SH2-catalytic domain linker heterogeneity influences allosteric coupling across the SFK family.

Science.gov (United States)

Register, A C; Leonard, Stephen E; Maly, Dustin J

2014-11-11

Src-family kinases (SFKs) make up a family of nine homologous multidomain tyrosine kinases whose misregulation is responsible for human disease (cancer, diabetes, inflammation, etc.). Despite overall sequence homology and identical domain architecture, differences in SH3 and SH2 regulatory domain accessibility and ability to allosterically autoinhibit the ATP-binding site have been observed for the prototypical SFKs Src and Hck. Biochemical and structural studies indicate that the SH2-catalytic domain (SH2-CD) linker, the intramolecular binding epitope for SFK SH3 domains, is responsible for allosterically coupling SH3 domain engagement to autoinhibition of the ATP-binding site through the conformation of the αC helix. As a relatively unconserved region between SFK family members, SH2-CD linker sequence variability across the SFK family is likely a source of nonredundant cellular functions between individual SFKs via its effect on the availability of SH3 and SH2 domains for intermolecular interactions and post-translational modification. Using a combination of SFKs engineered with enhanced or weakened regulatory domain intramolecular interactions and conformation-selective inhibitors that report αC helix conformation, this study explores how SH2-CD sequence heterogeneity affects allosteric coupling across the SFK family by examining Lyn, Fyn1, and Fyn2. Analyses of Fyn1 and Fyn2, isoforms that are identical but for a 50-residue sequence spanning the SH2-CD linker, demonstrate that SH2-CD linker sequence differences can have profound effects on allosteric coupling between otherwise identical kinases. Most notably, a dampened allosteric connection between the SH3 domain and αC helix leads to greater autoinhibitory phosphorylation by Csk, illustrating the complex effects of SH2-CD linker sequence on cellular function.

Butane-1,2,3,4-tetraol-based amphiphilic stereoisomers for membrane protein study: importance of chirality in the linker region

DEFF Research Database (Denmark)

Das, Manabendra; Du, Yang; Mortensen, Jonas S.

2017-01-01

of the targeted membrane proteins depending on the chirality of the linker region. These findings indicate an important role for detergent stereochemistry in membrane protein stabilization. In addition, we generally observed enhanced detergent efficacy with increasing alkyl chain length, reinforcing...

Crystal structure of the Src family kinase Hck SH3-SH2 linker regulatory region supports an SH3-dominant activation mechanism.

Science.gov (United States)

Alvarado, John J; Betts, Laurie; Moroco, Jamie A; Smithgall, Thomas E; Yeh, Joanne I

2010-11-12

Most mammalian cell types depend on multiple Src family kinases (SFKs) to regulate diverse signaling pathways. Strict control of SFK activity is essential for normal cellular function, and loss of kinase regulation contributes to several forms of cancer and other diseases. Previous x-ray crystal structures of the SFKs c-Src and Hck revealed that intramolecular association of their Src homology (SH) 3 domains and SH2 kinase linker regions has a key role in down-regulation of kinase activity. However, the amino acid sequence of the Hck linker represents a suboptimal ligand for the isolated SH3 domain, suggesting that it may form the polyproline type II helical conformation required for SH3 docking only in the context of the intact structure. To test this hypothesis directly, we determined the crystal structure of a truncated Hck protein consisting of the SH2 and SH3 domains plus the linker. Despite the absence of the kinase domain, the structures and relative orientations of the SH2 and SH3 domains in this shorter protein were very similar to those observed in near full-length, down-regulated Hck. However, the SH2 kinase linker adopted a modified topology and failed to engage the SH3 domain. This new structure supports the idea that these noncatalytic regions work together as a "conformational switch" that modulates kinase activity in a manner unique to the SH3 domain and linker topologies present in the intact Hck protein. Our results also provide fresh structural insight into the facile induction of Hck activity by HIV-1 Nef and other Hck SH3 domain binding proteins and implicate the existence of innate conformational states unique to individual Src family members that "fine-tune" their sensitivities to activation by SH3-based ligands.

A histidine-rich linker region in peptidylglycine α-amidating monooxygenase has the properties of a pH sensor.

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Vishwanatha, Kurutihalli; Bäck, Nils; Mains, Richard E; Eipper, Betty A

2014-05-02

Decreasing luminal pH is thought to play a role in the entry of newly synthesized and endocytosed membrane proteins into secretory granules. The two catalytic domains of peptidylglycine α-amidating monooxygenase (PAM), a type I integral membrane protein, catalyze the sequential reactions that convert peptidyl-Gly substrates into amidated products. We explored the hypothesis that a conserved His-rich cluster (His-Gly-His-His) in the linker region connecting its two catalytic domains senses pH and affects PAM trafficking by mutating these His residues to Ala (Ala-Gly-Ala-Ala; H3A). Purified recombinant wild-type and H3A linker peptides were examined using circular dichroism and tryptophan fluorescence; mutation of the His cluster largely eliminated its pH sensitivity. An enzymatically active PAM protein with the same mutations (PAM-1/H3A) was expressed in HEK293 cells and AtT-20 corticotrope tumor cells. Metabolic labeling followed by immunoprecipitation revealed more rapid loss of newly synthesized PAM-1/H3A than PAM-1; although release of newly synthesized monofunctional PHM/H3A was increased, release of soluble bifunctional PAM/H3A, a product of the endocytic pathway, was decreased. Surface biotinylation revealed rapid loss of PAM-1/H3A, with no detectable return of the mutant protein to secretory granules. Consistent with its altered endocytic trafficking, little PAM-1/H3A was subjected to regulated intramembrane proteolysis followed by release of a small nuclear-targeted cytosolic fragment. AtT-20 cells expressing PAM-1/H3A adopted the morphology of wild-type AtT-20 cells; secretory products no longer accumulated in the trans-Golgi network and secretory granule exocytosis was more responsive to secretagogue.

Disruption of the IS6-AID linker affects voltage-gated calcium channel inactivation and facilitation.

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Findeisen, Felix; Minor, Daniel L

2009-03-01

Two processes dominate voltage-gated calcium channel (Ca(V)) inactivation: voltage-dependent inactivation (VDI) and calcium-dependent inactivation (CDI). The Ca(V)beta/Ca(V)alpha(1)-I-II loop and Ca(2+)/calmodulin (CaM)/Ca(V)alpha(1)-C-terminal tail complexes have been shown to modulate each, respectively. Nevertheless, how each complex couples to the pore and whether each affects inactivation independently have remained unresolved. Here, we demonstrate that the IS6-alpha-interaction domain (AID) linker provides a rigid connection between the pore and Ca(V)beta/I-II loop complex by showing that IS6-AID linker polyglycine mutations accelerate Ca(V)1.2 (L-type) and Ca(V)2.1 (P/Q-type) VDI. Remarkably, mutations that either break the rigid IS6-AID linker connection or disrupt Ca(V)beta/I-II association sharply decelerate CDI and reduce a second Ca(2+)/CaM/Ca(V)alpha(1)-C-terminal-mediated process known as calcium-dependent facilitation. Collectively, the data strongly suggest that components traditionally associated solely with VDI, Ca(V)beta and the IS6-AID linker, are essential for calcium-dependent modulation, and that both Ca(V)beta-dependent and CaM-dependent components couple to the pore by a common mechanism requiring Ca(V)beta and an intact IS6-AID linker.

Novel Concepts of MS-Cleavable Cross-linkers for Improved Peptide Structure Analysis

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Hage, Christoph; Falvo, Francesco; Schäfer, Mathias; Sinz, Andrea

2017-10-01

The chemical cross-linking/mass spectrometry (MS) approach is gaining increasing importance as an alternative method for studying protein conformation and for deciphering protein interaction networks. This study is part of our ongoing efforts to develop innovative cross-linking principles for a facile and efficient assignment of cross-linked products. We evaluate two homobifunctional, amine-reactive, and MS-cleavable cross-linkers regarding their potential for automated analysis of cross-linked products. We introduce the bromine phenylurea (BrPU) linker that possesses a unique structure yielding a distinctive fragmentation pattern on collisional activation. Moreover, BrPU delivers the characteristic bromine isotope pattern and mass defect for all cross-linker-decorated fragments. We compare the fragmentation behavior of the BrPU linker with that of our previously described MS-cleavable TEMPO-Bz linker (which consists of a 2,2,6,6-tetramethylpiperidine-1-oxy moiety connected to a benzyl group) that was developed to perform free-radical-initiated peptide sequencing. Comparative collisional activation experiments (collision-induced dissociation and higher-energy collision-induced dissociation) with both cross-linkers were conducted in negative electrospray ionization mode with an Orbitrap Fusion mass spectrometer using five model peptides. As hypothesized in a previous study, the presence of a cross-linked N-terminal aspartic acid residue seems to be the prerequisite for the loss of an intact peptide from the cross-linked products. As the BrPU linker combines a characteristic mass shift with an isotope signature, it presents a more favorable combination for automated assignment of cross-linked products compared with the TEMPO-Bz linker. [Figure not available: see fulltext.

Structure of calmodulin complexed with an olfactory CNG channel fragment and role of the central linker: Residual dipolar couplings to evaluate calmodulin binding modes outside the kinase family

International Nuclear Information System (INIS)

Contessa, Gian Marco; Orsale, Maria; Melino, Sonia; Torre, Vincent; Paci, Maurizio; Desideri, Alessandro; Cicero, Daniel O.

2005-01-01

The NMR high-resolution structure of calmodulin complexed with a fragment of the olfactory cyclic-nucleotide gated channel is described. This structure shows features that are unique for this complex, including an active role of the linker connecting the N- and C-lobes of calmodulin upon binding of the peptide. Such linker is not only involved in the formation of an hydrophobic pocket to accommodate a bulky peptide residue, but it also provides a positively charged region complementary to a negative charge of the target. This complex of calmodulin with a target not belonging to the kinase family was used to test the residual dipolar coupling (RDC) approach for the determination of calmodulin binding modes to peptides. Although the complex here characterized belongs to the (1--14) family, high Q values were obtained with all the 1:1 complexes for which crystalline structures are available. Reduction of the RDC data set used for the correlation analysis to structured regions of the complex allowed a clear identification of the binding mode. Excluded regions comprise calcium binding loops and loops connecting the EF-hand motifs

Stability and function of interdomain linker variants of glucoamylase 1 from Aspergillus niger.

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Sauer, J; Christensen, T; Frandsen, T P; Mirgorodskaya, E; McGuire, K A; Driguez, H; Roepstorff, P; Sigurskjold, B W; Svensson, B

2001-08-07

Several variants of glucoamylase 1 (GA1) from Aspergillus niger were created in which the highly O-glycosylated peptide (aa 468--508) connecting the (alpha/alpha)(6)-barrel catalytic domain and the starch binding domain was substituted at the gene level by equivalent segments of glucoamylases from Hormoconis resinae, Humicola grisea, and Rhizopus oryzae encoding 5, 19, and 36 amino acid residues. Variants were constructed in which the H. resinae linker was elongated by proline-rich sequences as this linker itself apparently was too short to allow formation of the corresponding protein variant. Size and isoelectric point of GA1 variants reflected differences in linker length, posttranslational modification, and net charge. While calculated polypeptide chain molecular masses for wild-type GA1, a nonnatural proline-rich linker variant, H. grisea, and R. oryzae linker variants were 65,784, 63,777, 63,912, and 65,614 Da, respectively, MALDI-TOF-MS gave values of 82,042, 73,800, 73,413, and 90,793 Da, respectively, where the latter value could partly be explained by an N-glycosylation site introduced near the linker C-terminus. The k(cat) and K(m) for hydrolysis of maltooligodextrins and soluble starch, and the rate of hydrolysis of barley starch granules were essentially the same for the variants as for wild-type GA1. beta-Cyclodextrin, acarbose, and two heterobidentate inhibitors were found by isothermal titration calorimetry to bind to the catalytic and starch binding domains of the linker variants, indicating that the function of the active site and the starch binding site was maintained. The stability of GA1 linker variants toward GdnHCl and heat, however, was reduced compared to wild-type.

Modulation of procaspase-7 self-activation by PEST amino acid residues of the N-terminal prodomain and intersubunit linker.

Science.gov (United States)

Alves, Juliano; Garay-Malpartida, Miguel; Occhiucci, João M; Belizário, José E

2017-12-01

Procaspase-7 zymogen polypeptide is composed of a short prodomain, a large subunit (p20), and a small subunit (p10) connected to an intersubunit linker. Caspase-7 is activated by an initiator caspase-8 and -9, or by autocatalysis after specific cleavage at IQAD 198 ↓S located at the intersubunit linker. Previously, we identified that PEST regions made of amino acid residues Pro (P), Glu (E), Asp (D), Ser (S), Thr (T), Asn (N), and Gln (Q) are conserved flanking amino acid residues in the cleavage sites within a prodomain and intersubunit linker of all caspase family members. Here we tested the impact of alanine substitution of PEST amino acid residues on procaspase-7 proteolytic self-activation directly in Escherichia coli. The p20 and p10 subunit cleavage were significantly delayed in double caspase-7 mutants in the prodomain (N18A/P26A) and intersubunit linker (S199A/P201A), compared with the wild-type caspase-7. The S199A/P201A mutants effectively inhibited the p10 small subunit cleavage. However, the mutations did not change the kinetic parameters (k cat /K M ) and optimal tetrapeptide specificity (DEVD) of the purified mutant enzymes. The results suggest a role of PEST-amino acid residues in the molecular mechanism for prodomain and intersubunit cleavage and caspase-7 self-activation.

Dynamics of Linker Residues Modulate the Nucleic Acid Binding Properties of the HIV-1 Nucleocapsid Protein Zinc Fingers

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Zargarian, Loussiné; Tisné, Carine; Barraud, Pierre; Xu, Xiaoqian; Morellet, Nelly; René, Brigitte; Mély, Yves; Fossé, Philippe; Mauffret, Olivier

2014-01-01

The HIV-1 nucleocapsid protein (NC) is a small basic protein containing two zinc fingers (ZF) separated by a short linker. It is involved in several steps of the replication cycle and acts as a nucleic acid chaperone protein in facilitating nucleic acid strand transfers occurring during reverse transcription. Recent analysis of three-dimensional structures of NC-nucleic acids complexes established a new property: the unpaired guanines targeted by NC are more often inserted in the C-terminal zinc finger (ZF2) than in the N-terminal zinc finger (ZF1). Although previous NMR dynamic studies were performed with NC, the dynamic behavior of the linker residues connecting the two ZF domains remains unclear. This prompted us to investigate the dynamic behavior of the linker residues. Here, we collected 15N NMR relaxation data and used for the first time data at several fields to probe the protein dynamics. The analysis at two fields allows us to detect a slow motion occurring between the two domains around a hinge located in the linker at the G35 position. However, the amplitude of motion appears limited in our conditions. In addition, we showed that the neighboring linker residues R29, A30, P31, R32, K33 displayed restricted motion and numerous contacts with residues of ZF1. Our results are fully consistent with a model in which the ZF1-linker contacts prevent the ZF1 domain to interact with unpaired guanines, whereas the ZF2 domain is more accessible and competent to interact with unpaired guanines. In contrast, ZF1 with its large hydrophobic plateau is able to destabilize the double-stranded regions adjacent to the guanines bound by ZF2. The linker residues and the internal dynamics of NC regulate therefore the different functions of the two zinc fingers that are required for an optimal chaperone activity. PMID:25029439

A Class of Rigid Linker-bearing Glucosides for Membrane Protein Structural Study

DEFF Research Database (Denmark)

Sadaf, Aiman; Mortensen, Jonas S; Capaldi, Stefano

2016-01-01

with a branched tail group and a triglucoside head group. These head and tail groups were connected via an amide or ether linkage by using a tris(hydroxylmethyl)aminomethane (TRIS) or neopentyl glycol (NPG) linker to produce TRIS-derived triglucosides (TDTs) and NPG-derived triglucosides (NDTs), respectively...

Preferential 5-Methylcytosine Oxidation in the Linker Region of Reconstituted Positioned Nucleosomes by Tet1 Protein.

Science.gov (United States)

Kizaki, Seiichiro; Zou, Tingting; Li, Yue; Han, Yong-Woon; Suzuki, Yuki; Harada, Yoshie; Sugiyama, Hiroshi

2016-11-07

Tet (ten-eleven translocation) family proteins oxidize 5-methylcytosine (mC) to 5-hydroxymethylcytosine (hmC), 5-formylcytosine (fC), and 5-carboxycytosine (caC), and are suggested to be involved in the active DNA demethylation pathway. In this study, we reconstituted positioned mononucleosomes using CpG-methylated 382 bp DNA containing the Widom 601 sequence and recombinant histone octamer, and subjected the nucleosome to treatment with Tet1 protein. The sites of oxidized methylcytosine were identified by bisulfite sequencing. We found that, for the oxidation reaction, Tet1 protein prefers mCs located in the linker region of the nucleosome compared with those located in the core region. © 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Synthesis of Selective Butyrylcholinesterase Inhibitors Coupled between α-Lipoic Acid and Polyphenols by Using 2-(Piperazin-1-yl)ethanol Linker

International Nuclear Information System (INIS)

Yeun, Go Heun; Lee, Seung Hwan; LIm, Yong Bae; Lee, Hye Sook; Lee, Bong Ho; Park, Jeong Ho; Won, Mooho

2013-01-01

In the previous paper (Bull. Korean Chem. Soc., 2011, 32, 2997), the hybrid molecules between α-lipoic acid (ALA) and polyphenols (PPs) connected with neutral 2-(2-aminoethoxy)ethanol linker (linker-1) showed new biological activity such as butyrylcholinesterase (BuChE) inhibition. In order to increase the binding affinity of the hybrid compounds to cholinesterase (ChE), the neutral 2-(2-aminoethoxy)ethanol (linker 1) was switched to the cationic 2-(piperazin-1-yl)ethanol linker (linker 2). The IC 50 values of the linker-2 hybrid molecules for BuChE inhibition were lower than those of linker-1 hybrid molecules (except 9-2) and they also had the same great selectivity for BuChE over AChE (> 800 fold) as linker-1 hybrid molecules. ALA-acetyl caffeic acid (10-2, ALA-AcCA) was shown as an effective inhibitor of BuChE (IC 50 = 0.44 ± 0.24 μM). A kinetic study using 7-2 showed that it is the same mixed type inhibition as 7-1. Its inhibition constant (Ki) to BuChE is 4.3 ± 0.09 μM

Synthesis of Selective Butyrylcholinesterase Inhibitors Coupled between α-Lipoic Acid and Polyphenols by Using 2-(Piperazin-1-yl)ethanol Linker

Energy Technology Data Exchange (ETDEWEB)

Yeun, Go Heun; Lee, Seung Hwan; LIm, Yong Bae; Lee, Hye Sook; Lee, Bong Ho; Park, Jeong Ho [Hanbat National Univ., Daejeon (Korea, Republic of); Won, Mooho [Kangwon National Univ., Chuncheon (Korea, Republic of)

2013-04-15

In the previous paper (Bull. Korean Chem. Soc., 2011, 32, 2997), the hybrid molecules between α-lipoic acid (ALA) and polyphenols (PPs) connected with neutral 2-(2-aminoethoxy)ethanol linker (linker-1) showed new biological activity such as butyrylcholinesterase (BuChE) inhibition. In order to increase the binding affinity of the hybrid compounds to cholinesterase (ChE), the neutral 2-(2-aminoethoxy)ethanol (linker 1) was switched to the cationic 2-(piperazin-1-yl)ethanol linker (linker 2). The IC{sub 50} values of the linker-2 hybrid molecules for BuChE inhibition were lower than those of linker-1 hybrid molecules (except 9-2) and they also had the same great selectivity for BuChE over AChE (> 800 fold) as linker-1 hybrid molecules. ALA-acetyl caffeic acid (10-2, ALA-AcCA) was shown as an effective inhibitor of BuChE (IC{sub 50} = 0.44 ± 0.24 μM). A kinetic study using 7-2 showed that it is the same mixed type inhibition as 7-1. Its inhibition constant (Ki) to BuChE is 4.3 ± 0.09 μM.

Solid colloids with surface-mobile linkers

International Nuclear Information System (INIS)

Van der Meulen, Stef A J; Helms, Gesa; Dogterom, Marileen

2015-01-01

In this report we review the possibilities of using colloids with surface mobile linkers for the study of colloidal self-assembly processes. A promising route to create systems with mobile linkers is the use of lipid (bi-)layers. These lipid layers can be either used in the form of vesicles or as coatings for hard colloids and emulsion droplets. Inside the lipid bilayers molecules can be inserted via membrane anchors. Due to the fluidity of the lipid bilayer, the anchored molecules remain mobile. The use of different lipid mixtures even allows creating Janus-like particles that exhibit directional bonding if linkers are used which have a preference for a certain lipid phase. In nature mobile linkers can be found e.g. as receptors in cells. Therefore, towards the end of the review, we also briefly address the possibility of using colloids with surface mobile linkers as model systems to mimic cell–cell interactions and cell adhesion processes. (topical review)

Structural Mechanisms of Nucleosome Recognition by Linker Histones.

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Zhou, Bing-Rui; Jiang, Jiansheng; Feng, Hanqiao; Ghirlando, Rodolfo; Xiao, T Sam; Bai, Yawen

2015-08-20

Linker histones bind to the nucleosome and regulate the structure of chromatin and gene expression. Despite more than three decades of effort, the structural basis of nucleosome recognition by linker histones remains elusive. Here, we report the crystal structure of the globular domain of chicken linker histone H5 in complex with the nucleosome at 3.5 Å resolution, which is validated using nuclear magnetic resonance spectroscopy. The globular domain sits on the dyad of the nucleosome and interacts with both DNA linkers. Our structure integrates results from mutation analyses and previous cross-linking and fluorescence recovery after photobleach experiments, and it helps resolve the long debate on structural mechanisms of nucleosome recognition by linker histones. The on-dyad binding mode of the H5 globular domain is different from the recently reported off-dyad binding mode of Drosophila linker histone H1. We demonstrate that linker histones with different binding modes could fold chromatin to form distinct higher-order structures. Copyright © 2015 Elsevier Inc. All rights reserved.

Hydroquinone–pyrrole dyads with varied linkers

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Hao Huang

2016-01-01

Full Text Available A series of pyrroles functionalized in the 3-position with p-dimethoxybenzene via various linkers (CH2, CH2CH2, CH=CH, C≡C has been synthesized. Their electronic properties have been deduced from 1H NMR, 13C NMR, and UV–vis spectra to detect possible interactions between the two aromatic subunits. The extent of conjugation between the subunits is largely controlled by the nature of the linker, with the largest conjugation found with the trans-ethene linker and the weakest with the aliphatic linkers. DFT calculations revealed substantial changes in the HOMO–LUMO gap that correlated with the extent of conjugation found experimentally. The results of this work are expected to open up for use of the investigated compounds as components of redox-active materials in sustainable, organic electrical energy storage devices.

Structure and Functions of Linker Histones.

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Lyubitelev, A V; Nikitin, D V; Shaytan, A K; Studitsky, V M; Kirpichnikov, M P

2016-03-01

Linker histones such as variants H1, H5, and other similar proteins play an important role in regulation of chromatin structure and dynamics. However, interactions of linker histones with DNA and proteins, as well as specific functions of their different variants, are poorly studied. This is because they acquire tertiary structure only when interacting with a nucleosome, and because of limitations of currently available methods. However, deeper investigation of linker histones and their interactions with other proteins will address a number of important questions - from structure of compacted chromatin to regulation of early embryogenesis. In this review, structures of histone H1 variants and its interaction with chromatin DNA are considered. A possible functional significance of different H1 variants, a role of these proteins in maintaining interphase chromatin structure, and interactions of linker histones with other cellular proteins are also discussed.

ATPase Domain and Interdomain Linker Play a Key Role in Aggregation of Mitochondrial Hsp70 Chaperone Ssc1*

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Blamowska, Marta; Sichting, Martin; Mapa, Koyeli; Mokranjac, Dejana; Neupert, Walter; Hell, Kai

2010-01-01

The co-chaperone Hep1 is required to prevent the aggregation of mitochondrial Hsp70 proteins. We have analyzed the interaction of Hep1 with mitochondrial Hsp70 (Ssc1) and the determinants in Ssc1 that make it prone to aggregation. The ATPase and peptide binding domain (PBD) of Hsp70 proteins are connected by a linker segment that mediates interdomain communication between the domains. We show here that the minimal Hep1 binding entity of Ssc1 consists of the ATPase domain and the interdomain linker. In the absence of Hep1, the ATPase domain with the interdomain linker had the tendency to aggregate, in contrast to the ATPase domain with the mutated linker segment or without linker, and in contrast to the PBD. The closest homolog of Ssc1, bacterial DnaK, and a Ssc1 chimera, in which a segment of the ATPase domain of Ssc1 was replaced by the corresponding segment from DnaK, did not aggregate in Δhep1 mitochondria. The propensity to aggregate appears to be a specific property of the mitochondrial Hsp70 proteins. The ATPase domain in combination with the interdomain linker is crucial for aggregation of Ssc1. In conclusion, our results suggest that interdomain communication makes Ssc1 prone to aggregation. Hep1 counteracts aggregation by binding to this aggregation-prone conformer. PMID:20007714

ATPase domain and interdomain linker play a key role in aggregation of mitochondrial Hsp70 chaperone Ssc1.

Science.gov (United States)

Blamowska, Marta; Sichting, Martin; Mapa, Koyeli; Mokranjac, Dejana; Neupert, Walter; Hell, Kai

2010-02-12

The co-chaperone Hep1 is required to prevent the aggregation of mitochondrial Hsp70 proteins. We have analyzed the interaction of Hep1 with mitochondrial Hsp70 (Ssc1) and the determinants in Ssc1 that make it prone to aggregation. The ATPase and peptide binding domain (PBD) of Hsp70 proteins are connected by a linker segment that mediates interdomain communication between the domains. We show here that the minimal Hep1 binding entity of Ssc1 consists of the ATPase domain and the interdomain linker. In the absence of Hep1, the ATPase domain with the interdomain linker had the tendency to aggregate, in contrast to the ATPase domain with the mutated linker segment or without linker, and in contrast to the PBD. The closest homolog of Ssc1, bacterial DnaK, and a Ssc1 chimera, in which a segment of the ATPase domain of Ssc1 was replaced by the corresponding segment from DnaK, did not aggregate in Delta hep1 mitochondria. The propensity to aggregate appears to be a specific property of the mitochondrial Hsp70 proteins. The ATPase domain in combination with the interdomain linker is crucial for aggregation of Ssc1. In conclusion, our results suggest that interdomain communication makes Ssc1 prone to aggregation. Hep1 counteracts aggregation by binding to this aggregation-prone conformer.

Linker length dependent binding of a focal adhesion kinase derived peptide to the Src SH3-SH2 domains.

Science.gov (United States)

Lindfors, Hanna E; Venkata, Bharat Somireddy; Drijfhout, Jan W; Ubbink, Marcellus

2011-02-18

The interaction between a peptide encompassing the SH3 and SH2 binding motifs of focal adhesion kinase (FAK) and the Src SH3-SH2 domains has been investigated with NMR spectroscopy and calorimetry. The binding to both motifs is anti-cooperative. Reduction of the long linker connecting the motifs does not lead to cooperativity. Short linkers that do not allow simultaneous intramolecular binding of the peptide to both motifs cause peptide-mediated dimerisation, even with a linker of only three amino acids. The role of the SH3 binding motif is discussed in view of the independent nature of the SH interactions. Copyright © 2011 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

The unstructured linker arms of Mlh1-Pms1 are important for interactions with DNA during mismatch repair

Science.gov (United States)

Plys, Aaron J.; Rogacheva, Maria V.; Greene, Eric C.; Alani, Eric

2012-01-01

DNA mismatch repair (MMR) models have proposed that MSH proteins identify DNA polymerase errors while interacting with the DNA replication fork. MLH proteins (primarily Mlh1-Pms1 in baker’s yeast) then survey the genome for lesion-bound MSH proteins. The resulting MSH-MLH complex formed at a DNA lesion initiates downstream steps in repair. MLH proteins act as dimers and contain long (20 – 30 nanometers) unstructured arms that connect two terminal globular domains. These arms can vary between 100 to 300 amino acids in length, are highly divergent between organisms, and are resistant to amino acid substitutions. To test the roles of the linker arms in MMR, we engineered a protease cleavage site into the Mlh1 linker arm domain of baker’s yeast Mlh1-Pms1. Cleavage of the Mlh1 linker arm in vitro resulted in a defect in Mlh1-Pms1 DNA binding activity, and in vivo proteolytic cleavage resulted in a complete defect in MMR. We then generated a series of truncation mutants bearing Mlh1 and Pms1 linker arms of varying lengths. This work revealed that MMR is greatly compromised when portions of the Mlh1 linker are removed, whereas repair is less sensitive to truncation of the Pms1 linker arm. Purified complexes containing truncations in Mlh1 and Pms1 linker arms were analyzed and found to have differential defects in DNA binding that also correlated with the ability to form a ternary complex with Msh2-Msh6 and mismatch DNA. These observations are consistent with the unstructured linker domains of MLH proteins providing distinct interactions with DNA during MMR. PMID:22659005

Charged Triazole Cross-Linkers for Hyaluronan-Based Hybrid Hydrogels

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Maike Martini

2016-09-01

Full Text Available Polyelectrolyte hydrogels play an important role in tissue engineering and can be produced from natural polymers, such as the glycosaminoglycan hyaluronan. In order to control charge density and mechanical properties of hyaluronan-based hydrogels, we developed cross-linkers with a neutral or positively charged triazole core with different lengths of spacer arms and two terminal maleimide groups. These cross-linkers react with thiolated hyaluronan in a fast, stoichiometric thio-Michael addition. Introducing a positive charge on the core of the cross-linker enabled us to compare hydrogels with the same interconnectivity, but a different charge density. Positively charged cross-linkers form stiffer hydrogels relatively independent of the size of the cross-linker, whereas neutral cross-linkers only form stable hydrogels at small spacer lengths. These novel cross-linkers provide a platform to tune the hydrogel network charge and thus the mechanical properties of the network. In addition, they might offer a wide range of applications especially in bioprinting for precise design of hydrogels.

Saccharomyces cerevisiae Linker Histone—Hho1p Maintains Chromatin Loop Organization during Ageing

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Katya Uzunova

2013-01-01

Full Text Available Intricate, dynamic, and absolutely unavoidable ageing affects cells and organisms through their entire lifetime. Driven by diverse mechanisms all leading to compromised cellular functions and finally to death, this process is a challenge for researchers. The molecular mechanisms, the general rules that it follows, and the complex interplay at a molecular and cellular level are yet little understood. Here, we present our results showing a connection between the linker histones, the higher-order chromatin structures, and the process of chronological lifespan of yeast cells. By deleting the gene for the linker histone in Saccharomyces cerevisiae we have created a model for studying the role of chromatin structures mainly at its most elusive and so far barely understood higher-order levels of compaction in the processes of yeast chronological lifespan. The mutant cells demonstrated controversial features showing slower growth than the wild type combined with better survival during the whole process. The analysis of the global chromatin organization during different time points demonstrated certain loss of the upper levels of chromatin compaction in the cells without linker histone. The results underlay the importance of this histone for the maintenance of the chromatin loop structures during ageing.

The interdomain flexible linker of the polypeptide GalNAc transferases dictates their long-range glycosylation preferences

DEFF Research Database (Denmark)

Rivas, Matilde De Las; Lira-Navarrete, Erandi; Daniel, Earnest James Paul

2017-01-01

The polypeptide GalNAc-transferases (GalNAc-Ts), that initiate mucin-type O-glycosylation, consist of a catalytic and a lectin domain connected by a flexible linker. In addition to recognizing polypeptide sequence, the GalNAc-Ts exhibit unique long-range N- A nd/or C-terminal prior glycosylation ...

Initial conformation of kinesin's neck linker

International Nuclear Information System (INIS)

Geng Yi-Zhao; Yan Shi-Wei; Ji Qing; Liu Shu-Xia

2014-01-01

How ATP binding initiates the docking process of kinesin's neck linker is a key question in understanding kinesin mechanisms. By exploiting a molecular dynamics method, we investigate the initial conformation of kinesin's neck linker in its docking process. We find that, in the initial conformation, the neck linker has interactions with β0 and forms a ‘cover-neck bundle’ structure with β0. From this initial structure, the formation of extra turns and the docking of the cover-neck bundle structure can be achieved. The motor head provides a forward force on the initial cover-neck bundle structure through ATP-induced rotation. This force, together with the hydrophobic interaction of ILE327 with the hydrophobic pocket on the motor head, drives the formation of the extra turn and initiates the neck linker docking process. Based on these findings, a pathway from ATP binding-induced motor head rotation to neck linker docking is proposed. (interdisciplinary physics and related areas of science and technology)

Nanohashtag structures based on carbon nanotubes and molecular linkers

Science.gov (United States)

Frye, Connor W.; Rybolt, Thomas R.

2018-03-01

Molecular mechanics was used to study the noncovalent interactions between single-walled carbon nanotubes and molecular linkers. Groups of nanotubes have the tendency to form tight, parallel bundles (||||). Molecular linkers were introduced into our models to stabilize nanostructures with carbon nanotubes held in perpendicular orientations. Molecular mechanics makes it possible to estimate the strength of noncovalent interactions holding these structures together and to calculate the overall binding energy of the structures. A set of linkers were designed and built around a 1,3,5,7-cyclooctatetraene tether with two corannulene containing pincers that extend in opposite directions from the central cyclooctatetraene portion. Each pincer consists of a pairs of "arms." These molecular linkers were modified so that the "hand" portions of each pair of "arms" could close together to grab and hold two carbon nanotubes in a perpendicular arrangement. To illustrate the possibility of more complicated and open perpendicular CNTs structures, our primary goal was to create a model of a nanohashtag (#) CNT conformation that is more stable than any parallel CNT arrangements with bound linker molecules forming clumps of CNTs and linkers in non-hashtag arrangements. This goal was achieved using a molecular linker (C280H96) that utilizes van der Waals interactions to two perpendicular oriented CNTs. Hydrogen bonding was then added between linker molecules to augment the stability of the hashtag structure. In the hashtag structure with hydrogen bonding, four (5,5) CNTs of length 4.46 nm (18 rings) and four linkers (C276H92N8O8) stabilized the hashtag so that the average binding energy per pincer was 118 kcal/mol.

Lecithin-linker formulations for self-emulsifying delivery of nutraceuticals.

