation: Our findings provide the first evidence that the effects of glucocorticoids on hepatic metabolism require the mitochondrial fission protein Drp1. Conclusion: In summary, we demonstrate that the mitochondrial effects of dexamethasone both on mitochondrial respiration and on the gluconeogenic pathway depend on Drp1. Antioxid. Redox Signal. 19, 366–378. PMID:22703557

Hernandez-Alvarez, Maria Isabel; Paz, Jose C.; Sebastian, David; Munoz, Juan Pablo; Liesa, Marc; Segales, Jessica; Palacin, Manuel

2013-01-01

299

Measurement of the presampled two-dimensional modulation transfer function of digital imaging systems.  

PubMed

The purpose of this work was to develop methods to measure the presampled two-dimensional modulation transfer function (2D MTF) of digital imaging systems. A custom x-ray "point source" phantom was created by machining 256 holes with diameter 0.107 mm through a 0.5-mm-thick copper plate. The phantom was imaged several times, resulting in many images of individual x-ray "spots." The center of each spot (with respect to the pixel matrix) was determined to subpixel accuracy by fitting each spot to a 2D Gaussian function. The subpixel spot center locations were used to create a 5 x oversampled system point spread function (PSF), which characterizes the optical and electrical properties of the system and is independent of the pixel sampling of the original image. The modulus of the Fourier transform of the PSF was calculated. Next, the Fourier function was normalized to the zero frequency value. Finally, the Fourier transform function was divided by the first-order Bessel function that defined the frequency content of the holes, resulting in the presampled 2D MTF. The presampled 2D MTF of a 0.1 mm pixel pitch computed radiography system and 0.2 mm pixel pitch flat panel digital imaging system that utilized a cesium iodide scintillator was measured. Comparison of the axial components of the 2D MTF to one-dimensional MTF measurements acquired using an edge device method demonstrated that the two methods produced consistent results. PMID:12033588

Fetterly, Kenneth A; Hangiandreou, Nicholas J; Schueler, Beth A; Ritenour, E Russell

2002-05-01

300

Combinatorial Modulation of Signaling Pathways Reveals Cell-Type-Specific Requirements for Highly Efficient and Synchronous iPSC Reprogramming  

PubMed Central

Summary The differentiated state of somatic cells provides barriers for the derivation of induced pluripotent stem cells (iPSCs). To address why some cell types reprogram more readily than others, we studied the effect of combined modulation of cellular signaling pathways. Surprisingly, inhibition of transforming growth factor ? (TGF-?) together with activation of Wnt signaling in the presence of ascorbic acid allows >80% of murine fibroblasts to acquire pluripotency after 1 week of reprogramming factor expression. In contrast, hepatic and blood progenitors predominantly required only TGF-? inhibition or canonical Wnt activation, respectively, to reprogram at efficiencies approaching 100%. Strikingly, blood progenitors reactivated endogenous pluripotency loci in a highly synchronous manner, and we demonstrate that expression of specific chromatin-modifying enzymes and reduced TGF-?/mitogen-activated protein (MAP) kinase activity are intrinsic properties associated with the unique reprogramming response of these cells. Our observations define cell-type-specific requirements for the rapid and synchronous reprogramming of somatic cells. PMID:25358786

Vidal, Simon E.; Amlani, Bhishma; Chen, Taotao; Tsirigos, Aristotelis; Stadtfeld, Matthias

2014-01-01

301

Dopaminergic modulation of resting-state functional connectivity in de novo patients with Parkinson's disease.  

PubMed

Parkinson's disease (PD) is characterized by degenerative changes of nigral dopamine neurons, resulting in the dopaminergic denervation of the striatum. Resting state networks studies have demonstrated that dopamine modulates distinct network connectivity patterns in both a linear and a nonlinear fashion, but quantitative analyses of dopamine-dependent functional connectivity secondary to PD pathology were less informative. In the present study, we performed a correlation analysis between striatal dopamine levels assessed quantitatively by FP-CIT positron emission tomography imaging and resting-state functional connectivity in 23 drug naïve de novo patients with PD to elucidate dopamine-dependent functional networks. The major finding is that the patterns of dopamine-dependent positive functional connectivity varied depending on the location of striatal seeds. Dopamine-dependent functional connectivity with the caudate predominantly overlay pericentral cortical areas, whereas dopamine-dependent structures functionally connected with the posterior putamen predominantly involved cerebellar areas. The dorsolateral frontal area overlapped as a dopamine-dependent cortical region that was positively connected with the anterior and posterior putamen. On the other hand, cortical areas where functional connectivity from the posterior cingulate was negatively correlated with dopaminergic status in the posterior putamen were localized in the left anterior prefrontal area and the parietal area. Additionally, functional connectivity between the anterior putamen and mesiofrontal areas was negatively coupled with striatal dopamine levels. The present study demonstrated that dopamine-dependent functional network connectivity secondary to PD pathology mainly exhibits a consistent pattern, albeit with some variation. These patterns may reflect the diverse effects of dopaminergic medication on parkinsonian-related motor and cognitive performance. Hum Brain Mapp 35:5431-5441, 2014. © 2014 Wiley Periodicals, Inc. PMID:24938993

Baik, KyoungWon; Cha, Jungho; Ham, Jee Hyun; Baek, Gwang-Min; Sunwoo, Mun Kyung; Hong, Jin Yong; Shin, Na-Young; Kim, Jae Seung; Lee, Jong-Min; Lee, Seung-Koo; Sohn, Young Ho; Lee, Phil Hyu

2014-11-01

302

Fatty Acids Derived from Royal Jelly Are Modulators of Estrogen Receptor Functions  

PubMed Central

Royal jelly (RJ) excreted by honeybees and used as a nutritional and medicinal agent has estrogen-like effects, yet the compounds mediating these effects remain unidentified. The possible effects of three RJ fatty acids (FAs) (10-hydroxy-2-decenoic-10H2DA, 3,10-dihydroxydecanoic-3,10DDA, sebacic acid-SA) on estrogen signaling was investigated in various cellular systems. In MCF-7 cells, FAs, in absence of estradiol (E2), modulated the estrogen receptor (ER) recruitment to the pS2 promoter and pS2 mRNA levels via only ER? but not ER?, while in presence of E2 FAs modulated both ER? and ER?. Moreover, in presence of FAs, the E2-induced recruitment of the EAB1 co-activator peptide to ER? is masked and the E2-induced estrogen response element (ERE)-mediated transactivation is inhibited. In HeLa cells, in absence of E2, FAs inhibited the ERE-mediated transactivation by ER? but not ER?, while in presence of E2, FAs inhibited ERE-activity by both ER? and ER?. Molecular modeling revealed favorable binding of FAs to ER? at the co-activator-binding site, while binding assays showed that FAs did not bind to the ligand-binding pocket of ER? or ER?. In KS483 osteoblasts, FAs, like E2, induced mineralization via an ER-dependent way. Our data propose a possible molecular mechanism for the estrogenic activities of RJ's components which, although structurally entirely different from E2, mediate estrogen signaling, at least in part, by modulating the recruitment of ER?, ER? and co-activators to target genes. PMID:21203528

Kassi, Eva; Heldring, Nina; Zhao, Chunyan; Tsiapara, Anna; Melliou, Eleni; Chrousos, George P.; Chinou, Ioanna; Karshikoff, Andrey; Nilsson, Lennart; Dahlman-Wright, Karin

2010-01-01

303

Serotonin transporter genotype modulates functional connectivity between amygdala and PCC/PCu during mood recovery  

PubMed Central

The short (S) allele of the serotonin transporter-linked polymorphic region (5-HTTLPR) has been associated with increased susceptibility to depression. Previous neuroimaging studies have consistently showed increased amygdala activity during the presentation of negative stimuli or regulation of negative emotion in the homozygous short allele carriers, suggesting the key role of amygdala response in mediating increased risk for depression. The brain default mode network (DMN) has also been shown to modulate amygdala activity. However, it remains unclear whether 5-HTTLPR genetic variation modulates functional connectivity (FC) between the amygdala and regions of DMN. In this study, we re-analyzed our previous imaging dataset and examined the effects of 5-HTTLPR genetic variation on amygdala connectivity. A total of 15 homozygous short (S/S) and 15 homozygous long individuals (L/L) were scanned in functional magnetic resonance imaging (fMRI) during four blocks: baseline, sad mood, mood recovery, and return to baseline. The S/S and L/L groups showed a similar pattern of FC and no differences were found between the two groups during baseline and sad mood scans. However, during mood recovery, the S/S group showed significantly reduced anti-correlation between amygdala and posterior cingulate cortex/precuneus (PCC/PCu) compared to the L/L group. Moreover, PCC/PCu-amygdala connectivity correlated with amygdala activity in the S/S group but not the L/L group. These results suggest that 5-HTTLPR genetic variation modulates amygdala connectivity which subsequently affects its activity during mood regulation, providing an additional mechanism by which the S allele confers depression risk. PMID:24198772

Fang, Zhuo; Zhu, Senhua; Gillihan, Seth J.; Korczykowski, Marc; Detre, John A.; Rao, Hengyi

2013-01-01

304

Mitochondrial Reactive Oxygen Species Production in Excitable Cells: Modulators of Mitochondrial and Cell Function  

PubMed Central

Abstract The mitochondrion is a major source of reactive oxygen species (ROS). Superoxide (O2•?) is generated under specific bioenergetic conditions at several sites within the electron-transport system; most is converted to H2O2 inside and outside the mitochondrial matrix by superoxide dismutases. H2O2 is a major chemical messenger that, in low amounts and with its products, physiologically modulates cell function. The redox state and ROS scavengers largely control the emission (generation scavenging) of O2•?. Cell ischemia, hypoxia, or toxins can result in excess O2•? production when the redox state is altered and the ROS scavenger systems are overwhelmed. Too much H2O2 can combine with Fe2+ complexes to form reactive ferryl species (e.g., Fe(IV)?=?O•). In the presence of nitric oxide (NO•), O2•? forms the reactant peroxynitrite (ONOO?), and ONOOH-induced nitrosylation of proteins, DNA, and lipids can modify their structure and function. An initial increase in ROS can cause an even greater increase in ROS and allow excess mitochondrial Ca2+ entry, both of which are factors that induce cell apoptosis and necrosis. Approaches to reduce excess O2•? emission include selectively boosting the antioxidant capacity, uncoupling of oxidative phosphorylation to reduce generation of O2•? by inducing proton leak, and reversibly inhibiting electron transport. Mitochondrial cation channels and exchangers function to maintain matrix homeostasis and likely play a role in modulating mitochondrial function, in part by regulating O2•? generation. Cell-signaling pathways induced physiologically by ROS include effects on thiol groups and disulfide linkages to modify posttranslationally protein structure to activate/inactivate specific kinase/phosphatase pathways. Hypoxia-inducible factors that stimulate a cascade of gene transcription may be mediated physiologically by ROS. Our knowledge of the role played by ROS and their scavenging systems in modulation of cell function and cell death has grown exponentially over the past few years, but we are still limited in how to apply this knowledge to develop its full therapeutic potential. Antioxid. Redox Signal. 11, 1373–1414. PMID:19187004

Camara, Amadou K. S.