Science.gov (United States)

Chu, Jacquelene; Cheng, Yu-Ling; Rao, A Venketeshwer; Nouraei, Mehdi; Zarate-Muñoz, Silvia; Acosta, Edgar J

2014-08-25

Lecithin-linker microemulsions are formulations produced with soybean lecithin in combination with a highly lipophilic (lipophilic linker) and highly hydrophilic (hydrophilic linkers) surfactant-like additives. In this work, lecithin-linker systems were formulated to produce self-emulsifying delivery systems for β-carotene and β-sitosterol. The concentration of the lipophilic linker, sorbitan monooleate, was adjusted to minimize the formation of liquid crystals. The concentration of hydrophilic linkers, decaglyceryl caprylate/caprate and PEG-6-caprylic/capric glycerides, was gradually increased (scanned) until single phase clear microemulsions were obtained. For these scans, the oil (ethyl caprate) to water ratio was set to 1. The single phase, clear microemulsions were diluted with fed-state simulated intestinal fluid (FeSSIF) and produced stable emulsions, with drop sizes close to 200 nm. Using pseudo-ternary phase diagrams to evaluate the process of dilution of microemulsion preconcentrates (mixtures of oil, lecithin and linkers with little or no water) with FeSSIF, it was determined that self-emulsifying systems are obtained when the early stages of the dilution produce single phase microemulsions. If liquid crystals or multiple phase systems are obtained during those early stages, then the emulsification yields unstable emulsions with large drop sizes. An in vitro permeability study conducted using a Flow-Thru Dialyzer revealed that stable emulsions with drop sizes of 150-300 nm produce large and irreversible permeation of β-carotene to sheep intestine. On the other hand, unstable emulsions produced without the linker combination separated in the dialyzer chamber. Copyright © 2014 Elsevier B.V. All rights reserved.

Photolabile linker for the synthesis of hydroxamic acids

DEFF Research Database (Denmark)

2013-01-01

a hydroxylamine - functionalized photolabile linker, and the so produced hydroxylamine - functionalized photolabile solid support. The invention further provides a method for synthesizing a one-bead-one compound library of hydroxamic acid derivatives on a photolabile linker, as well as a method for screening...

Unusual and highly tunable missing-linker defects in zirconium metal-organic framework UiO-66 and their important effects on gas adsorption.

Science.gov (United States)

Wu, Hui; Chua, Yong Shen; Krungleviciute, Vaiva; Tyagi, Madhusudan; Chen, Ping; Yildirim, Taner; Zhou, Wei

2013-07-17

UiO-66 is a highly important prototypical zirconium metal-organic framework (MOF) compound because of its excellent stabilities not typically found in common porous MOFs. In its perfect crystal structure, each Zr metal center is fully coordinated by 12 organic linkers to form a highly connected framework. Using high-resolution neutron power diffraction technique, we found the first direct structural evidence showing that real UiO-66 material contains significant amount of missing-linker defects, an unusual phenomenon for MOFs. The concentration of the missing-linker defects is surprisingly high, ∼10% in our sample, effectively reducing the framework connection from 12 to ∼11. We show that by varying the concentration of the acetic acid modulator and the synthesis time, the linker vacancies can be tuned systematically, leading to dramatically enhanced porosity. We obtained samples with pore volumes ranging from 0.44 to 1.0 cm(3)/g and Brunauer-Emmett-Teller surface areas ranging from 1000 to 1600 m(2)/g, the largest values of which are ∼150% and ∼60% higher than the theoretical values of defect-free UiO-66 crystal, respectively. The linker vacancies also have profound effects on the gas adsorption behaviors of UiO-66, in particular CO2. Finally, comparing the gas adsorption of hydroxylated and dehydroxylated UiO-66, we found that the former performs systematically better than the latter (particularly for CO2) suggesting the beneficial effect of the -OH groups. This finding is of great importance because hydroxylated UiO-66 is the practically more relevant, non-air-sensitive form of this MOF. The preferred gas adsorption on the metal center was confirmed by neutron diffraction measurements, and the gas binding strength enhancement by the -OH group was further supported by our first-principles calculations.

Construction of hierarchically porous metal-organic frameworks through linker labilization

Science.gov (United States)

Yuan, Shuai; Zou, Lanfang; Qin, Jun-Sheng; Li, Jialuo; Huang, Lan; Feng, Liang; Wang, Xuan; Bosch, Mathieu; Alsalme, Ali; Cagin, Tahir; Zhou, Hong-Cai

2017-05-01

A major goal of metal-organic framework (MOF) research is the expansion of pore size and volume. Although many approaches have been attempted to increase the pore size of MOF materials, it is still a challenge to construct MOFs with precisely customized pore apertures for specific applications. Herein, we present a new method, namely linker labilization, to increase the MOF porosity and pore size, giving rise to hierarchical-pore architectures. Microporous MOFs with robust metal nodes and pro-labile linkers were initially synthesized. The mesopores were subsequently created as crystal defects through the splitting of a pro-labile-linker and the removal of the linker fragments by acid treatment. We demonstrate that linker labilization method can create controllable hierarchical porous structures in stable MOFs, which facilitates the diffusion and adsorption process of guest molecules to improve the performances of MOFs in adsorption and catalysis.

A Traceless Aryl-Triazene Linker for DNA-Directed Chemistry

DEFF Research Database (Denmark)

Hejesen, Christian; Pedersen, Lars Kolster; Gothelf, Kurt Vesterager

2013-01-01

DNA-directed synthesis of encoded combinatorial libraries of small organic compounds most often involves transfer of organic building blocks from one DNA strand to another. This requires cleavable linkers to enable cleavage of the link to the original DNA strand from which the building block...... is transferred. Relatively few cleavable linkers are available for DNA-directed synthesis and most often they leave an amino group at the organic molecule. Here we have extended the application of 10 aryltriazenes as traceless linkers for DNA-directed synthesis. After reaction of one building block...

The linker domain of poly(rC) binding protein 2 is a major determinant in poliovirus cap-independent translation.

Science.gov (United States)

Sean, Polen; Nguyen, Joseph H C; Semler, Bert L

2008-09-01

Poliovirus, a member of the enterovirus genus in the family Picornaviridae, is the causative agent of poliomyelitis. Translation of the viral genome is mediated through an internal ribosomal entry site (IRES) encoded within the 5' noncoding region (5' NCR). IRES elements are highly structured RNA sequences that facilitate the recruitment of ribosomes for translation. Previous studies have shown that binding of a cellular protein, poly(rC) binding protein 2 (PCBP2), to a major stem-loop structure in the genomic 5' NCR is necessary for the translation of picornaviruses containing type I IRES elements, including poliovirus, coxsackievirus, and human rhinovirus. PCBP1, an isoform that shares approximately 90% amino acid identity to PCBP2, cannot efficiently stimulate poliovirus IRES-mediated translation, most likely due to its reduced binding affinity to stem-loop IV within the poliovirus IRES. The primary differences between PCBP1 and PCBP2 are found in the so-called linker domain between the second and third K-homology (KH) domains of these proteins. We hypothesize that the linker region of PCBP2 augments binding to poliovirus stem-loop IV RNA. To test this hypothesis, we generated six PCBP1/PCBP2 chimeric proteins. The recombinant PCBP1/PCBP2 chimeric proteins were able to interact with poliovirus stem-loop I RNA and participate in protein-protein interactions. We demonstrated that the PCBP1/PCBP2 chimeric proteins with the PCBP2 linker, but not with the PCBP1 linker, were able to interact with poliovirus stem-loop IV RNA, and could subsequently stimulate poliovirus IRES-mediated translation. In addition, using a monoclonal anti-PCBP2 antibody (directed against the PCBP2 linker domain) in mobility shift assays, we showed that the PCBP2 linker domain modulates binding to poliovirus stem-loop IV RNA via a mechanism that is not inhibited by the antibody.

Backbone amide linker strategy

DEFF Research Database (Denmark)

Shelton, Anne Pernille Tofteng; Jensen, Knud Jørgen

2013-01-01

In the backbone amide linker (BAL) strategy, the peptide is anchored not at the C-terminus but through a backbone amide, which leaves the C-terminal available for various modifications. This is thus a very general strategy for the introduction of C-terminal modifications. The BAL strategy...

Rational design of molecularly imprinted polymer: the choice of cross-linker.

Science.gov (United States)

Muhammad, Turghun; Nur, Zohre; Piletska, Elena V; Yimit, Osmanjan; Piletsky, Sergey A

2012-06-07

The paper describes a rational approach for the selection of cross-linkers during the development of molecularly imprinted polymers (MIPs). As a model system for this research MIPs specific for the drug zidovudine (AZT) were designed and tested. Three cross-linkers trimethylolpropane trimethacrylate (TRIM), ethylene glycol dimethacrylate (EGDMA) and divinylbenzene (DVB) were studied. The analogue of zidovudine (AZT) ester (AZT-ES) was used as a dummy template. The imprinting factors for all of the polymers in the static adsorption experiments were calculated. The data on the AZT adsorption by control polymers (CP), which were prepared with different cross-linkers without a functional monomer, was also analyzed. DVB was found to be more inert towards zidovudine than EGDMA and TRIM, which was confirmed by both molecular modelling and adsorption experiments. It was demonstrated that DVB-based polymers had a higher imprinting factor (I = 1.85) compared with other tested cross-linked polymers. It was suggested that the selection of the cross-linker should be based on the strength of the interaction with the template: the cross-linker which displays lower binding of the template should be preferential because it generates MIPs with lower non-specific binding and a higher imprinting factor, and therefore specificity. Which cross-linker to use for the preparation of any particular MIP can be determined by analysis of the interactions between the cross-linker and template. This could be done either virtually using computational modelling or by template adsorption using a small library of polymers prepared using different cross-linkers.

Surface expression and subunit specific control of steady protein levels by the Kv7.2 helix A-B linker.

Directory of Open Access Journals (Sweden)

Paloma Aivar

Full Text Available Kv7.2 and Kv7.3 are the main components of the neuronal voltage-dependent M-current, which is a subthreshold potassium conductance that exerts an important control on neuronal excitability. Despite their predominantly intracellular distribution, these channels must reach the plasma membrane in order to control neuronal activity. Thus, we analyzed the amino acid sequence of Kv7.2 to identify intrinsic signals that may control its surface expression. Removal of the interlinker connecting helix A and helix B of the intracellular C-terminus produces a large increase in the number of functional channels at the plasma membrane. Moreover, elimination of this linker increased the steady-state amount of protein, which was not associated with a decrease of protein degradation. The magnitude of this increase was inversely correlated with the number of helix A - helix B linkers present in the tetrameric channel assemblies. In contrast to the remarkable effect on the amount of Kv7.2 protein, removal of the Kv7.2 linker had no detectable impact on the steady-state levels of Kv7.3 protein.

A Helix-Stabilizing Linker Improves Subcutaneous Bioavailability of a Helical Peptide Independent of Linker Lipophilicity

Science.gov (United States)

Zhang, Liang; Navaratna, Tejas; Thurber, Greg M.

2016-01-01

Stabilized peptides address several limitations to peptide-based imaging agents and therapeutics such as poor stability and low affinity due to conformational flexibility. There is also active research in developing these compounds for intracellular drug targeting, and significant efforts have been invested to determine the effects of helix stabilization on intracellular delivery. However, much less is known about the impact on other pharmacokinetic parameters such as plasma clearance and bioavailability. We investigated the effect of different fluorescent helix-stabilizing linkers with varying lipophilicity on subcutaneous (SC) bioavailability using the glucagon-like peptide-1 (GLP-1) receptor ligand exendin as a model system. The stabilized peptides showed significantly higher protease resistance and increased bioavailability independent of linker hydrophilicity, and all subcutaneously delivered conjugates were able to successfully target the islets of Langerhans with high specificity. The lipophilic peptide variants had slower absorption and plasma clearance than their respective hydrophilic conjugates, and the absolute bioavailability was also lower likely due to the longer residence times in the skin. The ease and efficiency of double-click helix stabilization chemistries is a useful tool for increasing the bioavailability of peptide therapeutics, many of which suffer from rapid in vivo protease degradation. Helix stabilization using linkers of varying lipophilicity can further control SC absorption and clearance rates to customize plasma pharmacokinetics. PMID:27327034

Open and closed: the roles of linker histones in plants and animals.

Science.gov (United States)

Over, Ryan S; Michaels, Scott D

2014-03-01

Histones package DNA in all eukaryotes and play key roles in regulating gene expression. Approximately 150 base pairs of DNA wraps around an octamer of core histones to form the nucleosome, the basic unit of chromatin. Linker histones compact chromatin further by binding to and neutralizing the charge of the DNA between nucleosomes. It is well established that chromatin packing is regulated by a complex pattern of posttranslational modifications (PTMs) to core histones, but linker histone function is less well understood. In this review, we describe the current understanding of the many roles that linker histones play in cellular processes, including gene regulation, cell division, and development, while putting the linker histone in the context of other nuclear proteins. Although intriguing roles for plant linker histones are beginning to emerge, much of our current understanding comes from work in animal systems. Many unanswered questions remain and additional work is required to fully elucidate the complex processes mediated by linker histones in plants.

The H1 linker histones: multifunctional proteins beyond the nucleosomal core particle.

Science.gov (United States)

Hergeth, Sonja P; Schneider, Robert

2015-11-01

The linker histone H1 family members are a key component of chromatin and bind to the nucleosomal core particle around the DNA entry and exit sites. H1 can stabilize both nucleosome structure and higher-order chromatin architecture. In general, H1 molecules consist of a central globular domain with more flexible tail regions at both their N- and C-terminal ends. The existence of multiple H1 subtypes and a large variety of posttranslational modifications brings about a considerable degree of complexity and makes studying this protein family challenging. Here, we review recent progress in understanding the function of linker histones and their subtypes beyond their role as merely structural chromatin components. We summarize current findings on the role of H1 in heterochromatin formation, transcriptional regulation and embryogenesis with a focus on H1 subtypes and their specific modifications. © 2015 The Authors.

A streptavidin linker layer that functions after drying.

Science.gov (United States)

Xia, Nan; Shumaker-Parry, Jennifer S; Zareie, M Hadi; Campbell, Charles T; Castner, David G

2004-04-27

The ability of streptavidin (SA) to simultaneously bind four biotins is often used in linker layers, where a biotinylated molecule is linked to a biotin-functionalized surface via SA. For biosensor and array applications, it is desirable that the SA linker layer be stable to drying and rehydration. In this study it was observed that a significant decrease in binding capacity of a SA layer occurred when that layer was dried. For this study a SA linker layer was constructed by binding SA to a biotin-containing alkylthiolate monolayer (BAT/OEG) self-assembled onto gold. Its stability after drying was investigated using surface plasmon resonance (SPR). Approximately a quarter of the SA layer was removed from the BAT/OEG surface upon drying and rehydration, suggesting disruption of SA-biotin binding when dry. This resulted in the dried SA layer losing approximately 40% of its biotinylated ferritin (BF) binding capacity. Coating the layer with trehalose before drying was found to inhibit the loss of SA from the BAT/OEG surface. SPR showed that the trehalose-protected SA linker layer retained approximately 91% of its original BF binding capacity after drying and rehydration. Atomic force microscopy, which was used to image individual surface-bound SA and BF molecules, qualitatively confirmed these observations.

Investigation of the Linker Swing Motion in the Zeolitic Imidazolate Framework ZIF-90

KAUST Repository

Zheng, Bin

2018-03-13

The linker swing motion in the zeolitic imidazolate framework ZIF-90 is investigated by density functional theory (DFT) calculation, molecular dynamics (MD) and grand-canonical Monte Carlo (GCMC) simulations. The relation between the terminal aldehyde group rotation and the linker swing motion is revealed. The extremely high activation energy of the linker swing motion in ZIF-90 can be attributed to the asymmetric geometry and electron distribution of aldehyde groups. The change in the gate structure resulting from the linker rotation is used to understand the guest adsorption in ZIF-90. This study shows that it is possible to tune the linker swing motion and then the properties of ZIF-90 by manipulating the terminal group rotation. The results highlight the importance of considering the internal freedom effects to correctly describe the linker swing motion and the flexibility of metal-organic frameworks (MOFs).

Dipolar cross-linkers for PDMS networks with enhanced dielectric permittivity and low dielectric loss

DEFF Research Database (Denmark)

Bahrt, Frederikke; Daugaard, Anders Egede; Hvilsted, Søren

2013-01-01

-(4-((4-nitrophenyl)diazenyl)phenoxy)-prop-1-yn-1-ylium, with a synthesized silicone compatible azide-functional cross-linker by click chemistry. The thermal, mechanical and electromechanical properties were investigated for PDMS films with 0 to 3.6 wt% of dipole-cross-linker. The relative dielectric permittivity......Dipole grafted cross-linkers were utilized to prepare polydimethylsiloxane (PDMS) elastomers with various chain lengths and with various concentrations of functional cross-linker. The grafted cross-linkers were prepared by reaction of two alkyne-functional dipoles, 1-ethynyl-4-nitrobenzene and 3...

Identification of novel post-translational modifications in linker histones from chicken erythrocytes.

Science.gov (United States)

Sarg, Bettina; Lopez, Rita; Lindner, Herbert; Ponte, Inma; Suau, Pedro; Roque, Alicia

2015-01-15

Chicken erythrocyte nuclei were digested with micrococcal nuclease and fractionated by centrifugation in low-salt buffer into soluble and insoluble fractions. Post-translational modifications of the purified linker histones of both fractions were analyzed by LC-ESI-MS/MS. All six histone H1 subtypes (H1.01, H1.02, H1.03, H1.10, H1.1L and H1.1R) and histone H5 were identified. Mass spectrometry analysis enabled the identification of a wide range of PTMs, including N(α)-terminal acetylation, acetylation, formylation, phosphorylation and oxidation. A total of nine new modifications in chicken linker histones were mapped, most of them located in the N-terminal and globular domains. Relative quantification of the modified peptides showed that linker histone PTMs were differentially distributed among both chromatin fractions, suggesting their relevance in the regulation of chromatin structure. The analysis of our results combined with previously reported data for chicken and some mammalian species showed that most of the modified positions were conserved throughout evolution, highlighting their importance in specific linker histone functions and epigenetics. Post-translational modifications of linker histones could have a role in the regulation of gene expression through the modulation of chromatin higher-order structure and chromatin remodeling. Finding new PTMs in linker histones is the first step to elucidate their role in the histone code. In this manuscript we report nine new post-translational modifications of the linker histones from chicken erythrocytes, one in H5 and eight in the H1 subtypes. Chromatin fractionated by centrifugation in low-salt buffer resulted in two fractions with different contents and compositions of linker histones and enriched in specific core histone PTMs. Of particular interest is the fact that linker histone PTMs were differentially distributed in both chromatin fractions, suggesting specific functions. Future studies are needed to

Groundwater connectivity of upland-embedded wetlands in the Prairie Pothole Region

Science.gov (United States)

Neff, Brian; Rosenberry, Donald O.

2018-01-01

Groundwater connections from upland-embedded wetlands to downstream waterbodies remain poorly understood. In principle, water from upland-embedded wetlands situated high in a landscape should flow via groundwater to waterbodies situated lower in the landscape. However, the degree of groundwater connectivity varies across systems due to factors such as geologic setting, hydrologic conditions, and topography. We use numerical models to evaluate the conditions suitable for groundwater connectivity between upland-embedded wetlands and downstream waterbodies in the prairie pothole region of North Dakota (USA). Results show groundwater connectivity between upland-embedded wetlands and other waterbodies is restricted when these wetlands are surrounded by a mounding water table. However, connectivity exists among adjacent upland-embedded wetlands where water–table mounds do not form. In addition, the presence of sand layers greatly facilitates groundwater connectivity of upland-embedded wetlands. Anisotropy can facilitate connectivity via groundwater flow, but only if it becomes unrealistically large. These findings help consolidate previously divergent views on the significance of local and regional groundwater flow in the prairie pothole region.

Monte Carlo analysis of neck linker extension in kinesin molecular motors.

Directory of Open Access Journals (Sweden)

Matthew L Kutys

2010-11-01

Full Text Available Kinesin stepping is thought to involve both concerted conformational changes and diffusive movement, but the relative roles played by these two processes are not clear. The neck linker docking model is widely accepted in the field, but the remainder of the step--diffusion of the tethered head to the next binding site--is often assumed to occur rapidly with little mechanical resistance. Here, we investigate the effect of tethering by the neck linker on the diffusive movement of the kinesin head, and focus on the predicted behavior of motors with naturally or artificially extended neck linker domains. The kinesin chemomechanical cycle was modeled using a discrete-state Markov chain to describe chemical transitions. Brownian dynamics were used to model the tethered diffusion of the free head, incorporating resistive forces from the neck linker and a position-dependent microtubule binding rate. The Brownian dynamics and chemomechanical cycle were coupled to model processive runs consisting of many 8 nm steps. Three mechanical models of the neck linker were investigated: Constant Stiffness (a simple spring, Increasing Stiffness (analogous to a Worm-Like Chain, and Reflecting (negligible stiffness up to a limiting contour length. Motor velocities and run lengths from simulated paths were compared to experimental results from Kinesin-1 and a mutant containing an extended neck linker domain. When tethered by an increasingly stiff spring, the head is predicted to spend an unrealistically short amount of time within the binding zone, and extending the neck is predicted to increase both the velocity and processivity, contrary to experiments. These results suggest that the Worm-Like Chain is not an adequate model for the flexible neck linker domain. The model can be reconciled with experimental data if the neck linker is either much more compliant or much stiffer than generally assumed, or if weak kinesin-microtubule interactions stabilize the diffusing

Linkers, resins, and general procedures for solid-phase peptide synthesis

DEFF Research Database (Denmark)

Shelton, Anne Pernille Tofteng; Jensen, Knud Jørgen

2013-01-01

and linkers for solid-phase synthesis is a key parameter for successful peptide synthesis. This chapter provides an overview of the most common and useful resins and linkers for the synthesis of peptides with C-terminal amides, carboxylic acids, and more. The chapter finishes with robust protocols for general...

Identification of a minimal functional linker in human topoisomerase I by domain swapping with Cre recombinase

DEFF Research Database (Denmark)

Hougaard, Rikke Frøhlich; Juul, Sissel; Vinther, Maria

2008-01-01

. In this study we replace 86 amino acids including the linker domain of the cellular type IB topoisomerase, human topoisomerase I, with four, six, or eight amino acids from the corresponding short loop region in Cre recombinase. In vitro characterization of the resulting chimeras, denoted Cropos, reveals...

Structural and Functional Analysis of the Signal-Transducing Linker in the pH-Responsive One-Component System CadC of Escherichia coli.

Science.gov (United States)

Buchner, Sophie; Schlundt, Andreas; Lassak, Jürgen; Sattler, Michael; Jung, Kirsten

2015-07-31

The pH-responsive one-component signaling system CadC in Escherichia coli belongs to the family of ToxR-like proteins, whose members share a conserved modular structure, with an N-terminal cytoplasmic winged helix-turn-helix DNA-binding domain being followed by a single transmembrane helix and a C-terminal periplasmic pH-sensing domain. In E. coli CadC, a cytoplasmic linker comprising approximately 50 amino acids is essential for transmission of the signal from the sensor to the DNA-binding domain. However, the mechanism of transduction is poorly understood. Using NMR spectroscopy, we demonstrate here that the linker region is intrinsically disordered in solution. Furthermore, mutational analyses showed that it tolerates a range of amino acid substitutions (altering polarity, rigidity and α-helix-forming propensity), is robust to extension but is sensitive to truncation. Indeed, truncations either reversed the expression profile of the target operon cadBA or decoupled expression from external pH altogether. CadC dimerizes via its periplasmic domain, but light-scattering analysis provided no evidence for dimerization of the isolated DNA-binding domain, with or without the linker region. However, bacterial two-hybrid analysis revealed that CadC forms stable dimers in a stimulus- and linker-dependent manner, interacting only at pHpH. Thus, we propose that the disordered CadC linker is required for transducing the pH-dependent response of the periplasmic sensor into a structural rearrangement that facilitates dimerization of the cytoplasmic CadC DNA-binding domain. Copyright © 2015 Elsevier Ltd. All rights reserved.

Water-soluble heterobifunctional fluorescent linkers

Czech Academy of Sciences Publication Activity Database

Bartoň, Jan; Cígler, Petr

2017-01-01

Roč. 15, č. 1 (2017), s. 4 ISSN 2336-7202. [Mezioborové setkání mladých biologů, biochemiků a chemiků /17./. 30.05.2017-01.06.2017, Milovy] Institutional support: RVO:61388963 Keywords : fluorescent probes * heterobifunctional linkers Subject RIV: CA - Inorganic Chemistry

Optimizing the relaxivity of GdIII complexes appended to InP/ZnS quantum dots by linker tuning.

Science.gov (United States)

Stasiuk, Graeme J; Tamang, Sudarsan; Imbert, Daniel; Gateau, Christelle; Reiss, Peter; Fries, Pascal; Mazzanti, Marinella

2013-06-21

Three bimodal MRI/optical nanosized contrast agents with high per-nanoparticle relaxivity (up to 2523 mM(-1) s(-1) at 35 MHz and 932 mM(-1) s(-1) at 200 MHz) have been prepared connecting up to 115 tris-aqua Gd(III) complexes to fluorescent non-toxic InP/ZnS quantum dots. The structure of the linker has an important effect on the relaxivity of the final multimeric contrast agent.

The stable problem of the black-hole connected region in the Schwarzschild black hole

OpenAIRE

Tian, Guihua

2005-01-01

The stability of the Schwarzschild black hole is studied. Using the Painlev\\'{e} coordinate, our region can be defined as the black-hole-connected region(r>2m, see text) of the Schwarzschild black hole or the white-hole-connected region(r>2m, see text) of the Schwarzschild black hole. We study the stable problems of the black-hole-connected region. The conclusions are: (1) in the black-hole-connected region, the initially regular perturbation fields must have real frequency or complex frequen...

Library of biphenyl privileged substructures using a safety-catch linker approach

DEFF Research Database (Denmark)

Severinsen, Rune; Bourne, Gregory T; Tran, Tran T

2008-01-01

A biphenyl privileged structure library containing three attachment points were synthesized using a catechol-based safety-catch linker strategy. The method requires the attachment of a bromo-acid to the linker, followed by a Pd-catalyzed Suzuki cross-coupling reaction. Further derivatization...

Differentiated parietal connectivity of frontal regions for "what" and "where" memory.

Science.gov (United States)

Rottschy, C; Caspers, S; Roski, C; Reetz, K; Dogan, I; Schulz, J B; Zilles, K; Laird, A R; Fox, P T; Eickhoff, S B

2013-11-01

In a previous meta-analysis across almost 200 neuroimaging experiments, working memory for object location showed significantly stronger convergence on the posterior superior frontal gyrus, whereas working memory for identity showed stronger convergence on the posterior inferior frontal gyrus (dorsal to, but overlapping with Brodmann's area BA 44). As similar locations have been discussed as part of a dorsal frontal-superior parietal reach system and an inferior frontal grasp system, the aim of the present study was to test whether the regions of working-memory related "what" and "where" processing show a similar distinction in parietal connectivity. The regions that were found in the previous meta-analysis were used as seeds for functional connectivity analyses using task-based meta-analytic connectivity modelling and task-independent resting state correlations. While the ventral seed showed significantly stronger connectivity with the bilateral intraparietal sulcus (IPS), the dorsal seed showed stronger connectivity with the bilateral posterior inferior parietal and the medial superior parietal lobule. The observed connections of regions involved in memory for object location and identity thus clearly demonstrate a distinction into separate pathways that resemble the parietal connectivity patterns of the dorsal and ventral premotor cortex in non-human primates and humans. It may hence be speculated that memory for a particular location and reaching towards it as well as object memory and finger positioning for manipulation may rely on shared neural systems. Moreover, the ensuing regions, in turn, featured differential connectivity with the bilateral ventral and dorsal extrastriate cortex, suggesting largely segregated bilateral connectivity pathways from the dorsal visual cortex via the superior and inferior parietal lobules to the dorsal posterior frontal cortex and from the ventral visual cortex via the IPS to the ventral posterior frontal cortex that may

Creating Hierarchical Pores by Controlled Linker Thermolysis in Multivariate Metal-Organic Frameworks

KAUST Repository

Feng, Liang; Yuan, Shuai; Zhang, Liang-Liang; Tan, Kui; Li, Jia-Luo; Kirchon, Angelo; Liu, Ling-Mei; Zhang, Peng; Han, Yu; Chabal, Yves J.; Zhou, Hong-Cai

2018-01-01

strate-gy, linker thermolysis, to construct ultra-stable hierarchically porous metal−organic frameworks (HP-MOFs) with tunable pore size distribution. Linker instability, usually an undesirable trait of MOFs, was exploited to create mesopores

Tunable CO 2 Adsorbents by Mixed-Linker Synthesis and Postsynthetic Modification of Zeolitic Imidazolate Frameworks

KAUST Repository

Thompson, Joshua A.; Brunelli, Nicholas A.; Lively, Ryan P.; Johnson, J. R.; Jones, Christopher W.; Nair, Sankar

2013-01-01

The incorporation of accessible amine functionality in zeolitic imidazolate frameworks (ZIFs) is used to improve the adsorption selectivity for CO 2/CH4 gas separation applications. Two synthetic approaches are described in this work to introduce functionality into the ZIF: (i) mixed-linker ZIF synthesis with 2-aminobenzimidazole as a substitution linker and (ii) postsynthetic modification of a mixed-linker ZIF with ethylenediamine. Using 2-aminobenzimidazole, a linker with a primary amine functional group, substitution of the ZIF-8 linker during synthesis allows for control over the adsorption properties while maintaining the ZIF-8 structure with up to nearly 50% substitution in the mixed-linker ZIF framework, producing a material with tunable pore size and amine functionality. Alternatively, postsynthetic modification of a mixed-linker ZIF containing an aldehyde functional group produces a ZIF material with a primary amine without detrimental loss of micropore volume by controlling the amount of functional group sites for modification. Both approaches using mixed-linker ZIFs yield new materials that show improvement in adsorption selectivity for the CO 2/CH4 gas pair over ZIF-8 and commercially available adsorbents as well as an increase in the heat of adsorption for CO2 without significant changes to the crystal structure. These results indicate that tuning the surface properties of ZIFs by either mixed-linker synthesis and/or postsynthetic modification may generate new materials with improved gas separation properties, thereby providing a new method for tailoring metal-organic frameworks. © 2013 American Chemical Society.

Tunable CO 2 Adsorbents by Mixed-Linker Synthesis and Postsynthetic Modification of Zeolitic Imidazolate Frameworks

KAUST Repository

Thompson, Joshua A.

2013-04-25

The incorporation of accessible amine functionality in zeolitic imidazolate frameworks (ZIFs) is used to improve the adsorption selectivity for CO 2/CH4 gas separation applications. Two synthetic approaches are described in this work to introduce functionality into the ZIF: (i) mixed-linker ZIF synthesis with 2-aminobenzimidazole as a substitution linker and (ii) postsynthetic modification of a mixed-linker ZIF with ethylenediamine. Using 2-aminobenzimidazole, a linker with a primary amine functional group, substitution of the ZIF-8 linker during synthesis allows for control over the adsorption properties while maintaining the ZIF-8 structure with up to nearly 50% substitution in the mixed-linker ZIF framework, producing a material with tunable pore size and amine functionality. Alternatively, postsynthetic modification of a mixed-linker ZIF containing an aldehyde functional group produces a ZIF material with a primary amine without detrimental loss of micropore volume by controlling the amount of functional group sites for modification. Both approaches using mixed-linker ZIFs yield new materials that show improvement in adsorption selectivity for the CO 2/CH4 gas pair over ZIF-8 and commercially available adsorbents as well as an increase in the heat of adsorption for CO2 without significant changes to the crystal structure. These results indicate that tuning the surface properties of ZIFs by either mixed-linker synthesis and/or postsynthetic modification may generate new materials with improved gas separation properties, thereby providing a new method for tailoring metal-organic frameworks. © 2013 American Chemical Society.

Design of Tail-Clamp Peptide Nucleic Acid Tethered with Azobenzene Linker for Sequence-Specific Detection of Homopurine DNA

Directory of Open Access Journals (Sweden)

Shinjiro Sawada

2017-10-01

Full Text Available DNA carries genetic information in its sequence of bases. Synthetic oligonucleotides that can sequence-specifically recognize a target gene sequence are a useful tool for regulating gene expression or detecting target genes. Among the many synthetic oligonucleotides, tail-clamp peptide nucleic acid (TC-PNA offers advantages since it has two homopyrimidine PNA strands connected via a flexible ethylene glycol-type linker that can recognize complementary homopurine sequences via Watson-Crick and Hoogsteen base pairings and form thermally-stable PNA/PNA/DNA triplex structures. Here, we synthesized a series of TC-PNAs that can possess different lengths of azobenzene-containing linkers and studied their binding behaviours to homopurine single-stranded DNA. Introduction of azobenzene at the N-terminus amine of PNA increased the thermal stability of PNA-DNA duplexes. Further extension of the homopyrimidine PNA strand at the N-terminus of PNA-AZO further increased the binding stability of the PNA/DNA/PNA triplex to the target homopurine sequence; however, it induced TC-PNA/DNA/TC-PNA complex formation. Among these TC-PNAs, 9W5H-C4-AZO consisting of nine Watson-Crick bases and five Hoogsteen bases tethered with a beta-alanine conjugated azobenzene linker gave a stable 1:1 TC-PNA/ssDNA complex and exhibited good mismatch recognition. Our design for TC-PNA-AZO can be utilized for detecting homopurine sequences in various genes.

Open and Closed: The Roles of Linker Histones in Plants and Animals

OpenAIRE

Over, Ryan S.; Michaels, Scott D.

2014-01-01

Linker histones play key roles alongside core histones in the regulation and maintenance of chromatin. Here, we illustrate our current understanding of the contributions of linker histones to the cell cycle, development, and chromatin structure in plants and animals.

Novel silicone compatible cross-linkers for controlled functionalization of PDMS networks

DEFF Research Database (Denmark)

Madsen, Frederikke Bahrt; Daugaard, Anders Egede; Hvilsted, Søren

2013-01-01

. In order to improve the dielectric properties of PDMS a novel system is developed where push-pull dipoles are grafted to a new silicone compatible cross-linker. The grafted cross-linkers are prepared by reaction of two different push-pull dipole alkynes as well as a fluorescent alkyne with the new azide...

Optimization of the Alkyl Linker of TO Base Surrogate in Triplex-Forming PNA for Enhanced Binding to Double-Stranded RNA.