2009-01-01

305

The Origin of Allosteric Functional Modulation: Multiple Pre-existing Pathways  

PubMed Central

While allostery draws increasing attention, not much is known about allosteric mechanisms. Here we argue that in all proteins, allosteric signals transmit through multiple, pre-existing pathways; which pathways dominate depend on protein topologies, specific binding events, covalent modifications and cellular (environmental) conditions. Further, perturbation events at any site on the protein surface (or in the interior) will not create new pathways but only shift the pre-existing ensemble of pathways. Drugs binding at different sites or mutational events in disease shift the ensemble toward the same conformations; however, the relative populations of the different states will change. Consequently the observed functional, conformational, and dynamic effects will be different. This is the origin of allosteric functional modulation in dynamic proteins: allostery does not necessarily need to invoke conformational rearrangements to control protein activity and pre-existing pathways are always defaulted to during allostery regardless of the stimulant and perturbation site in the protein. PMID:19679084

del Sol, Antonio; Tsai, Chung-Jung; Ma, Buyong; Nussinov, Ruth

2009-01-01

306

Sumoylation modulates oxidative stress relevant to the viability and functionality of pancreatic beta cells  

PubMed Central

Sumoylation is an evolutionarily conserved regulatory mechanism to play an important role in various cellular processes through modulation of protein localization, stability and functionality. Recent studies including ours have consistently demonstrated that sumoylation provides protection for cells against oxidative stress. Given that pancreatic beta cells are a vulnerable target of oxidative stress, we thus in this minireview, updated the advancement of sumoylation in the regulation of ROS generation, and discussed its impact on several critical signaling pathways relevant to beta cells against oxidative stress and maintenance of functionality. Specifically, we bring together how sumoylation represses intracellular ROS formation, and protects beta cells against oxidative stress through regulating I?B/NF?B, JNK/c-Jun, and Maf/Nrf2 pathways. The tight implication of sumoylation in oxidative stress reflects that it could be an essential mechanism for beta cells to adapt to the detrimental cellular microenvironment. PMID:25075252

Yang, Ping; Hu, Shuang; Yang, Fei; Guan, Xiang-Qian; Wang, Shi-Qiang; Zhu, Ping; Xiong, Fei; Zhang, Shu; Xu, Junfa; Yu, Qi-Lin; Wang, Cong-Yi

2014-01-01

307

Method for determining the modulation transfer function of X-ray fluorescence mapping system.  

PubMed

A method for determining the modulation transfer function (MTF) in direct X-ray fluorescence mapping (XFM) system is reported. With a standard container filled with homogeneous gold nanoparticle (GNP) solution (1% by weight), sharp edges are made and utilized to acquire the data for edge spread function (ESF). Through necessary data processing such as signal extraction, attenuation correction and curve fitting and proper calculations of differentiating and Fourier transform, MTF can be determined. Influencing factors of MTF determination in XFM system are thoroughly discussed in theory and validated by experiments. The results show that different mapping steps do not noticeably affect the measured MTF, while MTF is greatly degraded as the collimator-to-object distance increases. The theoretical analyses and experimental validations of the MTF determination are useful and helpful for imaging performance evaluation, system design and optimal operations. The presented methodology could be applied in other XRF based systems with modified imaging trajectories. PMID:25321501

Ren, Liqiang; Zhou, Zhongxing; Ghani, Muhammad U; Li, Yuhua; Liu, Hong

2014-09-01

308

Modulation of myosin function by isoform-specific properties of Saccharomyces cerevisiae and muscle tropomyosins.  

PubMed

Tropomyosin is an extended coiled-coil protein that influences actin function by binding longitudinally along thin filaments. The present work compares cardiac tropomyosin and the two tropomyosins from Saccharomyces cerevisiae, TPM1 and TPM2, that are much shorter than vertebrate tropomyosins. Unlike cardiac tropomyosin, the phase of the coiled-coil-forming heptad repeat of TPM2 is discontinuous; it is interrupted by a 4-residue deletion. TPM1 has two such deletions, which flank the 38-residue partial gene duplication that causes TPM1 to span five actins instead of the four of TPM2. Each of the three tropomyosin isoforms modulates actin-myosin interactions, with isoform-specific effects on cooperativity and strength of myosin binding. These different properties can be explained by a model that combines opposite effects, steric hindrance between myosin and tropomyosin when the latter is bound to a subset of its sites on actin, and also indirect, favorable interactions between tropomyosin and myosin, mediated by mutually promoted changes in actin. Both of these effects are influenced by which tropomyosin isoform is present. Finally, the tropomyosins have isoform-specific effects on in vitro sliding speed and on the myosin concentration dependence of this movement, suggesting that non-muscle tropomyosin isoforms exist, at least in part, to modulate myosin function. PMID:11457840

Strand, J; Nili, M; Homsher, E; Tobacman, L S

2001-09-14

309

Cytopiloyne, a novel polyacetylenic glucoside from Bidens pilosa, functions as a T helper cell modulator.  

PubMed

An extract of Bidens pilosa, an anti-diabetic Asteraceae plant, has recently been reported to modulate T cell differentiation and prevent the development of non-obese diabetes (NOD) in NOD mice. In this paper, a novel bioactive polyacetylenic glucoside, cytopiloyne (1), was identified from the Bidens pilosa extract using ex vivo T cell differentiation assays based on a bioactivity-guided fractionation and isolation procedure. Its structure was elucidated as 2beta-D-glucopyranosyloxy-1-hydroxytrideca-5,7,9,11-tetrayne by various spectroscopic methods. Functional studies showed that cytopiloyne was able to inhibit the differentiation of naïve T helper (Th0) cells into type I T helper (Th1) cells but to promote the differentiation of Th0 cells into type II T helper (Th2) cell. Accordingly, cytopiloyne also suppressed IFN-gamma expression and promoted IL-4 expression in mouse splenocytes ex vivo. These results suggest that cytopiloyne functions as a T cell modulator that may directly contribute to the ethnopharmacological effect of Bidens pilosa extract on preventing diabetes. Moreover, cytopiloyne can serve as an index compound for quality control of lot-to-lot extract preparations of Bidens pilosa. PMID:17101254

Chiang, Yi-Ming; Chang, Cicero Lee-Tian; Chang, Shu-Lin; Yang, Wen-Chin; Shyur, Lie-Fen

2007-04-01

310

Risk-Adaptive Volumetric Modulated Arc Therapy Using Biological Objective Functions for Subvolume Boosting in Radiotherapy  

PubMed Central

Objectives. Simultaneous integrated boost (SIB) for prostate cancer allows increases in tumor control probability while respecting normal tissue dose constraints. Biological optimization functions that optimize based on treatment outcome can be used to create SIB prostate plans. This study investigates the feasibility of biologically optimized volumetric modulated arc therapy (VMAT) for SIB prostate radiotherapy. Methods. Five prostate cancer patients with diffusion-weighted MR images were selected for analysis. A two-step VMAT optimization was performed, which consisted of an initial biological optimization of a static gantry angle delivery followed by conversion of the static delivery to a single arc VMAT plan. A dosimetric analysis was performed on the resulting plans. Results. The VMAT plans resulted in a ?EUD between the prostate and the boost volume of between 15.1?Gy and 20.3?Gy. Rectal volumes receiving 75.6?Gy ranged from 4.5 to 9.9%. Expected rectal normal tissue complication probabilities were between 8.6% and 21.4%. Maximum bladder doses ranged from 73.6?Gy to 75.8?Gy. Estimated treatment time was 120 s or less. Conclusions. The presented biological optimization method resulted in deliverable VMAT plans that achieved sufficient modulation for SIB without violating rectal and bladder dose constraints. Advances in knowledge. This study presents a method for creating simultaneous integrated boost VMAT treatments using biological outcome objective functions. PMID:22792127

Hardcastle, Nicholas; Tome, Wolfgang A.

2012-01-01

311

Differentially expressed microRNAs and affected biological pathways revealed by modulated modularity clustering (MMC) analysis of human preeclamptic and IUGR placentas  

PubMed Central

Introduction This study focuses on the implementation of modulated modularity clustering (MMC) a new cluster algorithm for the identification of molecular signatures of preeclampsia and intrauterine growth restriction (IUGR), and the identification of affected microRNAs Methods Eighty-six human placentas from normal (40), growth-restricted (27), and preeclamptic (19) term pregnancies were profiled using Illumina Human-6 Beadarrays. MMC was utilized to generate modules based on similarities in placental transcriptome. Gene Set Enrichment Analysis (GSEA) was used to predict affected microRNAs. Expression levels of these candidate microRNAs were investigated in seventy-one human term placentas as follows: control (29); IUGR (26); and preeclampsia (16). Results MMC identified two modules, one representing IUGR placentas and one representing preeclamptic placentas. 326 differentially expressed genes in the module representing IUGR and 889 differentially expressed genes in a module representing preeclampsia were identified. Functional analysis of molecular signatures associated with IUGR identified P13K/AKT, mTOR, p70S6K, apoptosis and IGF-1 signaling as being affected. Analysis of variance of GSEA-predicted microRNAs indicated that miR-194 was significantly down-regulated both in preeclampsia (p=0.0001) and IUGR (p=0.0304), and miR-149 was significantly down-regulated in preeclampsia (p=0.0168). Discussion Implementation of MMC, allowed identification of genes disregulated in IUGR and preeclampsia. The reliability of MMC was validated by comparing to previous linear modeling analysis of preeclamptic placentas. Conclusion MMC allowed the elucidation of a molecular signature associated with preeclampsia and a subset of IUGR samples. This allowed the identification of genes, pathways, and microRNAs affected in these diseases. PMID:23639576

Guo, Ling; Tsai, Shengdar; Harding, Nicholas; James, Andra; Motsinger-Reif, Alison; Thames, Betty; Stone, Eric; Deng, Changyan

2013-01-01

312

Differential modulation of GABA(A) receptor function by aryl pyrazoles.  

PubMed

Several aryl pyrazoles characterized by a different molecular structure (flexible vs constrained), but chemically related to rimonabant and AM251, were tested for their ability to modulate the function of recombinant ?1?2?2L GABAA receptors expressed in Xenopus laevis oocytes. The effects of 6Bio-R, 14Bio-R, NESS 0327, GP1a and GP2a (0.3-30 ?M) were evaluated using a two-electrode voltage-clamp technique. 6Bio-R and 14Bio-R potentiated GABA-evoked Cl(-) currents. NESS 0327, GP1a and GP2a did not affect the GABAA receptor function, but they acted as antagonists of 6Bio-R. Moreover, NESS 0327 inhibited the potentiation of the GABAA receptor function induced by rimonabant. The benzodiazepine site seems to participate in the action of these compounds. In fact, flumazenil antagonized the potentiation of the GABAA receptor induced by 6Bio-R, and NESS 0327 reduced the action of lorazepam and zolpidem. On the contrary, NESS 0327 did not antagonize the action of "classic" GABAergic modulators (propanol, anesthetics, barbiturates or steroids). In ?1?2 receptors 6Bio-R potentiated the GABAergic function, but flumazenil was still able to antagonize the potentiation induced by 6Bio-R. Aryl pyrazole derivatives activity at the GABAA receptor depends on their molecular structure. These compounds bind to both an ??? binding site, and to an ?/? site which do not require the ? subunit and that may provide structural leads for drugs with potential anticonvulsant effects. PMID:24704372

Mascia, Maria Paola; Ledda, Giovanni; Orrù, Alessandro; Marongiu, Alessandro; Loriga, Giovanni; Maciocco, Elisabetta; Biggio, Giovanni; Ruiu, Stefania

2014-06-15

313

Endothelial and neural factors functionally involved in the modulation of noradrenergic vasoconstriction in healthy pig internal mammary artery.  