Science.gov (United States)

Sato, Takaya; Sato, Yusuke; Nishizawa, Seiichi

2017-03-23

A series of triplex-forming peptide nucleic acid (TFP) probes carrying a thiazole orange (TO) base surrogate through an alkyl linker was synthesized, and the interactions between these so-called tFIT probes and purine-rich sequences within double-stranded RNA (dsRNA) were examined. We found that the TO base surrogate linker significantly affected both the binding affinity and the fluorescence response upon triplex formation with the target dsRNA. Among the probes examined, the TO base surrogate connected through the propyl linker in the tFIT probes increased the binding affinity by a factor of ten while maintaining its function as the fluorescent universal base. Isothermal titration calorimetry experiments revealed that the increased binding affinity resulted from the gain in the binding enthalpy, which could be explained by the enhanced π-stacking interaction between the TO base surrogate and the dsRNA part of the triplex. We expect that these results will provide a molecular basis for designing strong binding tFIT probes for fluorescence sensing of various kinds of purine-rich dsRNAs sequences including those carrying a pyrimidine-purine inversion. The obtained data also offers a new insight into further development of the universal bases incorporated in TFP. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

The effects of habitat connectivity and regional heterogeneity on artificial pond metacommunities.

Science.gov (United States)

Pedruski, Michael T; Arnott, Shelley E

2011-05-01

Habitat connectivity and regional heterogeneity represent two factors likely to affect biodiversity across different spatial scales. We performed a 3 × 2 factorial design experiment to investigate the effects of connectivity, heterogeneity, and their interaction on artificial pond communities of freshwater invertebrates at the local (α), among-community (β), and regional (γ) scales. Despite expectations that the effects of connectivity would depend on levels of regional heterogeneity, no significant interactions were found for any diversity index investigated at any spatial scale. While observed responses of biodiversity to connectivity and heterogeneity depended to some extent on the diversity index and spatial partitioning formula used, the general pattern shows that these factors largely act at the β scale, as opposed to the α or γ scales. We conclude that the major role of connectivity in aquatic invertebrate communities is to act as a homogenizing force with relatively little effect on diversity at the α or γ levels. Conversely, heterogeneity acts as a force maintaining differences between communities.

4,6-connected fsb topology networks obtained through two-step crystal engineering of decorated trigonal prismatic nodes

KAUST Repository

Schoedel, Alexander

2014-05-07

A two-step crystal engineering strategy has been utilized to synthesize a new and versatile class of metal-organic materials, the first to exhibit 4,6-connected fsb topology. The new fsb networks are constructed from simple and inexpensive nodes (4-connected Zn(CO2)(py)2 tetrahedra; 6-connected Cr(μ3-O)(RCO2)6 trigonal prisms) and linker ligands (isonicotinate and various dicarboxylates). Further, since interpenetration is precluded, they can exhibit extra-large void volumes. These fsb nets are prototypal for what should ultimately become a large family of related structures given the ready availability of functionalized and/or expanded variants of both linker ligands. The fsb nets described herein therefore represent platforms or blueprints for a new family of ultrahigh surface area porous materials. © 2014 American Chemical Society.

The measles virus phosphoprotein interacts with the linker domain of STAT1

International Nuclear Information System (INIS)

Devaux, Patricia; Priniski, Lauren; Cattaneo, Roberto

2013-01-01

The measles virus (MV) phosphoprotein (P) and V proteins block the interferon (IFN) response by impeding phosphorylation of the signal transducer and activator of transcription 1 (STAT1) by the Janus kinase 1 (JAK1). We characterized how STAT1 mutants interact with P and JAK1 phosphorylation. Certain mutants of the linker, the Src-homology 2 domain (SH2), or the transactivation domain had reduced or abolished phosphorylation through JAK1 after IFN treatment. Other mutants, mainly localized in the linker, failed to interact with P as documented by the lack of interference with nuclear translocation. Thus the functional footprint of P on STAT1 localizes mainly to the linker domain; there is also some overlap with the STAT1 phosphorylation functional footprint on the SH2 domain. Based on these observations, we discuss how the MV-P might operate to inhibit the JAK/STAT pathway. - Highlights: • Residue in the linker and SH2 domains of STAT1 are important for MV-P interaction. • Residue in the linker and SH2 domains of STAT1 are important for STAT1 phosphorylation. • Residues interferring with both functions have similar location on STAT1. • The viral P and V proteins may operate in concert to inhibit the JAK/STAT pathway

The measles virus phosphoprotein interacts with the linker domain of STAT1

Energy Technology Data Exchange (ETDEWEB)

Devaux, Patricia, E-mail: devaux.patricia@mayo.edu; Priniski, Lauren; Cattaneo, Roberto

2013-09-15

The measles virus (MV) phosphoprotein (P) and V proteins block the interferon (IFN) response by impeding phosphorylation of the signal transducer and activator of transcription 1 (STAT1) by the Janus kinase 1 (JAK1). We characterized how STAT1 mutants interact with P and JAK1 phosphorylation. Certain mutants of the linker, the Src-homology 2 domain (SH2), or the transactivation domain had reduced or abolished phosphorylation through JAK1 after IFN treatment. Other mutants, mainly localized in the linker, failed to interact with P as documented by the lack of interference with nuclear translocation. Thus the functional footprint of P on STAT1 localizes mainly to the linker domain; there is also some overlap with the STAT1 phosphorylation functional footprint on the SH2 domain. Based on these observations, we discuss how the MV-P might operate to inhibit the JAK/STAT pathway. - Highlights: • Residue in the linker and SH2 domains of STAT1 are important for MV-P interaction. • Residue in the linker and SH2 domains of STAT1 are important for STAT1 phosphorylation. • Residues interferring with both functions have similar location on STAT1. • The viral P and V proteins may operate in concert to inhibit the JAK/STAT pathway.

Iminodiacetic acid as bifunctional linker for dimerization of cyclic RGD peptides

International Nuclear Information System (INIS)

Xu, Dong; Zhao, Zuo-Quan; Chen, Shu-Ting; Yang, Yong; Fang, Wei; Liu, Shuang

2017-01-01

Introduction: In this study, I2P-RGD 2 was used as the example to illustrate a novel approach for dimerization of cyclic RGD peptides. The main objective of this study was to explore the impact of bifunctional linkers (glutamic acid vs. iminodiacetic acid) on tumor-targeting capability and excretion kinetics of the 99m Tc-labeled dimeric cyclic RGD peptides. Methods: HYNIC-I2P-RGD 2 was prepared by reacting I2P-RGD 2 with HYNIC-OSu in the presence of diisopropylethylamine, and was evaluated for its α v β 3 binding affinity against 125 I-echistatin bound to U87MG glioma cells. 99m Tc-I2P-RGD 2 was prepared with high specific activity (~185 GBq/μmol). The athymic nude mice bearing U87MG glioma xenografts were used to evaluate its biodistribution properties and image quality in comparison with those of 99m Tc-3P-RGD 2 . Results: The IC 50 value for HYNIC-I2P-RGD 2 was determined to be 39 ± 6 nM, which was very close to that (IC 50 = 33 ± 5 nM) of HYNIC-3P-RGD 2 . Replacing glutamic acid with iminodiacetic acid had little impact on α v β 3 binding affinity of cyclic RGD peptides. 99m Tc-I2P-RGD 2 and 99m Tc-3P-RGD 2 shared similar tumor uptake values over the 2 h period, and its α v β 3 -specificity was demonstrated by a blocking experiment. The uptake of 99m Tc-I2P-RGD 2 was significantly lower than 99m Tc-3P-RGD 2 in the liver and kidneys. The U87MG glioma tumors were visualized by SPECT with excellent contrast using both 99m Tc-I2P-RGD 2 and 99m Tc-3P-RGD 2 . Conclusion: Iminodiacetic acid is an excellent bifunctional linker for dimerization of cyclic RGD peptides. Bifunctional linkers have significant impact on the excretion kinetics of 99m Tc radiotracers. Because of its lower liver uptake and better tumor/liver ratios, 99m Tc-I2P-RGD 2 may have advantages over 99m Tc-3P-RGD 2 for diagnosis of tumors in chest region. -- Graphical abstract: This report presents novel approach for dimerization of cyclic RGD peptides using iminodiacetic acid as a

Development of Bioorthogonally Degradable Linkers and Polymers Using alpha-Azidoethers

Science.gov (United States)

Rajagopalan, Chandrasekhar Ramasubramanian

Degradable polymers have gained a lot of attention in recent years for applications in biotechnology and medicine. External control over polymer degradation can be obtained by incorporating functional groups that cleave in the presence of triggers that would normally be absent in biological environments, i.e. are bioorthogonal. This thesis explores the use of chemically cleavable alpha-azidoethers as a new method to obtain external control over the degradation behavior of polymers. My first goal is to illustrate the potential of alpha-azidoethers toward developing cleavable linkers. We have studied the relationship between alpha-azidoether structure and hydrolytic stability, to prepare linkers that withstand background hydrolytic cleavage until they are exposed to the cleaving trigger. The cleavage kinetics of the alpha-azidoether functional group was quantified. In addition to the conventionally used tris(2-carboxyethyl)phosphine (TCEP), dihydrolipoic acid (DHLA), a previously unexplored, biocompatible reducing agent, was also evaluated as a cleaving trigger. Based on these results, we have proposed design rules for utilizing alpha-azidoethers as cleavable linkers in applications that require bioorthogonal control over linker cleavage. Secondly, the alpha-azidoether cleavable linker chemistry was implemented into the development of polymeric materials. Two different types of polymers were developed. Polyamides incorporating alpha-azidoethers along the backbone were synthesized, and their physical properties and chemically triggered degradation behavior were characterized. The degradation timescale of these polymers can be tuned simply by manipulating the concentration of the externally applied chemical trigger. The alpha-azidoether functional group was then utilized to develop a unique triggered-release polymeric adhesive for potential applications in dental adhesive formulations. A methacrylamide-phosphonate adhesive monomer incorporating an alpha

Composite materials with metal oxide attached to lead chalcogenide nanocrystal quantum dots with linkers

Science.gov (United States)

Fuke, Nobuhiro; Koposov, Alexey Y; Sykora, Milan; Hoch, Laura

2014-12-16

Composite materials useful for devices such as photoelectrochemical solar cells include a substrate, a metal oxide film on the substrate, nanocrystalline quantum dots (NQDs) of lead sulfide, lead selenide, and lead telluride, and linkers that attach the NQDs to the metal oxide film. Suitable linkers preserve the 1s absorption peak of the NQDs. A suitable linker has a general structure A-B-C where A is a chemical group adapted for binding to a MO.sub.x and C is a chemical group adapted for binding to a NQD and B is a divalent, rigid, or semi-rigid organic spacer moiety. Other linkers that preserve the 1s absorption peak may also be used.

Elastin-like Polypeptide Linkers for Single-Molecule Force Spectroscopy.

Science.gov (United States)

Ott, Wolfgang; Jobst, Markus A; Bauer, Magnus S; Durner, Ellis; Milles, Lukas F; Nash, Michael A; Gaub, Hermann E

2017-06-27

Single-molecule force spectroscopy (SMFS) is by now well established as a standard technique in biophysics and mechanobiology. In recent years, the technique has benefitted greatly from new approaches to bioconjugation of proteins to surfaces. Indeed, optimized immobilization strategies for biomolecules and refined purification schemes are being steadily adapted and improved, which in turn has enhanced data quality. In many previously reported SMFS studies, poly(ethylene glycol) (PEG) was used to anchor molecules of interest to surfaces and/or cantilever tips. The limitation, however, is that PEG exhibits a well-known trans-trans-gauche to all-trans transition, which results in marked deviation from standard polymer elasticity models such as the worm-like chain, particularly at elevated forces. As a result, the assignment of unfolding events to protein domains based on their corresponding amino acid chain lengths is significantly obscured. Here, we provide a solution to this problem by implementing unstructured elastin-like polypeptides as linkers to replace PEG. We investigate the suitability of tailored elastin-like polypeptides linkers and perform direct comparisons to PEG, focusing on attributes that are critical for single-molecule force experiments such as linker length, monodispersity, and bioorthogonal conjugation tags. Our results demonstrate that by avoiding the ambiguous elastic response of mixed PEG/peptide systems and instead building the molecular mechanical systems with only a single bond type with uniform elastic properties, we improve data quality and facilitate data analysis and interpretation in force spectroscopy experiments. The use of all-peptide linkers allows alternative approaches for precisely defining elastic properties of proteins linked to surfaces.

A High-Throughput Small Molecule Screen for C. elegans Linker Cell Death Inhibitors.

Directory of Open Access Journals (Sweden)

Andrew R Schwendeman

Full Text Available Programmed cell death is a ubiquitous process in metazoan development. Apoptosis, one cell death form, has been studied extensively. However, mutations inactivating key mammalian apoptosis regulators do not block most developmental cell culling, suggesting that other cell death pathways are likely important. Recent work in the nematode Caenorhabditis elegans identified a non-apoptotic cell death form mediating the demise of the male-specific linker cell. This cell death process (LCD, linker cell-type death is morphologically conserved, and its molecular effectors also mediate axon degeneration in mammals and Drosophila. To develop reagents to manipulate LCD, we established a simple high-throughput screening protocol for interrogating the effects of small molecules on C. elegans linker cell death in vivo. From 23,797 compounds assayed, 11 reproducibly block linker cell death onset. Of these, five induce animal lethality, and six promote a reversible developmental delay. These results provide proof-of principle validation of our screening protocol, demonstrate that developmental progression is required for linker cell death, and suggest that larger scale screens may identify LCD-specific small-molecule regulators that target the LCD execution machinery.

Hemidesmosomal linker proteins regulate cell motility, invasion and tumorigenicity in oral squamous cell carcinoma derived cells.

Science.gov (United States)

Chaudhari, Pratik Rajeev; Charles, Silvania Emlit; D'Souza, Zinia Charlotte; Vaidya, Milind Murlidhar

2017-11-15

BPAG1e and Plectin are hemidesmosomal linker proteins which anchor intermediate filament proteins to the cell surface through β4 integrin. Recent reports indicate that these proteins play a role in various cellular processes apart from their known anchoring function. However, the available literature is inconsistent. Further, the previous study from our laboratory suggested that Keratin8/18 pair promotes cell motility and tumor progression by deregulating β4 integrin signaling in oral squamous cell carcinoma (OSCC) derived cells. Based on these findings, we hypothesized that linker proteins may have a role in neoplastic progression of OSCC. Downregulation of hemidesmosomal linker proteins in OSCC derived cells resulted in reduced cell migration accompanied by alterations in actin organization. Further, decreased MMP9 activity led to reduced cell invasion in linker proteins knockdown cells. Moreover, loss of these proteins resulted in reduced tumorigenic potential. SWATH analysis demonstrated upregulation of N-Myc downstream regulated gene 1 (NDRG1) in linker proteins downregulated cells as compared to vector control cells. Further, the defects in phenotype upon linker proteins ablation were rescued upon loss of NDRG1 in linker proteins knockdown background. These data together indicate that hemidesmosomal linker proteins regulate cell motility, invasion and tumorigenicity possibly through NDRG1 in OSCC derived cells. Copyright © 2017 Elsevier Inc. All rights reserved.

Linker-dependent Junction Formation Probability in Single-Molecule Junctions

Energy Technology Data Exchange (ETDEWEB)

Yoo, Pil Sun; Kim, Taekyeong [HankukUniversity of Foreign Studies, Yongin (Korea, Republic of)

2015-01-15

We compare the junction formation probabilities of single-molecule junctions with different linker molecules by using a scanning tunneling microscope-based break-junction technique. We found that the junction formation probability varies as SH > SMe > NH2 for the benzene backbone molecule with different types of anchoring groups, through quantitative statistical analysis. These results are attributed to different bonding forces according to the linker groups formed with Au atoms in the electrodes, which is consistent with previous works. Our work allows a better understanding of the contact chemistry in the metal.molecule junction for future molecular electronic devices.

Effect of the linkers between the zinc fingers in zinc finger protein 809 on gene silencing and nuclear localization

Energy Technology Data Exchange (ETDEWEB)

Ichida, Yu, E-mail: ichida-y@ncchd.go.jp; Utsunomiya, Yuko; Onodera, Masafumi

2016-03-18

Zinc finger protein 809 (ZFP809) belongs to the Kruppel-associated box-containing zinc finger protein (KRAB-ZFP) family and functions in repressing the expression of Moloney murine leukemia virus (MoMLV). ZFP809 binds to the primer-binding site (PBS)located downstream of the MoMLV-long terminal repeat (LTR) and induces epigenetic modifications at integration sites, such as repressive histone modifications and de novo DNA methylation. KRAB-ZFPs contain consensus TGEKP linkers between C2H2 zinc fingers. The phosphorylation of threonine residues within linkers leads to the inactivation of zinc finger binding to target sequences. ZFP809 also contains consensus linkers between zinc fingers. However, the function of ZFP809 linkers remains unknown. In the present study, we constructed ZFP809 proteins containing mutated linkers and examined their ability to silence transgene expression driven by MLV, binding ability to MLV PBS, and cellular localization. The results of the present study revealed that the linkers affected the ability of ZFP809 to silence transgene expression. Furthermore, this effect could be partly attributed to changes in the localization of ZFP809 proteins containing mutated linkers. Further characterization of ZFP809 linkers is required for understanding the functions and features of KRAB-ZFP-containing linkers. - Highlights: • ZFP809 has three consensus linkers between the zinc fingers. • Linkers are required for ZFP809 to silence transgene expression driven by MLV-LTR. • Linkers affect the precise nuclear localization of ZFP809.

Connected Operators : A review of region-based morphological image processing techniques

NARCIS (Netherlands)

Salembier, Philippe; Wilkinson, Michael H. F.

2009-01-01

Connected operators are filtering tools that act by merging elementary regions called flat zones. Connecting operators cannot create new contours nor modify their position. Therefore, they have very good contour preservation properties and are capable of both low-level filtering and higher-level

Connected Operators : A review of region-based morphological image processing techniques

NARCIS (Netherlands)

Salembier, Philippe; Wilkinson, Michael H. F.

Connected operators are filtering tools that act by merging elementary regions called flat zones. Connecting operators cannot create new contours nor modify their position. Therefore, they have very good contour preservation properties and are capable of both low-level filtering and higher-level

Development and characterization of polyclonal antibodies against the linker region of the telomere-binding protein TRF2

Directory of Open Access Journals (Sweden)

Nadya V. Ilicheva

2018-03-01

Full Text Available Background: TRF2 (telomeric repeat binding factor 2 is an essential component of the telomere-binding protein complex shelterin. TRF2 induces the formation of a special structure of telomeric DNA and counteracts activation of DNA damage-response pathways telomeres. TRF2 has a poorly characterized linker region (udTRF2 between its homodimerization and DNA-binding domains. Some lines of evidence have shown that this region could be involved in TRF2 interaction with nuclear lamina. Results: In this study, the fragment of the TERF2 gene encoding udTRF2 domain of telomere-binding protein TRF2 was produced by PCR and cloned into the pET32a vector. The resulting plasmid pET32a-udTRF2 was used for the expression of the recombinant udTRF2 in E. coli RosettaBlue (DE3. The protein was isolated and purified using ammonium sulfate precipitation followed by ion-exchange chromatography. The purified recombinant protein udTRF2 was injected into guinea pigs to generate polyclonal antibodies. The ability of anti-udTRF2 antibodies to bind endogenous TRF2 in human skin fibroblasts was tested by western blotting and immunofluorescent staining. Conclusions: In this study, the recombinant protein udTRF2 and antibodies to it were generated. Both protein and antibodies will provide a useful tool for investigation of the functions of the udTRF2 domain and its role in the interaction between TRF2 and nuclear lamina. Keywords: Chromosomes, Molecular cloning, Nuclear lamina, Nucleoprotein complexes, Polyclonal antibodies, Recombinant polypeptide, Shelterin, Telomere-binding protein TRF2, Telomeres, Telomeric DNA, TTAGGG repeats

Mixed-linker zeolitic imidazolate framework mixed-matrix membranes for aggressive CO2 separation from natural gas

KAUST Repository

Thompson, Joshua A.

2014-07-01

Zeolitic imidazolate framework (ZIF) materials are a promising subclass of metal-organic frameworks (MOF) for gas separations. However, due to the deleterious effects of gate-opening phenomena associated with organic linker rotation near the limiting pore apertures of ZIFs, there have been few demonstrations of improved gas separation properties over pure polymer membranes when utilizing ZIF materials in composite membranes for CO2-based gas separations. Here, we report a study of composite ZIF/polymer membranes, containing mixed-linker ZIF materials with ZIF-8 crystal topologies but composed of different organic linker compositions. Characterization of the mixed-linker ZIFs shows that the mixed linker approach offers control over the porosity and pore size distribution of the materials, as determined from nitrogen physisorption and Horváth-Kawazoe analysis. Single gas permeation measurements on mixed-matrix membranes reveal that inclusion of mixed-linker ZIFs yields membranes with better ideal CO2/CH4 selectivity than membranes containing ZIF-8. This improvement is shown to likely occur from enhancement in the diffusion selectivity of the membranes associated with controlling the pore size distribution of the ZIF filler. Mixed-gas permeation experiments show that membranes with mixed-linker ZIFs display an effective plasticization resistance that is not typical of the pure polymeric matrix. Overall, we demonstrate that mixed-linker ZIFs can improve the gas separation properties in composite membranes and may be applicable to aggressive CO2 concentrations in natural gas feeds. © 2013 Elsevier Inc. All rights reserved.

The Abl SH2-kinase linker naturally adopts a conformation competent for SH3 domain binding.

Science.gov (United States)

Chen, Shugui; Brier, Sébastien; Smithgall, Thomas E; Engen, John R

2007-04-01

The core of the Abelson tyrosine kinase (c-Abl) is structurally similar to Src-family kinases where SH3 and SH2 domains pack against the backside of the kinase domain in the down-regulated conformation. Both kinase families depend upon intramolecular association of SH3 with the linker joining the SH2 and kinase domains for suppression of kinase activity. Hydrogen deuterium exchange (HX) and mass spectrometry (MS) were used to probe intramolecular interaction of the c-Abl SH3 domain with the linker in recombinant constructs lacking the kinase domain. Under physiological conditions, the c-Abl SH3 domain undergoes partial unfolding, which is stabilized by ligand binding, providing a unique assay for SH3:linker interaction in solution. Using this approach, we observed dynamic association of the SH3 domain with the linker in the absence of the kinase domain. Truncation of the linker before W254 completely prevented cis-interaction with SH3, while constructs containing amino acids past this point showed SH3:linker interactions. The observation that the Abl linker sequence exhibits SH3-binding activity in the absence of the kinase domain is unique to Abl and was not observed with Src-family kinases. These results suggest that SH3:linker interactions may have a more prominent role in Abl regulation than in Src kinases, where the down-regulated conformation is further stabilized by a second intramolecular interaction between the C-terminal tail and the SH2 domain.

Quantum mechanics in a multiply connected region

International Nuclear Information System (INIS)

Miyazawa, H.

1986-01-01

It is usually assumed that wave fields or wave functions are single valued functions of space-time. However, the phase of a complex field is an unobservable quantity and there is no obvious reason that it must be single valued. On this point quantum mechanics in a multiply connected regions is not well formulated. This ambiguity appears e.g., in the case of the Bohm-Aharonov effect concerning the observability of the vector potential around a magnetic flux. The author discusses the single or multiple valuedness of wave functions and attempts to see if such an effect really exists or not. The wave function of a charged particle in a multiply connected region is not necessarily single valued. The condition that the ground state energy be a minimum fixes the character of the multiple valuedness. For a charged particle around a magnetic flux a multiple valued wave function is preferable and no Bohm-Aharonov effect is observed. The minimum energy principle is proved if one also considers the interaction of a charged particle with external objects. Then theoretically the Bohm-Aharonov effect should not be observed. Experiments are not yet conclusive on this point

High-resolution two-dimensional liquid chromatography analysis of key linker drug intermediate used in antibody drug conjugates.

Science.gov (United States)

Venkatramani, C J; Huang, Shu Rong; Al-Sayah, Mohammad; Patel, Ila; Wigman, Larry

2017-10-27

In this manuscript, the application of high-resolution sampling (HRS) two-dimensional liquid chromatography (2D-LC) in the detailed analysis of key linker drug intermediate is presented. Using HRS, selected regions of the primary column eluent were transferred to a secondary column with fidelity enabling qualitative and quantitative analysis of linker drugs. The primary column purity of linker drug intermediate ranged from 88.9% to 94.5% and the secondary column purity ranged from 99.6% to 99.9%, showing lot-to-lot variability, significant differences between the three lots, and substantiating the synthetic and analytical challenges of ADCs. Over 15 impurities co-eluting with the linker drug intermediate in the primary dimension were resolved in the secondary dimension. The concentrations of most of these impurities were over three orders of magnitude lower than the linker drug. Effective peak focusing and high-speed secondary column analysis resulted in sharp peaks in the secondary dimension, improving the signal-to-noise ratios. The sensitivity of 2D-LC separation was over five fold better than conventional HPLC separation. The limit of quantitation (LOQ) was less than 0.01%. Many peaks originating from primary dimension were resolved into multiple components in the complementary secondary dimension, demonstrating the complexity of these samples. The 2D-LC was highly reproducible, showing good precision between runs with%RSD of peak areas less than 0.1 for the main component. The absolute difference in the peak areas of impurities less than 0.1% were within ±0.01% and for impurities in the range of 0.1%-0.3%, the absolute difference were ±0.02%, which are comparable to 1D-LC. The overall purity of the linker drug intermediate was determined from the product of primary and secondary column purity (HPLC Purity=%peak area of main component in the primary dimension×%peak area of main component in the secondary dimension). Additionally, the 2D-LC separation enables

Description of a cellulose-binding domain and a linker sequence from Aspergillus fungi

NARCIS (Netherlands)

Quentin, M; Ebbelaar, M; Derksen, J; Mariani, C; van der Valk, H

A family I cellulose-binding domain (CBD) and a serine- and threonine-rich linker peptide were cloned from the fungi Aspergillus japonicus and Aspergillus aculeatus. A glutathione S-transferase (GST) fusion protein comprising GST and a peptide linker with the CBD fused to its C-terminus, was

Functional Connectome Analysis of Dopamine Neuron Glutamatergic Connections in Forebrain Regions.

Science.gov (United States)

Mingote, Susana; Chuhma, Nao; Kusnoor, Sheila V; Field, Bianca; Deutch, Ariel Y; Rayport, Stephen

2015-12-09

In the ventral tegmental area (VTA), a subpopulation of dopamine neurons express vesicular glutamate transporter 2 and make glutamatergic connections to nucleus accumbens (NAc) and olfactory tubercle (OT) neurons. However, their glutamatergic connections across the forebrain have not been explored systematically. To visualize dopamine neuron forebrain projections and to enable photostimulation of their axons independent of transmitter status, we virally transfected VTA neurons with channelrhodopsin-2 fused to enhanced yellow fluorescent protein (ChR2-EYFP) and used DAT(IREScre) mice to restrict expression to dopamine neurons. ChR2-EYFP-expressing neurons almost invariably stained for tyrosine hydroxylase, identifying them as dopaminergic. Dopamine neuron axons visualized by ChR2-EYFP fluorescence projected most densely to the striatum, moderately to the amygdala and entorhinal cortex (ERC), sparsely to prefrontal and cingulate cortices, and rarely to the hippocampus. Guided by ChR2-EYFP fluorescence, we recorded systematically from putative principal neurons in target areas and determined the incidence and strength of glutamatergic connections by activating all dopamine neuron terminals impinging on recorded neurons with wide-field photostimulation. This revealed strong glutamatergic connections in the NAc, OT, and ERC; moderate strength connections in the central amygdala; and weak connections in the cingulate cortex. No glutamatergic connections were found in the dorsal striatum, hippocampus, basolateral amygdala, or prefrontal cortex. These results indicate that VTA dopamine neurons elicit widespread, but regionally distinct, glutamatergic signals in the forebrain and begin to define the dopamine neuron excitatory functional connectome. Dopamine neurons are important for the control of motivated behavior and are involved in the pathophysiology of several major neuropsychiatric disorders. Recent studies have shown that some ventral midbrain dopamine neurons are

Functional connectivity in cortical regions in dementia with Lewy bodies and Alzheimer's disease.

Science.gov (United States)

Kenny, Eva R; Blamire, Andrew M; Firbank, Michael J; O'Brien, John T

2012-02-01

Using resting-state functional magnetic resonance imaging, spontaneous low-frequency fluctuations in the blood oxygenation level-dependent signal were measured to investigate connectivity between key brain regions hypothesized to be differentially affected in dementia with Lewy bodies compared with Alzheimer's disease and healthy controls. These included connections of the hippocampus, because of its role in learning, and parietal and occipital areas involved in memory, attention and visual processing. Connectivity was investigated in 47 subjects aged 60 years and over: 15 subjects with dementia with Lewy bodies, 16 subjects with Alzheimer's disease and 16 control subjects. Subjects were scanned using a 3 Tesla magnetic resonance imaging system. The mean blood oxygenation level-dependent signal time series was extracted from seed regions in the hippocampus, posterior cingulate cortex, precuneus and primary visual cortex and correlated with all other brain voxels to determine functional connectivity. Both subjects with dementia with Lewy bodies and Alzheimer's disease showed greater connectivity than control subjects. Compared with controls, the dementia with Lewy bodies group had greater connectivity between the right posterior cingulate cortex and other brain areas. In dementia with Lewy bodies, there were no significant differences in hippocampal connectivity compared with controls, but in Alzheimer's disease left hippocampal connectivity was greater compared with controls. There were no significant differences between groups for precuneus or primary visual cortex connectivity. No seed regions showed significantly less connectivity in subjects with dementia with Lewy bodies or Alzheimer's disease compared with controls. We found greater connectivity with the posterior cingulate in dementia with Lewy bodies and with the hippocampus in Alzheimer's disease. Consistent with the known relative preservation of memory in dementia with Lewy bodies compared with Alzheimer

High-Flux Zeolitic Imidazolate Framework Membranes for Propylene/Propane Separation by Postsynthetic Linker Exchange.

Science.gov (United States)

Lee, Moon Joo; Kwon, Hyuk Taek; Jeong, Hae-Kwon

2018-01-02

While zeolitic imidazolate framework, ZIF-8, membranes show impressive propylene/propane separation, their throughput needs to be greatly improved for practical applications. A method is described that drastically reduces the effective thickness of ZIF-8 membranes, thereby substantially improving their propylene permeance (that is, flux). The new strategy is based on a controlled single-crystal to single-crystal linker exchange of 2-methylimidazole in ZIF-8 membrane grains with 2-imidazolecarboxaldehyde (ZIF-90 linker), thereby enlarging the effective aperture size of ZIF-8. The linker-exchanged ZIF-8 membranes showed a drastic increase in propylene permeance by about four times, with a negligible loss in propylene/propane separation factor when compared to as-prepared membranes. The linker-exchange effect depends on the membrane synthesis method. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Rapid construction of mechanically- confined multi- cellular structures using dendrimeric intercellular linker.

Science.gov (United States)

Mo, Xuejun; Li, Qiushi; Yi Lui, Lena Wai; Zheng, Baixue; Kang, Chiang Huen; Nugraha, Bramasta; Yue, Zhilian; Jia, Rui Rui; Fu, Hong Xia; Choudhury, Deepak; Arooz, Talha; Yan, Jie; Lim, Chwee Teck; Shen, Shali; Hong Tan, Choon; Yu, Hanry

2010-10-01

Tissue constructs that mimic the in vivo cell-cell and cell-matrix interactions are especially useful for applications involving the cell- dense and matrix- poor internal organs. Rapid and precise arrangement of cells into functional tissue constructs remains a challenge in tissue engineering. We demonstrate rapid assembly of C3A cells into multi- cell structures using a dendrimeric intercellular linker. The linker is composed of oleyl- polyethylene glycol (PEG) derivatives conjugated to a 16 arms- polypropylenimine hexadecaamine (DAB) dendrimer. The positively charged multivalent dendrimer concentrates the linker onto the negatively charged cell surface to facilitate efficient insertion of the hydrophobic oleyl groups into the cellular membrane. Bringing linker- treated cells into close proximity to each other via mechanical means such as centrifugation and micromanipulation enables their rapid assembly into multi- cellular structures within minutes. The cells exhibit high levels of viability, proliferation, three- dimensional (3D) cell morphology and other functions in the constructs. We constructed defined multi- cellular structures such as rings, sheets or branching rods that can serve as potential tissue building blocks to be further assembled into complex 3D tissue constructs for biomedical applications. 2010 Elsevier Ltd. All rights reserved.

Effect of linkers on the αvβ3 integrin targeting efficiency of cyclic RGD-conjugates

Science.gov (United States)

Karmakar, Partha; Grabowska, Dorota; Sudlow, Gail; Ziabrev, Kostiantyn; Sanyal, Nibedita; Achilefu, Samuel

2018-02-01

Cyclic arginine-glycine-aspartic acid (cRGD) peptides are well known to target ανβ3 integrin expressed on cancer cells and neovasculature. Conjugation of these peptides with dyes, drugs, antibodies and other biomolecules through covalent linkers provides a facile way to deliver these products to tumor cells for targeted cancer therapy and diagnosis. Click chemistry and acid-amine couplings are widely used conjugation strategies. However, the effects of different linkers and the distance between the cRGD and the conjugates on the binding of cRGD ligand with ανβ3 has been underexplored. In this present study, we prepared cRGD-conjugates using different linkers and determined how they altered the tumor targeting efficiency in vitro and in vivo. The results demonstrate that different linkers significantly altered the pharmacokinetics of the cRGD conjugates and the tumor uptake kinetics. Unlike large antibodies, this preliminary finding shows that linkers used to attach drugs and fluorescent molecular probes to small peptides play a major role in the accuracy of tumor targeting and treatment outcomes. As a result, considerable attention should be paid to the nature of linkers used in the design of molecular probes and targeted therapeutics.

The centrosomal linker and microtubules provide dual levels of spatial coordination of centrosomes.