PubMed

The role of endothelial and neural factors as modulators of neurogenic- and noradrenaline-induced vasoconstriction was examined in healthy pig internal mammary artery (IMA). Tetrodotoxin-, guanethidine-sensitive electrical field stimulation (EFS)-, and noradrenaline-elicited contractions were significantly diminished by prazosin (n=8, P<0.001) and less so by rauwolscine, indicating functional ??- and ??-adrenoceptor-mediated noradrenergic innervation of the IMA. Endothelium removal reduced neurogenic (n=8, P<0.01) but augmented noradrenaline responses (n=8, P<0.01), suggesting the release of two endothelium-dependent factors with opposite effects. In the presence of endothelium, neurogenic and exogenous noradrenaline vasoconstrictions were enhanced by L-NOArg (n=7, P<0.05 and P<0.01 respectively) and ODQ (n=7, both P<0.05); in denuded arteries, nNOS inhibition with N(?)-propyl-L-arginine increased neurogenic contraction (n=7, P<0.05). Western blotting indicated the presence of neural and endothelial origin NO (n=6, P<0.001). Tetraethylammonium (n=9, P<0.001), iberiotoxin (n=7, P<0.001) and 4-aminopyridine (n=8, P<0.01) enhanced vasoconstrictions revealing a modulatory role of big conductance Ca²?-activated K? (BK(Ca)) and voltage-dependent K? (K(v)) channels in noradrenergic responses. Bosentan pretreatment (n=8, P<0.05) suggested endothelin-1 as the inferred contractile neurogenic endothelial-dependent factor. Indomethacin-induced inhibition involved a muscular prostanoid (n=9, P<0.05), functionally and immunologically localized, and derived from cyclooxygenase (COX)-1 and COX-2, as revealed by Western blots (n=5, P=0.1267). Thus, noradrenergic IMA contractions are controlled by contractile prostanoid activation and endothelin-1 release, and offset by BK(Ca) and K(v) channels and neural and endothelial NO. These results help clarify the mechanisms of vasospasm in IMA, as the preferred vessel for coronary bypass. PMID:22260985

Pagán, Rosa María; Martínez, Ana Cristina; Hernández, Medardo; Martínez, María Pilar; García-Sacristán, Albino; Correa, Carlos; Novella, Susana; Hermenegildo, Carlos; Prieto, Dolores; Benedito, Sara

2012-04-01

314

Electron Spin-Echo Envelope Modulation (ESEEM) Reveals Water and Phosphate Interactions with the KcsA Potassium Channel  

SciTech Connect

Electron spin-echo envelope modulation (ESEEM) spectroscopy is a well-established technique for the study of naturally occurring paramagnetic metal centers. The technique has been used to study copper complexes, hemes, enzyme mechanisms, micellar water content, and water permeation profiles in membranes, among other applications. In the present study, we combine ESEEM spectroscopy with site-directed spin labeling (SDSL) and X-ray crystallography in order to evaluate the technique's potential as a structural tool to describe the native environment of membrane proteins. Using the KcsA potassium channel as a model system, we demonstrate that deuterium ESEEM can detect water permeation along the lipid-exposed surface of the KcsA outer helix. We further demonstrate that {sup 31}P ESEEM is able to identify channel residues that interact with the phosphate headgroup of the lipid bilayer. In combination with X-ray crystallography, the {sup 31}P data may be used to define the phosphate interaction surface of the protein. The results presented here establish ESEEM as a highly informative technique for SDSL studies of membrane proteins.

Cieslak, John A.; Focia, Pamela J.; Gross, Adrian (NWU)

2010-08-13

315

Equilibrium-fluctuation-analysis of single liposome binding events reveals how cholesterol and Ca2+ modulate glycosphingolipid trans-interactions  

PubMed Central

Carbohydrate?carbohydrate interactions (CCIs) are of central importance for several biological processes. However, the ultra-weak nature of CCIs generates difficulties in studying this interaction, thus only little is known about CCIs. Here we present a highly sensitive equilibrium-fluctuation-analysis of single liposome binding events to supported lipid bilayers (SLBs) based on total internal reflection fluorescence (TIRF) microscopy that allows us to determine apparent kinetic rate constants of CCIs. The liposomes and SLBs both contained natural Lex glycosphingolipids (Gal?4(Fuc?3)GlcNAc?3Gal?4Glc?1Cer), which were employed to mimic cell?cell contacts. The kinetic parameters of the self-interaction between Lex-containing liposomes and SLBs were measured and found to be modulated by bivalent cations. Even more interestingly, upon addition of cholesterol, the strength of the CCIs increases, suggesting that this interaction is strongly influenced by a cholesterol-dependent presentation and/or spatial organization of glycosphingolipids in cell membranes. PMID:23486243

Kunze, Angelika; Bally, Marta; Hook, Fredrik; Larson, Goran

2013-01-01

316

Catechol-O-Methyltransferase Val158Met Polymorphism Modulates Gray Matter Volume and Functional Connectivity of the Default Mode Network  

PubMed Central

The effect of catechol-O-methyltransferase (COMT) Val158Met polymorphism on brain structure and function has been previously investigated separately and regionally; this prevents us from obtaining a full picture of the effect of this gene variant. Additionally, gender difference must not be overlooked because estrogen exerts an interfering effect on COMT activity. We examined 323 young healthy Chinese Han subjects and analyzed the gray matter volume (GMV) differences between Val/Val individuals and Met carriers in a voxel-wise manner throughout the whole brain. We were interested in genotype effects and genotype × gender interactions. We then extracted these brain regions with GMV differences as seeds to compute resting-state functional connectivity (rsFC) with the rest of the brain; we also tested the genotypic differences and gender interactions in the rsFCs. Val/Val individuals showed decreased GMV in the posterior cingulate cortex (PCC) compared with Met carriers; decreased GMV in the medial superior frontal gyrus (mSFG) was found only in male Val/Val subjects. The rsFC analysis revealed that both the PCC and mSFG were functionally correlated with brain regions of the default mode network (DMN). Both of these regions showed decreased rsFCs with different parts of the frontopolar cortex of the DMN in Val/Val individuals than Met carriers. Our findings suggest that the COMT Val158Met polymorphism modulates both the structure and functional connectivity within the DMN and that gender interactions should be considered in studies of the effect of this genetic variant, especially those involving prefrontal morphology. PMID:24147141

Tian, Tian; Qin, Wen; Liu, Bing; Wang, Dawei; Wang, Junping; Jiang, Tianzi; Yu, Chunshui

2013-01-01

317

Genome-wide mapping of conserved RNA Secondary Structures Reveals Evidence for Thousands of functional  

E-print Network

conserved RNAs in the human genome. Results Selection of conserved sequences and screening for structuralGenome-wide mapping of conserved RNA Secondary Structures Reveals Evidence for Thousands to the fairly reliable and complete annotation of the protein coding genes in the human genome, comparable

Stadler, Peter F.

318

Genomewide mapping of conserved RNA Secondary Structures Reveals Evidence for Thousands of functional  

E-print Network

conserved RNAs in the human genome. Results Selection of conserved sequences and screening for structuralGenome­wide mapping of conserved RNA Secondary Structures Reveals Evidence for Thousands to the fairly reliable and complete annotation of the protein coding genes in the human genome, comparable

Stadler, Peter F.

319

Nitrogen cycling in Yellowstone National Park thermal features: using gene expression to reveal ecological function  

Microsoft Academic Search

Studies of biodiversity, metabolic strategies, and functional ecology in modern hydrothermal systems have the potential to provide insight into the metabolism and evolution of life. The geochemical and microbial diversity present at Yellowstone National Park (YNP), Wyoming, USA, makes it an ideal place for studying the functional ecology and metabolic processes of prokaryotic organisms. While much work in terrestrial hydrothermal

S. T. Lafree; M. S. Burton; D. R. Meyer-Dombard

2010-01-01

320

Epigenomics Reveals a Functional Genome Anatomy and a New Approach to Common Disease  

PubMed Central

Standfirst header Epigenomics provides the functional context of genome sequence, analogous to the functional anatomy of the human body provided by Vesalius a half millennium ago. Much of what appear to be inconclusive genetic data for common disease could therefore become meaningful in an epigenomic context. PMID:20944596

Feinberg, Andrew P.

2010-01-01

321

Comparative genome analysis of PHB gene family reveals deep evolutionary origins and diverse gene function  

Microsoft Academic Search

BACKGROUND: PHB (Prohibitin) gene family is involved in a variety of functions important for different biological processes. PHB genes are ubiquitously present in divergent species from prokaryotes to eukaryotes. Human PHB genes have been found to be associated with various diseases. Recent studies by our group and others have shown diverse function of PHB genes in plants for development, senescence,

Chao Di; Wenying Xu; Zhen Su; Joshua S Yuan

2010-01-01

322

Faculty Perceptions of Institutional Characteristics as Revealed through the "Institutional Functioning Inventory."  

ERIC Educational Resources Information Center

In May 1974, the Institutional Functioning Inventory (IFI), which measures individual and collective perceptions or orientations of respondents concerning institutional functions generally agreed to be important in the context of higher education in contemporary American society, was administered to a "stratified-volunteer-quota" sample of the…

Dumont, Richard G.

323

Large-scale mapping of sequence-function relations in small regulatory RNAs reveals plasticity and modularity  

PubMed Central

Two decades into the genomics era the question of mapping sequence to function has evolved from identifying functional elements to characterizing their quantitative properties including, in particular, their specificity and efficiency. Here, we use a large-scale approach to establish a quantitative map between the sequence of a bacterial regulatory RNA and its efficiency in modulating the expression of its targets. Our approach generalizes the sort-seq method, introduced recently to analyze promoter sequences, in order to accurately quantify the efficiency of a large library of sequence variants. We focus on two small RNAs (sRNAs) in E. coli, DsrA and RyhB, and their regulation of both repressed and activated targets. In addition to precisely identifying functional elements in the sRNAs, our data establish quantitative relationships between structural and energetic features of the sRNAs and their regulatory activity, and characterize a large set of direct and indirect interactions between nucleotides. A core of these interactions supports a model where specificity can be enhanced by a rigid molecular structure. Both sRNAs exhibit a modular design with limited cross-interactions, dividing the requirements for structural stability and target binding among modules. PMID:25262352

Peterman, Neil; Lavi-Itzkovitz, Anat; Levine, Erel

2014-01-01

324

Large-scale mapping of sequence-function relations in small regulatory RNAs reveals plasticity and modularity.  

PubMed

Two decades into the genomics era the question of mapping sequence to function has evolved from identifying functional elements to characterizing their quantitative properties including, in particular, their specificity and efficiency. Here, we use a large-scale approach to establish a quantitative map between the sequence of a bacterial regulatory RNA and its efficiency in modulating the expression of its targets. Our approach generalizes the sort-seq method, introduced recently to analyze promoter sequences, in order to accurately quantify the efficiency of a large library of sequence variants. We focus on two small RNAs (sRNAs) in E. coli, DsrA and RyhB, and their regulation of both repressed and activated targets. In addition to precisely identifying functional elements in the sRNAs, our data establish quantitative relationships between structural and energetic features of the sRNAs and their regulatory activity, and characterize a large set of direct and indirect interactions between nucleotides. A core of these interactions supports a model where specificity can be enhanced by a rigid molecular structure. Both sRNAs exhibit a modular design with limited cross-interactions, dividing the requirements for structural stability and target binding among modules. PMID:25262352

Peterman, Neil; Lavi-Itzkovitz, Anat; Levine, Erel

2014-10-29

325

Structural and Functional Dissection of the Abp1 ADFH Actin-binding Domain Reveals Versatile In Vivo Adapter Functions  

SciTech Connect

Abp1 is a multidomain protein that regulates the Arp2/3 complex and links proteins involved in endocytosis to the actin cytoskeleton. All of the proposed cellular functions of Abp1 involve actin filament binding, yet the actin binding site(s) on Abp1 have not been identified, nor has the importance of actin binding for Abp1 localization and function in vivo been tested. Here, we report the crystal structure of the Saccharomyces cerevisiae Abp1 actin-binding actin depolymerizing factor homology (ADFH) domain and dissect its activities by mutagenesis. Abp1-ADFH domain and ADF/cofilin structures are similar, and they use conserved surfaces to bind actin; however, there are also key differences that help explain their differential effects on actin dynamics. Using point mutations, we demonstrate that actin binding is required for localization of Abp1 in vivo, the lethality caused by Abp1 overexpression, and the ability of Abp1 to activate Arp2/3 complex. Furthermore, we genetically uncouple ABP1 functions that overlap with SAC6, SLA1, and SLA2, showing they require distinct combinations of activities and interactions. Together, our data provide the first structural and functional view of the Abp1-actin interaction and show that Abp1 has distinct cellular roles as an adapter, linking different sets of ligands for each function.

Quintero-Monzon,O.; Rodal, A.; Strokopytov, B.; Almo, S.; Goode, B.