Directory of Open Access Journals (Sweden)

Marko Panic

2015-05-01

Full Text Available The centrosome is the principal microtubule organizing center in most animal cells. It consists of a pair of centrioles surrounded by pericentriolar material. The centrosome, like DNA, duplicates exactly once per cell cycle. During interphase duplicated centrosomes remain closely linked by a proteinaceous linker. This centrosomal linker is composed of rootletin filaments that are anchored to the centrioles via the protein C-Nap1. At the onset of mitosis the linker is dissolved by Nek2A kinase to support the formation of the bipolar mitotic spindle. The importance of the centrosomal linker for cell function during interphase awaits characterization. Here we assessed the phenotype of human RPE1 C-Nap1 knockout (KO cells. The absence of the linker led to a modest increase in the average centrosome separation from 1 to 2.5 μm. This small impact on the degree of separation is indicative of a second level of spatial organization of centrosomes. Microtubule depolymerisation or stabilization in C-Nap1 KO cells dramatically increased the inter-centrosomal separation (> 8 μm. Thus, microtubules position centrosomes relatively close to one another in the absence of linker function. C-Nap1 KO cells had a Golgi organization defect with a two-fold expansion of the area occupied by the Golgi. When the centrosomes of C-Nap1 KO cells showed considerable separation, two spatially distinct Golgi stacks could be observed. Furthermore, migration of C-Nap1 KO cells was slower than their wild type RPE1 counterparts. These data show that the spatial organization of centrosomes is modulated by a combination of centrosomal cohesion and microtubule forces. Furthermore a modest increase in centrosome separation has major impact on Golgi organization and cell migration.

Linker Histone Phosphorylation Regulates Global Timing of Replication Origin Firing*S⃞

Science.gov (United States)

Thiriet, Christophe; Hayes, Jeffrey J.

2009-01-01

Despite the presence of linker histone in all eukaryotes, the primary function(s) of this histone have been difficult to clarify. Knock-out experiments indicate that H1s play a role in regulation of only a small subset of genes but are an essential component in mouse development. Here, we show that linker histone (H1) is involved in the global regulation of DNA replication in Physarum polycephalum. We find that genomic DNA of H1 knock-down cells is more rapidly replicated, an effect due at least in part to disruption of the native timing of replication fork firing. Immunoprecipitation experiments demonstrate that H1 is transiently lost from replicating chromatin via a process facilitated by phosphorylation. Our results suggest that linker histones generate a chromatin environment refractory to replication and that their transient removal via protein phosphorylation during S phase is a critical step in the epigenetic regulation of replication timing. PMID:19015270

The Responsive Amygdala: Treatment-induced Alterations in Functional Connectivity in Pediatric Complex Regional Pain Syndrome

Science.gov (United States)

Simons, LE; Pielech, M; Erpelding, N; Linnman, C; Moulton, E; Sava, S; Lebel, A; Serrano, P; Sethna, N; Berde, C; Becerra, L; Borsook, D

2014-01-01

The amygdala is a key brain region with efferent and afferent neural connections that involve complex behaviors such as pain, reward, fear and anxiety. This study evaluated resting state functional connectivity of the amygdala with cortical and subcortical regions in a group of chronic pain patients (pediatric complex regional pain syndrome) with age-gender matched controls before and after intensive physical-biobehavioral pain treatment. Our main findings include (1) enhanced functional connectivity from the amygdala to multiple cortical, subcortical, and cerebellar regions in patients compared to controls, with differences predominantly in the left amygdala in the pre-treated condition (disease state); (2) dampened hyperconnectivity from the left amygdala to the motor cortex, parietal lobe, and cingulate cortex after intensive pain rehabilitation treatment within patients with nominal differences observed among healthy controls from Time 1 to Time 2 (treatment effects); (3) functional connectivity to several regions key to fear circuitry (prefrontal cortex, bilateral middle temporal lobe, bilateral cingulate, hippocampus) correlated with higher pain-related fear scores and (4) decreases in pain-related fear associated with decreased connectivity between the amygdala and the motor and somatosensory cortex, cingulate, and frontal areas. Our data suggest that there are rapid changes in amygdala connectivity following an aggressive treatment program in children with chronic pain and intrinsic amygdala functional connectivity activity serving as a potential indicator of treatment response. PMID:24861582

Specific distribution of the Saccharomyces cerevisiae linker histone homolog HHO1p in the chromatin

OpenAIRE

Freidkin, Ilya; Katcoff, Don J.

2001-01-01

In virtually all eukaryotic organisms, linker DNA between nucleosomes is associated with a histone termed linker histone or histone H1. In Saccharomyces cerevisiae, HHO1 encodes a putative linker histone with very significant homology to histone H1. The encoded protein is expressed in the nucleus, but has not been shown to affect global chromatin structure, nor has its deletion shown any detectable phenotype. In vitro chromatin assembly experiments with recombinant HHO1p have shown that it is...

Chemical and enzymatic stability of amino acid prodrugs containing methoxy, ethoxy and propylene glycol linkers.

Science.gov (United States)

Gupta, Deepak; Gupta, Sheeba Varghese; Lee, Kyung-Dall; Amidon, Gordon L

2009-01-01

We evaluated the chemical and enzymatic stabilities of prodrugs containing methoxy, ethoxy and propylene glycol linkers in order to find a suitable linker for prodrugs of carboxylic acids with amino acids. l-Valine and l-phenylalanine prodrugs of model compounds (benzoic acid and phenyl acetic acid) containing methoxy, ethoxy and propylene glycol linkers were synthesized. The hydrolysis rate profile of each compound was studied at physiologically relevant pHs (1.2, 4, 6 and 7.4). Enzymatic hydrolysis of propylene glycol containing compounds was studied using Caco-2 homogenate as well as purified enzyme valacyclovirase. It was observed that the stability of the prodrugs increases with the linker length (propyl > ethyl > methyl). The model prodrugs were stable at acidic pH as compared to basic pH. It was observed that the prodrug with the aliphatic amino acid promoiety was more stable compared to its aromatic counterpart. The comparison between benzyl and the phenyl model compounds revealed that the amino acid side chain is significant in determining the stability of the prodrug whereas the benzyl or phenyl carboxylic acid had little or no effect on the stability. The enzymatic activation studies of propylene glycol linker prodrug in the presence of valacyclovirase and cell homogenate showed faster generation of the parent drug at pH 7.4. The half-life of prodrugs at pH 7.4 was more than 12 h, whereas in the presence of cell homogenate the half-lives were less than 1 h. Hydrolysis by Caco-2 homogenate generated the parent compound in two steps, where the prodrug was first converted to the intermediate, propylene glycol benzoate, which was then converted to the parent compound (benzoic acid). Enzymatic hydrolysis of propylene glycol containing prodrugs by valacyclovirase showed hydrolysis of the amino acid ester part to generate the propylene glycol ester of model compound (propylene glycol benzoate) as the major product. The amino acid prodrugs containing methoxy

The flexibility of modified-linker MIL-53 materials.

Science.gov (United States)

Munn, Alexis S; Pillai, Renjith S; Biswas, Shyam; Stock, Norbert; Maurin, Guillaume; Walton, Richard I

2016-03-14

The flexibility of eight aluminium hydroxo terephthalates [Al(OH)(BDC-X)]·n(guest) (BDC = 1,4-benzene-dicarboxylate; X = -H, -CH3, -Cl, -Br, -NH2, -NO2, -(OH)2, -CO2H) crystallising in the MIL-53-type structure was investigated upon thermal dehydration of as-made samples, superhydration and methanol adsorption/desorption using in situ powder X-ray diffraction (PXRD). Profile fitting was used to determine lattice parameters as a function of time and/or temperature to describe their structural evolution. It has thus been shown that while methanol vapour adsorption induces an opening of all the modified frameworks, except the -NH2 material, superhydration only leads to open structures for Al-MIL-53-NO2, -Br and -(OH)2. All the MIL-53 solids, except Al-MIL-53-(OH)2 are present in the open structures upon thermal dehydration. In addition to the exploration of the breathing behavior of this MIL-53 series, the issue of disorder in the distribution of the functional groups between the organic linkers was explored. As a typical illustration, density functional theory calculations were carried out on different structures of Al-MIL-53-Cl, in which the distribution of -Cl within two adjacent BDC linkers is varied. The results show that the most energetically stable configuration leads to the best agreement with the experimental PXRD pattern. This observation supports that the distribution of the selected linker substituent in the functionalised solid is governed by energetics and that there is a preference for an ordering of this arrangement.

Rapid One-Pot Microwave Synthesis of Mixed-Linker Hybrid Zeolitic-Imidazolate Framework Membranes for Tunable Gas Separations.

Science.gov (United States)

Hillman, Febrian; Brito, Jordan; Jeong, Hae-Kwon

2018-02-14

The relatively slow and complex fabrication processes of polycrystalline metal-organic framework (MOF) membranes often times restrict their way to commercialization, despite their potential for molecular separation applications. Herein, we report a rapid one-pot microwave synthesis of mixed-linker hybrid zeolitic-imidazolate framework (ZIF) membranes consisting of 2-methylimidazolate (ZIF-8 linker) and benzimidazolate (ZIF-7 linker) linkers, termed ZIF-7-8 membranes. The fast-volumetric microwave heating in conjunction with a unique counter diffusion of metal and linker solutions enabled unprecedented rapid synthesis of well-intergrown ZIF-7-8 membranes in ∼90 s, the fastest MOF membrane preparation up to date. Furthermore, we were able to tune the molecular sieving properties of the ZIF-7-8 membranes by varying the benzimidazole-to-2-methylimidazole (bIm-to-mIm) linker ratio in the hybrid frameworks. The tuning of their molecular sieving properties led to the systematic change in the permeance and selectivity of various small gases. The unprecedented rapid synthesis of well-intergrown ZIF-7-8 membranes with tunable molecular sieving properties is an important step forward for the commercial gas separation applications of ZIF membranes.

Regulation of Cellular Dynamics and Chromosomal Binding Site Preference of Linker Histones H1.0 and H1.X.

Science.gov (United States)

Okuwaki, Mitsuru; Abe, Mayumi; Hisaoka, Miharu; Nagata, Kyosuke

2016-11-01

Linker histones play important roles in the genomic organization of mammalian cells. Of the linker histone variants, H1.X shows the most dynamic behavior in the nucleus. Recent research has suggested that the linker histone variants H1.X and H1.0 have different chromosomal binding site preferences. However, it remains unclear how the dynamics and binding site preferences of linker histones are determined. Here, we biochemically demonstrated that the DNA/nucleosome and histone chaperone binding activities of H1.X are significantly lower than those of other linker histones. This explains why H1.X moves more rapidly than other linker histones in vivo Domain swapping between H1.0 and H1.X suggests that the globular domain (GD) and C-terminal domain (CTD) of H1.X independently contribute to the dynamic behavior of H1.X. Our results also suggest that the N-terminal domain (NTD), GD, and CTD cooperatively determine the preferential binding sites, and the contribution of each domain for this determination is different depending on the target genes. We also found that linker histones accumulate in the nucleoli when the nucleosome binding activities of the GDs are weak. Our results contribute to understanding the molecular mechanisms of dynamic behaviors, binding site selection, and localization of linker histones. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Bioinformatic Analysis Reveals Conservation of Intrinsic Disorder in the Linker Sequences of Prokaryotic Dual-family Immunophilin Chaperones.

Science.gov (United States)

Barik, Sailen

2018-01-01

The two classical immunophilin families, found essentially in all living cells, are: cyclophilin (CYN) and FK506-binding protein (FKBP). We previously reported a novel class of immunophilins that are natural chimera of these two, which we named dual-family immunophilin (DFI). The DFIs were found in either of two conformations: CYN-linker-FKBP (CFBP) or FKBP-3TPR-CYN (FCBP). While the 3TPR domain can serve as a flexible linker between the FKBP and CYN modules in the FCBP-type DFI, the linker sequences in the CFBP-type DFIs are relatively short, diverse in sequence, and contain no discernible motif or signature. Here, I present several lines of computational evidence that, regardless of their primary structure, these CFBP linkers are intrinsically disordered. This report provides the first molecular foundation for the model that the CFBP linker acts as an unstructured, flexible loop, allowing the two flanking chaperone modules function independently while linked in cis , likely to assist in the folding of multisubunit client complexes.

P-Link: A method for generating multicomponent cytochrome P450 fusions with variable linker length

DEFF Research Database (Denmark)

Belsare, Ketaki D.; Ruff, Anna Joelle; Martinez, Ronny

2014-01-01

Fusion protein construction is a widely employed biochemical technique, especially when it comes to multi-component enzymes such as cytochrome P450s. Here we describe a novel method for generating fusion proteins with variable linker lengths, protein fusion with variable linker insertion (P...

Rostro-Caudal Organization of Connectivity between Cingulate Motor Areas and Lateral Frontal Regions

Directory of Open Access Journals (Sweden)

Kep Kee Loh

2018-01-01

Full Text Available According to contemporary views, the lateral frontal cortex is organized along a rostro-caudal functional axis with increasingly complex cognitive/behavioral control implemented rostrally, and increasingly detailed motor control implemented caudally. Whether the medial frontal cortex follows the same organization remains to be elucidated. To address this issue, the functional connectivity of the 3 cingulate motor areas (CMAs in the human brain with the lateral frontal cortex was investigated. First, the CMAs and their representations of hand, tongue, and eye movements were mapped via task-related functional magnetic resonance imaging (fMRI. Second, using resting-state fMRI, their functional connectivity with lateral prefrontal and lateral motor cortical regions of interest (ROIs were examined. Importantly, the above analyses were conducted at the single-subject level to account for variability in individual cingulate morphology. The results demonstrated a rostro-caudal functional organization of the CMAs in the human brain that parallels that in the lateral frontal cortex: the rostral CMA has stronger functional connectivity with prefrontal regions and weaker connectivity with motor regions; conversely, the more caudal CMAs have weaker prefrontal and stronger motor connectivity. Connectivity patterns of the hand, tongue and eye representations within the CMAs are consistent with that of their parent CMAs. The parallel rostral-to-caudal functional organization observed in the medial and lateral frontal cortex could likely contribute to different hierarchies of cognitive-motor control.

Modulations of DNA Contacts by Linker Histones and Post-translational Modifications Determine the Mobility and Modifiability of Nucleosomal H3 Tails.

Science.gov (United States)

Stützer, Alexandra; Liokatis, Stamatios; Kiesel, Anja; Schwarzer, Dirk; Sprangers, Remco; Söding, Johannes; Selenko, Philipp; Fischle, Wolfgang

2016-01-21

Post-translational histone modifications and linker histone incorporation regulate chromatin structure and genome activity. How these systems interface on a molecular level is unclear. Using biochemistry and NMR spectroscopy, we deduced mechanistic insights into the modification behavior of N-terminal histone H3 tails in different nucleosomal contexts. We find that linker histones generally inhibit modifications of different H3 sites and reduce H3 tail dynamics in nucleosomes. These effects are caused by modulations of electrostatic interactions of H3 tails with linker DNA and largely depend on the C-terminal domains of linker histones. In agreement, linker histone occupancy and H3 tail modifications segregate on a genome-wide level. Charge-modulating modifications such as phosphorylation and acetylation weaken transient H3 tail-linker DNA interactions, increase H3 tail dynamics, and, concomitantly, enhance general modifiability. We propose that alterations of H3 tail-linker DNA interactions by linker histones and charge-modulating modifications execute basal control mechanisms of chromatin function. Copyright © 2016 Elsevier Inc. All rights reserved.

Numerical conformal mapping and its inverse of unbounded multiply connected regions onto logarithmic spiral slit regions and straight slit regions.

Science.gov (United States)

Yunus, A A M; Murid, A H M; Nasser, M M S

2014-02-08

This paper presents a boundary integral equation method with the adjoint generalized Neumann kernel for computing conformal mapping of unbounded multiply connected regions and its inverse onto several classes of canonical regions. For each canonical region, two integral equations are solved before one can approximate the boundary values of the mapping function. Cauchy's-type integrals are used for computing the mapping function and its inverse for interior points. This method also works for regions with piecewise smooth boundaries. Three examples are given to illustrate the effectiveness of the proposed method.

Impact of connection density on regional cost differences for network operators in the Netherlands

International Nuclear Information System (INIS)

2009-04-01

The Dutch Office of Energy Regulation ('Energiekamer') has an obligation to investigate the extent to which the electricity and gas distribution businesses (DNOs) in the Netherlands face different structural environments that result in regional cost differences which, in turn, could justify tariff differences. On the basis of previous studies, Energiekamer has identified 'water crossings' and 'local taxes' as allowable regional differences. To account for them, Energiekamer has introduced an adjustment to the regulated revenues formula in order to guarantee a level-playing field to the Dutch DNOs. In addition to these factors, it has been claimed that connection density may have an impact on distribution costs and that, therefore, regulated revenues should be adjusted to compensate for regional differences in connection density between DNOs. However, so far, the research in this field has been unable to identify a sufficiently robust relationship between cost and connection density to support this claim. In order to address this issue, Energiekamer has asked Frontier Economics and Consentec to further investigate the relationship between connection density and distribution costs in the Netherlands. Therefore, our analysis has aimed at determining whether, and to what extent, connection density in the Netherlands is a significant driver of the costs of electricity and gas distribution networks. The following three questions are answered: (1) Is connection density a significant cost driver in electricity and gas networks in the Netherlands?; (2) If so, which functional form (e.g. U-shaped) does this relationship have in the Netherlands?; (3) Finally, based on the evidence collected, is the influence of connection density sufficiently well-determined to be considered a regional difference in the Dutch regulatory framework?

Tethering metal ions to photocatalyst particulate surfaces by bifunctional molecular linkers for efficient hydrogen evolution

KAUST Repository

Yu, Weili

2014-08-19

A simple and versatile method for the preparation of photocatalyst particulates modified with effective cocatalysts is presented; the method involves the sequential soaking of photocatalyst particulates in solutions containing bifunctional organic linkers and metal ions. The modification of the particulate surfaces is a universal and reproducible method because the molecular linkers utilize strong covalent bonds, which in turn result in modified monolayer with a small but controlled quantity of metals. The photocatalysis results indicated that the CdS with likely photochemically reduced Pd and Ni, which were initially immobilized via ethanedithiol (EDT) as a linker, were highly efficient for photocatalytic hydrogen evolution from Na2S-Na2SO3-containing aqueous solutions. The method developed in this study opens a new synthesis route for the preparation of effective photocatalysts with various combinations of bifunctional linkers, metals, and photocatalyst particulate materials. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Tethering metal ions to photocatalyst particulate surfaces by bifunctional molecular linkers for efficient hydrogen evolution

KAUST Repository

Yu, Weili; Isimjan, Tayirjan T.; Del Gobbo, Silvano; Anjum, Dalaver Hussain; Abdel-Azeim, Safwat; Cavallo, Luigi; Garcia Esparza, Angel T.; Domen, Kazunari; Xu, Wei; Takanabe, Kazuhiro

2014-01-01

A simple and versatile method for the preparation of photocatalyst particulates modified with effective cocatalysts is presented; the method involves the sequential soaking of photocatalyst particulates in solutions containing bifunctional organic linkers and metal ions. The modification of the particulate surfaces is a universal and reproducible method because the molecular linkers utilize strong covalent bonds, which in turn result in modified monolayer with a small but controlled quantity of metals. The photocatalysis results indicated that the CdS with likely photochemically reduced Pd and Ni, which were initially immobilized via ethanedithiol (EDT) as a linker, were highly efficient for photocatalytic hydrogen evolution from Na2S-Na2SO3-containing aqueous solutions. The method developed in this study opens a new synthesis route for the preparation of effective photocatalysts with various combinations of bifunctional linkers, metals, and photocatalyst particulate materials. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Functional connectivity mapping of regions associated with self- and other-processing.

Science.gov (United States)

Murray, Ryan J; Debbané, Martin; Fox, Peter T; Bzdok, Danilo; Eickhoff, Simon B

2015-04-01

Neuroscience literature increasingly suggests a conceptual self composed of interacting neural regions, rather than independent local activations, yet such claims have yet to be investigated. We, thus, combined task-dependent meta-analytic connectivity modeling (MACM) with task-independent resting-state (RS) connectivity analysis to delineate the neural network of the self, across both states. Given psychological evidence implicating the self's interdependence on social information, we also delineated the neural network underlying conceptual other-processing. To elucidate the relation between the self-/other-networks and their function, we mined the MACM metadata to generate a cognitive-behavioral profile for an empirically identified region specific to conceptual self, the pregenual anterior cingulate (pACC), and conceptual other, posterior cingulate/precuneus (PCC/PC). Mining of 7,200 published, task-dependent, neuroimaging studies, using healthy human subjects, yielded 193 studies activating the self-related seed and were conjoined with RS connectivity analysis to delineate a differentiated self-network composed of the pACC (seed) and anterior insula, relative to other functional connectivity. Additionally, 106 studies activating the other-related seed were conjoined with RS connectivity analysis to delineate a differentiated other-network of PCC/PC (seed) and angular gyrus/temporoparietal junction, relative to self-functional connectivity. The self-network seed related to emotional conflict resolution and motivational processing, whereas the other-network seed related to socially oriented processing and contextual information integration. Notably, our findings revealed shared RS connectivity between ensuing self-/other-networks within the ventromedial prefrontal cortex and medial orbitofrontal cortex, suggesting self-updating via integration of self-relevant social information. We, therefore, present initial neurobiological evidence corroborating the increasing

Effect of the SH3-SH2 domain linker sequence on the structure of Hck kinase.

Science.gov (United States)

Meiselbach, Heike; Sticht, Heinrich

2011-08-01

The coordination of activity in biological systems requires the existence of different signal transduction pathways that interact with one another and must be precisely regulated. The Src-family tyrosine kinases, which are found in many signaling pathways, differ in their physiological function despite their high overall structural similarity. In this context, the differences in the SH3-SH2 domain linkers might play a role for differential regulation, but the structural consequences of linker sequence remain poorly understood. We have therefore performed comparative molecular dynamics simulations of wildtype Hck and of a mutant Hck in which the SH3-SH2 domain linker is replaced by the corresponding sequence from the homologous kinase Lck. These simulations reveal that linker replacement not only affects the orientation of the SH3 domain itself, but also leads to an alternative conformation of the activation segment in the Hck kinase domain. The sequence of the SH3-SH2 domain linker thus exerts a remote effect on the active site geometry and might therefore play a role in modulating the structure of the inactive kinase or in fine-tuning the activation process itself.

The development of regional functional connectivity in preterm infants into early childhood.

Science.gov (United States)

Lee, Wayne; Morgan, Benjamin R; Shroff, Manohar M; Sled, John G; Taylor, Margot J

2013-09-01

Resting state networks are proposed to reflect the neuronal connectivity that underlies cognitive processes. Consequently, abnormal behaviour of these networks due to disease or altered development may predict poor cognitive outcome. To understand how very preterm birth may affect the development of resting state connectivity, we followed a cohort of very preterm-born infants from birth through to 4 years of age using resting state functional MRI. From a larger longitudinal cohort of infants born very preterm (regions and left and right temporal lobes, we investigated local and inter-region connectivity as a function of group and age. We found strong local connectivity during the preterm period, which matured into inter-hemispheric and preliminary default-mode network correlations by 4 years of age. This development is comparable to the resting state networks found in term-born infants of equivalent age. The results of this study suggest that differences in developmental trajectory between preterm-born and term-born infants are small and, if present, would require a large sample from both populations to be detected.

Financial literacy is associated with medial brain region functional connectivity in old age.

Science.gov (United States)

Han, S Duke; Boyle, Patricia A; Yu, Lei; Fleischman, Debra A; Arfanakis, Konstantinos; Leurgans, Sue; Bennett, David A

2014-01-01

Financial literacy refers to the ability to access and utilize financial information in ways that promote better outcomes. In old age, financial literacy has been associated with a wide range of positive characteristics; however, the neural correlates remain unclear. Recent work has suggested greater co-activity between anterior-posterior medial brain regions is associated with better brain functioning. We hypothesized financial literacy would be associated with this pattern. We assessed whole-brain functional connectivity to a posterior cingulate cortex (PCC) seed region of interest (ROI) in 138 participants of the Rush Memory and Aging Project. Results revealed financial literacy was associated with greater functional connectivity between the PCC and three regions: the right ventromedial prefrontal cortex (vmPFC), the left postcentral gyrus, and the right precuneus. Results also revealed financial literacy was associated negatively with functional connectivity between the PCC and left caudate. Post hoc analyses showed the PCC-vmPFC relationship accounted for the most variance in a regression model adjusted for all four significant functional connectivity relationships, demographic factors, and global cognition. These findings provide information on the neural mechanisms associated with financial literacy in old age. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Agricultural transformations, livelihoods and rural-city connections. Policy implications for regional development

NARCIS (Netherlands)

Steel, G.|info:eu-repo/dai/nl/304349828; van Lindert, P.H.C.M.|info:eu-repo/dai/nl/069299382; Fold, Niels; Mynborg, Tobias

2016-01-01

This report analyses agricultural transformations, livelihoods and rural-city connections in Sub-Saharan Africa with the aim to identify key policy areas for regional development. The report draws on the results from comparative empirical studies in various dynamic rural regions characterized by

Functional connections between activated and deactivated brain regions mediate emotional interference during externally directed cognition.

Science.gov (United States)

Di Plinio, Simone; Ferri, Francesca; Marzetti, Laura; Romani, Gian Luca; Northoff, Georg; Pizzella, Vittorio

2018-04-24

Recent evidence shows that task-deactivations are functionally relevant for cognitive performance. Indeed, higher cognitive engagement has been associated with higher suppression of activity in task-deactivated brain regions - usually ascribed to the Default Mode Network (DMN). Moreover, a negative correlation between these regions and areas actively engaged by the task is associated with better performance. DMN regions show positive modulation during autobiographical, social, and emotional tasks. However, it is not clear how processing of emotional stimuli affects the interplay between the DMN and executive brain regions. We studied this interplay in an fMRI experiment using emotional negative stimuli as distractors. Activity modulations induced by the emotional interference of negative stimuli were found in frontal, parietal, and visual areas, and were associated with modulations of functional connectivity between these task-activated areas and DMN regions. A worse performance was predicted both by lower activity in the superior parietal cortex and higher connectivity between visual areas and frontal DMN regions. Connectivity between right inferior frontal gyrus and several DMN regions in the left hemisphere was related to the behavioral performance. This relation was weaker in the negative than in the neutral condition, likely suggesting less functional inhibitions of DMN regions during emotional processing. These results show that both executive and DMN regions are crucial for the emotional interference process and suggest that DMN connections are related to the interplay between externally-directed and internally-focused processes. Among DMN regions, superior frontal gyrus may be a key node in regulating the interference triggered by emotional stimuli. © 2018 Wiley Periodicals, Inc.

A photolabile linker for the solid-phase synthesis of 4-substituted NH-1,2,3-triazoles

DEFF Research Database (Denmark)

Qvortrup, Katrine; Nielsen, Thomas Eiland

2011-01-01

A novel photolabile linker for solid-phase synthesis is presented. The linker displays an azido handle for copper-catalyzed azide–alkyne cycloaddition reactions with a variety of alkynes, remains intact under typical solid-phase reaction conditions, and enables a mild photolytic release of 4...

cis-Apa: a practical linker for the microwave-assisted preparation of cyclic pseudopeptides via RCM cyclative cleavage.

Science.gov (United States)

Baron, Alice; Verdié, Pascal; Martinez, Jean; Lamaty, Frédéric

2011-02-04

A new linker cis-5-aminopent-3-enoic acid (cis-Apa) was prepared for the synthesis of cyclic pseudopeptides by cyclization-cleavage by using ring-closing methatesis (RCM). We developed a new synthetic pathway for the preparation of the cis-Apa linker that was tested in the cyclization-cleavage process of different RGD peptide sequences. Different macrocyclic peptidomimetics were prepared by using this integrated microwave-assisted method, showing that the readily available cis-Apa amino acid is well adapted as a linker in the cyclization-cleavage process.

A Photolabile Linker for the Solid-Phase Synthesis of Peptide Hydrazides and Heterocycles

DEFF Research Database (Denmark)

Qvortrup, Katrine; Komnatnyy, Vitaly V.; Nielsen, Thomas Eiland

2014-01-01

A photolabile hydrazine linker for the solid-phase synthesis of peptide hydrazides and hydrazine-derived heterocycles is presented. The developed protocols enable the efficient synthesis of structurally diverse peptide hydrazides derived from the standard amino adds, including those with side......-chain protected residues at the C-terminal of the resulting peptide hydrazide, and are useful for the synthesis of dihydropyrano[2,3-c]pyrazoles. The linker is compatible with most commonly used coupling reagents and protecting groups for solid-phase peptide synthesis....

A Novel MS-Cleavable Azo Cross-Linker for Peptide Structure Analysis by Free Radical Initiated Peptide Sequencing (FRIPS)

Science.gov (United States)

Iacobucci, Claudio; Hage, Christoph; Schäfer, Mathias; Sinz, Andrea

2017-10-01

The chemical cross-linking/mass spectrometry (MS) approach is a growing research field in structural proteomics that allows gaining insights into protein conformations. It relies on creating distance constraints between cross-linked amino acid side chains that can further be used to derive protein structures. Currently, the most urgent task for designing novel cross-linking principles is an unambiguous and automated assignment of the created cross-linked products. Here, we introduce the homobifunctional, amine-reactive, and water soluble cross-linker azobisimidoester (ABI) as a prototype of a novel class of cross-linkers. The ABI-linker possesses an innovative modular scaffold combining the benefits of collisional activation lability with open shell chemistry. This MS-cleavable cross-linker can be efficiently operated via free radical initiated peptide sequencing (FRIPS) in positive ionization mode. Our proof-of-principle study challenges the gas phase behavior of the ABI-linker for the three amino acids, lysine, leucine, and isoleucine, as well as the model peptide thymopentin. The isomeric amino acids leucine and isoleucine could be discriminated by their characteristic side chain fragments. Collisional activation experiments were conducted via positive electrospray ionization (ESI) on two Orbitrap mass spectrometers. The ABI-mediated formation of odd electron product ions in MS/MS and MS3 experiments was evaluated and compared with a previously described azo-based cross-linker. All cross-linked products were amenable to automated analysis by the MeroX software, underlining the future potential of the ABI-linker for structural proteomics studies. [Figure not available: see fulltext.

How to remain nonfolded and pliable: the linkers in modular α-amylases as a case study.

Science.gov (United States)

Feller, Georges; Dehareng, Dominique; Lage, Jean-Luc Da

2011-07-01

The primary structure of linkers in a new class of modular α-amylases constitutes a paradigm of the structural basis that allows a polypeptide to remain nonfolded, extended and pliable. Unfolding is mediated through a depletion of hydrophobic residues and an enrichment of hydrophilic residues, amongst which Ser and Thr are over-represented. An extended and flexible conformation is promoted by the sequential arrangement of Pro and Gly, which are the most abundant residues in these linkers. This is complemented by charge repulsion, charge clustering and disulfide-bridged loops. Molecular dynamics simulations suggest the existence of conformational transitions resulting from a transient and localized hydrophobic collapse, arising from the peculiar composition of the linkers. Accordingly, these linkers should not be regarded as fully disordered, but rather as possessing various discrete structural patterns allowing them to fulfill their biological function as a free energy reservoir for concerted motions between structured domains. © 2011 The Authors Journal compilation © 2011 FEBS.

Finding significantly connected voxels based on histograms of connection strengths

DEFF Research Database (Denmark)

Kasenburg, Niklas; Pedersen, Morten Vester; Darkner, Sune

2016-01-01

We explore a new approach for structural connectivity based segmentations of subcortical brain regions. Connectivity based segmentations are usually based on fibre connections from a seed region to predefined target regions. We present a method for finding significantly connected voxels based...... on the distribution of connection strengths. Paths from seed voxels to all voxels in a target region are obtained from a shortest-path tractography. For each seed voxel we approximate the distribution with a histogram of path scores. We hypothesise that the majority of estimated connections are false-positives...... and that their connection strength is distributed differently from true-positive connections. Therefore, an empirical null-distribution is defined for each target region as the average normalized histogram over all voxels in the seed region. Single histograms are then tested against the corresponding null...

Functional MRI neurofeedback training on connectivity between two regions induces long-lasting changes in intrinsic functional network

Directory of Open Access Journals (Sweden)

Fukuda eMegumi

2015-03-01

Full Text Available Motor or perceptual learning is known to influence functional connectivity between brain regions and induce short-term changes in the intrinsic functional networks revealed as correlations in slow blood-oxygen-level dependent (BOLD signal fluctuations. However, no cause-and-effect relationship has been elucidated between a specific change in connectivity and a long-term change in global networks. Here, we examine the hypothesis that functional connectivity (i.e. temporal correlation between two regions is increased and preserved for a long time when two regions are simultaneously activated or deactivated. Using the connectivity-neurofeedback training paradigm, subjects successfully learned to increase the correlation of activity between the lateral parietal and primary motor areas, regions that belong to different intrinsic networks and negatively correlated before training under the resting conditions. Furthermore, whole-brain hypothesis-free analysis as well as functional network analyses demonstrated that the correlation in the resting state between these areas as well as the correlation between the intrinsic networks that include the areas increased for at least two months. These findings indicate that the connectivity-neurofeedback training can cause long-term changes in intrinsic connectivity and that intrinsic networks can be shaped by experience-driven modulation of regional correlation.

Fivefold increase of hydrogen uptake in MOF74 through linker decorations

Science.gov (United States)

Arter, C. A.; Zuluaga, S.; Harrison, D.; Welchman, E.; Thonhauser, T.

2016-10-01

We present ab initio results for linker decorations in Mg-MOF74, i.e., attaching various metals M =Li, Na, K, Sc, Cr, Mn, Fe, Ni, Cu, Zn, Rb, Pd, Ag, and Pt near the ring of the linker, creating new strong adsorption sites and thus maximizing small-molecule uptake. We find that in most cases these decorations influence the overall form and structure of Mg-MOF74 only marginally. After the initial screening, we chose metals that bind favorably to the linker and further investigated adsorption of H2,CO2, and H2O for M =Li , Na, K, and Sc. For the case of H2 we show that up to 24 additional guest molecules can be adsorbed in the metal-organic framework (MOF) unit cell, with binding energies comparable to the original open-metal sites at the six corners of the channel. This leads to a fivefold increase of the molecule uptake in Mg-MOF74, with tremendous impact on many applications in general and hydrogen storage in particular, where the gravimetric hydrogen density increases from 1.63 to 7.28 mass % and the volumetric density increases from 15.10 to 75.50 g H2L-1 .

[Construction of cTnC-linker-TnI (P) Genes, Expression of Fusion Protein and Preparation of Lyophilized Protein].