2005-01-01

326

Structure Function Studies of Vaccinia Virus Host Range Protein K1 Reveal a Novel Functional Surface for Ankyrin Repeat Proteins  

SciTech Connect

Poxvirus host tropism at the cellular level is regulated by virus-encoded host range proteins acting downstream of virus entry. The functioning mechanisms of most host range proteins are unclear, but many contain multiple ankyrin (ANK) repeats, a motif that is known for ligand interaction through a concave surface. We report here the crystal structure of one of the ANK repeat-containing host range proteins, the vaccinia virus K1 protein. The structure, at a resolution of 2.3 {angstrom}, showed that K1 consists entirely of ANK repeats, including seven complete ones and two incomplete ones, one each at the N and C terminus. Interestingly, Phe82 and Ser83, which were previously shown to be critical for K1's function, are solvent exposed and located on a convex surface, opposite the consensus ANK interaction surface. The importance of this convex surface was further supported by our additional mutagenesis studies. We found that K1's host range function was negatively affected by substitution of either Asn51 or Cys47 and completely abolished by substitution of both residues. Cys47 and Asn51 are also exposed on the convex surface, spatially adjacent to Phe82 and Ser83. Altogether, our data showed that K1 residues on a continuous convex ANK repeat surface are critical for the host range function, suggesting that K1 functions through ligand interaction and does so with a novel ANK interaction surface.

Li, Yongchao; Meng, Xiangzhi; Xiang, Yan; Deng, Junpeng (Texas-HSC); (OKLU)

2010-06-15

327

Distribution of neurons in functional areas of the mouse cerebral cortex reveals quantitatively different cortical zones  

PubMed Central

How are neurons distributed along the cortical surface and across functional areas? Here we use the isotropic fractionator (Herculano-Houzel and Lent, 2005) to analyze the distribution of neurons across the entire isocortex of the mouse, divided into 18 functional areas defined anatomically. We find that the number of neurons underneath a surface area (the N/A ratio) varies 4.5-fold across functional areas and neuronal density varies 3.2-fold. The face area of S1 contains the most neurons, followed by motor cortex and the primary visual cortex. Remarkably, while the distribution of neurons across functional areas does not accompany the distribution of surface area, it mirrors closely the distribution of cortical volumes—with the exception of the visual areas, which hold more neurons than expected for their volume. Across the non-visual cortex, the volume of individual functional areas is a shared linear function of their number of neurons, while in the visual areas, neuronal densities are much higher than in all other areas. In contrast, the 18 functional areas cluster into three different zones according to the relationship between the N/A ratio and cortical thickness and neuronal density: these three clusters can be called visual, sensory, and, possibly, associative. These findings are remarkably similar to those in the human cerebral cortex (Ribeiro et al., 2013) and suggest that, like the human cerebral cortex, the mouse cerebral cortex comprises two zones that differ in how neurons form the cortical volume, and three zones that differ in how neurons are distributed underneath the cortical surface, possibly in relation to local differences in connectivity through the white matter. Our results suggest that beyond the developmental divide into visual and non-visual cortex, functional areas initially share a common distribution of neurons along the parenchyma that become delimited into functional areas according to the pattern of connectivity established later. PMID:24155697

Herculano-Houzel, Suzana; Watson, Charles; Paxinos, George

2013-01-01

328

Functional connectivity as revealed by spatial independent component analysis of fMRI measurements during rest.  

PubMed

Cortical functional connectivity, as indicated by the concurrent spontaneous activity of spatially segregated regions, is being studied increasingly because it may determine the reaction of the brain to external stimuli and task requirements and it is reportedly altered in many neurological and psychiatric disorders. In functional magnetic resonance imaging (fMRI), such functional connectivity is investigated commonly by correlating the time course of a chosen "seed voxel" with the remaining voxel time courses in a voxel-by-voxel manner. This approach is biased by the actual choice of the seed voxel, however, because it only shows functional connectivity for the chosen brain region while ignoring other potentially interesting patterns of coactivation. We used spatial independent component analysis (sICA) to assess cortical functional connectivity maps from resting state data. SICA does not depend on any chosen temporal profile of local brain activity. We hypothesized that sICA would be able to find functionally connected brain regions within sensory and motor regions in the absence of task-related brain activity. We also investigated functional connectivity patterns of several parietal regions including the superior parietal cortex and the posterior cingulate gyrus. The components of interest were selected in an automated fashion using predefined anatomical volumes of interest. SICA yielded connectivity maps of bilateral auditory, motor and visual cortices. Moreover, it showed that prefrontal and parietal areas are also functionally connected within and between hemispheres during the resting state. These connectivity maps showed an extremely high degree of consistency in spatial, temporal, and frequency parameters within and between subjects. These results are discussed in the context of the recent debate on the functional relevance of fluctuations of neural activity in the resting state. PMID:15195284

van de Ven, Vincent G; Formisano, Elia; Prvulovic, David; Roeder, Christian H; Linden, David E J

2004-07-01

329

Bidirectional modulation of deep cerebellar nuclear cells revealed by optogenetic manipulation of inhibitory inputs from Purkinje cells.  

PubMed

In the mammalian cerebellum, deep cerebellar nuclear (DCN) cells convey all information from cortical Purkinje cells (PCs) to premotor nuclei and other brain regions. However, how DCN cells integrate inhibitory input from PCs with excitatory inputs from other sources has been difficult to assess, in part due to the large spatial separation between cortical PCs and their target cells in the nuclei. To circumvent this problem we have used a Cre-mediated genetic approach to generate mice in which channelrhodopsin-2 (ChR2), fused with a fluorescent reporter, is selectively expressed by GABAergic neurons, including PCs. In recordings from brain slice preparations from this model, mammalian PCs can be robustly depolarized and discharged by brief photostimulation. In recordings of postsynaptic DCN cells, photostimulation of PC axons induces a strong inhibition that resembles these cells' responses to focal electrical stimulation, but without a requirement for the glutamate receptor blockers typically applied in such experiments. In this optogenetic model, laser pulses as brief as 1ms can reliably induce an inhibition that shuts down the spontaneous spiking of a DCN cell for ?50ms. If bursts of such brief light pulses are delivered, a fixed pattern of bistable bursting emerges. If these pulses are delivered continuously to a spontaneously bistable cell, the immediate response to such photostimulation is inhibitory in the cell's depolarized state and excitatory when the membrane has repolarized; a less regular burst pattern then persists after stimulation has been terminated. These results indicate that the spiking activity of DCN cells can be bidirectionally modulated by the optically activated synaptic inhibition of cortical PCs. PMID:25020121

Han, V Z; Magnus, G; Zhang, Y; Wei, A D; Turner, E E

2014-09-26

330

Selective GABAA ?5 Positive Allosteric Modulators Improve Cognitive Function in Aged Rats with Memory Impairment  

PubMed Central

A condition of excess activity in the hippocampal formation is observed in the aging brain and in conditions that confer additional risk during aging for Alzheimer’s disease. Compounds that act as positive allosteric modulators at GABAA ?5 receptors might be useful in targeting this condition because GABAA ?5 receptors mediate tonic inhibition of principal neurons in the affected network. While agents to improve cognitive function in the past focused on inverse agonists, which are negative allosteric modulators at GABAA ?5 receptors, research supporting that approach used only young animals and predated current evidence for excessive hippocampal activity in age-related conditions of cognitive impairment. Here, we used two compounds, Compound 44 [6,6-dimethyl-3-(3-hydroxypropyl)thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one] and Compound 6 [methyl 3,5-diphenylpyridazine-4-carboxylate], with functional activity as potentiators of ?-aminobutyric acid at GABAA ?5 receptors, to test their ability to improve hippocampal-dependent memory in aged rats with identified cognitive impairment. Improvement was obtained in aged rats across protocols differing in motivational and performance demands and across varying retention intervals. Significant memory improvement occurred after either intracereboventricular infusion with Compound 44 (100 ?g) in a water maze task or systemic administration with Compound 6 (3 mg/kg) in a radial arm maze task. Furthermore, systemic administration improved behavioral performance at dosing shown to provide drug exposure in the brain and in vivo receptor occupancy in the hippocampus. These data suggest a novel approach to improve neural network function in clinical conditions of excess hippocampal activity. PMID:22732440

Koh, Ming Teng; Rosenzweig-Lipson, Sharon; Gallagher, Michela

2012-01-01

331

Interhemispheric Modulation of Dual-Mode, Noninvasive Brain Stimulation on Motor Function  

PubMed Central

Objective To investigate the effects of simultaneous, bihemispheric, dual-mode stimulation using repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) on motor functions and cortical excitability in healthy individuals. Methods Twenty-five healthy, right-handed volunteers (10 men, 15 women; mean age, 25.5 years) were enrolled. All participants received four randomly arranged, dual-mode, simultaneous stimulations under the following conditions: condition 1, high-frequency rTMS over the right primary motor cortex (M1) and sham tDCS over the left M1; condition 2, high-frequency rTMS over the right M1 and anodal tDCS over the left M1; condition 3, high-frequency rTMS over the right M1 and cathodal tDCS over the left M1; and condition 4, sham rTMS and sham tDCS. The cortical excitability of the right M1 and motor functions of the left hand were assessed before and after each simulation. Results Motor evoked potential (MEP) amplitudes after stimulation were significantly higher than before stimulation, under the conditions 1 and 2. The MEP amplitude in condition 2 was higher than both conditions 3 and 4, while the MEP amplitude in condition 1 was higher than condition 4. The results of the Purdue Pegboard test and the box and block test showed significant improvement in conditions 1 and 2 after stimulation. Conclusion Simultaneous stimulation by anodal tDCS over the left M1 with high-frequency rTMS over the right M1 could produce interhemispheric modulation and homeostatic plasticity, which resulted in modulation of cortical excitability and motor functions. PMID:25024951

Park, Eunhee; Chang, Won Hyuk; Kwon, Tae Gun; Shin, Yong-Il

2014-01-01

332

Selective visual responses to expansion and rotation in the human MT complex revealed by functional magnetic  

E-print Network

sensitivity to optic flow in the human occipital cortex using an event-related functional magnetic resonance, a technique has recently been developed that allows the disentanglement of responses from functi

Royal Holloway, University of London

333

Spectral imaging reveals microvessel physiology and function from anastomoses to thromboses.  

PubMed

Abnormal microvascular physiology and function is common in many diseases. Numerous pathologies include hypervascularity, aberrant angiogenesis, or abnormal vascular remodeling among the characteristic features of the disease, and quantitative imaging and measurement of microvessel function can be important to increase understanding of these diseases. Several optical techniques are useful for direct imaging of microvascular function. Spectral imaging is one such technique that can be used to assess microvascular oxygen transport function with high spatial and temporal resolution in microvessel networks through measurements of hemoglobin saturation. We highlight novel observation made with our intravital microscopy spectral imaging system employed with mouse dorsal skin-fold window chambers for imaging hemoglobin saturation in microvessel networks. Specifically, we image acute oxygenation fluctuations in a tumor microvessel network, the development of arteriovenous malformations in a mouse model of hereditary hemorrhagic telangiectasia, and the formation of spontaneous and induced microvascular thromboses and occlusions. PMID:20210437

Wankhede, Mamta; Agarwal, Nikita; Fraga-Silva, Rodrigo A; deDeugd, Casey; Raizada, Mohan K; Oh, S Paul; Sorg, Brian S

2010-01-01

334

Functional genomics reveals serine synthesis is essential in PHGDH-amplified breast cancer  

E-print Network

Cancer cells adapt their metabolic processes to drive macromolecular biosynthesis for rapid cell growth and proliferation[superscript 1, 2]. RNA interference (RNAi)-based loss-of-function screening has proven powerful for ...

Possemato, Richard

335

Identification of a novel protein that regulates mitochondrial fusion by modulating mitofusin (Mfn) protein function.  

PubMed

Mitofusin proteins 1 and 2 (Mfn1 and Mfn2, respectively) of the mammalian mitochondrial outer membrane are homologues of Drosophila FZO and yeast Fzo1, and both are essential for GTP-dependent mitochondrial fusion. We identified a 55-kDa Mfn-binding protein named MIB. It is a member of the medium-chain dehydrogenase/reductase protein superfamily, and has a conserved coenzyme-binding domain (CBD). The majority of MIB is localized in the cytoplasm but a small amount is associated with mitochondria. Exogenous expression of MIB in HeLa cells induced mitochondrial fragmentation, which was prevented by coexpression of Mfn1, suggesting a functional interaction of MIB with Mfn proteins; the GGVG sequence in the CBD of MIB is essential for its function. By contrast, MIB knockdown resulted in growth arrest of the cells, although apoptotic sensitivity was not affected by either its knockdown or its overexpression. Furthermore, MIB knockdown induced a large extension of mitochondrial network structures. By contrast, a double knockdown of MIB and Mfn1 resulted in mitochondrial fragmentation and reversal of the growth arrest, the morphology and growth phenotype induced by knockdown of Mfn1 alone, again suggesting that MIB modulates Mfn1 function. Together, these findings suggest that MIB is essential for cellular function by regulating mitochondrial membrane dynamics in cooperation with Mfn proteins. PMID:17105775

Eura, Yuka; Ishihara, Naotada; Oka, Toshihiko; Mihara, Katsuyoshi

2006-12-01

336

Flexible establishment of functional brain networks supports attentional modulation of unconscious cognition.  

PubMed

In classical theories of attention, unconscious automatic processes are thought to be independent of higher-level attentional influences. Here, we propose that unconscious processing depends on attentional enhancement of task-congruent processing pathways implemented by a dynamic modulation of the functional communication between brain regions. Using functional magnetic resonance imaging, we tested our model with a subliminally primed lexical decision task preceded by an induction task preparing either a semantic or a perceptual task set. Subliminal semantic priming was significantly greater after semantic compared to perceptual induction in ventral occipito-temporal (vOT) and inferior frontal cortex, brain areas known to be involved in semantic processing. The functional connectivity pattern of vOT varied depending on the induction task and successfully predicted the magnitude of behavioral and neural priming. Together, these findings support the proposal that dynamic establishment of functional networks by task sets is an important mechanism in the attentional control of unconscious processing. Hum Brain Mapp 35:5500-5516, 2014. © 2014 Wiley Periodicals, Inc. PMID:24954512

Ulrich, Martin; Adams, Sarah C; Kiefer, Markus

2014-11-01

337

Electro-acupuncture at different acupoints modulating the relative specific brain functional network  

NASA Astrophysics Data System (ADS)

Objective: The specific brain effects of acupoint are important scientific concern in acupuncture. However, previous acupuncture fMRI studies focused on acupoints in muscle layer on the limb. Therefore, researches on acupoints within connective tissue at trunk are warranted. Material and Methods: Brain effects of acupuncture on abdomen at acupoints Guanyuan (CV4) and Zhongwan (CV12) were tested using fMRI on 21 healthy volunteers. The data acquisition was performed at resting state, during needle retention, electroacupuncture (EA) and post-EA resting state. Needling sensations were rated after every electroacupuncture (EA) procedure. The needling sensations and the brain functional activity and connectivity were compared between CV4 and CV12 using SPSS, SPM2 and the local and remote connectivity maps. Results and conclusion: EA at CV4 and CV12 induced apparent deactivation effects in the limbic-paralimbic-neocortical network. The default mode of the brain was modified by needle retention and EA, respectively. The functional brain network was significantly changed post EA. However, the minor differences existed between these two acupoints. The results demonstrated similarity between functional brain network mode of acupuncture modulation and functional circuits of emotional and cognitive regulation. Acupuncture may produce analgesia, anti-anxiety and anti-depression via the limbic-paralimbic-neocortical network (LPNN).

Fang, Jiliang; Wang, Xiaoling; Wang, Yin; Liu, Hesheng; Hong, Yang; Liu, Jun; Zhou, Kehua; Wang, Lei; Xue, Chao; Song, Ming; Liu, Baoyan; Zhu, Bing

2010-11-01

338

Acupuncture modulates cortical thickness and functional connectivity in knee osteoarthritis patients  

PubMed Central

In this study, we investigated cortical thickness and functional connectivity across longitudinal acupuncture treatments in patients with knee osteoarthritis (OA). Over a period of four weeks (six treatments), we collected resting state functional magnetic resonance imaging (fMRI) scans from 30 patients before their first, third and sixth treatments. Clinical outcome showed a significantly greater Knee Injury and Osteoarthritis Outcome Score (KOOS) pain score (improvement) with verum acupuncture compared to the sham acupuncture. Longitudinal cortical thickness analysis showed that the cortical thickness at left posterior medial prefrontal cortex (pMPFC) decreased significantly in the sham group across treatment sessions as compared with verum group. Resting state functional connectivity (rsFC) analysis using the left pMPFC as a seed showed that after longitudinal treatments, the rsFC between the left pMPFC and the rostral anterior cingulate cortex (rACC), medial frontal pole (mFP) and periaquiduct grey (PAG) are significantly greater in the verum acupuncture group as compared with the sham group. Our results suggest that acupuncture may achieve its therapeutic effect on knee OA pain by preventing cortical thinning and decreases in functional connectivity in major pain related areas, therefore modulating pain in the descending pain modulatory pathway. PMID:25258037

Chen, Xiaoyan; Spaeth, Rosa B.; Retzepi, Kallirroi; Ott, Daniel; Kong, Jian

2014-01-01

339

Small molecule screening reveals a transcription-independent pro-survival function of androgen receptor in castration-resistant prostate cancer  

PubMed Central

In prostate cancer (PCa) patients, initial responsiveness to androgen deprivation therapy is frequently followed by relapse due to development of treatment-resistant androgen-independent PCa. This is typically associated with acquisition of mutations in AR that allow activity as a transcription factor in the absence of ligand, indicating that androgen-independent PCa remains dependent on AR function. Our strategy to effectively target AR in androgen-independent PCa involved using a cell-based readout to isolate small molecules that inhibit AR transactivation function through mechanisms other than modulation of ligand binding. A number of the identified inhibitors were toxic to AR-expressing PCa cells regardless of their androgen dependence. Among these, some only suppressed PCa cell growth (ARTIS), while others induced cell death (ARTIK). ARTIK, but not ARTIS, compounds caused disappearance of AR protein from treated cells. siRNA against AR behaved like ARTIK compounds, while a dominant negative AR mutant that prevents AR-mediated transactivation but does not eliminate the protein showed only a growth suppressive effect. These observations reveal a transcription-independent function of AR that is essential for PCa cell viability and, therefore, is an ideal target for anti-PCa treatment. Indeed, several of the identified AR inhibitors demonstrated in vivo efficacy in mouse models of PCa and are candidates for pharmacologic optimization. PMID:19946220

Narizhneva, Natalia V.; Tararova, Natalia D.; Ryabokon, Petro; Shyshynova, Inna; Prokvolit, Anatoly; Komarov, Pavel G.; Purmal, Andrei A.; Gudkov, Andrei V.; Gurova, Katerina V.

2010-01-01

340

Annotation of Protein Domains Reveals Remarkable Conservation in the Functional Make up of Proteomes Across Superkingdoms  

PubMed Central

The functional repertoire of a cell is largely embodied in its proteome, the collection of proteins encoded in the genome of an organism. The molecular functions of proteins are the direct consequence of their structure and structure can be inferred from sequence using hidden Markov models of structural recognition. Here we analyze the functional annotation of protein domain structures in almost a thousand sequenced genomes, exploring the functional and structural diversity of proteomes. We find there is a remarkable conservation in the distribution of domains with respect to the molecular functions they perform in the three superkingdoms of life. In general, most of the protein repertoire is spent in functions related to metabolic processes but there are significant differences in the usage of domains for regulatory and extra-cellular processes both within and between superkingdoms. Our results support the hypotheses that the proteomes of superkingdom Eukarya evolved via genome expansion mechanisms that were directed towards innovating new domain architectures for regulatory and extra/intracellular process functions needed for example to maintain the integrity of multicellular structure or to interact with environmental biotic and abiotic factors (e.g., cell signaling and adhesion, immune responses, and toxin production). Proteomes of microbial superkingdoms Archaea and Bacteria retained fewer numbers of domains and maintained simple and smaller protein repertoires. Viruses appear to play an important role in the evolution of superkingdoms. We finally identify few genomic outliers that deviate significantly from the conserved functional design. These include Nanoarchaeum equitans, proteobacterial symbionts of insects with extremely reduced genomes, Tenericutes and Guillardia theta. These organisms spend most of their domains on information functions, including translation and transcription, rather than on metabolism and harbor a domain repertoire characteristic of parasitic organisms. In contrast, the functional repertoire of the proteomes of the Planctomycetes-Verrucomicrobia-Chlamydiae superphylum was no different than the rest of bacteria, failing to support claims of them representing a separate superkingdom. In turn, Protista and Bacteria shared similar functional distribution patterns suggesting an ancestral evolutionary link between these groups. PMID:24710297

Nasir, Arshan; Naeem, Aisha; Khan, Muhammad Jawad; Lopez-Nicora, Horacio D.; Caetano-Anolles, Gustavo

2011-01-01

341

Functional Heterogeneity of an Isolated Mitochondrial Population Revealed by Cytofluorometric Analysis at the Single Organelle Level  

Microsoft Academic Search

Isolated rat liver mitochondria were incubated under various metabolic conditions to determine their membrane potential (MMP) as measured continuously by a tetraphenylphosphonium (TPP+)-selective electrode. By flow cytometry, a parallel analysis of fluorescence emissions observing single mitochondria stained with the lipophilic cation 5,5?,6,6?-tetrachloro-1,1?,3,3?-tetraethylbenzimidazolcarbocyanine iodide (JC-1) revealed linear correlation between the median orange fluorescence (FL2) due to J-aggregate formations and MMP values

Andrea Cossarizza; Daniela Ceccarelli; Alberto Masini

1996-01-01

342

Single-molecule studies reveal the function of a third polymerase in the replisome  

PubMed Central

The Escherichia coli replisome contains three polymerases, one more than necessary to duplicate the two parental strands. Using single-molecule studies, we reveal two advantages conferred by the third polymerase. First, dipolymerase replisomes are inefficient at synthesizing lagging strands, leaving single-strand gaps, whereas tripolymerase replisomes fill strands almost to completion. Second, tripolymerase replisomes are much more processive than dipolymerase replisomes. These features account for the unexpected three-polymerase-structure of bacterial replisomes. PMID:22157955

Georgescu, Roxana E; Kurth, Isabel; O'Donnell, Mike E

2013-01-01

343

Functional characterization of chicken TLR5 reveals species-specific recognition of flagellin  

Microsoft Academic Search

Mammalian Toll-like receptor 5 (TLR5) senses flagellin of several bacterial species and activates the innate immune system. The avian TLR repertoire exhibits considerable functional diversity compared to mammalian TLRs and evidence of a functional TLR5 in the avian species is lacking. In the present study we cloned and successfully expressed chicken TLR5 (chTLR5) in HeLa cells, as indicated by laser

A. Marijke Keestra; Marcel R. de Zoete; Rémon A. M. H. van Aubel; Jos P. M. van Putten

2008-01-01

344

Gas7Deficient Mouse Reveals Roles in Motor Function and Muscle Fiber Composition during Aging  

Microsoft Academic Search

BackgroundGrowth 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 FindingsOur data show that aged

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

2012-01-01

345

Novel cardiovascular gene functions revealed via systematic phenotype prediction in zebrafish.  