Science.gov (United States)

Song, Xiaoli; Liu, Xiaoyun; Cai, Lei; Wu, Jianwei; Wang, Jihua

2015-12-01

In order to construct and express human cardiac troponin C-linker-troponin I(P) [ cTnC-linker-TnI(P)] fusion protein, detect its activity and prepare lyophilized protein, we searched the CDs of human cTnC and cTnI from GenBank, synthesized cTnC and cTnI(30-110aa) into cloning vector by a short DNA sequence coding for 15 neutral amino acid residues. pCold I-cTnC-linker-TnI(P) was constructed and transformed into E. coli BL21(DE3). Then, cTnC-linker-TnI(P) fusion protein was induced by isopropyl-β-D-thiogalactopyranoside (IPTG). Soluable expression of cTnC-linker-TnI(P) in prokaryotic system was successfully obtained. The fusion protein was purified by Ni²⁺ Sepharose 6 Fast Flow affinity chromatography with over 95% purity and prepared into lyophilized protein. The activity of purified cTnC-linker-TnI(P) and its lyophilized protein were detected by Wondfo Finecare™ cTnI Test. Lyophilized protein of cTnC-linker-TnI(P) was stable for 10 or more days at 37 °C and 4 or more months at 25 °C and 4 °C. The expression system established in this research is feasible and efficient. Lyophilized protein is stable enough to be provided as biological raw materials for further research.

Effective generation of transgenic pigs and mice by linker based sperm-mediated gene transfer.

OpenAIRE

Chang, Keejong; Qian, Jin; Jiang, MeiSheng; Liu, Yi-Hsin; Wu, Ming-Che; Chen, Chi-Dar; Lai, Chao-Kuen; Lo, Hsin-Lung; Hsiao, Chin-Ton; Brown, Lucy; Bolen, James; Huang, Hsiao-I; Ho, Pei-Yu; Shih, Ping Yao; Yao, Chen-Wen

2002-01-01

Abstract Background Transgenic animals have become valuable tools for both research and applied purposes. The current method of gene transfer, microinjection, which is widely used in transgenic mouse production, has only had limited success in producing transgenic animals of larger or higher species. Here, we report a linker based sperm-mediated gene transfer method (LB-SMGT) that greatly improves the production efficiency of large transgenic animals. Results The linker protein, a monoclonal ...

Differential structural and resting state connectivity between insular subdivisions and other pain-related brain regions.

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Wiech, K; Jbabdi, S; Lin, C S; Andersson, J; Tracey, I

2014-10-01

Functional neuroimaging studies suggest that the anterior, mid, and posterior division of the insula subserve different functions in the perception of pain. The anterior insula (AI) has predominantly been associated with cognitive-affective aspects of pain, while the mid and posterior divisions have been implicated in sensory-discriminative processing. We examined whether this functional segregation is paralleled by differences in (1) structural and (2) resting state connectivity and (3) in correlations with pain-relevant psychological traits. Analyses were restricted to the 3 insular subdivisions and other pain-related brain regions. Both type of analyses revealed largely overlapping results. The AI division was predominantly connected to the ventrolateral prefrontal cortex (structural and resting state connectivity) and orbitofrontal cortex (structural connectivity). In contrast, the posterior insula showed strong connections to the primary somatosensory cortex (SI; structural connectivity) and secondary somatosensory cortex (SII; structural and resting state connectivity). The mid insula displayed a hybrid connectivity pattern with strong connections with the ventrolateral prefrontal cortex, SII (structural and resting state connectivity) and SI (structural connectivity). Moreover, resting state connectivity revealed strong connectivity of all 3 subdivisions with the thalamus. On the behavioural level, AI structural connectivity was related to the individual degree of pain vigilance and awareness that showed a positive correlation with AI-amygdala connectivity and a negative correlation with AI-rostral anterior cingulate cortex connectivity. In sum, our findings show a differential structural and resting state connectivity for the anterior, mid, and posterior insula with other pain-relevant brain regions, which might at least partly explain their different functional profiles in pain processing. Copyright © 2014 The Authors. Published by Elsevier B.V. All

A Class of Rigid Linker-bearing Glucosides for Membrane Protein Structural Study.

Science.gov (United States)

Sadaf, Aiman; Mortensen, Jonas S; Capaldi, Stefano; Tikhonova, Elena; Hariharan, Parameswaran; de Castro Ribeiro, Orquidea; Loland, Claus J; Guan, Lan; Byrne, Bernadette; Chae, Pil Seok

2016-03-01

Membrane proteins are amphipathic bio-macromolecules incompatible with the polar environments of aqueous media. Conventional detergents encapsulate the hydrophobic surfaces of membrane proteins allowing them to exist in aqueous solution. Membrane proteins stabilized by detergent micelles are used for structural and functional analysis. Despite the availability of a large number of detergents, only a few agents are sufficiently effective at maintaining the integrity of membrane proteins to allow successful crystallization. In the present study, we describe a novel class of synthetic amphiphiles with a branched tail group and a triglucoside head group. These head and tail groups were connected via an amide or ether linkage by using a tris(hydroxylmethyl)aminomethane (TRIS) or neopentyl glycol (NPG) linker to produce TRIS-derived triglucosides (TDTs) and NPG-derived triglucosides (NDTs), respectively. Members of this class conferred enhanced stability on target membrane proteins compared to conventional detergents. Because of straightforward synthesis of the novel agents and their favourable effects on a range of membrane proteins, these agents should be of wide applicability to membrane protein science.

Novel mixing method for cross linker introduction into droplet emulsions

CSIR Research Space (South Africa)

Land, KJ

2013-10-01

Full Text Available the introduction of cross linker after droplet formation, together with the utilisation of topological microfluidic channel structures, allowing for the novel manufacture of particles. Flow over these structures has been simulated in order to choose the most...

Resting-state functional connectivity of ventral parietal regions associated with attention reorienting and episodic recollection

Directory of Open Access Journals (Sweden)

Sander M Daselaar

2013-02-01

Full Text Available In functional neuroimaging studies, ventral parietal cortex (VPC is recruited by very different cognitive tasks. Explaining the contributions VPC to these tasks has become a topic of intense study and lively debate. Perception studies frequently find VPC activations during tasks involving attention-reorienting, and memory studies frequently find them during tasks involving episodic recollection. According to the Attention to Memory (AtoM model, both phenomena can be explained by the same VPC function: bottom-up attention. Yet, a recent functional MRI (fMRI meta-analysis suggested that attention-reorienting activations are more frequent in anterior VPC, whereas recollection activations are more frequent in posterior VPC. Also, there is evidence that anterior and posterior VPC regions have different functional connectivity patterns. To investigate these issues, we conducted a resting-state functional connectivity analysis using as seeds the center-of-mass of attention-reorienting and recollection activations in the meta-analysis, which were located in the supramarginal gyrus (SMG, around the temporo-parietal junction—TPJ and in the angular gyrus (AG, respectively. The SMG seed showed stronger connectivity with ventrolateral prefrontal cortex (VLPFC and occipito-temporal cortex, whereas the AG seed showed stronger connectivity with the hippocampus and default network regions. To investigate whether these connectivity differences were graded or sharp, VLPFC and hippocampal connectivity was measured in VPC regions traversing through the SMG and AG seeds. The results showed a graded pattern: VLPFC connectivity gradually decreases from SMG to AG, whereas hippocampal connectivity gradually increases from SMG to AG. Importantly, both gradients showed an abrupt break when extended beyond VPC borders. This finding suggests that functional differences between SMG and AG are more subtle than previously thought. These connectivity differences can be

One-pot preparation of mRNA/cDNA display by a novel and versatile puromycin-linker DNA.

Science.gov (United States)

Mochizuki, Yuki; Biyani, Manish; Tsuji-Ueno, Sachika; Suzuki, Miho; Nishigaki, Koichi; Husimi, Yuzuru; Nemoto, Naoto

2011-09-12

A rapid, easy, and robust preparation method for mRNA/cDNA display using a newly designed puromycin-linker DNA is presented. The new linker is structurally simple, easy to synthesize, and cost-effective for use in "in vitro peptide and protein selection". An introduction of RNase T1 nuclease site to the new linker facilitates the easy recovery of mRNA/cDNA displayed protein by an improvement of the efficiency of ligating the linker to mRNAs and efficient release of mRNA/cDNA displayed protein from the solid-phase (magnetic bead). For application demonstration, affinity selections were successfully performed. Furthermore, we introduced a "one-pot" preparation protocol to perform mRNA display easy. Unlike conventional approaches that require tedious and downstream multistep process including purification, this protocol will make the mRNA/cDNA display methods more practical and convenient and also facilitate the development of next-generation, high-throughput mRNA/cDNA display systems amenable to automation.

Accurate distance determination of nucleic acids via Förster resonance energy transfer: implications of dye linker length and rigidity.

Science.gov (United States)

Sindbert, Simon; Kalinin, Stanislav; Nguyen, Hien; Kienzler, Andrea; Clima, Lilia; Bannwarth, Willi; Appel, Bettina; Müller, Sabine; Seidel, Claus A M

2011-03-02

In Förster resonance energy transfer (FRET) experiments, the donor (D) and acceptor (A) fluorophores are usually attached to the macromolecule of interest via long flexible linkers of up to 15 Å in length. This causes significant uncertainties in quantitative distance measurements and prevents experiments with short distances between the attachment points of the dyes due to possible dye-dye interactions. We present two approaches to overcome the above problems as demonstrated by FRET measurements for a series of dsDNA and dsRNA internally labeled with Alexa488 and Cy5 as D and A dye, respectively. First, we characterize the influence of linker length and flexibility on FRET for different dye linker types (long, intermediate, short) by analyzing fluorescence lifetime and anisotropy decays. For long linkers, we describe a straightforward procedure that allows for very high accuracy of FRET-based structure determination through proper consideration of the position distribution of the dye and of linker dynamics. The position distribution can be quickly calculated with geometric accessible volume (AV) simulations, provided that the local structure of RNA or DNA in the proximity of the dye is known and that the dye diffuses freely in the sterically allowed space. The AV approach provides results similar to molecular dynamics simulations (MD) and is fully consistent with experimental FRET data. In a benchmark study for ds A-RNA, an rmsd value of 1.3 Å is achieved. Considering the case of undefined dye environments or very short DA distances, we introduce short linkers with a propargyl or alkenyl unit for internal labeling of nucleic acids to minimize position uncertainties. Studies by ensemble time correlated single photon counting and single-molecule detection show that the nature of the linker strongly affects the radius of the dye's accessible volume (6-16 Å). For short propargyl linkers, heterogeneous dye environments are observed on the millisecond time scale. A

Solid-phase synthesis of polyfunctional polylysine dendrons using aldehyde linkers

DEFF Research Database (Denmark)

Svenssen, Daniel K.; Mirsharghi, Sahar; Boas, Ulrik

2014-01-01

A straightforward method for the solid-phase synthesis of C-terminally modified polylysine dendrons has been developed by applying bisalkoxybenzaldehyde and trisalkoxybenzaldehyde linkers. The method has been used for the synthesis of polylysine dendrons with a variety of C-terminal ‘tail groups’...

Synthesis, DNA Binding, and Anticancer Properties of Bis-Naphthalimide Derivatives with Lysine-Modified Polyamine Linkers

Directory of Open Access Journals (Sweden)

Yu Huang

2018-01-01

Full Text Available A series of bis-naphthalimide derivatives with different diamine linkers were designed and synthesized. All of the synthesized bis-naphthalimide derivatives were characterized by NMR and HRMS spectra. The binding ability between the compounds and CT DNA was evaluated by using UV–Vis titration experiments. The bis-naphthalimide compound with an ethylenediamine linker showed the largest binding constant with CT DNA. Hence, it was used as the model compound to study the DNA binding selectivity by UV–Vis titration aiming at different DNA duplexes. As a result, this compound showed binding preference to AT-rich duplexes. The DNA binding modes of the compounds were also measured by viscosity titration. The cytotoxicity of the compounds was evaluated by MTT assay. Compounds with 1,6-diaminohexane or 1,4-phenylenedimethanamine linkers showed higher cytotoxicity compared with other bis-naphthalimide derivatives.

Structural covariance of brain region volumes is associated with both structural connectivity and transcriptomic similarity.

Science.gov (United States)

Yee, Yohan; Fernandes, Darren J; French, Leon; Ellegood, Jacob; Cahill, Lindsay S; Vousden, Dulcie A; Spencer Noakes, Leigh; Scholz, Jan; van Eede, Matthijs C; Nieman, Brian J; Sled, John G; Lerch, Jason P

2018-05-18

An organizational pattern seen in the brain, termed structural covariance, is the statistical association of pairs of brain regions in their anatomical properties. These associations, measured across a population as covariances or correlations usually in cortical thickness or volume, are thought to reflect genetic and environmental underpinnings. Here, we examine the biological basis of structural volume covariance in the mouse brain. We first examined large scale associations between brain region volumes using an atlas-based approach that parcellated the entire mouse brain into 318 regions over which correlations in volume were assessed, for volumes obtained from 153 mouse brain images via high-resolution MRI. We then used a seed-based approach and determined, for 108 different seed regions across the brain and using mouse gene expression and connectivity data from the Allen Institute for Brain Science, the variation in structural covariance data that could be explained by distance to seed, transcriptomic similarity to seed, and connectivity to seed. We found that overall, correlations in structure volumes hierarchically clustered into distinct anatomical systems, similar to findings from other studies and similar to other types of networks in the brain, including structural connectivity and transcriptomic similarity networks. Across seeds, this structural covariance was significantly explained by distance (17% of the variation, up to a maximum of 49% for structural covariance to the visceral area of the cortex), transcriptomic similarity (13% of the variation, up to maximum of 28% for structural covariance to the primary visual area) and connectivity (15% of the variation, up to a maximum of 36% for structural covariance to the intermediate reticular nucleus in the medulla) of covarying structures. Together, distance, connectivity, and transcriptomic similarity explained 37% of structural covariance, up to a maximum of 63% for structural covariance to the

Learning a Weighted Sequence Model of the Nucleosome Core and Linker Yields More Accurate Predictions in Saccharomyces cerevisiae and Homo sapiens

Science.gov (United States)

Reynolds, Sheila M.; Bilmes, Jeff A.; Noble, William Stafford

2010-01-01

DNA in eukaryotes is packaged into a chromatin complex, the most basic element of which is the nucleosome. The precise positioning of the nucleosome cores allows for selective access to the DNA, and the mechanisms that control this positioning are important pieces of the gene expression puzzle. We describe a large-scale nucleosome pattern that jointly characterizes the nucleosome core and the adjacent linkers and is predominantly characterized by long-range oscillations in the mono, di- and tri-nucleotide content of the DNA sequence, and we show that this pattern can be used to predict nucleosome positions in both Homo sapiens and Saccharomyces cerevisiae more accurately than previously published methods. Surprisingly, in both H. sapiens and S. cerevisiae, the most informative individual features are the mono-nucleotide patterns, although the inclusion of di- and tri-nucleotide features results in improved performance. Our approach combines a much longer pattern than has been previously used to predict nucleosome positioning from sequence—301 base pairs, centered at the position to be scored—with a novel discriminative classification approach that selectively weights the contributions from each of the input features. The resulting scores are relatively insensitive to local AT-content and can be used to accurately discriminate putative dyad positions from adjacent linker regions without requiring an additional dynamic programming step and without the attendant edge effects and assumptions about linker length modeling and overall nucleosome density. Our approach produces the best dyad-linker classification results published to date in H. sapiens, and outperforms two recently published models on a large set of S. cerevisiae nucleosome positions. Our results suggest that in both genomes, a comparable and relatively small fraction of nucleosomes are well-positioned and that these positions are predictable based on sequence alone. We believe that the bulk of the

Learning a weighted sequence model of the nucleosome core and linker yields more accurate predictions in Saccharomyces cerevisiae and Homo sapiens.

Directory of Open Access Journals (Sweden)

Sheila M Reynolds

2010-07-01

Full Text Available DNA in eukaryotes is packaged into a chromatin complex, the most basic element of which is the nucleosome. The precise positioning of the nucleosome cores allows for selective access to the DNA, and the mechanisms that control this positioning are important pieces of the gene expression puzzle. We describe a large-scale nucleosome pattern that jointly characterizes the nucleosome core and the adjacent linkers and is predominantly characterized by long-range oscillations in the mono, di- and tri-nucleotide content of the DNA sequence, and we show that this pattern can be used to predict nucleosome positions in both Homo sapiens and Saccharomyces cerevisiae more accurately than previously published methods. Surprisingly, in both H. sapiens and S. cerevisiae, the most informative individual features are the mono-nucleotide patterns, although the inclusion of di- and tri-nucleotide features results in improved performance. Our approach combines a much longer pattern than has been previously used to predict nucleosome positioning from sequence-301 base pairs, centered at the position to be scored-with a novel discriminative classification approach that selectively weights the contributions from each of the input features. The resulting scores are relatively insensitive to local AT-content and can be used to accurately discriminate putative dyad positions from adjacent linker regions without requiring an additional dynamic programming step and without the attendant edge effects and assumptions about linker length modeling and overall nucleosome density. Our approach produces the best dyad-linker classification results published to date in H. sapiens, and outperforms two recently published models on a large set of S. cerevisiae nucleosome positions. Our results suggest that in both genomes, a comparable and relatively small fraction of nucleosomes are well-positioned and that these positions are predictable based on sequence alone. We believe that the

Learning a weighted sequence model of the nucleosome core and linker yields more accurate predictions in Saccharomyces cerevisiae and Homo sapiens.

Science.gov (United States)

Reynolds, Sheila M; Bilmes, Jeff A; Noble, William Stafford

2010-07-08

DNA in eukaryotes is packaged into a chromatin complex, the most basic element of which is the nucleosome. The precise positioning of the nucleosome cores allows for selective access to the DNA, and the mechanisms that control this positioning are important pieces of the gene expression puzzle. We describe a large-scale nucleosome pattern that jointly characterizes the nucleosome core and the adjacent linkers and is predominantly characterized by long-range oscillations in the mono, di- and tri-nucleotide content of the DNA sequence, and we show that this pattern can be used to predict nucleosome positions in both Homo sapiens and Saccharomyces cerevisiae more accurately than previously published methods. Surprisingly, in both H. sapiens and S. cerevisiae, the most informative individual features are the mono-nucleotide patterns, although the inclusion of di- and tri-nucleotide features results in improved performance. Our approach combines a much longer pattern than has been previously used to predict nucleosome positioning from sequence-301 base pairs, centered at the position to be scored-with a novel discriminative classification approach that selectively weights the contributions from each of the input features. The resulting scores are relatively insensitive to local AT-content and can be used to accurately discriminate putative dyad positions from adjacent linker regions without requiring an additional dynamic programming step and without the attendant edge effects and assumptions about linker length modeling and overall nucleosome density. Our approach produces the best dyad-linker classification results published to date in H. sapiens, and outperforms two recently published models on a large set of S. cerevisiae nucleosome positions. Our results suggest that in both genomes, a comparable and relatively small fraction of nucleosomes are well-positioned and that these positions are predictable based on sequence alone. We believe that the bulk of the

Linker histones: novel insights into structure-specific recognition of the nucleosome.

Science.gov (United States)

Cutter, Amber R; Hayes, Jeffrey J

2017-04-01

Linker histones (H1s) are a primary component of metazoan chromatin, fulfilling numerous functions, both in vitro and in vivo, including stabilizing the wrapping of DNA around the nucleosome, promoting folding and assembly of higher order chromatin structures, influencing nucleosome spacing on DNA, and regulating specific gene expression. However, many molecular details of how H1 binds to nucleosomes and recognizes unique structural features on the nucleosome surface remain undefined. Numerous, confounding studies are complicated not only by experimental limitations, but the use of different linker histone isoforms and nucleosome constructions. This review summarizes the decades of research that has resulted in several models of H1 association with nucleosomes, with a focus on recent advances that suggest multiple modes of H1 interaction in chromatin, while highlighting the remaining questions.

A New Achiral Linker Reagent for the Incorporation of Multiple Amino Groups Into Oligonucleotides

DEFF Research Database (Denmark)

1997-01-01

The present invention relates to a new functionalized achiral linker reagent for incorporating multiple primary amino groups or reporter groups into oligonucleotides following the phosphoramidite methodology. It is possible to substitute any ribodeoxynucleotide, deoxynucleotide, or nucleotide......-oxyl-2,2,5,5-tetramethylpyrrolidine), TEMPO (N-oxyl-2,2,6,6-tetramethylpiperidine), dinitrophenyl, texas red, tetramethyl rhodamine, 7-nitrobenzo-2-oxa-1-diazole (NBD), or pyrene. The present invention also relates to a solid phase support, e.g. a Controlled Pore Glass (CPG), immobilized linker reagent...

Impaired insula functional connectivity associated with persistent pain perception in patients with complex regional pain syndrome

Science.gov (United States)

Jang, Joon Hwan; Lee, Do-Hyeong; Lee, Kyung-Jun; Lee, Won Joon; Moon, Jee Youn; Kim, Yong Chul

2017-01-01

Given that the insula plays a contributory role in the perception of chronic pain, we examined the resting-state functional connectivity between the insular cortex and other brain regions to investigate neural underpinnings of persisting perception of background pain in patients with complex regional pain syndrome (CRPS). A total of 25 patients with CRPS and 25 matched healthy controls underwent functional magnetic resonance imaging at rest. With the anterior and posterior insular cortices as seed regions, we compared the strength of the resting-state functional connectivity between the two groups. Functional connectivity between the anterior and posterior insular cortices and the postcentral and inferior frontal gyri, cingulate cortices was reduced in patients with CRPS compared with controls. Additionally, greater reductions in functional connectivity between the anterior insula and right postcentral gyrus were associated with more severe sensory pain in patients with CRPS (short-form McGill Pain Questionnaire sensory subscores, r = -.517, P = .023). The present results imply a possible role of the insula in aberrant processing of pain information in patients with CRPS. The findings suggest that a functional derangement of the connection between one of the somatosensory cortical functions of perception and one of the insular functions of awareness can play a significant role in the persistent experience of regional pain that is not confined to a specific nerve territory. PMID:28692702

5-fold increase of hydrogen uptake in MOF74 through linker decorations

Science.gov (United States)

Thonhauser, T.; Zuluaga, S.; Harrison, D.; Welchman, E.; Arter, C.

We present ab initio results for linker decorations in Mg-MOF74-i.e. attaching various metals  = Li, Na, K, Sc, Cr, Mn, Fe, Ni, Cu, Zn, Rb, Pd, Ag, and Pt near the ring of the linker-creating new strong adsorption sites and thus maximizing small molecule uptake. We find that in most cases these decorations influence the overall form and structure of Mg-MOF74 only marginally. After the initial screening we chose metals that bind favorably to the linker and further investigate adsorption of H2, CO2, and H2O for  = Li, Na, K, and Sc. For the case of H2 we show that up to 24 additional guest molecules can be adsorbed in the MOF unit cell, with binding energies comparable to the original open-metal sites at the six corners of the channel. This leads to a 5-fold increase of the molecule uptake in Mg-MOF74, with tremendous impact on many applications in general and hydrogen storage in particular-where the gravimetric hydrogen density increases from 1 . 63 mass% to 7 . 28 mass% and the volumetric density from 15.10 g H2 L-1 to 75.50 g H2 L-1. This work was supported by NSF Grant No. DMR-1145968.

Functional Connectivity of Multiple Brain Regions Required for the Consolidation of Social Recognition Memory.

Science.gov (United States)

Tanimizu, Toshiyuki; Kenney, Justin W; Okano, Emiko; Kadoma, Kazune; Frankland, Paul W; Kida, Satoshi

2017-04-12

Social recognition memory is an essential and basic component of social behavior that is used to discriminate familiar and novel animals/humans. Previous studies have shown the importance of several brain regions for social recognition memories; however, the mechanisms underlying the consolidation of social recognition memory at the molecular and anatomic levels remain unknown. Here, we show a brain network necessary for the generation of social recognition memory in mice. A mouse genetic study showed that cAMP-responsive element-binding protein (CREB)-mediated transcription is required for the formation of social recognition memory. Importantly, significant inductions of the CREB target immediate-early genes c-fos and Arc were observed in the hippocampus (CA1 and CA3 regions), medial prefrontal cortex (mPFC), anterior cingulate cortex (ACC), and amygdala (basolateral region) when social recognition memory was generated. Pharmacological experiments using a microinfusion of the protein synthesis inhibitor anisomycin showed that protein synthesis in these brain regions is required for the consolidation of social recognition memory. These findings suggested that social recognition memory is consolidated through the activation of CREB-mediated gene expression in the hippocampus/mPFC/ACC/amygdala. Network analyses suggested that these four brain regions show functional connectivity with other brain regions and, more importantly, that the hippocampus functions as a hub to integrate brain networks and generate social recognition memory, whereas the ACC and amygdala are important for coordinating brain activity when social interaction is initiated by connecting with other brain regions. We have found that a brain network composed of the hippocampus/mPFC/ACC/amygdala is required for the consolidation of social recognition memory. SIGNIFICANCE STATEMENT Here, we identify brain networks composed of multiple brain regions for the consolidation of social recognition memory. We

Temperature-triggered release of a liquid cross-linker micro-encapsulated in a glassy polymer for low temperature curing

NARCIS (Netherlands)

Senatore, D.; Cate, ten A.T.; Laven, J.; Benthem, van R.A.T.M.; With, de G.

2013-01-01

In order to prevent a liquid epoxy cross-linker from premature, Arrhenius-law predicted, reaction with an acid-functional polyester resin, the liquid cross-linker has been physically separated from the resin by encapsulation while release is only possible by a temperature-controlled trigger. The

Patterns and drivers for wetland connections in the Prairie Pothole Region, United States

Science.gov (United States)

Vanderhoof, Melanie; Christensen, Jay R.; Alexander, Laurie C.

2017-01-01

Ecosystem function in rivers, lakes and coastal waters depends on the functioning of upstream aquatic ecosystems, necessitating an improved understanding of watershed-scale interactions including variable surface-water flows between wetlands and streams. As surface water in the Prairie Pothole Region expands in wet years, surface-water connections occur between many depressional wetlands and streams. Minimal research has explored the spatial patterns and drivers for the abundance of these connections, despite their potential to inform resource management and regulatory programs including the U.S. Clean Water Act. In this study, wetlands were identified that did not intersect the stream network, but were shown with Landsat images (1990–2011) to become merged with the stream network as surface water expanded. Wetlands were found to spill into or consolidate with other wetlands within both small (2–10 wetlands) and large (>100 wetlands) wetland clusters, eventually intersecting a stream channel, most often via a riparian wetland. These surface-water connections occurred over a wide range of wetland distances from streams (averaging 90–1400 m in different ecoregions). Differences in the spatial abundance of wetlands that show a variable surface-water connection to a stream were best explained by smaller wetland-to-wetland distances, greater wetland abundance, and maximum surface-water extent. This analysis demonstrated that wetland arrangement and surface water expansion are important mechanisms for depressional wetlands to connect to streams and provides a first step to understanding the frequency and abundance of these surface-water connections across the Prairie Pothole Region.

The connection between migration and regional structure in Finland around 1990 - a GIS viewpoint

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Jarkko Kauppinen

2000-01-01

Full Text Available The connection between migration and regional structure in Finland in the early 19905 is discussed on the basis of Geographic Irformation Systems (GIS data from Statistics Finland, compiled for map coordinate grid cells of 1 x 1 km. The results indicate that data of this kind enable a more detailed typology to be drawn up for migration. At the regional level, this allows the defining of places of "passing through '' which gain population from other local government districts but lose population through migration within their own district. The connection between migration and regional structure is manifested in the fact that flows both between and within local government districts mainly involve the more urbanised population centres and areas with: high levels of unemployment.

Network analysis of mesoscale optical recordings to assess regional, functional connectivity.

Science.gov (United States)

Lim, Diana H; LeDue, Jeffrey M; Murphy, Timothy H

2015-10-01

With modern optical imaging methods, it is possible to map structural and functional connectivity. Optical imaging studies that aim to describe large-scale neural connectivity often need to handle large and complex datasets. In order to interpret these datasets, new methods for analyzing structural and functional connectivity are being developed. Recently, network analysis, based on graph theory, has been used to describe and quantify brain connectivity in both experimental and clinical studies. We outline how to apply regional, functional network analysis to mesoscale optical imaging using voltage-sensitive-dye imaging and channelrhodopsin-2 stimulation in a mouse model. We include links to sample datasets and an analysis script. The analyses we employ can be applied to other types of fluorescence wide-field imaging, including genetically encoded calcium indicators, to assess network properties. We discuss the benefits and limitations of using network analysis for interpreting optical imaging data and define network properties that may be used to compare across preparations or other manipulations such as animal models of disease.

Repeated verum but not placebo acupuncture normalizes connectivity in brain regions dysregulated in chronic pain

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Natalia Egorova

2015-01-01

Full Text Available Acupuncture, an ancient East Asian therapy, is aimed at rectifying the imbalance within the body caused by disease. Studies evaluating the efficacy of acupuncture with neuroimaging tend to concentrate on brain regions within the pain matrix, associated with acute pain. We, however, focused on the effect of repeated acupuncture treatment specifically on brain regions known to support functions dysregulated in chronic pain disorders. Transition to chronic pain is associated with increased attention to pain, emotional rumination, nociceptive memory and avoidance learning, resulting in brain connectivity changes, specifically affecting the periaqueductal gray (PAG, medial frontal cortex (MFC and bilateral hippocampus (Hpc. We demonstrate that the PAG–MFC and PAG–Hpc connectivity in patients with chronic pain due to knee osteoarthritis indeed correlates with clinical severity scores and further show that verum acupuncture-induced improvement in pain scores (compared to sham is related to the modulation of PAG–MFC and PAG–Hpc connectivity in the predicted direction. This study shows that repeated verum acupuncture might act by restoring the balance in the connectivity of the key pain brain regions, altering pain-related attention and memory.

Extremely stretchable thermosensitive hydrogels by introducing slide-ring polyrotaxane cross-linkers and ionic groups into the polymer network

Science.gov (United States)

Bin Imran, Abu; Esaki, Kenta; Gotoh, Hiroaki; Seki, Takahiro; Ito, Kohzo; Sakai, Yasuhiro; Takeoka, Yukikazu

2014-01-01

Stimuli-sensitive hydrogels changing their volumes and shapes in response to various stimulations have potential applications in multiple fields. However, these hydrogels have not yet been commercialized due to some problems that need to be overcome. One of the most significant problems is that conventional stimuli-sensitive hydrogels are usually brittle. Here we prepare extremely stretchable thermosensitive hydrogels with good toughness by using polyrotaxane derivatives composed of α-cyclodextrin and polyethylene glycol as cross-linkers and introducing ionic groups into the polymer network. The ionic groups help the polyrotaxane cross-linkers to become well extended in the polymer network. The resulting hydrogels are surprisingly stretchable and tough because the cross-linked α-cyclodextrin molecules can move along the polyethylene glycol chains. In addition, the polyrotaxane cross-linkers can be used with a variety of vinyl monomers; the mechanical properties of the wide variety of polymer gels can be improved by using these cross-linkers. PMID:25296246

Impact of cathepsin B-sensitive triggers and hydrophilic linkers on in vitro efficacy of novel site-specific antibody-drug conjugates.

Science.gov (United States)

Bryden, Francesca; Martin, Camille; Letast, Stéphanie; Lles, Eva; Viéitez-Villemin, Inmaculada; Rousseau, Anaïs; Colas, Cyril; Brachet-Botineau, Marie; Allard-Vannier, Emilie; Larbouret, Christel; Viaud-Massuard, Marie-Claude; Joubert, Nicolas

2018-03-14

Herein we describe the synthesis and evaluation of four novel HER2-targeting, cathepsin B-sensitive antibody-drug conjugates bearing a monomethylauristatin E (MMAE) cytotoxic payload, constructed via the conjugation of cleavable linkers to trastuzumab using a site-specific bioconjugation methodology. These linkers vary by both cleavable trigger motif and hydrophilicity, containing one of two cathepsin B sensitive dipeptides (Val-Cit and Val-Ala), and engendered with either hydrophilic or hydrophobic character via application of a PEG 12 spacer. Through evaluation of physical properties, in vitro cytotoxicity, and receptor affinity of the resulting antibody-drug conjugates (ADCs), we have demonstrated that while both dipeptide triggers are effective, the increased hydrophobicity of the Val-Ala pair limits its utility within this type of linker. In addition, while PEGylation augments linker hydrophilicity, this change does not translate to more favourable ADC hydrophilicity or potency. While all described structures demonstrated excellent and similar in vitro cytotoxicity, the ADC with the ValCitPABMMAE linker shows the most promising combination of in vitro potency, structural homogeneity, and hydrophilicity, warranting further evaluation into its therapeutic potential.

Bifunctional bridging linker-assisted synthesis and characterization of TiO{sub 2}/Au nanocomposites

Energy Technology Data Exchange (ETDEWEB)

Žunič, Vojka, E-mail: vojka.zunic@ijs.si, E-mail: vojka13@gmail.com; Kurtjak, Mario; Suvorov, Danilo [Jožef Stefan Institute, Advanced Materials Department (Slovenia)

2016-11-15

Using a simple organic bifunctional bridging linker, titanium dioxide (TiO{sub 2}) nanoparticles were coupled with the Au nanoparticles to form TiO{sub 2}/Au nanocomposites with a variety of Au loadings. This organic bifunctional linker, meso-2,3-dimercaptosuccinic acid, contains two types of functional groups: (i) the carboxyl group, which enables binding to the TiO{sub 2}, and (ii) the thiol group, which enables binding to the Au. In addition, the organic bifunctional linker acts as a stabilizing agent to prevent the agglomeration and growth of the Au particles, resulting in the formation of highly dispersed Au nanoparticles. To form the TiO{sub 2}/Au nanocomposites in a simple way, we deliberately applied a synthetic method that simultaneously ensures: (i) the capping of the Au nanoparticles and (ii) the binding of different amounts of Au to the TiO{sub 2}. The TiO{sub 2}/Au nanocomposites formed with this method show enhanced UV and Vis photocatalytic activities when compared to the pure TiO{sub 2} nanopowders.Graphical Abstract.

Release of 3-methyladenine from linker and core DNA of chromatin by a purified DNA glycosylase

International Nuclear Information System (INIS)

Heller, E.P.; Goldthwait, D.A.