PubMed

Comprehensive functional annotation of vertebrate genomes is fundamental to biological discovery. Reverse genetic screening has been highly useful for determination of gene function, but is untenable as a systematic approach in vertebrate model organisms given the number of surveyable genes and observable phenotypes. Unbiased prediction of gene-phenotype relationships offers a strategy to direct finite experimental resources towards likely phenotypes, thus maximizing de novo discovery of gene functions. Here we prioritized genes for phenotypic assay in zebrafish through machine learning, predicting the effect of loss of function of each of 15,106 zebrafish genes on 338 distinct embryonic anatomical processes. Focusing on cardiovascular phenotypes, the learning procedure predicted known knockdown and mutant phenotypes with high precision. In proof-of-concept studies we validated 16 high-confidence cardiac predictions using targeted morpholino knockdown and initial blinded phenotyping in embryonic zebrafish, confirming a significant enrichment for cardiac phenotypes as compared with morpholino controls. Subsequent detailed analyses of cardiac function confirmed these results, identifying novel physiological defects for 11 tested genes. Among these we identified tmem88a, a recently described attenuator of Wnt signaling, as a discrete regulator of the patterning of intercellular coupling in the zebrafish cardiac epithelium. Thus, we show that systematic prioritization in zebrafish can accelerate the pace of developmental gene function discovery. PMID:24346703

Musso, Gabriel; Tasan, Murat; Mosimann, Christian; Beaver, John E; Plovie, Eva; Carr, Logan A; Chua, Hon Nian; Dunham, Julie; Zuberi, Khalid; Rodriguez, Harold; Morris, Quaid; Zon, Leonard; Roth, Frederick P; MacRae, Calum A

2014-01-01

346

An integrative architecture for general intelligence and executive function revealed by lesion mapping  

PubMed Central

Although cognitive neuroscience has made remarkable progress in understanding the involvement of the prefrontal cortex in executive control, the broader functional networks that support high-level cognition and give rise to general intelligence remain to be well characterized. Here, we investigated the neural substrates of the general factor of intelligence (g) and executive function in 182 patients with focal brain damage using voxel-based lesion–symptom mapping. The Wechsler Adult Intelligence Scale and Delis–Kaplan Executive Function System were used to derive measures of g and executive function, respectively. Impaired performance on these measures was associated with damage to a distributed network of left lateralized brain areas, including regions of frontal and parietal cortex and white matter association tracts, which bind these areas into a coordinated system. The observed findings support an integrative framework for understanding the architecture of general intelligence and executive function, supporting their reliance upon a shared fronto-parietal network for the integration and control of cognitive representations and making specific recommendations for the application of the Wechsler Adult Intelligence Scale and Delis–Kaplan Executive Function System to the study of high-level cognition in health and disease. PMID:22396393

Colom, Roberto; Solomon, Jeffrey; Krueger, Frank; Forbes, Chad; Grafman, Jordan

2012-01-01

347

Novel cardiovascular gene functions revealed via systematic phenotype prediction in zebrafish  

PubMed Central

Comprehensive functional annotation of vertebrate genomes is fundamental to biological discovery. Reverse genetic screening has been highly useful for determination of gene function, but is untenable as a systematic approach in vertebrate model organisms given the number of surveyable genes and observable phenotypes. Unbiased prediction of gene-phenotype relationships offers a strategy to direct finite experimental resources towards likely phenotypes, thus maximizing de novo discovery of gene functions. Here we prioritized genes for phenotypic assay in zebrafish through machine learning, predicting the effect of loss of function of each of 15,106 zebrafish genes on 338 distinct embryonic anatomical processes. Focusing on cardiovascular phenotypes, the learning procedure predicted known knockdown and mutant phenotypes with high precision. In proof-of-concept studies we validated 16 high-confidence cardiac predictions using targeted morpholino knockdown and initial blinded phenotyping in embryonic zebrafish, confirming a significant enrichment for cardiac phenotypes as compared with morpholino controls. Subsequent detailed analyses of cardiac function confirmed these results, identifying novel physiological defects for 11 tested genes. Among these we identified tmem88a, a recently described attenuator of Wnt signaling, as a discrete regulator of the patterning of intercellular coupling in the zebrafish cardiac epithelium. Thus, we show that systematic prioritization in zebrafish can accelerate the pace of developmental gene function discovery. PMID:24346703

Musso, Gabriel; Tasan, Murat; Mosimann, Christian; Beaver, John E.; Plovie, Eva; Carr, Logan A.; Chua, Hon Nian; Dunham, Julie; Zuberi, Khalid; Rodriguez, Harold; Morris, Quaid; Zon, Leonard; Roth, Frederick P.; MacRae, Calum A.

2014-01-01

348

A Phylogenomic Analysis of the Shikimate Dehydrogenases Reveals Broadscale Functional Diversification and Identifies One Functionally Distinct Subclass  

E-print Network

as an antimicrobial target due to its conserved and rather essential nature (Fonseca et al. 2006). Indeed, Escherichia biochemical and functional differences ranging from amino acid biosynthesis to antibiotic production. Despite to identify suitable novel targets for antimicrobial drug development. The re- cent surge in microbial genome

Guttman, David S.

349

Functional Analyses Reveal Extensive RRE Plasticity in Primary HIV-1 Sequences Selected under Selective Pressure  

PubMed Central

Background HIV-1 Rev response element (RRE) is a functional region of viral RNA lying immediately downstream to the junction of gp120 and gp41 in the env coding sequence. The RRE is essential for HIV replication and binds with the Rev protein to facilitate the export of viral mRNA from nucleus to cytoplasm. It has been suggested that changes in the predicted secondary structure of primary RRE sequences impact the function of the RREs; however, functional assays have not yet been performed. The aim of this study was to characterize the genetic, structural and functional variation in the RRE primary sequences selected in vivo by Enfuvirtide pressure. Results Multiple RRE variants were obtained from viruses isolated from patients who failed an Enfuvirtide-containing regimen. Different alterations were observed in the predicted RRE secondary structures, with the abrogation of the primary Rev binding site in one of the variants. In spite of this, most of the RRE variants were able to bind Rev and promote the cytoplasmic export of the viral mRNAs with equivalent efficiency in a cell-based assay. Only RRE45 and RRE40-45 showed an impaired ability to bind Rev in a gel-shift binding assay. Unexpectedly, this impairment was not reflected in functional capacity when RNA export was evaluated using a reporter assay, or during virus replication in lymphoid cells, suggesting that in vivo the RRE would be highly malleable. Conclusions The Rev-RRE functionality is unaffected in RRE variants selected in patients failing an ENF-containing regimen. Our data show that the current understanding of the Rev-RRE complex structure does not suffice and fails to rationally predict the function of naturally occurring RRE mutants. Therefore, this data should be taken into account in the development of antiviral agents that target the RRE-Rev complex. PMID:25170621

Cunyat, Francesc; Beerens, Nancy; Garcia, Elisabet; Clotet, Bonaventura; Kjems, J?rgen; Cabrera, Cecilia

2014-01-01

350

A Reporter Assay in Lamprey Embryos Reveals Both Functional Conservation and Elaboration of Vertebrate Enhancers  

PubMed Central

The sea lamprey is an important model organism for investigating the evolutionary origins of vertebrates. As more vertebrate genome sequences are obtained, evolutionary developmental biologists are becoming increasingly able to identify putative gene regulatory elements across the breadth of the vertebrate taxa. The identification of these regions makes it possible to address how changes at the genomic level have led to changes in developmental gene regulatory networks and ultimately to the evolution of morphological diversity. Comparative genomics approaches using sea lamprey have already predicted a number of such regulatory elements in the lamprey genome. Functional characterisation of these sequences and other similar elements requires efficient reporter assays in lamprey. In this report, we describe the development of a transient transgenesis method for lamprey embryos. Focusing on conserved non-coding elements (CNEs), we use this method to investigate their functional conservation across the vertebrate subphylum. We find instances of both functional conservation and lineage-specific functional evolution of CNEs across vertebrates, emphasising the utility of functionally testing homologous CNEs in their host species. PMID:24416417

Parker, Hugo J.; Sauka-Spengler, Tatjana; Bronner, Marianne; Elgar, Greg

2014-01-01

351

Fundamental gaps with approximate density functionals: The derivative discontinuity revealed from ensemble considerations  

NASA Astrophysics Data System (ADS)

The fundamental gap is a central quantity in the electronic structure of matter. Unfortunately, the fundamental gap is not generally equal to the Kohn-Sham gap of density functional theory (DFT), even in principle. The two gaps differ precisely by the derivative discontinuity, namely, an abrupt change in slope of the exchange-correlation energy as a function of electron number, expected across an integer-electron point. Popular approximate functionals are thought to be devoid of a derivative discontinuity, strongly compromising their performance for prediction of spectroscopic properties. Here we show that, in fact, all exchange-correlation functionals possess a derivative discontinuity, which arises naturally from the application of ensemble considerations within DFT, without any empiricism. This derivative discontinuity can be expressed in closed form using only quantities obtained in the course of a standard DFT calculation of the neutral system. For small, finite systems, addition of this derivative discontinuity indeed results in a greatly improved prediction for the fundamental gap, even when based on the most simple approximate exchange-correlation density functional - the local density approximation (LDA). For solids, the same scheme is exact in principle, but when applied to LDA it results in a vanishing derivative discontinuity correction. This failure is shown to be directly related to the failure of LDA in predicting fundamental gaps from total energy differences in extended systems.

Kraisler, Eli; Kronik, Leeor

2014-05-01

352

Protein similarity networks reveal relationships among sequence, structure, and function within the Cupin superfamily.  

PubMed

The cupin superfamily is extremely diverse and includes catalytically inactive seed storage proteins, sugar-binding metal-independent epimerases, and metal-dependent enzymes possessing dioxygenase, decarboxylase, and other activities. Although numerous proteins of this superfamily have been structurally characterized, the functions of many of them have not been experimentally determined. We report the first use of protein similarity networks (PSNs) to visualize trends of sequence and structure in order to make functional inferences in this remarkably diverse superfamily. PSNs provide a way to visualize relatedness of structure and sequence among a given set of proteins. Structure- and sequence-based clustering of cupin members reflects functional clustering. Networks based only on cupin domains and networks based on the whole proteins provide complementary information. Domain-clustering supports phylogenetic conclusions that the N- and C-terminal domains of bicupin proteins evolved independently. Interestingly, although many functionally similar enzymatic cupin members bind the same active site metal ion, the structure and sequence clustering does not correlate with the identity of the bound metal. It is anticipated that the application of PSNs to this superfamily will inform experimental work and influence the functional annotation of databases. PMID:24040257

Uberto, Richard; Moomaw, Ellen W

2013-01-01

353

A regulon conserved in monocot and dicot plants defines a functional module in antifungal plant immunity.  

PubMed

At least two components that modulate plant resistance against the fungal powdery mildew disease are ancient and have been conserved since the time of the monocot-dicot split (? 200 Mya). These components are the seven transmembrane domain containing MLO/MLO2 protein and the syntaxin ROR2/PEN1, which act antagonistically and have been identified in the monocot barley (Hordeum vulgare) and the dicot Arabidopsis thaliana, respectively. Additionally, syntaxin-interacting N-ethylmaleimide sensitive factor adaptor protein receptor proteins (VAMP721/722 and SNAP33/34) as well as a myrosinase (PEN2) and an ABC transporter (PEN3) contribute to antifungal resistance in both barley and/or Arabidopsis. Here, we show that these genetically defined defense components share a similar set of coexpressed genes in the two plant species, comprising a statistically significant overrepresentation of gene products involved in regulation of transcription, posttranslational modification, and signaling. Most of the coexpressed Arabidopsis genes possess a common cis-regulatory element that may dictate their coordinated expression. We exploited gene coexpression to uncover numerous components in Arabidopsis involved in antifungal defense. Together, our data provide evidence for an evolutionarily conserved regulon composed of core components and clade/species-specific innovations that functions as a module in plant innate immunity. PMID:21098265

Humphry, Matt; Bednarek, Pawel; Kemmerling, Birgit; Koh, Serry; Stein, Mónica; Göbel, Ulrike; Stüber, Kurt; Pislewska-Bednarek, Mariola; Loraine, Ann; Schulze-Lefert, Paul; Somerville, Shauna; Panstruga, Ralph

2010-12-14

354

Functional network reorganization in motor cortex can be explained by reward-modulated Hebbian learning  

PubMed Central

The control of neuroprosthetic devices from the activity of motor cortex neurons benefits from learning effects where the function of these neurons is adapted to the control task. It was recently shown that tuning properties of neurons in monkey motor cortex are adapted selectively in order to compensate for an erroneous interpretation of their activity. In particular, it was shown that the tuning curves of those neurons whose preferred directions had been misinterpreted changed more than those of other neurons. In this article, we show that the experimentally observed self-tuning properties of the system can be explained on the basis of a simple learning rule. This learning rule utilizes neuronal noise for exploration and performs Hebbian weight updates that are modulated by a global reward signal. In contrast to most previously proposed reward-modulated Hebbian learning rules, this rule does not require extraneous knowledge about what is noise and what is signal. The learning rule is able to optimize the performance of the model system within biologically realistic periods of time and under high noise levels. When the neuronal noise is fitted to experimental data, the model produces learning effects similar to those found in monkey experiments.

Legenstein, Robert; Chase, Steven M.; Schwartz, Andrew B.; Maass, Wolfgang

2011-01-01

355

Combined zebrafish-yeast chemical-genetic screens reveal gene-copper-nutrition interactions that modulate melanocyte pigmentation.  

PubMed

Hypopigmentation is a feature of copper deficiency in humans, as caused by mutation of the copper (Cu(2+)) transporter ATP7A in Menkes disease, or an inability to absorb copper after gastric surgery. However, many causes of copper deficiency are unknown, and genetic polymorphisms might underlie sensitivity to suboptimal environmental copper conditions. Here, we combined phenotypic screens in zebrafish for compounds that affect copper metabolism with yeast chemical-genetic profiles to identify pathways that are sensitive to copper depletion. Yeast chemical-genetic interactions revealed that defects in intracellular trafficking pathways cause sensitivity to low-copper conditions; partial knockdown of the analogous Ap3s1 and Ap1s1 trafficking components in zebrafish sensitized developing melanocytes to hypopigmentation in low-copper environmental conditions. Because trafficking pathways are essential for copper loading into cuproproteins, our results suggest that hypomorphic alleles of trafficking components might underlie sensitivity to reduced-copper nutrient conditions. In addition, we used zebrafish-yeast screening to identify a novel target pathway in copper metabolism for the small-molecule MEK kinase inhibitor U0126. The zebrafish-yeast screening method combines the power of zebrafish as a disease model with facile genome-scale identification of chemical-genetic interactions in yeast to enable the discovery and dissection of complex multigenic interactions in disease-gene networks. PMID:20713646

Ishizaki, Hironori; Spitzer, Michaela; Wildenhain, Jan; Anastasaki, Corina; Zeng, Zhiqiang; Dolma, Sonam; Shaw, Michael; Madsen, Erik; Gitlin, Jonathan; Marais, Richard; Tyers, Mike; Patton, E Elizabeth

2010-01-01

356

A 106 year monthly coral record reveals that the East Asian summer monsoon modulates winter PDO variability  

NASA Astrophysics Data System (ADS)

Pacific Decadal Oscillation (PDO) is a dominant climate mode in the Pacific Ocean and thought to be related to seasonal to decadal changes in sea surface conditions. Colonies of long-living Porites coral, widely used to reconstruct monthly to century-scale tropical sea surface temperature and sea surface salinity records, were discovered near Koshiki Island, Japan (31°N, 129°E). A monthly resolved, 106 year ?18O record revealed that distinct decadal-scale variability was significantly correlated with the PDO index. Our comparison showed 1 to 3 years lead-lag correlation of summer coral ?18O with the winter PDO index, suggesting that the East Asian summer monsoon (EASM) may act as the driving force of winter PDO variability over the last 100 years. Cross-spectral analysis between the winter PDO index and summer coral ?18O suggested that recent and future global warming may lead to a more frequent and/or stronger teleconnection between EASM and PDO.

Watanabe, Tsuyoshi; Kawamura, Takashi; Yamazaki, Atsuko; Murayama, Masafumi; Yamano, Hiroya

2014-05-01

357

The scaling behavior of hand motions reveals self-organization during an executive function task  

NASA Astrophysics Data System (ADS)

Recent approaches to cognition explain cognitive phenomena in terms of interaction-dominant dynamics. In the current experiment, we extend this approach to executive function, a construct used to describe flexible, goal-oriented behavior. Participants were asked to perform a widely used executive function task, card sorting, under two conditions. In one condition, participants were given a rule with which to sort the cards. In the other condition, participants had to induce the rule from experimenter feedback. The motion of each participant’s hand was tracked during the sorting task. Detrended fluctuation analysis was performed on the inter-point time series using a windowing strategy to capture changes over each trial. For participants in the induction condition, the Hurst exponent sharply increased and then decreased. The Hurst exponents for the explicit condition did not show this pattern. Our results suggest that executive function may be understood in terms of changes in stability that arise from interaction-dominant dynamics.

Anastas, Jason R.; Stephen, Damian G.; Dixon, James A.

2011-05-01

358

A CapG Gain-of-Function Mutant Reveals Critical Structure and Functional Determinants for Actin Filament Severing  

SciTech Connect

CapG is the only member of the gelsolin family unable to sever actin filaments. Changing amino acids 84-91 (severing domain) and 124-137 (WH2-containing segment) simultaneously to the sequences of gelsolin results in a mutant, CapG-sev, capable of severing actin filaments. The gain of severing function does not alter actin filament capping, but is accompanied by a higher affinity for monomeric actin, and the capacity to bind and sequester two actin monomers. Analysis of CapG-sev crystal structure suggests a more loosely folded inactive conformation than gelsolin, with a shorter S1-S2 latch. Calcium binding to S1 opens this latch and S1 becomes separated from a closely interfaced S2-S3 complex by an extended arm consisting of amino acids 118-137. Modeling with F-actin predicts that the length of this WH2-containing arm is critical for severing function, and the addition of a single amino acid (alanine or histidine) eliminates CapG-sev severing activity, confirming this prediction. We conclude that efficient severing utilizes two actin monomer-binding sites, and that the length of the WH2-containing segment is a critical functional determinant for severing.

Zhang,Y.; Vorobiev, S.; Gibson, B.; Hao, B.; Dishu, G.; Mishra, V.; Yarmola, E.; Bubb, M.; Almo, S.; Southwick, F.

2006-01-01

359

A CapG gain-of-function mutant reveals critical structural and functional determinants for actin filament severing  

PubMed Central

CapG is the only member of the gelsolin family unable to sever actin filaments. Changing amino acids 84–91 (severing domain) and 124–137 (WH2-containing segment) simultaneously to the sequences of gelsolin results in a mutant, CapG-sev, capable of severing actin filaments. The gain of severing function does not alter actin filament capping, but is accompanied by a higher affinity for monomeric actin, and the capacity to bind and sequester two actin monomers. Analysis of CapG-sev crystal structure suggests a more loosely folded inactive conformation than gelsolin, with a shorter S1–S2 latch. Calcium binding to S1 opens this latch and S1 becomes separated from a closely interfaced S2–S3 complex by an extended arm consisting of amino acids 118–137. Modeling with F-actin predicts that the length of this WH2-containing arm is critical for severing function, and the addition of a single amino acid (alanine or histidine) eliminates CapG-sev severing activity, confirming this prediction. We conclude that efficient severing utilizes two actin monomer-binding sites, and that the length of the WH2-containing segment is a critical functional determinant for severing. PMID:16977317

Zhang, Y; Vorobiev, Sergey M; Gibson, Bruce G; Hao, Binghua; Sidhu, Gurjit S; Mishra, Vishnu S; Yarmola, Elena G; Bubb, Michael R; Almo, Steven C; Southwick, Frederick S

2006-01-01

360

Analysis of Graph Invariants in Functional Neocortical Circuitry Reveals Generalized Features Common to Three Areas of Sensory Cortex  

PubMed Central

Correlations in local neocortical spiking activity can provide insight into the underlying organization of cortical microcircuitry. However, identifying structure in patterned multi-neuronal spiking remains a daunting task due to the high dimensionality of the activity. Using two-photon imaging, we monitored spontaneous circuit dynamics in large, densely sampled neuronal populations within slices of mouse primary auditory, somatosensory, and visual cortex. Using the lagged correlation of spiking activity between neurons, we generated functional wiring diagrams to gain insight into the underlying neocortical circuitry. By establishing the presence of graph invariants, which are label-independent characteristics common to all circuit topologies, our study revealed organizational features that generalized across functionally distinct cortical regions. Regardless of sensory area, random and -nearest neighbors null graphs failed to capture the structure of experimentally derived functional circuitry. These null models indicated that despite a bias in the data towards spatially proximal functional connections, functional circuit structure is best described by non-random and occasionally distal connections. Eigenvector centrality, which quantifies the importance of a neuron in the temporal flow of circuit activity, was highly related to feedforwardness in all functional circuits. The number of nodes participating in a functional circuit did not scale with the number of neurons imaged regardless of sensory area, indicating that circuit size is not tied to the sampling of neocortex. Local circuit flow comprehensively covered angular space regardless of the spatial scale that we tested, demonstrating that circuitry itself does not bias activity flow toward pia. Finally, analysis revealed that a minimal numerical sample size of neurons was necessary to capture at least 90 percent of functional circuit topology. These data and analyses indicated that functional circuitry exhibited rules of organization which generalized across three areas of sensory neocortex. PMID:25010654

Gururangan, Suchin S.; Sadovsky, Alexander J.; MacLean, Jason N.

2014-01-01

361

Comparative genome analysis of PHB gene family reveals deep evolutionary origins and diverse gene function  

PubMed Central

Background PHB (Prohibitin) gene family is involved in a variety of functions important for different biological processes. PHB genes are ubiquitously present in divergent species from prokaryotes to eukaryotes. Human PHB genes have been found to be associated with various diseases. Recent studies by our group and others have shown diverse function of PHB genes in plants for development, senescence, defence, and others. Despite the importance of the PHB gene family, no comprehensive gene family analysis has been carried to evaluate the relatedness of PHB genes across different species. In order to better guide the gene function analysis and understand the evolution of the PHB gene family, we therefore carried out the comparative genome analysis of the PHB genes across different kingdoms. Results The relatedness, motif distribution, and intron/exon distribution all indicated that PHB genes is a relatively conserved gene family. The PHB genes can be classified into 5 classes and each class have a very deep evolutionary origin. The PHB genes within the class maintained the same motif patterns during the evolution. With Arabidopsis as the model species, we found that PHB gene intron/exon structure and domains are also conserved during the evolution. Despite being a conserved gene family, various gene duplication events led to the expansion of the PHB genes. Both segmental and tandem gene duplication were involved in Arabidopsis PHB gene family expansion. However, segmental duplication is predominant in Arabidopsis. Moreover, most of the duplicated genes experienced neofunctionalization. The results highlighted that PHB genes might be involved in important functions so that the duplicated genes are under the evolutionary pressure to derive new function. Conclusion PHB gene family is a conserved gene family and accounts for diverse but important biological functions based on the similar molecular mechanisms. The highly diverse biological function indicated that more research needs to be carried out to dissect the PHB gene function. The conserved gene evolution indicated that the study in the model species can be translated to human and mammalian studies. PMID:20946606

2010-01-01

362

Integrating abundance and functional traits reveals new global hotspots of fish diversity.  