1983-01-01

Oligonucleosomes were isolated from [ 14 C]thymidine-labeled HeLa cells by digestion of the nuclei with micrococcal nuclease and were then alkylated with [ 3 H]methylnitrosourea. Nucleosome core particles were also prepared by further digestion of the oligonucleosomes. The distribution of 3 H-labeled methyl groups in the linker versus the core DNA was established by a determination of 3 H: 14 C ratios in oligonucleosome and core DNA. The ratios in the core DNA of 145 and 165 base pair DNA fragments were 5.2 and 5.4, respectively, while the ratio in the oligonucleosomal DNA was 8.2. Assuming an equal mixture (as determined) of 145 and 165 base pair fragments of DNA in the 185 base pair repeat, the relative concentration of 3 H methyl groups in the linker versus the core DNA was 4.2. Thus, 45% of the 3 H methyl groups were in the linker DNA, and 55% were in the core DNA. Some shielding of the DNA was evident during alkylation. The concentrations of alkyl groups on the linker and core DNA were 67 and 12% of that found on free DNA alkylated under comparable conditions. No evidence for preferential shielding of the major or minor groove was observed. The purified 3-methyladenine DNA glycosylase I of Escherichia coli released approximately 37% of the 3-methyladenine from the linker DNA and 13% from the core DNA. The limited enzymatic removal of 3-methyladenine in vitro compared to the efficient removal in vivo suggests that conformational changes of the oligonucleosome and core structure must occur for total repair

The S4-S5 linker acts as a signal integrator for HERG K+ channel activation and deactivation gating.

Directory of Open Access Journals (Sweden)

Chai Ann Ng

Full Text Available Human ether-à-go-go-related gene (hERG K(+ channels have unusual gating kinetics. Characterised by slow activation/deactivation but rapid inactivation/recovery from inactivation, the unique gating kinetics underlie the central role hERG channels play in cardiac repolarisation. The slow activation and deactivation kinetics are regulated in part by the S4-S5 linker, which couples movement of the voltage sensor domain to opening of the activation gate at the distal end of the inner helix of the pore domain. It has also been suggested that cytosolic domains may interact with the S4-S5 linker to regulate activation and deactivation kinetics. Here, we show that the solution structure of a peptide corresponding to the S4-S5 linker of hERG contains an amphipathic helix. The effects of mutations at the majority of residues in the S4-S5 linker of hERG were consistent with the previously identified role in coupling voltage sensor movement to the activation gate. However, mutations to Ser543, Tyr545, Gly546 and Ala548 had more complex phenotypes indicating that these residues are involved in additional interactions. We propose a model in which the S4-S5 linker, in addition to coupling VSD movement to the activation gate, also contributes to interactions that stabilise the closed state and a separate set of interactions that stabilise the open state. The S4-S5 linker therefore acts as a signal integrator and plays a crucial role in the slow deactivation kinetics of the channel.

Onset of grain filling is associated with a change in properties of linker histone variants in maize kernels

DEFF Research Database (Denmark)

Kalamajka, R.; Finnie, Christine; Grasser, K.D.

2010-01-01

) initiation of storage synthesis. Six linker histone gene products were identified by MALDI-TOF mass spectrometry. A marked shift of around 4 pH units was observed for the linker histone spot pattern after 2D-gel electrophoresis when comparing the proteins of 11 and 16 dap kernels. The shift from acidic...

Synthesis of two new alkyne-bearing linkers used for the preparation of siRNA for labeling by click chemistry with fluorine-18

International Nuclear Information System (INIS)

Flagothier, Jessica; Kaisin, Geoffroy; Mercier, Frederic; Thonon, David; Teller, Nathalie; Wouters, Johan; Luxen, André

2012-01-01

Oligonucleotides (ONs) and more particularly siRNAs are promising drugs but their pharmacokinetics and biodistribution are widely unknown. Positron Emission Tomography (PET) using fluorine-18 is a suitable technique to quantify these biological processes. Click chemistry (Huisgen cycloaddition) is the current method for labeling siRNA. In order to study the influence of a linker bearing by [ 18 F] labeled ONs, on the in vivo pharmacokinetic and metabolism, we have developed two modified ONs by two new linkers. Here we report the synthesis of two alkyne-bearing linkers, the incorporation onto a ONs and the conjugation by click chemistry with a [ 18 F] prosthetic group. - Highlights: ► Synthesis of two new alkyne linkers. ► Functionalization at the 3′-end siRNA by alkyne linker derived of proline. ► Click chemistry between alkyne modified siRNA and [ 18 F] prosthetic group.

No Reef Is an Island: Integrating Coral Reef Connectivity Data into the Design of Regional-Scale Marine Protected Area Networks.

Science.gov (United States)

Schill, Steven R; Raber, George T; Roberts, Jason J; Treml, Eric A; Brenner, Jorge; Halpin, Patrick N

2015-01-01

We integrated coral reef connectivity data for the Caribbean and Gulf of Mexico into a conservation decision-making framework for designing a regional scale marine protected area (MPA) network that provides insight into ecological and political contexts. We used an ocean circulation model and regional coral reef data to simulate eight spawning events from 2008-2011, applying a maximum 30-day pelagic larval duration and 20% mortality rate. Coral larval dispersal patterns were analyzed between coral reefs across jurisdictional marine zones to identify spatial relationships between larval sources and destinations within countries and territories across the region. We applied our results in Marxan, a conservation planning software tool, to identify a regional coral reef MPA network design that meets conservation goals, minimizes underlying threats, and maintains coral reef connectivity. Our results suggest that approximately 77% of coral reefs identified as having a high regional connectivity value are not included in the existing MPA network. This research is unique because we quantify and report coral larval connectivity data by marine ecoregions and Exclusive Economic Zones (EZZ) and use this information to identify gaps in the current Caribbean-wide MPA network by integrating asymmetric connectivity information in Marxan to design a regional MPA network that includes important reef network connections. The identification of important reef connectivity metrics guides the selection of priority conservation areas and supports resilience at the whole system level into the future.

No Reef Is an Island: Integrating Coral Reef Connectivity Data into the Design of Regional-Scale Marine Protected Area Networks.

Directory of Open Access Journals (Sweden)

Steven R Schill

Full Text Available We integrated coral reef connectivity data for the Caribbean and Gulf of Mexico into a conservation decision-making framework for designing a regional scale marine protected area (MPA network that provides insight into ecological and political contexts. We used an ocean circulation model and regional coral reef data to simulate eight spawning events from 2008-2011, applying a maximum 30-day pelagic larval duration and 20% mortality rate. Coral larval dispersal patterns were analyzed between coral reefs across jurisdictional marine zones to identify spatial relationships between larval sources and destinations within countries and territories across the region. We applied our results in Marxan, a conservation planning software tool, to identify a regional coral reef MPA network design that meets conservation goals, minimizes underlying threats, and maintains coral reef connectivity. Our results suggest that approximately 77% of coral reefs identified as having a high regional connectivity value are not included in the existing MPA network. This research is unique because we quantify and report coral larval connectivity data by marine ecoregions and Exclusive Economic Zones (EZZ and use this information to identify gaps in the current Caribbean-wide MPA network by integrating asymmetric connectivity information in Marxan to design a regional MPA network that includes important reef network connections. The identification of important reef connectivity metrics guides the selection of priority conservation areas and supports resilience at the whole system level into the future.

Crystallization and preliminary X-ray analysis of Acetivibrio cellulolyticus cellulosomal type II cohesin module: two versions having different linker lengths

International Nuclear Information System (INIS)

Noach, Ilit; Alber, Orly; Bayer, Edward A.; Lamed, Raphael; Levy-Assaraf, Maly; Shimon, Linda J. W.; Frolow, Felix

2007-01-01

The cloning, expression, purification, crystallization and preliminary X-ray characterization of two protein constructs of the second type II cohesin module from A. cellulolyticus ScaB are described. Both constructs contain the native N-terminal linker, but only one of them contains the full-length 45-residue C-terminal linker; the other contains a five-residue segment of this linker. The second type II cohesin module of the cellulosomal scaffoldin polypeptide ScaB from Acetivibrio cellulolyticus (CohB2) was cloned into two constructs: one containing a short (five-residue) C-terminal linker (CohB2-S) and the second incorporating the full native 45-residue linker (CohB2-L). Both constructs encode proteins that also include the full native six-residue N-terminal linker. The CohB2-S and CohB2-L proteins were expressed, purified and crystallized in the orthorhombic crystal system, but with different unit cells and symmetries: space group P2 1 2 1 2 1 with unit-cell parameters a = 90.36, b = 68.65, c = 111.29 Å for CohB2-S and space group P2 1 2 1 2 with unit-cell parameters a = 68.76, b = 159.22, c = 44.21 Å for CohB2-L. The crystals diffracted to 2.0 and 2.9 Å resolution, respectively. The asymmetric unit of CohB2-S contains three cohesin molecules, while that of CohB2-L contains two molecules

Crucial role of dynamic linker histone binding and divalent ions for DNA accessibility and gene regulation revealed by mesoscale modeling of oligonucleosomes

Science.gov (United States)

Collepardo-Guevara, Rosana; Schlick, Tamar

2012-01-01

Monte Carlo simulations of a mesoscale model of oligonucleosomes are analyzed to examine the role of dynamic-linker histone (LH) binding/unbinding in high monovalent salt with divalent ions, and to further interpret noted chromatin fiber softening by dynamic LH in monovalent salt conditions. We find that divalent ions produce a fiber stiffening effect that competes with, but does not overshadow, the dramatic softening triggered by dynamic-LH behavior. Indeed, we find that in typical in vivo conditions, dynamic-LH binding/unbinding reduces fiber stiffening dramatically (by a factor of almost 5, as measured by the elasticity modulus) compared with rigidly fixed LH, and also the force needed to initiate chromatin unfolding, making it consistent with those of molecular motors. Our data also show that, during unfolding, divalent ions together with LHs induce linker-DNA bending and DNA–DNA repulsion screening, which guarantee formation of heteromorphic superbeads-on-a-string structures that combine regions of loose and compact fiber independently of the characteristics of the LH–core bond. These structures might be important for gene regulation as they expose regions of the DNA selectively. Dynamic control of LH binding/unbinding, either globally or locally, in the presence of divalent ions, might constitute a mechanism for regulation of gene expression. PMID:22790986

Regional vulnerability of longitudinal cortical association connectivity

Directory of Open Access Journals (Sweden)

Rafael Ceschin

2015-01-01

correlated with alteration in eigenvector centrality, clustering coefficient (inter-regional and participation co-efficient (inter-modular alterations of frontal–striatal and fronto-limbic nodes suggesting re-organization of these pathways. Both along tract and structural topology network measurements correlated strongly with motor and visual clinical outcome scores. This study shows the value of combining along-tract analysis and structural network topology in depicting not only selective parietal occipital regional vulnerability but also reorganization of frontal–striatal and frontal–limbic pathways in preterm children with cerebral palsy. These finding also support the concept that widespread, but selective posterior–anterior neural network connectivity alterations in preterm children with cerebral palsy likely contribute to the pathogenesis of neurosensory and cognitive impairment in this group.

Aerosols: connection between regional climatic change and air quality (Iupac Technical Report)

NARCIS (Netherlands)

Slanina, J.; Zhang, Y.H.

2004-01-01

yAerosols play an important role in all problems connected with air pollution, ranging from very local effects and human health problems to regional problems such as acid deposition and eutrophication up to continental and global questions such as stratospheric ozone loss and climatic change. In

Functional connectivity analysis of fMRI data using parameterized regions-of-interest.

NARCIS (Netherlands)

Weeda, W.D.; Waldorp, L.J.; Grasman, R.P.P.P.; van Gaal, S.; Huizenga, H.M.

2011-01-01

Connectivity analysis of fMRI data requires correct specification of regions-of-interest (ROIs). Selection of ROIs based on outcomes of a GLM analysis may be hindered by conservativeness of the multiple comparison correction, while selection based on brain anatomy may be biased due to inconsistent

Associations of resting-state fMRI functional connectivity with flow-BOLD coupling and regional vasculature.

Science.gov (United States)

Tak, Sungho; Polimeni, Jonathan R; Wang, Danny J J; Yan, Lirong; Chen, J Jean

2015-04-01

There has been tremendous interest in applying functional magnetic resonance imaging-based resting-state functional connectivity (rs-fcMRI) measurements to the study of brain function. However, a lack of understanding of the physiological mechanisms of rs-fcMRI limits their ability to interpret rs-fcMRI findings. In this work, the authors examine the regional associations between rs-fcMRI estimates and dynamic coupling between the blood oxygenation level-dependent (BOLD) and cerebral blood flow (CBF), as well as resting macrovascular volume. Resting-state BOLD and CBF data were simultaneously acquired using a dual-echo pseudocontinuous arterial spin labeling (pCASL) technique, whereas macrovascular volume fraction was estimated using time-of-flight MR angiography. Functional connectivity within well-known functional networks—including the default mode, frontoparietal, and primary sensory-motor networks—was calculated using a conventional seed-based correlation approach. They found the functional connectivity strength to be significantly correlated with the regional increase in CBF-BOLD coupling strength and inversely proportional to macrovascular volume fraction. These relationships were consistently observed within all functional networks considered. Their findings suggest that highly connected networks observed using rs-fcMRI are not likely to be mediated by common vascular drainage linking distal cortical areas. Instead, high BOLD functional connectivity is more likely to reflect tighter neurovascular connections, attributable to neuronal pathways.

Two-dimensional layer architecture assembled by Keggin polyoxotungstate, Cu(II)-EDTA complex and sodium linker: Synthesis, crystal structures, and magnetic properties

International Nuclear Information System (INIS)

Liu Hong; Xu Lin; Gao Guanggang; Li Fengyan; Yang Yanyan; Li Zhikui; Sun Yu

2007-01-01

Reaction of Keggin polyoxotungstate with copper(II)-EDTA (EDTA=ethylenediamine tetraacetate) complex under mild conditions led to the formation of hybrid inorganic-organic compounds Na 4 (OH)[(Cu 2 EDTA)PW 12 O 40 ].17H 2 O (1) and Na 4 [(Cu 2 EDTA)SiW 12 O 40 ].19H 2 O (2). The single-crystal X-ray diffraction analyses reveal their two structural features: (1) one-dimensional chain structure consisting of Keggin polyoxotungstate and copper(II)-EDTA complex; (2) Two-dimensional layer architecture assembled by the one-dimensional chain structure and sodium linker. The results of magnetic measurements in the temperature range 300-2 K indicated the existence of ferromagnetic exchange interactions between the Cu II ions for both compounds. In addition, TGA analysis, IR spectra, and electrochemical properties were also investigated to well characterize these two compounds. - Graphical abstract: Two new polyoxometalate-based hybrids, Na 4 (OH)[Cu 2 (EDTA)PW 12 O 40 ].17H 2 O (1) and Na 4 [Cu 2 (EDTA)SiW 12 O 40 ].19H 2 O (2), have been synthesized and structurally characterized, which consist of one-dimensional chain structure assembled by Keggin polyoxotungstate and copper(II)-EDTA complex. The chains are further connected to form two-dimensional layer architecture assembled by the one-dimensional chain structure and sodium linker

Germline-specific H1 variants: the "sexy" linker histones.

Science.gov (United States)

Pérez-Montero, Salvador; Carbonell, Albert; Azorín, Fernando

2016-03-01

The eukaryotic genome is packed into chromatin, a nucleoprotein complex mainly formed by the interaction of DNA with the abundant basic histone proteins. The fundamental structural and functional subunit of chromatin is the nucleosome core particle, which is composed by 146 bp of DNA wrapped around an octameric protein complex formed by two copies of each core histone H2A, H2B, H3, and H4. In addition, although not an intrinsic component of the nucleosome core particle, linker histone H1 directly interacts with it in a monomeric form. Histone H1 binds nucleosomes near the exit/entry sites of linker DNA, determines nucleosome repeat length and stabilizes higher-order organization of nucleosomes into the ∼30 nm chromatin fiber. In comparison to core histones, histone H1 is less well conserved through evolution. Furthermore, histone H1 composition in metazoans is generally complex with most species containing multiple variants that play redundant as well as specific functions. In this regard, a characteristic feature is the presence of specific H1 variants that replace somatic H1s in the germline and during early embryogenesis. In this review, we summarize our current knowledge about their structural and functional properties.

Bilingualism alters brain functional connectivity between "control" regions and "language" regions: Evidence from bimodal bilinguals.

Science.gov (United States)

Li, Le; Abutalebi, Jubin; Zou, Lijuan; Yan, Xin; Liu, Lanfang; Feng, Xiaoxia; Wang, Ruiming; Guo, Taomei; Ding, Guosheng

2015-05-01

Previous neuroimaging studies have revealed that bilingualism induces both structural and functional neuroplasticity in the dorsal anterior cingulate cortex (dACC) and the left caudate nucleus (LCN), both of which are associated with cognitive control. Since these "control" regions should work together with other language regions during language processing, we hypothesized that bilingualism may also alter the functional interaction between the dACC/LCN and language regions. Here we tested this hypothesis by exploring the functional connectivity (FC) in bimodal bilinguals and monolinguals using functional MRI when they either performed a picture naming task with spoken language or were in resting state. We found that for bimodal bilinguals who use spoken and sign languages, the FC of the dACC with regions involved in spoken language (e.g. the left superior temporal gyrus) was stronger in performing the task, but weaker in the resting state as compared to monolinguals. For the LCN, its intrinsic FC with sign language regions including the left inferior temporo-occipital part and right inferior and superior parietal lobules was increased in the bilinguals. These results demonstrate that bilingual experience may alter the brain functional interaction between "control" regions and "language" regions. For different control regions, the FC alters in different ways. The findings also deepen our understanding of the functional roles of the dACC and LCN in language processing. Copyright © 2015 Elsevier Ltd. All rights reserved.

A Linker for the Solid-Phase Synthesis of Hydroxamic Acids and Identification of HDAC6 Inhibitors

DEFF Research Database (Denmark)

Bang, Claus Gunnar; Jensen, Jakob Feldthusen; Cohrt, Anders Emil O'Hanlon

2017-01-01

We herein present broadly useful, readily available and nonintegral hydroxylamine linkers for the routine solid-phase synthesis of hydroxamic acids. The developed protocols enable the efficient synthesis and release of a wide range of hydroxamic acids from various resins, relying on high control...... and flexibility with respect to reagents and synthetic processes. A trityl-based hydroxylamine linker was used to synthesize a library of peptide hydroxamic acids. The inhibitory effects of the compounds were examined for seven HDAC enzyme subtypes using a chemiluminescence-based assay....

Desorption of 3,3′-diindolylmethane from imprinted particles: An impact of cross-linker structure on binding capacity and selectivity

Energy Technology Data Exchange (ETDEWEB)

Klejn, Dorota; Luliński, Piotr; Maciejewska, Dorota, E-mail: dorota.maciejewska@wum.edu.pl

2015-11-01

Here, seven cross-linkers (six polar diacrylates or dimethacrylates of different lengths between double bonds, and one aromatic-divinylbenzene) were used to examine the impact of the cross-linker on binding capacity and selectivity of 3,3′-diindolylmethane (DIM) imprinted material. DIM participates in the suppression of viability of human ovarian and human breast cancer cell lines, but has low bioavailability. The investigations of novel imprinted polymer matrices for improvement of DIM release could allow to utilize not only a potency of DIM but also similar alkaloids, which are the important compounds with pharmacological activity. The bulk, thermal radical copolymerization of the cross-linkers in the presence of 3,3′-diindolylmethane (the template) and allylamine (the functional monomer) in dimethyl sulfoxide or in carbon tetrachloride (porogens) was carried out. The binding capacities of imprinted and non-imprinted polymers were compared, and two polymers (these were prepared using ethylene glycol dimethacrylate and polyethylene glycol dimethacrylate as the cross-linkers) with the highest selectivity and binding capacity were selected to desorption test. The desorption profile of polymer prepared using polyethylene glycol dimethacrylate as the cross-linker revealed sustained release of 3,3′-diindolylmethane, and this system was selected for further optimization of the cross-linker amounts. The morphology and structure of the selected particles were analyzed using SEM micrographs, {sup 13}C CP/MAS NMR spectroscopy, and BET measurements. The desorption of 3,3′-diindolylmethane from poly(allylamine-co-polyethylene glycol dimethacrylate) particles was in accordance with pseudo-second-order kinetics and the simplified Higuchi model indicated the diffusion controlled release of 3,3′-diindolylmethane. - Graphical abstract: Sustained release of 3,3′-diindolylmethane from cavity in imprinted poly(allylamine-co-polyethylene glycol dimethacrylate

Desorption of 3,3′-diindolylmethane from imprinted particles: An impact of cross-linker structure on binding capacity and selectivity

International Nuclear Information System (INIS)

Klejn, Dorota; Luliński, Piotr; Maciejewska, Dorota

2015-01-01

Here, seven cross-linkers (six polar diacrylates or dimethacrylates of different lengths between double bonds, and one aromatic-divinylbenzene) were used to examine the impact of the cross-linker on binding capacity and selectivity of 3,3′-diindolylmethane (DIM) imprinted material. DIM participates in the suppression of viability of human ovarian and human breast cancer cell lines, but has low bioavailability. The investigations of novel imprinted polymer matrices for improvement of DIM release could allow to utilize not only a potency of DIM but also similar alkaloids, which are the important compounds with pharmacological activity. The bulk, thermal radical copolymerization of the cross-linkers in the presence of 3,3′-diindolylmethane (the template) and allylamine (the functional monomer) in dimethyl sulfoxide or in carbon tetrachloride (porogens) was carried out. The binding capacities of imprinted and non-imprinted polymers were compared, and two polymers (these were prepared using ethylene glycol dimethacrylate and polyethylene glycol dimethacrylate as the cross-linkers) with the highest selectivity and binding capacity were selected to desorption test. The desorption profile of polymer prepared using polyethylene glycol dimethacrylate as the cross-linker revealed sustained release of 3,3′-diindolylmethane, and this system was selected for further optimization of the cross-linker amounts. The morphology and structure of the selected particles were analyzed using SEM micrographs, 13 C CP/MAS NMR spectroscopy, and BET measurements. The desorption of 3,3′-diindolylmethane from poly(allylamine-co-polyethylene glycol dimethacrylate) particles was in accordance with pseudo-second-order kinetics and the simplified Higuchi model indicated the diffusion controlled release of 3,3′-diindolylmethane. - Graphical abstract: Sustained release of 3,3′-diindolylmethane from cavity in imprinted poly(allylamine-co-polyethylene glycol dimethacrylate). - Highlights: �

Region-specific connectivity in patients with periventricular nodular heterotopia and epilepsy: A study combining diffusion tensor imaging and functional MRI.

Science.gov (United States)

Liu, Wenyu; An, Dongmei; Tong, Xin; Niu, Running; Gong, Qiyong; Zhou, Dong

2017-10-01

Periventricular nodular heterotopia (PNH) is an important cause of chronic epilepsy. The purpose of this study was to evaluate region-specific connectivity in PNH patients with epilepsy and assess correlation between connectivity strength and clinical factors including duration and prognosis. Diffusion tensor imaging (DTI) and resting state functional MRI (fMRI) were performed in 28 subjects (mean age 27.4years; range 9-56years). The structural connectivity of fiber bundles passing through the manually-selected segmented nodules and other brain regions were analyzed by tractography. Cortical lobes showing functional correlations to nodules were also determined. For all heterotopic gray matter nodules, including at least one in each subject, the most frequent segments to which nodular heterotopia showed structural (132/151) and functional (146/151) connectivity were discrete regions of the ipsilateral overlying cortex. Agreement between diffusion tensor tractography and functional connectivity analyses was conserved in 81% of all nodules (122/151). In patients with longer duration or refractory epilepsy, the connectivity was significantly stronger, particularly to the frontal and temporal lobes (P<0.05). Nodules in PNH were structurally and functionally connected to the cortex. The extent is stronger in patients with longstanding or intractable epilepsy. These findings suggest the region-specific interactions may help better evaluate prognosis and seek medical or surgical interventions of PNH-related epilepsy. Copyright © 2017 Elsevier B.V. All rights reserved.

Investigation of the Linker Swing Motion in the Zeolitic Imidazolate Framework ZIF-90

KAUST Repository

Zheng, Bin; Fu, Fang; Wang, Lian Li; Yang, Limin; Zhu, Yihan; Du, Huiling

2018-01-01

The linker swing motion in the zeolitic imidazolate framework ZIF-90 is investigated by density functional theory (DFT) calculation, molecular dynamics (MD) and grand-canonical Monte Carlo (GCMC) simulations. The relation between the terminal

Evaluation of ¹¹¹in-labelled exendin-4 derivatives containing different meprin β-specific cleavable linkers.

Directory of Open Access Journals (Sweden)

Andreas Jodal

Full Text Available Cleavable linkers, which are specifically cleaved by defined conditions or enzymes, are powerful tools that can be used for various purposes. Amongst other things, they have been successfully used to deliver toxic payloads as prodrugs into target tissues. In this work novel linker sequences targeting meprin β, a metalloprotease expressed in the kidney brush-border membrane, were designed and included in the sequence of three radiolabelled exendin-4 derivatives. As radiolabelled exendin-4 derivatives strongly accumulate in the kidneys, we hypothesised that specific cleavage of the radiolabelled moiety at the kidney brush-border membrane would allow easier excretion of the activity into the urine and therefore improve the pharmacological properties of the peptide.The insertion of a cleavable linker did not negatively influence the in vitro properties of the peptides. They showed a good affinity to the GLP-1 receptor expressed in CHL cells, a high internalisation and sufficiently high stability in fresh human blood plasma. In vitro digestion with recombinant meprin β rapidly metabolised the corresponding linker sequences. After 60 min the majority of the corresponding peptides were digested and at the same time the anticipated fragments were formed. The peptides were also quickly metabolised in CD1 nu/nu mouse kidney homogenates. Immunofluorescence staining of meprin β in kidney sections confirmed the expression of the protease in the kidney brush-border membrane. Biodistribution in GLP-1 receptor positive tumour-xenograft bearing mice revealed high specific uptake of the 111In-labelled tracers in receptor positive tissue. Accumulation in the kidneys, however, was still high and comparable to the lead compound 111In-Ex4NOD40.In conclusion, we show that the concept of cleavable linkers specific for meprin β is feasible, as the peptides are rapidly cleaved by the enzyme while retaining their biological properties.

Long distance dispersal and connectivity in amphi-Atlantic corals at regional and basin scales.

Directory of Open Access Journals (Sweden)

Flavia L D Nunes

Full Text Available Among Atlantic scleractinian corals, species diversity is highest in the Caribbean, but low diversity and high endemism are observed in various peripheral populations in central and eastern Atlantic islands and along the coasts of Brazil and West Africa. The degree of connectivity between these distantly separated populations is of interest because it provides insight into processes at both evolutionary and ecological time scales, such as speciation, recruitment dynamics and the persistence of coral populations. To assess connectivity in broadly distributed coral species of the Atlantic, DNA sequence data from two nuclear markers were obtained for six coral species spanning their distributional ranges. At basin-wide scales, significant differentiation was generally observed among populations in the Caribbean, Brazil and West Africa. Concordance of patterns in connectivity among co-distributed taxa indicates that extrinsic barriers, such as the Amazon freshwater plume or long stretches of open ocean, restrict dispersal of coral larvae from region to region. Within regions, dispersal ability appears to be influenced by aspects of reproduction and life history. Two broadcasting species, Siderastrea siderea and Montastraea cavernosa, were able to maintain gene flow among populations separated by as much as 1,200 km along the coast of Brazil. In contrast, brooding species, such as Favia gravida and Siderastrea radians, had more restricted gene flow along the Brazilian coast.

Efficient Naphthalenediimide-Based Hole Semiconducting Polymer with Vinylene Linkers between Donor and Acceptor Units

KAUST Repository

Zhang, Lei

2016-11-04

We demonstrate a new method to reverse the polarity and charge transport behavior of naphthalenediimide (NDI)-based copolymers by inserting a vinylene linker between the donor and acceptor units. The vinylene linkers minimize the intrinsic steric congestion between the NDI and thiophene moieties to prompt backbone planarity. The polymers with vinylene linkers exhibit electron n-channel transport characteristics under vacuum, similar to the benchmark polymer, P(NDI2OD-T2). To our surprise, when the polymers are measured in air, the dominant carrier type switches from n- to p-type and yield hole mobilities up to 0.45 cm(2) s(-1) with hole to electron mobility ratio of three (mu(h)/mu(e), similar to 3), which indicates that the hole density in the active layer can be significantly increased by exposure to air. This increase is consistent with the intrinsic more delocalized nature of the highest occupied molecular orbital of the charged vinylene polymer, as estimated by density functional theory (DFT) calculations, which facilitates hole transport within the polymer chains. This is the first demonstration of an efficient NDI-based hole semiconducting polymer, which will enable new developments in all-polymer solar cells, complementary circuits, and dopable polymers for use in thermoelectrics.

Efficient Naphthalenediimide-Based Hole Semiconducting Polymer with Vinylene Linkers between Donor and Acceptor Units

KAUST Repository

Zhang, Lei; Rose, Bradley Daniel; Liu, Yao; Nahid, Masrur M.; Gann, Eliot; Ly, Jack; Zhao, Wei; Rosa, Stephen J.; Russell, Thomas P.; Facchetti, Antonio; McNei, Christopher R.; Bredas, Jean-Luc; Briseno, Alejandro L.

2016-01-01

We demonstrate a new method to reverse the polarity and charge transport behavior of naphthalenediimide (NDI)-based copolymers by inserting a vinylene linker between the donor and acceptor units. The vinylene linkers minimize the intrinsic steric congestion between the NDI and thiophene moieties to prompt backbone planarity. The polymers with vinylene linkers exhibit electron n-channel transport characteristics under vacuum, similar to the benchmark polymer, P(NDI2OD-T2). To our surprise, when the polymers are measured in air, the dominant carrier type switches from n- to p-type and yield hole mobilities up to 0.45 cm(2) s(-1) with hole to electron mobility ratio of three (mu(h)/mu(e), similar to 3), which indicates that the hole density in the active layer can be significantly increased by exposure to air. This increase is consistent with the intrinsic more delocalized nature of the highest occupied molecular orbital of the charged vinylene polymer, as estimated by density functional theory (DFT) calculations, which facilitates hole transport within the polymer chains. This is the first demonstration of an efficient NDI-based hole semiconducting polymer, which will enable new developments in all-polymer solar cells, complementary circuits, and dopable polymers for use in thermoelectrics.

Numerical conformal mapping methods for exterior and doubly connected regions

Energy Technology Data Exchange (ETDEWEB)

DeLillo, T.K. [Wichita State Univ., KS (United States); Pfaltzgraff, J.A. [Univ. of North Carolina, Chapel Hill, NC (United States)

1996-12-31

Methods are presented and analyzed for approximating the conformal map from the exterior of the disk to the exterior a smooth, simple closed curve and from an annulus to a bounded, doubly connected region with smooth boundaries. The methods are Newton-like methods for computing the boundary correspondences and conformal moduli similar to Fornberg`s method for the interior of the disk. We show that the linear systems are discretizations of the identity plus a compact operator and, hence, that the conjugate gradient method converges superlinearly.

Transient thermal stresses in multiple connected region exhibiting temperature dependence of material properties

International Nuclear Information System (INIS)

Sugano, Yoshihiro; Maekawa, Toshiya.

1983-01-01

The examples of the analysis of thermal stress in multiple connection regions such as heat exchangers, nuclear reactor cores, ingot cases and polygonal region with elliptic holes are not few, but the temperature dependence of material constants was neglected in these researches because of the difficulty of analysis though the industrial problems related to thermal stress are apt to occur in the condition of relatively large temperature gradient. Also, the analysis of heat conduction problems taking the temperature dependence of material constants into account was limited to one-dimensional problems for which Kirchhoff's transmission can be used. The purpose of this study is to derive the equation of condition which assures the one-value property of rotation and displacement, taking the temperature dependence of material constants into account, and to complete the formulation of the plane thermal stress problems in multiple connection regions by stress function method. Also the method of numerical analysis using difference method is shown to examine the effectiveness of various formulated equations and the effect of the temperature dependence of material constants on temperature and thermal stress. The example of numerical calculation on a thin rectangular plate with a rectangular hole is shown. (Kako, I.)

Preparation of value-added metal-organic frameworks (MOFs) using waste PET bottles as source of acid linker

CSIR Research Space (South Africa)

Dyosiba, Xoliswa

2016-12-01

Full Text Available of Value-added Metal-organic Frameworks (MOFs) Using Waste PET Bottles as Source of Acid Linker Xoliswa Dyosiba, Jianwei Ren, Nicholas M. Musyoka, Henrietta W. Langmi, Mkhulu Mathe, Maurice S. Onyango PII: S2214-9937(16)30053-7 DOI: doi:10.1016/j..., Hen- rietta W. Langmi, Mkhulu Mathe, Maurice S. Onyango, Preparation of Value-added Metal-organic Frameworks (MOFs) Using Waste PET Bottles as Source of Acid Linker, Sustainable Materials and Technologies (2016), doi:10.1016/j.susmat.2016...

G-CSF receptor-binding cyclic peptides designed with artificial amino-acid linkers

International Nuclear Information System (INIS)

Shibata, Kenji; Maruyama-Takahashi, Kumiko; Yamasaki, Motoo; Hirayama, Noriaki

2006-01-01

Designing small molecules that mimic the receptor-binding local surface structure of large proteins such as cytokines or growth factors is fascinating and challenging. In this study, we designed cyclic peptides that reproduce the receptor-binding loop structures of G-CSF. We found it is important to select a suitable linker to join two or more discontinuous sequences and both termini of the peptide corresponding to the receptor-binding loop. Structural simulations based on the crystallographic structure of KW-2228, a stable and potent analog of human G-CSF, led us to choose 4-aminobenzoic acid (Abz) as a part of the linker. A combination of 4-Abz with β-alanine or glycine, and disulfide bridges between cysteins or homocysteins, gave a structure suitable for receptor binding. In this structure, the side-chains of several amino acids important for the interactions with the receptor are protruding from one side of the peptide ring. This artificial peptide showed G-CSF antagonistic activity in a cell proliferation assay

Distribution of linker histone variants during plant cell differentiation in the developmental zones of the maize root, dedifferentiation in callus culture after auxin treatment

Directory of Open Access Journals (Sweden)

ANASTASIOS ALATZAS

2008-01-01

Full Text Available Although several linker histone variants have been studied in both animal and plant organisms, little is known about their distribution during processes that involve alterations in chromatin function, such as differentiation, dedifferentiation and hormone treatment. In this study, we identified linker histone variants by using specific anti-histone Hl antibodies. Each variant's ratio to total Hl in the three developmental zones of maize (Zea mays L. root and in callus cultures derived from them was estimated in order to define possible alterations either during plant cell differentiation or during their dedifferentiation. We also evaluated linker histone variants' ratios in the developmental zones of maize roots treated with auxin in order to examine the effects of exogenous applied auxin to linker histone variant distribution. Finally, immunohistochemical detection was used to identify the root tissues containing each variant and correlate them with the physiological status of the plant cells. According to the results presented in this study, linker histone variants' ratios are altered in the developmental zones of maize root, while they are similar to the meristematic zone in samples from callus cultures and to the differentiation zone in samples from roots treated with auxin. We propose that the alterations in linker histone variants' ratios are correlated with plant cell differentiation and dedifferentiation.