PubMed

Species richness has dominated our view of global biodiversity patterns for centuries. The dominance of this paradigm is reflected in the focus by ecologists and conservation managers on richness and associated occurrence-based measures for understanding drivers of broad-scale diversity patterns and as a biological basis for management. However, this is changing rapidly, as it is now recognized that not only the number of species but the species present, their phenotypes and the number of individuals of each species are critical in determining the nature and strength of the relationships between species diversity and a range of ecological functions (such as biomass production and nutrient cycling). Integrating these measures should provide a more relevant representation of global biodiversity patterns in terms of ecological functions than that provided by simple species counts. Here we provide comparisons of a traditional global biodiversity distribution measure based on richness with metrics that incorporate species abundances and functional traits. We use data from standardized quantitative surveys of 2,473 marine reef fish species at 1,844 sites, spanning 133 degrees of latitude from all ocean basins, to identify new diversity hotspots in some temperate regions and the tropical eastern Pacific Ocean. These relate to high diversity of functional traits amongst individuals in the community (calculated using Rao's Q), and differ from previously reported patterns in functional diversity and richness for terrestrial animals, which emphasize species-rich tropical regions only. There is a global trend for greater evenness in the number of individuals of each species, across the reef fish species observed at sites ('community evenness'), at higher latitudes. This contributes to the distribution of functional diversity hotspots and contrasts with well-known latitudinal gradients in richness. Our findings suggest that the contribution of species diversity to a range of ecosystem functions varies over large scales, and imply that in tropical regions, which have higher numbers of species, each species contributes proportionally less to community-level ecological processes on average than species in temperate regions. Metrics of ecological function usefully complement metrics of species diversity in conservation management, including when identifying planning priorities and when tracking changes to biodiversity values. PMID:24067714

Stuart-Smith, Rick D; Bates, Amanda E; Lefcheck, Jonathan S; Duffy, J Emmett; Baker, Susan C; Thomson, Russell J; Stuart-Smith, Jemina F; Hill, Nicole A; Kininmonth, Stuart J; Airoldi, Laura; Becerro, Mikel A; Campbell, Stuart J; Dawson, Terence P; Navarrete, Sergio A; Soler, German A; Strain, Elisabeth M A; Willis, Trevor J; Edgar, Graham J

2013-09-26

363

A systems approach to orbitofrontal cortex function: recordings in rat orbitofrontal cortex reveal interactions with different learning systems.  

PubMed

The recognition that certain aspects of prefrontal function can be effectively modeled in rats has led to a slow expansion of interest in rat prefrontal cortex over the past decade. One of the most promising of these model systems is the orbitofrontal cortex of the rat. Rat orbitofrontal cortex is anatomically similar to the orbital prefrontal region in primates, and this similarity is borne out by behavioral and neurophysiological findings. Here we will present data on orbitofrontal cortex function from a number of parallel studies from our laboratories that employed single unit recording techniques to probe neural encoding in rat orbitofrontal cortex and related parts of the amygdala and the hippocampal memory systems. Together, these reports and associated behavioral studies suggest that the orbitofrontal region, in both rats and primates, is specialized to integrate concrete and abstract sensory constructs with information regarding the incentive value of associated outcomes to guide or modulate behavior. To the extent that monkey prefrontal function can model certain aspects of human prefrontal function, we argue that this model can now be extended to the rat orbitofrontal cortex. In addition, we argue that the function of orbitofrontal cortex needs to be considered in terms of its interactions with other brain systems. PMID:14643456

Schoenbaum, Geoffrey; Setlow, Barry; Ramus, Seth J

2003-11-30

364

Modulated electromagnetic fields in inhomogeneous media, hyperbolic pseudoanalytic functions and transmutations  

E-print Network

The time-dependent Maxwell system describing electromagnetic wave propagation in inhomogeneous isotropic media in the one-dimensional case reduces to a Vekua-type equation for bicomplex-valued functions of a hyperbolic variable (see arXiv:1001.0552). Using this relation we solve the problem of the transmission through an inhomogeneous layer of a normally incident electromagnetic time-dependent plane wave. The solution is written in terms of a pair of Darboux-associated transmutation operators (see arXiv:1111.4449), and combined with the recent results on their construction (see arXiv:1208.6166, arXiv:1306.2914) can be used for efficient computation of the transmitted modulated signals. We develop the corresponding numerical method and illustrate its performance with examples.

Kira V. Khmelnytskaya; Vladislav V. Kravchenko; Sergii M. Torba

2014-10-17

365

Analyzing wavelength behavior of a cubic phase mask imaging system based on modulation transfer function  

NASA Astrophysics Data System (ADS)

The wavefront coding technology is an effectively method for extending the depth of field. However, the phase delayed by the phase mask changes with light wavelength, and the chromatic aberration is caused by chromatic dispersion of the optical elements. The modulation transfer function (MTF) of the cubic phase mask (CPM) system is derived with considering the axial chromatic aberration and optical path difference variation with wavelength, and the wavelength behavior of CPM system is analyzed in details. We yield that the MTF is approximately wavelength invariant within a certain frequency bandwidth, and the bandwidth is nearly inverse proportional to wavelength and varies with axial chromatic aberration. The effect induced by dispersion of the CPM material is very weak. If the CPM system is illuminated by wideband spectral light and the ACA exists, then the frequency bandwidth may become narrower than the monochromatic case, and the position of image sensor can be relocated to balance frequency bandwidth among all wavelengths.

Zhang, Rongfu; Zhang, Min; Lu, Kang; Wang, Tao; Wang, Liangliang; Zhuang, Songlin

2012-03-01

366

A method for modulation transfer function determination from blood vessel profiles measured in computed tomography  

NASA Astrophysics Data System (ADS)

The recent CT systems yield high spatial resolution in all directions of volumetric images in clinical routine. The quantitative characterization of the performance of CT systems is important for comparing the effects of different scan and reconstruction parameters, for comparing between different CT systems, and for evaluating the accuracy of size and density measurements of fine details in CT images. This paper presents a method to determine the modulation transfer function (MTF) in the scan plane obtained by CT system from profiles of human anatomical structures such as blood vessel measured by clinical measurement conditions without magnified reconstruction. MTF estimations are performed for cylindrical tube phantoms with three different diameters (1 mm, 2 mm, and 3 mm) injected by solution of contrast material and human blood vessels measured by the clinical measurement conditions. We demonstrate the potential usefulness of the method for estimating the MTF from blood vessel profiles measured in CT systems.

Nakaya, Y.; Kawata, Y.; Niki, N.; Ohmatsu, H.; Moriyama, N.

2012-03-01

367

Numerical Simulation of the Modulation Transfer Function in HgCdTe Detector Arrays  

NASA Astrophysics Data System (ADS)

In this work, we develop a method for simulating the modulation transfer function (MTF) of infrared detector arrays, which is based on numerical evaluation of the detector physics. The finite-difference time-domain and finite element methods are used to solve the electromagnetic and electrical equations for the device, respectively. We show how the total MTF can be deconvolved to examine the effects of specific physical processes. We introduce the MTF area difference and use it to quantify the effectiveness of several crosstalk mitigation techniques in improving the system MTF. We then apply our simulation methods to two-thirds generation mercury cadmium telluride (HgCdTe) detector architectures. The methodology is general, can be implemented with commercially available software, has experimentally realizable analogs, and is extendable to other material systems and device designs.

Pinkie, Benjamin; Bellotti, Enrico

2014-08-01

368

Materials for inductive and microwave function integration in LTCC-technology multichip modules  

NASA Astrophysics Data System (ADS)

Low Temperature cofired ceramics technology (LTCC) receives considerable industrial interest as a multichip module integration technology, particularly because its very good performance-cost combination. The integration potential of the LTCC technology will be significantly extended with the availability of LTCC-compatible low firing magnetic materials that will enable the integration of high frequency inductive functions. In this article the preparation of low firing cobalt containing hexagonal ferrite materials of the Z-structure (Ba3Co2Fe24O41, or Co-Z) is described using a PbO-WO3 eutectic mixture as liquid phase sintering additive. Layers from the previous materials are prepared by the slip-casting technique and cofired with commercially available, low dielectric constant, LTCC tapes. Crack free multilayer structures are achieved after firing at 950-1000°C.

Zaspalis, V. T.; Kolenbrander, M.; Boerekamp, J.

2005-01-01

369

An ATP-competitive inhibitor modulates the allosteric function of the HER3 pseudokinase.  

PubMed

Human epidermal growth factor receptor 3 (HER3) is a receptor tyrosine kinase that lacks catalytic activity but is essential for cellular homeostasis due to its ability to allosterically activate EGFR and HER2. Although catalytically inactive, HER3 binds ATP tightly, hinting at a possible role of the nucleotide-binding pocket in modulating HER3 function. We report a structure of the HER3 pseudokinase bound to the ATP-competitive inhibitor bosutinib. Previously solved structures show that bosutinib can potently interact with multiple kinase domain conformations. In complex with HER3, bosutinib binds to yet another conformation, which is nearly identical to that observed in the HER3-ATP complex. Interestingly, occupation of the ATP-binding site by bosutinib improves the ability of HER3 to act as an allosteric activator of EGFR in vitro by increasing the affinity of the HER3-EGFR heterodimer in a membrane-dependent manner. PMID:24656791

Littlefield, Peter; Moasser, Mark M; Jura, Natalia

2014-04-24

370

Selective attention modulates neural substrates of repetition priming and "implicit" visual memory: suppressions and enhancements revealed by FMRI.  

PubMed

Attention can enhance processing for relevant information and suppress this for ignored stimuli. However, some residual processing may still arise without attention. Here we presented overlapping outline objects at study, with subjects attending to those in one color but not the other. Attended objects were subsequently recognized on a surprise memory test, whereas there was complete amnesia for ignored items on such direct explicit testing; yet reliable behavioral priming effects were found on indirect testing. Event-related fMRI examined neural responses to previously attended or ignored objects, now shown alone in the same or mirror-reversed orientation as before, intermixed with new items. Repetition-related decreases in fMRI responses for objects previously attended and repeated in the same orientation were found in the right posterior fusiform, lateral occipital, and left inferior frontal cortex. More anterior fusiform regions also showed some repetition decreases for ignored objects, irrespective of orientation. View-specific repetition decreases were found in the striate cortex, particularly for previously attended items. In addition, previously ignored objects produced some fMRI response increases in the bilateral lingual gyri, relative to new objects. Selective attention at exposure can thus produce several distinct long-term effects on processing of stimuli repeated later, with neural response suppression stronger for previously attended objects, and some response enhancement for previously ignored objects, with these effects arising in different brain areas. Although repetition decreases may relate to positive priming phenomena, the repetition increases for ignored objects shown here for the first time might relate to processes that can produce "negative priming" in some behavioral studies. These results reveal quantitative and qualitative differences between neural substrates of long-term repetition effects for attended versus unattended objects. PMID:16197681

Vuilleumier, Patrik; Schwartz, Sophie; Duhoux, Stéphanie; Dolan, Raymond J; Driver, Jon

2005-08-01

371

Functional Dynamics of the Folded Ankyrin Repeats of I?B? Revealed by Nuclear Magnetic Resonance†  

PubMed Central

Inhibition of nuclear factor ?B (NF-?B) is mainly accomplished by I?B?, which consists of a signal response sequence at the N-terminus, a six-ankyrin repeat domain (ARD) that binds NF-?B, and a C-terminal PEST sequence. Previous studies with the ARD revealed that the fifth and sixth repeats are only partially folded in the absence of NF-?B. Here we report NMR studies of a truncated version of I?B?, containing only the first four ankyrin repeats, I?B?(67?206). This four-repeat segment is well-structured in the free state, enabling full resonance assignments to be made. H?D exchange, backbone dynamics, and residual dipolar coupling (RDC) experiments reveal regions of flexibility. In addition, regions consistent with the presence of micro- to millisecond motions occur periodically throughout the repeat structure. Comparison of the RDCs with the crystal structure gave only moderate agreement, but an ensemble of structures generated by accelerated molecular dynamics gave much better agreement with the measured RDCs. The regions showing flexibility correspond to those implicated in entropic compensation for the loss of flexibility in ankyrin repeats 5 and 6 upon binding to NF-?B. The regions showing micro- to millisecond motions in the free protein are the ends of the ?-hairpins that directly interact with NF-?B in the complex. PMID:19591507

2009-01-01

372

Argonne University scientists reveal insect respiratory function with x-rays  

NSDL National Science Digital Library

This article from The University of Chicago Chronicle describes a visualization of airways in a living insect using x-rays produced by a particle accelerator. The focus of the article is the understanding of insect morphology and function. Two images vividly illustrate insect respiration.

2013-06-27

373

Coupling of functional connectivity and regional cerebral blood flow reveals a physiological basis  

E-print Network

of human brain functional connectome. fMRI | connectomics | graph theory | modularity | metabolism for network hubs of the human brain Xia Lianga,b,1 , Qihong Zouc,1 , Yong Heb,2 , and Yihong Yanga,2, St. Louis, MO, and approved December 11, 2012 (received for review August 29, 2012) Human brain

Reber, Paul J.