SEVA Linkers: A Versatile and Automatable DNA Backbone Exchange Standard for Synthetic Biology

DEFF Research Database (Denmark)

Kim, Se Hyeuk; Cavaleiro, Mafalda; Rennig, Maja

2016-01-01

flexibility, and different researchers prefer and master different molecular technologies. Here, we describe a new, highly versatile and automatable standard “SEVA linkers” for vector exchange. SEVA linkers enable backbone swapping with 20 combinations of classical enzymatic restriction/ligation, Gibson...

Construction of Multivalent Homo- and Heterofunctional ABO Blood Group Glycoconjugates Using a Trifunctional Linker Strategy.

Science.gov (United States)

Daskhan, Gour Chand; Tran, Hanh-Thuc Ton; Meloncelli, Peter J; Lowary, Todd L; West, Lori J; Cairo, Christopher W

2018-02-21

The design and synthesis of multivalent ligands displaying complex oligosaccharides is necessary for the development of therapeutics, diagnostics, and research tools. Here, we report an efficient conjugation strategy to prepare complex glycoconjugates with 4 copies of 1 or 2 separate glycan epitopes, providing 4-8 carbohydrate residues on a tetravalent poly(ethylene glycol) scaffold. This strategy provides complex glycoconjugates that approach the size of glycoproteins (15-18 kDa) while remaining well-defined. The synthetic strategy makes use of three orthogonal functional groups, including a reactive N-hydroxysuccinimide (NHS)-ester moiety on the linker to install the first carbohydrate epitope via reaction with an amine. A masked amine functionality on the linker is revealed after the removal of a fluorenylmethyloxycarbonyl (Fmoc)-protecting group, allowing the attachment to the NHS-activated poly(ethylene glycol) (PEG) scaffold. An azide group in the linker was then used to incorporate the second carbohydrate epitope via catalyzed alkyne-azide cycloaddition. Using a known tetravalent PEG scaffold (PDI, 1.025), we prepared homofunctional glycoconjugates that display four copies of lactose and the A-type II or the B-type II human blood group antigens. Using our trifunctional linker, we expanded this strategy to produce heterofunctional conjugates with four copies of two separate glycan epitopes. These heterofunctional conjugates included Neu5Ac, 3'-sialyllactose, or 6'-sialyllactose as a second antigen. Using an alternative strategy, we generated heterofunctional conjugates with three copies of the glycan epitope and one fluorescent group (on average) using a sequential dual-amine coupling strategy. These conjugation strategies should be easily generalized for conjugation of other complex glycans. We demonstrate that the glycan epitopes of heterofunctional conjugates engage and cluster target B-cell receptors and CD22 receptors on B cells, supporting the

Prescreening of Nicotine Hapten Linkers in Vitro To Select Hapten-Conjugate Vaccine Candidates for Pharmacokinetic Evaluation in Vivo.

Science.gov (United States)

Arutla, Viswanath; Leal, Joseph; Liu, Xiaowei; Sokalingam, Sriram; Raleigh, Michael; Adaralegbe, Adejimi; Liu, Li; Pentel, Paul R; Hecht, Sidney M; Chang, Yung

2017-05-08

Since the demonstration of nicotine vaccines as a possible therapeutic intervention for the effects of tobacco smoke, extensive effort has been made to enhance nicotine specific immunity. Linker modifications of nicotine haptens have been a focal point for improving the immunogenicity of nicotine, in which the evaluation of these modifications usually relies on in vivo animal models, such as mice, rats or nonhuman primates. Here, we present two in vitro screening strategies to estimate and predict the immunogenic potential of our newly designed nicotine haptens. One utilizes a competition enzyme-linked immunoabsorbent assay (ELISA) to profile the interactions of nicotine haptens or hapten-protein conjugates with nicotine specific antibodies, both polyclonal and monoclonal. Another relies on computational modeling of the interactions between haptens and amino acid residues near the conjugation site of the carrier protein to infer linker-carrier protein conjugation effect on antinicotine antibody response. Using these two in vitro methods, we ranked the haptens with different linkers for their potential as viable vaccine candidates. The ELISA-based hapten ranking was in an agreement with the results obtained by in vivo nicotine pharmacokinetic analysis. A correlation was found between the average binding affinity (IC 50 ) of the haptens to an anti-Nic monoclonal antibody and the average brain nicotine concentration in the immunized mice. The computational modeling of hapten and carrier protein interactions helps exclude conjugates with strong linker-carrier conjugation effects and low in vivo efficacy. The simplicity of these in vitro screening strategies should facilitate the selection and development of more effective nicotine conjugate vaccines. In addition, these data highlight a previously under-appreciated contribution of linkers and hapten-protein conjugations to conjugate vaccine immunogenicity by virtue of their inclusion in the epitope that binds and

Geometric Structure of 3D Spinal Curves: Plane Regions and Connecting Zones

Science.gov (United States)

Berthonnaud, E.; Hilmi, R.; Dimnet, J.

2012-01-01

This paper presents a new study of the geometric structure of 3D spinal curves. The spine is considered as an heterogeneous beam, compound of vertebrae and intervertebral discs. The spine is modeled as a deformable wire along which vertebrae are beads rotating about the wire. 3D spinal curves are compound of plane regions connected together by zones of transition. The 3D spinal curve is uniquely flexed along the plane regions. The angular offsets between adjacent regions are concentrated at level of the middle zones of transition, so illustrating the heterogeneity of the spinal geometric structure. The plane regions along the 3D spinal curve must satisfy two criteria: (i) a criterion of minimum distance between the curve and the regional plane and (ii) a criterion controlling that the curve is continuously plane at the level of the region. The geometric structure of each 3D spinal curve is characterized by the sizes and orientations of regional planes, by the parameters representing flexed regions and by the sizes and functions of zones of transition. Spinal curves of asymptomatic subjects show three plane regions corresponding to spinal curvatures: lumbar, thoracic and cervical curvatures. In some scoliotic spines, four plane regions may be detected. PMID:25031873

CNS activation and regional connectivity during pantomime observation: no engagement of the mirror neuron system for deaf signers.

Science.gov (United States)

Emmorey, Karen; Xu, Jiang; Gannon, Patrick; Goldin-Meadow, Susan; Braun, Allen

2010-01-01

Deaf signers have extensive experience using their hands to communicate. Using fMRI, we examined the neural systems engaged during the perception of manual communication in 14 deaf signers and 14 hearing non-signers. Participants passively viewed blocked video clips of pantomimes (e.g., peeling an imaginary banana) and action verbs in American Sign Language (ASL) that were rated as meaningless by non-signers (e.g., TO-DANCE). In contrast to visual fixation, pantomimes strongly activated fronto-parietal regions (the mirror neuron system, MNS) in hearing non-signers, but only bilateral middle temporal regions in deaf signers. When contrasted with ASL verbs, pantomimes selectively engaged inferior and superior parietal regions in hearing non-signers, but right superior temporal cortex in deaf signers. The perception of ASL verbs recruited similar regions as pantomimes for deaf signers, with some evidence of greater involvement of left inferior frontal gyrus for ASL verbs. Functional connectivity analyses with left hemisphere seed voxels (ventral premotor, inferior parietal lobule, fusiform gyrus) revealed robust connectivity with the MNS for the hearing non-signers. Deaf signers exhibited functional connectivity with the right hemisphere that was not observed for the hearing group for the fusiform gyrus seed voxel. We suggest that life-long experience with manual communication, and/or auditory deprivation, may alter regional connectivity and brain activation when viewing pantomimes. We conclude that the lack of activation within the MNS for deaf signers does not support an account of human communication that depends upon automatic sensorimotor resonance between perception and action.

The Effects of Anchor Groups on (1) TiO2-Catalyzed Photooxidation and (2) Linker-Assisted Assembly on TiO2

Science.gov (United States)

Anderson, Ian Mark

Quantum dot-sensitized solar cells (QDSSCs) are a popular target for research due to their potential for highly efficient, easily tuned absorption. Typically, light is absorbed by quantum dots attached to a semiconductor substrate, such as TiO2, via bifunctional linker molecules. This research aims to create a patterned monolayer of linker molecules on a TiO2 film, which would in turn allow the attachment of a patterned layer of quantum dots. One method for the creation of a patterned monolayer is the functionalization of a TiO2 film with a linker molecule, followed by illumination with a laser at 355 nm. This initiates a TiO 2-catalyzed oxidation reaction, causing loss of surface coverage. A second linker molecule can then be adsorbed onto the TiO2 surface in the illuminated area. Towards that end, the behaviors of carboxylic and phosphonic acids adsorbed on TiO2 have been studied. TiO2 films were functionalized by immersion in solutions a single adsorbate and surface coverage was determined by IR spectroscopy. It is shown that phosphonic acids attain higher surface coverage than carboxylic acids, and will displace them from TiO2 when in a polar solvent. Alkyl chain lengths, which can influence stabilities of monolayers, are shown not to have an effect on this relationship. Equilibrium binding data for the adsorption of n-hexadecanoic acid to TiO2 from a THF solution are presented. It is shown that solvent polarity can affect monolayer stability; carboxylates and phosphonates undergo more desorption into polar solvents than nonpolar. Through illumination, it was possible to remove nearly all adsorbed linkers from TiO2. However, the illuminated areas were found not to be receptive to attachment by a second adsorbate. A possible reason for this behavior is presented. I also report on the synthesis and characterization of a straight-chain, thiol-terminated phosphonic acid. Initial experiments involving monolayer formation and quantum dot attachment are presented

Effective connectivity among the working memory regions during preparation for and during performance of the n-back task.

Science.gov (United States)

Manelis, Anna; Reder, Lynne M

2014-01-01

Recent neuroimaging studies have shown that working memory (WM) task difficulty can be decoded from patterns of brain activation in the WM network during preparation to perform those tasks. The inter-regional connectivity among the WM regions during task preparation has not yet been investigated. We examined this question using the graph modeling methods IMaGES and LOFS, applied to the previously published fMRI data of Manelis and Reder (2013). In that study, subjects performed 1-, 2-, and 3-back tasks. Each block of n-back was preceded by a preparation period and followed by a rest period. The analyses of task-related brain activity identified a network of 18 regions that increased in activation from 1- to 3-back (Increase network) and a network of 17 regions that decreased in activation from 1- to 3-back (Decrease network). The graph analyses revealed two types of connectivity sub-networks within the Increase and Decrease networks: "default" and "preparation-related." The "default" connectivity was present not only during task performance, but also during task preparation and during rest. We propose that this sub-network may serve as a core system that allows one to quickly activate cognitive, perceptual and motor systems in response to the relevant stimuli. The "preparation-related" connectivity was present during task preparation and task performance, but not at rest, and depended on the n-back condition. The role of this sub-network may be to pre-activate a connectivity "road map" in order to establish a top-down and bottom-up regulation of attention prior to performance on WM tasks.

Effective connectivity among the working memory regions during preparation for and during performance of the n-back task.

Directory of Open Access Journals (Sweden)

Anna eManelis

2014-08-01

Full Text Available Recent neuroimaging studies have shown that working memory (WM task difficulty can be decoded from patterns of brain activation in the WM network during preparation to perform those tasks. The inter-regional connectivity among the WM regions during task preparation has not yet been investigated. We examined this question using the graph modeling methods IMaGES and LOFS, applied to the previously published fMRI data of Manelis and Reder (2013. In that study, subjects performed 1-, 2-, and 3-back tasks. Each block of n-back was preceded by a preparation period and followed by a rest period. The analyses of task-related brain activity identified a network of 18 regions that increased in activation from 1- to 3-back (Increase network and a network of 17 regions that decreased in activation from 1- to 3-back (Decrease network. The graph analyses revealed two types of connectivity sub-networks within the Increase and Decrease networks: default and preparation-related. The default connectivity was present not only during task performance, but also during task preparation and during rest. We propose that this sub-network may serve as a core system that allows one to quickly activate cognitive, perceptual and motor systems in response to the relevant stimuli. The preparation-related connectivity was present during task preparation and task performance, but not at rest, and depended on the n-back condition. The role of this sub-network may be to pre-activate a connectivity road map in order to establish a top-down and bottom-up regulation of attention prior to performance on WM tasks.

Changes in behavioural responses to infrastructure affect local and regional connectivity – a simulation study on pond breeding amphibians

DEFF Research Database (Denmark)

Pontoppidan, Maj-Britt; Nachman, Gøsta Støger

2013-01-01

An extensive and expanding infrastructural network destroys and fragments natural habitat and has detrimental effect on abundance and population viability of many amphibian species. Roads function as barriers in the landscape. They separate local populations from each other or prevent access...... to necessary resources. Therefore, road density and traffic intensity in a region may have severe impact on regional as well as local connectivity. Amphibians may be able to detect and avoid unsuitable habitat. Individuals’ ability to avoid roads can reduce road mortality but at the same time road...... avoidance behaviour, can increase the barrier effect of the road and reduce connectivity. We use an individual based model to explore how changes in road mortality and road avoidance behaviour affect local and regional connectivity in a population of Moor frogs (Rana arvalis). The results indicate that road...

Inverse Effects on Gating and Modulation Caused by a Mutation in the M2-M3 Linker of the GABAA Receptor γ SubunitS⃞

OpenAIRE

O'Shea, Sean M.; Williams, Carrie A.; Jenkins, Andrew

2009-01-01

M2-M3 linkers are receptor subunit domains known to be critical for the normal function of cysteine-loop ligand-gated ion channels. Previous studies of α and β subunits of type “A” GABA receptors suggest that these linkers couple extracellular elements involved in GABA binding to the transmembrane segments that control the opening of the ion channel. To study the importance of the γ subunit M2-M3 linker, we examined the macroscopic and single-channel effects of an engi...

Connecting to Regional Markets?

DEFF Research Database (Denmark)

Coulibaly, Souleymane; Thomsen, Lotte

2016-01-01

Central Asian food processors face a number of constraints when they attempt to export to the region and beyond. The Central Asian economies in focus here are landlocked, and thus lack easy access to sea transport. In addition, the region's transport network was built to reinforce the interdepend......Central Asian food processors face a number of constraints when they attempt to export to the region and beyond. The Central Asian economies in focus here are landlocked, and thus lack easy access to sea transport. In addition, the region's transport network was built to reinforce...... the interdependence of the then Soviet republics, while conflicting economic interests make cross-border cooperation difficult. Based on extensive fieldwork on infrastructure systems and firm export strategies, this paper identifies contemporary infrastructure and transportation issues within the Central Asian region...

Tinnitus alters resting state functional connectivity (RSFC) in human auditory and non-auditory brain regions as measured by functional near-infrared spectroscopy (fNIRS).

Science.gov (United States)

San Juan, Juan; Hu, Xiao-Su; Issa, Mohamad; Bisconti, Silvia; Kovelman, Ioulia; Kileny, Paul; Basura, Gregory

2017-01-01

Tinnitus, or phantom sound perception, leads to increased spontaneous neural firing rates and enhanced synchrony in central auditory circuits in animal models. These putative physiologic correlates of tinnitus to date have not been well translated in the brain of the human tinnitus sufferer. Using functional near-infrared spectroscopy (fNIRS) we recently showed that tinnitus in humans leads to maintained hemodynamic activity in auditory and adjacent, non-auditory cortices. Here we used fNIRS technology to investigate changes in resting state functional connectivity between human auditory and non-auditory brain regions in normal-hearing, bilateral subjective tinnitus and controls before and after auditory stimulation. Hemodynamic activity was monitored over the region of interest (primary auditory cortex) and non-region of interest (adjacent non-auditory cortices) and functional brain connectivity was measured during a 60-second baseline/period of silence before and after a passive auditory challenge consisting of alternating pure tones (750 and 8000Hz), broadband noise and silence. Functional connectivity was measured between all channel-pairs. Prior to stimulation, connectivity of the region of interest to the temporal and fronto-temporal region was decreased in tinnitus participants compared to controls. Overall, connectivity in tinnitus was differentially altered as compared to controls following sound stimulation. Enhanced connectivity was seen in both auditory and non-auditory regions in the tinnitus brain, while controls showed a decrease in connectivity following sound stimulation. In tinnitus, the strength of connectivity was increased between auditory cortex and fronto-temporal, fronto-parietal, temporal, occipito-temporal and occipital cortices. Together these data suggest that central auditory and non-auditory brain regions are modified in tinnitus and that resting functional connectivity measured by fNIRS technology may contribute to conscious phantom

Tinnitus alters resting state functional connectivity (RSFC in human auditory and non-auditory brain regions as measured by functional near-infrared spectroscopy (fNIRS.

Directory of Open Access Journals (Sweden)

Juan San Juan

Full Text Available Tinnitus, or phantom sound perception, leads to increased spontaneous neural firing rates and enhanced synchrony in central auditory circuits in animal models. These putative physiologic correlates of tinnitus to date have not been well translated in the brain of the human tinnitus sufferer. Using functional near-infrared spectroscopy (fNIRS we recently showed that tinnitus in humans leads to maintained hemodynamic activity in auditory and adjacent, non-auditory cortices. Here we used fNIRS technology to investigate changes in resting state functional connectivity between human auditory and non-auditory brain regions in normal-hearing, bilateral subjective tinnitus and controls before and after auditory stimulation. Hemodynamic activity was monitored over the region of interest (primary auditory cortex and non-region of interest (adjacent non-auditory cortices and functional brain connectivity was measured during a 60-second baseline/period of silence before and after a passive auditory challenge consisting of alternating pure tones (750 and 8000Hz, broadband noise and silence. Functional connectivity was measured between all channel-pairs. Prior to stimulation, connectivity of the region of interest to the temporal and fronto-temporal region was decreased in tinnitus participants compared to controls. Overall, connectivity in tinnitus was differentially altered as compared to controls following sound stimulation. Enhanced connectivity was seen in both auditory and non-auditory regions in the tinnitus brain, while controls showed a decrease in connectivity following sound stimulation. In tinnitus, the strength of connectivity was increased between auditory cortex and fronto-temporal, fronto-parietal, temporal, occipito-temporal and occipital cortices. Together these data suggest that central auditory and non-auditory brain regions are modified in tinnitus and that resting functional connectivity measured by fNIRS technology may contribute to

Novel cross-linkers for PDMS networks for controlled and well distributed grafting of functionalities by click chemistry

DEFF Research Database (Denmark)

Bahrt, Frederikke; Dimitrov, Ivaylo; Daugaard, Anders Egede

2013-01-01

by 35%. The contact angle of PDMS films was increased from 108° to 116° by the introduction of a small poly(pentafluorostyrene) chain. Finally, 17α-ethynyl-1,3,5(10)-estratriene-3,17β-diol and 1-ethynyl-3,5- bis(trifluoromethyl)benzene were incorporated as examples of other functional groups. © 2013......-linkers have been utilized to prepare novel polydimethylsiloxane (PDMS) networks. All functional cross-linkers were successfully incorporated into the networks and were demonstrated to be well distributed within the PDMS films. This was substantiated by fluorescence microscopy of a film prepared with the 4...

Destabilization of the Outer and Inner Mitochondrial Membranes by Core and Linker Histones

Science.gov (United States)

Cascone, Annunziata; Bruelle, Celine; Lindholm, Dan; Bernardi, Paolo; Eriksson, Ove

2012-01-01

Background Extensive DNA damage leads to apoptosis. Histones play a central role in DNA damage sensing and may mediate signals of genotoxic damage to cytosolic effectors including mitochondria. Methodology/Principal Findings We have investigated the effects of histones on mitochondrial function and membrane integrity. We demonstrate that both linker histone H1 and core histones H2A, H2B, H3, and H4 bind strongly to isolated mitochondria. All histones caused a rapid and massive release of the pro-apoptotic intermembrane space proteins cytochrome c and Smac/Diablo, indicating that they permeabilize the outer mitochondrial membrane. In addition, linker histone H1, but not core histones, permeabilized the inner membrane with a collapse of the membrane potential, release of pyridine nucleotides, and mitochondrial fragmentation. Conclusions We conclude that histones destabilize the mitochondrial membranes, a mechanism that may convey genotoxic signals to mitochondria and promote apoptosis following DNA damage. PMID:22523586

Regional homogeneity and resting state functional connectivity: associations with exposure to early life stress.

Science.gov (United States)

Philip, Noah S; Kuras, Yuliya I; Valentine, Thomas R; Sweet, Lawrence H; Tyrka, Audrey R; Price, Lawrence H; Carpenter, Linda L

2013-12-30

Early life stress (ELS) confers risk for psychiatric illness. Previous literature suggests ELS is associated with decreased resting-state functional connectivity (rs-FC) in adulthood, but there are no studies of resting-state neuronal activity in this population. This study investigated whether ELS-exposed individuals demonstrate resting-state activity patterns similar to those found in PTSD. Twenty-seven adults (14 with at least moderate ELS), who were medication-free and without psychiatric or medical illness, underwent MRI scans during two 4-minute rest periods. Resting-state activity was examined using regional homogeneity (ReHo), which estimates regional activation patterns through indices of localized concordance. ReHo values were compared between groups, followed by rs-FC analyses utilizing ReHo-localized areas as seeds to identify other involved regions. Relative to controls, ELS subjects demonstrated diminished ReHo in the inferior parietal lobule (IPL) and superior temporal gyrus (STG). ReHo values were inversely correlated with ELS severity. Secondary analyses revealed decreased rs-FC between the IPL and right precuneus/posterior cingulate, left fusiform gyrus, cerebellum and caudate in ELS subjects. These findings indicate that ELS is associated with altered resting-state activity and connectivity in brain regions involved in trauma-related psychiatric disorders. Future studies are needed to evaluate whether these associations represent potential imaging biomarkers of stress exposure. Published by Elsevier Ireland Ltd.

Synthesis of highly fluorescent and thio-linkers stabilize gold quantum dots and nano clusters in DMF for bio-labeling

Energy Technology Data Exchange (ETDEWEB)

Rastogi, Shiva K., E-mail: srastogi@uidaho.edu [University of Idaho, Department of Chemistry (United States); Denn, Benjamin D.; Branen, A. Larry [University of Idaho, Coeur D' Alene, Biosensors and Nanotechnology Application Laboratory (BNAL) (United States)

2012-01-15

This study demonstrates a one versus two-step synthesis of fluorescent gold quantum dots (F-AuQDs) and nano clusters (F-AuNCs) functionalized with thiolated organic linkers using reduction of gold precursor in N,N Prime -dimethylformamide in 1 h of reaction. The F-AuQDs and F-AuNCs show fluorescence emission at 425 {+-} 5 nm upon excitation at 345 {+-} 5 nm of wavelength, with good water solubility and stability. Five different thiolated organic binary linkers consisting of various functional groups including: carboxylic acid, hydroxyl, and aromatic amine, were conjugated with the F-AuQDs and F-AuNCs. The formation mechanism and functionalization of the F-AuQDs and F-AuNCs was characterized using UV-vis absorption spectra, UV-vis light, fluorescent emission spectra, pH, TEM, and FTIR. The fluorescence emission of the F-AuQDs and F-AuNCs is greatly dependent on the thio-linker. This novel one-step approach provides facile and fast synthesis of F-AuQDs and F-AuNCs over the two-step method, with less than 5 h of reaction and workup compared to more than 28 h of reaction for the two-step approach. These thio-linker functionalized F-AuQDs and F-AuNCs have a wide application in fluorescent labeling of biomolecules, optical devices, imaging, energy transfer, and biosensing.

Differential solvation of intrinsically disordered linkers drives the formation of spatially organized droplets in ternary systems of linear multivalent proteins

Science.gov (United States)

Harmon, Tyler S.; Holehouse, Alex S.; Pappu, Rohit V.

2018-04-01

Intracellular biomolecular condensates are membraneless organelles that encompass large numbers of multivalent protein and nucleic acid molecules. The bodies assemble via a combination of liquid–liquid phase separation and gelation. A majority of condensates included multiple components and show multilayered organization as opposed to being well-mixed unitary liquids. Here, we put forward a simple thermodynamic framework to describe the emergence of spatially organized droplets in multicomponent systems comprising of linear multivalent polymers also known as associative polymers. These polymers, which mimic proteins and/or RNA have the architecture of domains or motifs known as stickers that are interspersed by flexible spacers known as linkers. Using a minimalist numerical model for a four-component system, we have identified features of linear multivalent molecules that are necessary and sufficient for generating spatially organized droplets. We show that differences in sequence-specific effective solvation volumes of disordered linkers between interaction domains enable the formation of spatially organized droplets. Molecules with linkers that are preferentially solvated are driven to the interface with the bulk solvent, whereas molecules that have linkers with negligible effective solvation volumes form cores in the core–shell architectures that emerge in the minimalist four-component systems. Our modeling has relevance for understanding the physical determinants of spatially organized membraneless organelles.

Focus Studies of Geographically Connected Countries: Analysis of Regionally Oriented Studies in Political Science Publications 1996-2012

Directory of Open Access Journals (Sweden)

Andreja Petković

2013-01-01

Full Text Available This article studies the focus studies of geographically connected and geographically not connected countries, i.e. regional and comparative regional studies. In the first part of the article, a description of the role and development of this type of studies as a subdiscipline of comparative politics is provided. In the second part, I present the results of quantitative analysis of the content of articles published in the academic journals published or co-published by the Faculty of Political Science, University of Zagreb. The objects of analysis are regional studies of South-East Europe published in the journals. The main goal of this article is to determine which countries in their regional surroundings are researched the most by Croatian political scientists (and other authors who publish such articles in Croatian or English language in those journals, and which countries Croatia is most often compared to. This research has shown that, with regard to studies of the region, Croatian political scientists mostly focus on the countries of the former Yugoslavia.

Resting-state functional connectivity of antero-medial prefrontal cortex sub-regions in major depression and relationship to emotional intelligence.

Science.gov (United States)

Sawaya, Helen; Johnson, Kevin; Schmidt, Matthew; Arana, Ashley; Chahine, George; Atoui, Mia; Pincus, David; George, Mark S; Panksepp, Jaak; Nahas, Ziad

2015-03-05

Major depressive disorder has been associated with abnormal resting-state functional connectivity (FC), especially in cognitive processing and emotional regulation networks. Although studies have found abnormal FC in regions of the default mode network (DMN), no study has investigated the FC of specific regions within the anterior DMN based on cytoarchitectonic subdivisions of the antero-medial pre-frontal cortex (PFC). Studies from different areas in the field have shown regions within the anterior DMN to be involved in emotional intelligence. Although abnormalities in this region have been observed in depression, the relationship between the ventromedial PFC (vmPFC) function and emotional intelligence has yet to be investigated in depressed individuals. Twenty-one medication-free, non-treatment resistant, depressed patients and 21 healthy controls underwent a resting state functional magnetic resonance imaging session. The participants also completed an ability-based measure of emotional intelligence: the Mayer-Salovey-Caruso Emotional Intelligence Test. FC maps of Brodmann areas (BA) 25, 10 m, 10r, and 10p were created and compared between the two groups. Mixed-effects analyses showed that the more anterior seeds encompassed larger areas of the DMN. Compared to healthy controls, depressed patients had significantly lower connectivity between BA10p and the right insula and between BA25 and the perigenual anterior cingulate cortex. Exploratory analyses showed an association between vmPFC connectivity and emotional intelligence. These results suggest that individuals with depression have reduced FC between antero-medial PFC regions and regions involved in emotional regulation compared to control subjects. Moreover, vmPFC functional connectivity appears linked to emotional intelligence. © The Author 2015. Published by Oxford University Press on behalf of CINP.

Multiple-region directed functional connectivity based on phase delays.

Science.gov (United States)

Goelman, Gadi; Dan, Rotem

2017-03-01

Network analysis is increasingly advancing the field of neuroimaging. Neural networks are generally constructed from pairwise interactions with an assumption of linear relations between them. Here, a high-order statistical framework to calculate directed functional connectivity among multiple regions, using wavelet analysis and spectral coherence has been presented. The mathematical expression for 4 regions was derived and used to characterize a quartet of regions as a linear, combined (nonlinear), or disconnected network. Phase delays between regions were used to obtain network's temporal hierarchy and directionality. The validity of the mathematical derivation along with the effects of coupling strength and noise on its outcomes were studied by computer simulations of the Kuramoto model. The simulations demonstrated correct directionality for a large range of coupling strength and low sensitivity to Gaussian noise compared with pairwise coherences. The analysis was applied to resting-state fMRI data of 40 healthy young subjects to characterize the ventral visual system, motor system and default mode network (DMN). It was shown that the ventral visual system was predominantly composed of linear networks while the motor system and the DMN were composed of combined (nonlinear) networks. The ventral visual system exhibits its known temporal hierarchy, the motor system exhibits center ↔ out hierarchy and the DMN has dorsal ↔ ventral and anterior ↔ posterior organizations. The analysis can be applied in different disciplines such as seismology, or economy and in a variety of brain data including stimulus-driven fMRI, electrophysiology, EEG, and MEG, thus open new horizons in brain research. Hum Brain Mapp 38:1374-1386, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Regional homogeneity and functional connectivity patterns in major depressive disorder, cognitive vulnerability to depression and healthy subjects.

Science.gov (United States)

Sun, Hui; Luo, Lizhu; Yuan, Xinru; Zhang, Lu; He, Yini; Yao, Shuqiao; Wang, Jiaojian; Xiao, Jing

2018-08-01

Cognitive vulnerability to depression (CVD) is a high risk for depressive disorder. Recent studies focus on individuals with CVD to determine the neural basis of major depressive disorder (MDD) neuropathology. However, whether CVD showed specific or similar brain functional activity and connectivity patterns, compared to MDD, remain largely unknown. Here, using resting-state functional magnetic resonance imaging in subjects with CVD, healthy controls (HC) and MDD, regional homogeneity (ReHo) and resting-state functional connectivity (R-FC) analyses were conducted to assess local synchronization and changes in functional connectivity patterns. Significant ReHo differences were found in right posterior lobe of cerebellum (PLC), left lingual gyrus (LG) and precuneus. Compared to HC, CVD subjects showed increased ReHo in the PLC, which was similar to the difference found between MDD and HC. Compared to MDD patients, CVD subjects showed decreased ReHo in PLC, LG, and precuneus. R-FC analyses found increased functional connections between LG and left inferior parietal lobule, posterior cingulate cortex, and dorsolateral prefrontal cortex in CVD compared to both HC and MDD. Moreover, Regional mean ReHo values were positively correlated with Center for Epidemiologic Studies Depression Scale scores. These analyses revealed that PLC and functional connections between LG and left inferior parietal lobule, posterior cingulate cortex, and dorsolateral prefrontal cortex may be a potential marker for CVD. Copyright © 2018 Elsevier B.V. All rights reserved.

Substitution of the Lys linker with the β-Ala linker dramatically decreased the renal uptake of 99mTc-labeled Arg-X-Asp-conjugated and X-Ala-Asp-conjugated α-melanocyte stimulating hormone peptides.

Science.gov (United States)

Flook, Adam M; Yang, Jianquan; Miao, Yubin

2014-11-13

The purpose of this study was to examine whether the substitution of the Lys linker with the β-Ala could reduce the renal uptake of (99m)Tc-labeled Arg-X-Asp-conjugated and X-Ala-Asp-conjugated α-melanocyte stimulating hormone (α-MSH) peptides. RSD-β-Ala-(Arg(11))CCMSH (1) {c[Arg-Ser-Asp-dTyr-Asp]-β-Ala-Cys-Cys-Glu-His-dPhe-Arg-Trp-Cys-Arg-Pro-Val-NH2}, RTD-β-Ala-(Arg(11))CCMSH (2), RVD-β-Ala-(Arg(11))CCMSH (3), RAD-β-Ala-(Arg(11))CCMSH (4), NAD-β-Ala-(Arg(11))CCMSH (5), and EAD-β-Ala-(Arg(11))CCMSH (6) peptides were synthesized and evaluated for their melanocortin 1 (MC1) receptor binding affinities in B16/F1 melanoma cells. The biodistribution of their (99m)Tc-conjugates were determined in B16/F1 melanoma-bearing C57 mice. The substitution of the Lys linker with β-Ala linker dramatically reduced the renal uptake of all six (99m)Tc-peptides. (99m)Tc-4 exhibited the highest melanoma uptake (15.66 ± 6.19% ID/g) and the lowest kidney uptake (20.18 ± 3.86% ID/g) among these (99m)Tc-peptides at 2 h postinjection. The B16/F1 melanoma lesions could be clearly visualized by single photon emission computed tomography (SPECT)/CT using (99m)Tc-4 as an imaging probe.

Module discovery by exhaustive search for densely connected, co-expressed regions in biomolecular interaction networks.

Directory of Open Access Journals (Sweden)

Recep Colak

2010-10-01

Full Text Available Computational prediction of functionally related groups of genes (functional modules from large-scale data is an important issue in computational biology. Gene expression experiments and interaction networks are well studied large-scale data sources, available for many not yet exhaustively annotated organisms. It has been well established, when analyzing these two data sources jointly, modules are often reflected by highly interconnected (dense regions in the interaction networks whose participating genes are co-expressed. However, the tractability of the problem had remained unclear and methods by which to exhaustively search for such constellations had not been presented.We provide an algorithmic framework, referred to as Densely Connected Biclustering (DECOB, by which the aforementioned search problem becomes tractable. To benchmark the predictive power inherent to the approach, we computed all co-expressed, dense regions in physical protein and genetic interaction networks from human and yeast. An automatized filtering procedure reduces our output which results in smaller collections of modules, comparable to state-of-the-art approaches. Our results performed favorably in a fair benchmarking competition which adheres to standard criteria. We demonstrate the usefulness of an exhaustive module search, by using the unreduced output to more quickly perform GO term related function prediction tasks. We point out the advantages of our exhaustive output by predicting functional relationships using two examples.We demonstrate that the computation of all densely connected and co-expressed regions in interaction networks is an approach to module discovery of considerable value. Beyond confirming the well settled hypothesis that such co-expressed, densely connected interaction network regions reflect functional modules, we open up novel computational ways to comprehensively analyze the modular organization of an organism based on prevalent and largely

Module discovery by exhaustive search for densely connected, co-expressed regions in biomolecular interaction networks.

Science.gov (United States)

Colak, Recep; Moser, Flavia; Chu, Jeffrey Shih-Chieh; Schönhuth, Alexander; Chen, Nansheng; Ester, Martin

2010-10-25

Computational prediction of functionally related groups of genes (functional modules) from large-scale data is an important issue in computational biology. Gene expression experiments and interaction networks are well studied large-scale data sources, available for many not yet exhaustively annotated organisms. It has been well established, when analyzing these two data sources jointly, modules are often reflected by highly interconnected (dense) regions in the interaction networks whose participating genes are co-expressed. However, the tractability of the problem had remained unclear and methods by which to exhaustively search for such constellations had not been presented. We provide an algorithmic framework, referred to as Densely Connected Biclustering (DECOB), by which the aforementioned search problem becomes tractable. To benchmark the predictive power inherent to the approach, we computed all co-expressed, dense regions in physical protein and genetic interaction networks from human and yeast. An automatized filtering procedure reduces our output which results in smaller collections of modules, comparable to state-of-the-art approaches. Our results performed favorably in a fair benchmarking competition which adheres to standard criteria. We demonstrate the usefulness of an exhaustive module search, by using the unreduced output to more quickly perform GO term related function prediction tasks. We point out the advantages of our exhaustive output by predicting functional relationships using two examples. We demonstrate that the computation of all densely connected and co-expressed regions in interaction networks is an approach to module discovery of considerable value. Beyond confirming the well settled hypothesis that such co-expressed, densely connected interaction network regions reflect functional modules, we open up novel computational ways to comprehensively analyze the modular organization of an organism based on prevalent and largely available large

Optogenetic fMRI and electrophysiological identification of region-specific connectivity between the cerebellar cortex and forebrain.

Science.gov (United States)

Choe, Katrina Y; Sanchez, Carlos F; Harris, Neil G; Otis, Thomas S; Mathews, Paul J

2018-06-01

Complex animal behavior is produced by dynamic interactions between discrete regions of the brain. As such, defining functional connections between brain regions is critical in gaining a full understanding of how the brain generates behavior. Evidence suggests that discrete regions of the cerebellar cortex functionally project to the forebrain, mediating long-range communication potentially important in motor and non-motor behaviors. However, the connectivity map remains largely incomplete owing to the challenge of driving both reliable and selective output from the cerebellar cortex, as well as the need for methods to detect region specific activation across the entire forebrain. Here we utilize a paired optogenetic and fMRI (ofMRI) approach to elucidate the downstream forebrain regions modulated by activating a region of the cerebellum that induces stereotypical, ipsilateral forelimb movements. We demonstrate with ofMRI, that activating this forelimb motor region of the cerebellar cortex results in functional activation of a variety of forebrain and midbrain areas of the brain, including the hippocampus and primary motor, retrosplenial and anterior cingulate cortices. We further validate these findings using optogenetic stimulation paired with multi-electrode array recordings and post-hoc staining for molecular markers of activated neurons (i.e. c-Fos). Together, these findings demonstrate that a single discrete region of the cerebellar cortex is capable of influencing motor output and the activity of a number of downstream forebrain as well as midbrain regions thought to be involved in different aspects of behavior. Copyright © 2018 Elsevier Inc. All rights reserved.

Greenland Subglacial Drainage Evolution Regulated by Weakly Connected Regions of the Bed

Science.gov (United States)

Hoffman, Matthew J.; Andrews, Lauren C.; Price, Stephen F.; Catania, Ginny A.; Neumann, Thomas A.; Luthi, Martin P.; Gulley, Jason; Ryser, Claudia; Hawley, Robert L.; Morriss, Blaine

2016-01-01

Penetration of surface meltwater to the bed of the Greenland Ice Sheet each summer causes an initial increase in ice speed due to elevated basal water pressure, followed by slowdown in late summer that continues into fall and winter. While this seasonal pattern is commonly explained by an evolution of the subglacial drainage system from an inefficient distributed to efficient channelized configuration, mounting evidence indicates that subglacial channels are unable to explain important aspects of hydrodynamic coupling in late summer and fall. Here we use numerical models of subglacial drainage and ice flow to show that limited, gradual leakage of water and lowering of water pressure in weakly connected regions of the bed can explain the dominant features in late and post melt season ice dynamics. These results suggest that a third weakly connected drainage component should be included in the conceptual model of subglacial hydrology.

Functional connectivity and structural covariance between regions of interest can be measured more accurately using multivariate distance correlation.

Science.gov (United States)

Geerligs, Linda; Cam-Can; Henson, Richard N

2016-07-15

Studies of brain-wide functional connectivity or structural covariance typically use measures like the Pearson correlation coefficient, applied to data that have been averaged across voxels within regions of interest (ROIs). However, averaging across voxels may result in biased connectivity estimates when there is inhomogeneity within those ROIs, e.g., sub-regions that exhibit different patterns of functional connectivity or structural covariance. Here, we propose a new measure based on "distance correlation"; a test of multivariate dependence of high dimensional vectors, which allows for both linear and non-linear dependencies. We used simulations to show how distance correlation out-performs Pearson correlation in the face of inhomogeneous ROIs. To evaluate this new measure on real data, we use resting-state fMRI scans and T1 structural scans from 2 sessions on each of 214 participants from the Cambridge Centre for Ageing & Neuroscience (Cam-CAN) project. Pearson correlation and distance correlation showed similar average connectivity patterns, for both functional connectivity and structural covariance. Nevertheless, distance correlation was shown to be 1) more reliable across sessions, 2) more similar across participants, and 3) more robust to different sets of ROIs. Moreover, we found that the similarity between functional connectivity and structural covariance estimates was higher for distance correlation compared to Pearson correlation. We also explored the relative effects of different preprocessing options and motion artefacts on functional connectivity. Because distance correlation is easy to implement and fast to compute, it is a promising alternative to Pearson correlations for investigating ROI-based brain-wide connectivity patterns, for functional as well as structural data. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Preparation and in vivo evaluation of linkers for 211At labeling of humanized anti-Tac

International Nuclear Information System (INIS)

Yordanov, A.T.; Garmestani, K.; Zhang, M.; Zhang, Z.; Yao, Z.; Phillips, K.E.; Herring, B.; Horak, E.; Beitzel, M.P.; Schwarz, U.P.; Gansow, O.A.; Plascjak, P.S.; Eckelman, W.C.; Waldmann, T.A.; Brechbiel, M.W.

2001-01-01

The syntheses, radiolabeling, antibody conjugation, and in vivo evaluation of new linkers for 211 At labeling of humanized anti-Tac (Hu-anti-Tac), an antibody to the α-chain of the IL-2 receptor (IL-2Rα) shown to be a useful target for radioimmunotherapy are described. Synthesis of the organometallic linker precursors is accomplished by reaction of the corresponding bromo- or iodoaryl esters with bis(tributyltin) in the presence of a palladium catalyst. Subsequent conversion to the corresponding N-succinimidyl ester and labeling with 211 At of two new linkers, N-succinimidyl 4-[ 211 At]astato-3-methylbenzoate and N-succinimidyl N-(4-[ 211 At]astatophenethyl)succinamate (SAPS), together with the previously reported N-succinimidyl 4-[ 211 At]astatobenzoate and N-succinimidyl 3-[ 211 At]astato-4-methylbenzoate, are each conjugated to Hu-anti-Tac. The plasma survival times of these conjugates are compared to those of directly iodinated ( 125 I) Hu-anti-Tac. The N-succinimidyl N-(4-[ 211 At]astatophenethyl)succinamate compound (SAPS) emerged from this assay as the most viable candidate for 211 At-labeling of Hu-anti-Tac. SAPS, along with the directly analogous radio-iodinated reagent, N-succinimidyl N-(4-[ 125 I]astatophenethyl)succinamate (SIPS), are evaluated in a biodistribution study along with directly iodinated ( 125 I) Hu-anti-Tac. Blood clearance and biological accretion results indicate that SAPS is a viable candidate for further evaluation for radioimmunotherapy of cancer

Doxorubicin conjugation and drug linker chemistry alter the intravenous and pulmonary pharmacokinetics of a PEGylated Generation 4 polylysine dendrimer in rats.

Science.gov (United States)

Leong, Nathania J; Mehta, Dharmini; McLeod, Victoria M; Kelly, Brian D; Pathak, Rashmi; Owen, David J; Porter, Christopher Jh; Kaminskas, Lisa M

2018-05-28

PEGylated polylysine dendrimers have demonstrated potential as inhalable drug delivery systems that can improve the treatment of lung cancers. Their treatment potential may be enhanced by developing constructs that display prolonged lung retention, together with good systemic absorption, the capacity to passively target lung tumours from the blood and highly selective, yet rapid liberation in the tumour microenvironment. This study sought to characterise how the nature of cathepsin B cleavable peptide linkers, used to conjugate doxorubicin to a PEGylated (PEG570) G4 polylysine dendrimer, affect drug liberation kinetics and intravenous and pulmonary pharmacokinetics in rats. The construct bearing a self-emolative diglycolic acid-V-Citrulline linker exhibited faster doxorubicin release kinetics compared to constructs bearing self emolative diglycolic acid-GLFG, or non-self emolative glutaric acid-GLFG linkers. The V-Citrulline construct exhibited slower plasma clearance, but faster absorption from the lungs than a GLFG construct, although mucociliary clearance and urinary elimination were unchanged. Doxorubicin-conjugation enhanced localisation in the bronchoalveolar lavage fluid compared to lung tissue, suggesting that projection of doxorubicin from the dendrimer surface reduced tissue uptake. These data show that the linker chemistry employed to conjugate drugs to PEGylated carriers can affect drug release profiles and systemic and lung disposition. Copyright © 2018. Published by Elsevier Inc.

Measuring the magnetic connectivity of the geosynchronous region of the magnetosphere

International Nuclear Information System (INIS)

Thomsen, M.; Hones, E.; McComas, D.; Reeves, G.; Weiss, L.

1996-01-01

This is the final report of a three-year, Laboratory-Directed Research and Development (LDRD) project at the Los Alamos National Laboratory (LANL). The purpose of this project was to determine the magnetic connectivity of the geosynchronous region of the magnetosphere to the auroral zone in the polar ionosphere in order to test and refine current magnetospheric magnetic field models. The authors used plasma data from LANL instruments on three geosynchronous satellites and from USAF instruments on three low-altitude, polar-orbiting, DMSP satellites. Magnetic connectivity is tested by comparing plasma energy spectra at DMSP and geosynchronous satellites when they are in near conjunction. The times of closest conjugacy are used to evaluate the field models. They developed the tools for each step of the process and applied them to the study of a one-week test set of conjunctions. They automated the analysis tools and applied them to four months of two-satellite observations. This produced a database of about 130 definitive magnetic conjunctions. They compared this database with the predictions of the widely-used Tsyganenko magnetic field model and showed that in most cases one of the various parameterizations of the model could reproduce the observed field line connection. Further, they explored various measurables (e.g., magnetospheric activity indices or the geosynchronous field orientation) that might point to the appropriate parameterization of the model for these conjunctions, and ultimately, for arbitrary times

Hydrologic connectivity and the contribution of stream headwaters to ecological integrity at regional scales

Science.gov (United States)

Freeman, Mary C.; Pringle, C.M.; Jackson, C.R.

2007-01-01

Cumulatively, headwater streams contribute to maintaining hydrologic connectivity and ecosystem integrity at regional scales. Hydrologic connectivity is the water-mediated transport of matter, energy and organisms within or between elements of the hydrologic cycle. Headwater streams compose over two-thirds of total stream length in a typical river drainage and directly connect the upland and riparian landscape to the rest of the stream ecosystem. Altering headwater streams, e.g., by channelization, diversion through pipes, impoundment and burial, modifies fluxes between uplands and downstream river segments and eliminates distinctive habitats. The large-scale ecological effects of altering headwaters are amplified by land uses that alter runoff and nutrient loads to streams, and by widespread dam construction on larger rivers (which frequently leaves free-flowing upstream portions of river systems essential to sustaining aquatic biodiversity). We discuss three examples of large-scale consequences of cumulative headwater alteration. Downstream eutrophication and coastal hypoxia result, in part, from agricultural practices that alter headwaters and wetlands while increasing nutrient runoff. Extensive headwater alteration is also expected to lower secondary productivity of river systems by reducing stream-system length and trophic subsidies to downstream river segments, affecting aquatic communities and terrestrial wildlife that utilize aquatic resources. Reduced viability of freshwater biota may occur with cumulative headwater alteration, including for species that occupy a range of stream sizes but for which headwater streams diversify the network of interconnected populations or enhance survival for particular life stages. Developing a more predictive understanding of ecological patterns that may emerge on regional scales as a result of headwater alterations will require studies focused on components and pathways that connect headwaters to river, coastal and

Interannual variability in the extent of wetland-stream connectivity within the Prairie Pothole Region

Science.gov (United States)

Melanie Vanderhoof; Laurie Alexander

2016-01-01

The degree of hydrological connectivity between wetland systems and downstream receiving waters can be expected to influence the volume and variability of stream discharge. The Prairie Pothole Region contains a high density of depressional wetland features, a consequence of glacial retreat. Spatial variability in wetland density, drainage evolution, and precipitation...

Rational assembly of nanoparticle superlattices with designed lattice symmetries

Science.gov (United States)

Gang, Oleg; Lu, Fang; Tagawa, Miho

2017-09-05

A method for lattice design via multivalent linkers (LDML) is disclosed that introduces a rationally designed symmetry of connections between particles in order to achieve control over the morphology of their assembly. The method affords the inclusion of different programmable interactions within one linker that allow an assembly of different types of particles. The designed symmetry of connections is preferably provided utilizing DNA encoding. The linkers may include fabricated "patchy" particles, DNA scaffold constructs and Y-shaped DNA linkers, anisotropic particles, which are preferably functionalized with DNA, multimeric protein-DNA complexes, and particles with finite numbers of DNA linkers.

Mixed-linker zeolitic imidazolate framework mixed-matrix membranes for aggressive CO2 separation from natural gas

KAUST Repository

Thompson, Joshua A.; Vaughn, Justin T.; Brunelli, Nicholas A.; Koros, William J.; Jones, Christopher W.; Nair, Sankar

2014-01-01

Zeolitic imidazolate framework (ZIF) materials are a promising subclass of metal-organic frameworks (MOF) for gas separations. However, due to the deleterious effects of gate-opening phenomena associated with organic linker rotation near

Identification of Epithelial-Mesenchymal Transition-related Target Genes Induced by the Mutation of Smad3 Linker Phosphorylation

Science.gov (United States)

Park, Sujin; Yang, Kyung-Min; Park, Yuna; Hong, Eunji; Hong, Chang Pyo; Park, Jinah; Pang, Kyoungwha; Lee, Jihee; Park, Bora; Lee, Siyoung; An, Haein; Kwak, Mi-Kyung; Kim, Junil; Kang, Jin Muk; Kim, Pyunggang; Xiao, Yang; Nie, Guangjun; Ooshima, Akira

2018-01-01

Background Smad3 linker phosphorylation plays essential roles in tumor progression and metastasis. We have previously reported that the mutation of Smad3 linker phosphorylation sites (Smad3-Erk/Pro-directed kinase site mutant constructs [EPSM]) markedly reduced the tumor progression while increasing the lung metastasis in breast cancer. Methods We performed high-throughput RNA-Sequencing of the human prostate cancer cell lines infected with adenoviral Smad3-EPSM to identify the genes regulated by Smad3-EPSM. Results In this study, we identified genes which are differentially regulated in the presence of Smad3-EPSM. We first confirmed that Smad3-EPSM strongly enhanced a capability of cell motility and invasiveness as well as the expression of epithelial-mesenchymal transition marker genes, CDH2, SNAI1, and ZEB1 in response to TGF-β1 in human pancreatic and prostate cancer cell lines. We identified GADD45B, CTGF, and JUNB genes in the expression profiles associated with cell motility and invasiveness induced by the Smad3-EPSM. Conclusions These results suggested that inhibition of Smad3 linker phosphorylation may enhance cell motility and invasiveness by inducing expression of GADD45B, CTGF, and JUNB genes in various cancers. PMID:29629343

Applying circuit theory for corridor expansion and management at regional scales: tiling, pinch points, and omnidirectional connectivity.

Directory of Open Access Journals (Sweden)

David Pelletier

Full Text Available Connectivity models are useful tools that improve the ability of researchers and managers to plan land use for conservation and preservation. Most connectivity models function in a point-to-point or patch-to-patch fashion, limiting their use for assessing connectivity over very large areas. In large or highly fragmented systems, there may be so many habitat patches of interest that assessing connectivity among all possible combinations is prohibitive. To overcome these conceptual and practical limitations, we hypothesized that minor adaptation of the Circuitscape model can allow the creation of omnidirectional connectivity maps illustrating flow paths and variations in the ease of travel across a large study area. We tested this hypothesis in a 24,300 km(2 study area centered on the Montérégie region near Montréal, Québec. We executed the circuit model in overlapping tiles covering the study region. Current was passed across the surface of each tile in orthogonal directions, and then the tiles were reassembled to create directional and omnidirectional maps of connectivity. The resulting mosaics provide a continuous view of connectivity in the entire study area at the full original resolution. We quantified differences between mosaics created using different tile and buffer sizes and developed a measure of the prominence of seams in mosaics formed with this approach. The mosaics clearly show variations in current flow driven by subtle aspects of landscape composition and configuration. Shown prominently in mosaics are pinch points, narrow corridors where organisms appear to be required to traverse when moving through the landscape. Using modest computational resources, these continuous, fine-scale maps of nearly unlimited size allow the identification of movement paths and barriers that affect connectivity. This effort develops a powerful new application of circuit models by pinpointing areas of importance for conservation, broadening the

Landscape connectivity among remnant populations of guanaco (Lama guanicoe Müller, 1776) in an arid region of Chile impacted by global change.

Science.gov (United States)

Espinosa, Mara I; Gouin, Nicolas; Squeo, Francisco A; López, David; Bertin, Angéline

2018-01-01

Connectivity between populations plays a key role in the long-term persistence of species in fragmented habitats. This is of particular concern for biodiversity preservation in drylands, since water limited landscapes are typically characterized by little suitable habitat cover, high habitat fragmentation, harsh matrices, and are being rapidly degraded at a global scale. In this study, we modelled landscape connectivity between 11 guanaco Lama guanicoe populations in Chile's arid Norte Chico, a region that supports the last remnant coastal populations of this emblematic herbivore indigenous to South America. We produced a habitat suitability model to derive a regional surface resistance map, and used circuit theory to map functional connectivity, investigate the relative isolation between populations, and identify those that contribute most to the patch connectivity network. Predicted suitable habitat for L. guanicoe represented about 25% of the study region (i.e., 29,173 km 2 ) and was heterogeneously distributed along a continuous stretch along the Andes, and discontinuous patches along the coast. As a result, we found that high connectivity current flows in the mid and high Andes formed a wide, continuous connectivity corridor, enabling connectivity between all high Andean populations. Coastal populations, in contrast, were more isolated. These groups demonstrate no inter-population connectivity between themselves, only with higher altitude populations, and for two of them, animal movement was linked to the effectiveness of wildlife crossings along the Pan-American highway. Our results indicate that functional connectivity is an issue of concern for L. guanicoe in Chile's Norte Chico, implying that future conservation and management plans should emphasize strategies aimed at conserving functional connectivity between coastal and Andean populations, as well as the protection of habitat patches likely to act as stepping stones within the connectivity network.

Landscape connectivity among remnant populations of guanaco (Lama guanicoe Müller, 1776 in an arid region of Chile impacted by global change

Directory of Open Access Journals (Sweden)

Mara I. Espinosa

2018-03-01

Full Text Available Connectivity between populations plays a key role in the long-term persistence of species in fragmented habitats. This is of particular concern for biodiversity preservation in drylands, since water limited landscapes are typically characterized by little suitable habitat cover, high habitat fragmentation, harsh matrices, and are being rapidly degraded at a global scale. In this study, we modelled landscape connectivity between 11 guanaco Lama guanicoe populations in Chile’s arid Norte Chico, a region that supports the last remnant coastal populations of this emblematic herbivore indigenous to South America. We produced a habitat suitability model to derive a regional surface resistance map, and used circuit theory to map functional connectivity, investigate the relative isolation between populations, and identify those that contribute most to the patch connectivity network. Predicted suitable habitat for L. guanicoe represented about 25% of the study region (i.e., 29,173 km2 and was heterogeneously distributed along a continuous stretch along the Andes, and discontinuous patches along the coast. As a result, we found that high connectivity current flows in the mid and high Andes formed a wide, continuous connectivity corridor, enabling connectivity between all high Andean populations. Coastal populations, in contrast, were more isolated. These groups demonstrate no inter-population connectivity between themselves, only with higher altitude populations, and for two of them, animal movement was linked to the effectiveness of wildlife crossings along the Pan-American highway. Our results indicate that functional connectivity is an issue of concern for L. guanicoe in Chile’s Norte Chico, implying that future conservation and management plans should emphasize strategies aimed at conserving functional connectivity between coastal and Andean populations, as well as the protection of habitat patches likely to act as stepping stones within the

Network performance, hub connectivity potential, and competitive position of primary airports in Asia/Pacific region

NARCIS (Netherlands)

Matsumoto, H.; Veldhuis, J.; de Wit, J.; Burghouwt, G.

2008-01-01

Recently, hub-and-spoke network configurations are more and more developed in the Asia/Pacific region. In this paper, it is argued that the measurement of network performance in hub-and-spoke systems should take into account the quantity and quality of both direct and indirect connections. The

Effects of land use on lake nutrients: The importance of scale, hydrologic connectivity, and region

Science.gov (United States)

Soranno, Patricia A.; Cheruvelil, Kendra Spence; Wagner, Tyler; Webster, Katherine E.; Bremigan, Mary Tate

2015-01-01

Catchment land uses, particularly agriculture and urban uses, have long been recognized as major drivers of nutrient concentrations in surface waters. However, few simple models have been developed that relate the amount of catchment land use to downstream freshwater nutrients. Nor are existing models applicable to large numbers of freshwaters across broad spatial extents such as regions or continents. This research aims to increase model performance by exploring three factors that affect the relationship between land use and downstream nutrients in freshwater: the spatial extent for measuring land use, hydrologic connectivity, and the regional differences in both the amount of nutrients and effects of land use on them. We quantified the effects of these three factors that relate land use to lake total phosphorus (TP) and total nitrogen (TN) in 346 north temperate lakes in 7 regions in Michigan, USA. We used a linear mixed modeling framework to examine the importance of spatial extent, lake hydrologic class, and region on models with individual lake nutrients as the response variable, and individual land use types as the predictor variables. Our modeling approach was chosen to avoid problems of multi-collinearity among predictor variables and a lack of independence of lakes within regions, both of which are common problems in broad-scale analyses of freshwaters. We found that all three factors influence land use-lake nutrient relationships. The strongest evidence was for the effect of lake hydrologic connectivity, followed by region, and finally, the spatial extent of land use measurements. Incorporating these three factors into relatively simple models of land use effects on lake nutrients should help to improve predictions and understanding of land use-lake nutrient interactions at broad scales.

Influence of urban form on landscape pattern and connectivity in metropolitan regions: a comparative case study of Phoenix, AZ, USA, and Izmir, Turkey.

Science.gov (United States)

Park, Sohyun; Hepcan, Çiğdem C; Hepcan, Şerif; Cook, Edward A

2014-10-01

Although ecological connectivity conservation in urban areas has recently been recognized as an important issue, less is known about its relationship to urban form and landscape pattern. This study investigates how urban morphology influences regional ecosystem pattern and landscape connectivity. Two metropolitan landscapes, Phoenix, AZ, USA, and Izmir, Turkey, were compared, both of which are fast-growing regions in their national context. A wide range of variables were considered for identifying natural and urban properties. The natural characteristics include typology of urban ecosystems, urban to natural cover ratio, dominant habitat type, urban biodiversity, landscape context, and connectivity conservation efforts. Urban parameters examine urban form, urban extent, urban cover proportion, growth rate, populations, urban gradient, major drivers of urbanization, urban density, and mode/approach of urban development. Twelve landscape metrics were measured and compared across the natural patches. Results show that there is little difference in landscape connectivity in the rural zones of Phoenix and Izmir, although Phoenix has slightly higher connectivity values. The connectivity variance in urbanized areas, however, is significantly dependent on the region. For example, Phoenix urban zones have substantially lower connectivity than either urban or suburban zones in Izmir. Findings demonstrate that small and compact urban settlements with more dense populations are more likely to conserve landscape connectivity compared to multiple-concentric but amalgamated urban form spreading all over the landscape (aka urban sprawl).

Directing the breathing behavior of pillared-layered metal-organic frameworks via a systematic library of functionalized linkers bearing flexible substituents.

Science.gov (United States)

Henke, Sebastian; Schneemann, Andreas; Wütscher, Annika; Fischer, Roland A

2012-06-06

Flexible metal-organic frameworks (MOFs), also referred to as soft porous crystals (SPCs), show reversible structural transitions dependent on the nature and quantity of adsorbed guest molecules. In recent studies it has been reported that covalent functionalization of the organic linker can influence or even integrate framework flexibility ("breathing") in MOFs. However, rational fine-tuning of such responsive properties is very desirable but challenging as well. Here we present a powerful approach for the targeted manipulation of responsiveness and framework flexibility of an important family of pillared-layered MOFs based on the parent structure [Zn(2)(bdc)(2)(dabco)](n) (bdc = 1,4-benzenedicarboxylate; dabco = 1,4-diazabicyclo[2.2.2]octane). A library of functionalized bdc-type linkers (fu-bdc), which bear additional dangling side groups at different positions of the benzene core (alkoxy groups of varying chain length with diverse functionalities and polarity), was generated. Synthesis of the materials [Zn(2)(fu-bdc)(2)(dabco)](n) yields the respective collection of highly responsive MOFs. The parent MOF is only weakly flexible; however, the substituted frameworks of [Zn(2)(fu-bdc)(2)(dabco)](n) contract drastically upon guest removal and expand again upon adsorption of DMF (N,N-dimethylformamide), EtOH, or CO(2), etc., while N(2) is hardly adsorbed and does not open the narrow-pored form. These "breathing" dynamics are attributed to the dangling side chains that act as immobilized "guests", which interact with mobile guest molecules as well as with themselves and with the framework backbone. The structural details of the guest-free, contracted form and the gas sorption behavior (phase transition pressure, hysteresis loop) are highly dependent on the nature of the substituent at the linker and can therefore be adjusted using our approach. Combining our library of functionalized linkers with the concept of mixed-component MOFs (solid solutions) offers very rich

Synthetic incorporation of Nile Blue into DNA using 2′-deoxyriboside substitutes: Representative comparison of (R- and (S-aminopropanediol as an acyclic linker

Directory of Open Access Journals (Sweden)

Daniel Lachmann

2010-02-01

Full Text Available The Nile Blue chromophore was incorporated into oligonucleotides using “click” chemistry for the postsynthetic modification of oligonucleotides. These were synthesized using DNA building block 3 bearing an alkyne group and reacted with the azide 4. (R-3-amino-1,2-propanediol was applied as the linker between the phosphodiester bridges. Two sets of DNA duplexes were prepared. One set carried the chromophore in an A-T environment, the second set in a G-C environment. Both were characterized by optical spectroscopy. Sequence-dependent fluorescence quenching was applied as a sensitive tool to compare the stacking interactions with respect to the chirality of the acyclic linker attachment. The results were compared to recent results from duplexes that carried the Nile Blue label in a sequentially and structurally identical context, except for the opposite chirality of the linker ((S-3-amino-1,2-propandiol. Only minor, negligible differences were observed. Melting temperatures, UV–vis absorption spectra together with fluorescence quenching data indicate that Nile Blue stacks perfectly between the adjacent base pairs regardless of whether it has been attached via an S- or R-configured linker. This result was supported by geometrically optimized DNA models.

Distinct DNA-binding surfaces in the ATPase and linker domains of MutLγ determine its substrate specificities and exert separable functions in meiotic recombination and mismatch repair.

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Corentin Claeys Bouuaert

2017-05-01

Full Text Available Mlh1-Mlh3 (MutLγ is a mismatch repair factor with a central role in formation of meiotic crossovers, presumably through resolution of double Holliday junctions. MutLγ has DNA-binding, nuclease, and ATPase activities, but how these relate to one another and to in vivo functions are unclear. Here, we combine biochemical and genetic analyses to characterize Saccharomyces cerevisiae MutLγ. Limited proteolysis and atomic force microscopy showed that purified recombinant MutLγ undergoes ATP-driven conformational changes. In vitro, MutLγ displayed separable DNA-binding activities toward Holliday junctions (HJ and, surprisingly, single-stranded DNA (ssDNA, which was not predicted from current models. MutLγ bound DNA cooperatively, could bind multiple substrates simultaneously, and formed higher-order complexes. FeBABE hydroxyl radical footprinting indicated that the DNA-binding interfaces of MutLγ for ssDNA and HJ substrates only partially overlap. Most contacts with HJ substrates were located in the linker regions of MutLγ, whereas ssDNA contacts mapped within linker regions as well as the N-terminal ATPase domains. Using yeast genetic assays for mismatch repair and meiotic recombination, we found that mutations within different DNA-binding surfaces exert separable effects in vivo. For example, mutations within the Mlh1 linker conferred little or no meiotic phenotype but led to mismatch repair deficiency. Interestingly, mutations in the N-terminal domain of Mlh1 caused a stronger meiotic defect than mlh1Δ, suggesting that the mutant proteins retain an activity that interferes with alternative recombination pathways. Furthermore, mlh3Δ caused more chromosome missegregation than mlh1Δ, whereas mlh1Δ but not mlh3Δ partially alleviated meiotic defects of msh5Δ mutants. These findings illustrate functional differences between Mlh1 and Mlh3 during meiosis and suggest that their absence impinges on chromosome segregation not only via reduced

Models of regional habitat quality and connectivity for pumas (Puma concolor) in the southwestern United States.

Science.gov (United States)

Dickson, Brett G; Roemer, Gary W; McRae, Brad H; Rundall, Jill M

2013-01-01

The impact of landscape changes on the quality and connectivity of habitats for multiple wildlife species is of global conservation concern. In the southwestern United States, pumas (Puma concolor) are a well distributed and wide-ranging large carnivore that are sensitive to loss of habitat and to the disruption of pathways that connect their populations. We used an expert-based approach to define and derive variables hypothesized to influence the quality, location, and permeability of habitat for pumas within an area encompassing the entire states of Arizona and New Mexico. Survey results indicated that the presence of woodland and forest cover types, rugged terrain, and canyon bottom and ridgeline topography were expected to be important predictors of both high quality habitat and heightened permeability. As road density, distance to water, or human population density increased, the quality and permeability of habitats were predicted to decline. Using these results, we identified 67 high quality patches across the study area, and applied concepts from electronic circuit theory to estimate regional patterns of connectivity among these patches. Maps of current flow among individual pairs of patches highlighted possible pinch points along two major interstate highways. Current flow summed across all pairs of patches highlighted areas important for keeping the entire network connected, regardless of patch size. Cumulative current flow was highest in Arizona north of the Colorado River and around Grand Canyon National Park, and in the Sky Islands region owing to the many small habitat patches present. Our outputs present a first approximation of habitat quality and connectivity for dispersing pumas in the southwestern United States. Map results can be used to help target finer-scaled analyses in support of planning efforts concerned with the maintenance of puma metapopulation structure, as well as the protection of landscape features that facilitate the dispersal

Models of regional habitat quality and connectivity for pumas (Puma concolor in the southwestern United States.

Directory of Open Access Journals (Sweden)

Brett G Dickson

Full Text Available The impact of landscape changes on the quality and connectivity of habitats for multiple wildlife species is of global conservation concern. In the southwestern United States, pumas (Puma concolor are a well distributed and wide-ranging large carnivore that are sensitive to loss of habitat and to the disruption of pathways that connect their populations. We used an expert-based approach to define and derive variables hypothesized to influence the quality, location, and permeability of habitat for pumas within an area encompassing the entire states of Arizona and New Mexico. Survey results indicated that the presence of woodland and forest cover types, rugged terrain, and canyon bottom and ridgeline topography were expected to be important predictors of both high quality habitat and heightened permeability. As road density, distance to water, or human population density increased, the quality and permeability of habitats were predicted to decline. Using these results, we identified 67 high quality patches across the study area, and applied concepts from electronic circuit theory to estimate regional patterns of connectivity among these patches. Maps of current flow among individual pairs of patches highlighted possible pinch points along two major interstate highways. Current flow summed across all pairs of patches highlighted areas important for keeping the entire network connected, regardless of patch size. Cumulative current flow was highest in Arizona north of the Colorado River and around Grand Canyon National Park, and in the Sky Islands region owing to the many small habitat patches present. Our outputs present a first approximation of habitat quality and connectivity for dispersing pumas in the southwestern United States. Map results can be used to help target finer-scaled analyses in support of planning efforts concerned with the maintenance of puma metapopulation structure, as well as the protection of landscape features that facilitate

Regional connectivity in continental ASEAN

OpenAIRE

Taguchi, Hiroyuki; Nozaki, Kenji

2014-01-01

This chapter examines the issue on Mekong region’s connectivity on quantitative base through the analysis of the gravity trade model and its modified fragmentation model. The main findings are as follows: First, the evolution of international production networks (IPNs) between Thailand and Vietnam as well as the other advanced ASEAN could be identified in terms of their two-way trade integration of machinery parts and components beyond the gravity trade standard. Second, the trade intensity o...

The First MS-Cleavable, Photo-Thiol-Reactive Cross-Linker for Protein Structural Studies

Science.gov (United States)

Iacobucci, Claudio; Piotrowski, Christine; Rehkamp, Anne; Ihling, Christian H.; Sinz, Andrea

2018-04-01

Cleavable cross-linkers are gaining increasing importance for chemical cross-linking/mass spectrometry (MS) as they permit a reliable and automated data analysis in structural studies of proteins and protein assemblies. Here, we introduce 1,3-diallylurea (DAU) as the first CID-MS/MS-cleavable, photo-thiol-reactive cross-linker. DAU is a commercially available, inexpensive reagent that efficiently undergoes an anti-Markovnikov hydrothiolation with cysteine residues in the presence of a radical initiator upon UV-A irradiation. Radical cysteine cross-linking proceeds via an orthogonal "click reaction" and yields stable alkyl sulfide products. DAU reacts at physiological pH and cross-linking reactions with peptides, and proteins can be performed at temperatures as low as 4 °C. The central urea bond is efficiently cleaved upon collisional activation during tandem MS experiments generating characteristic product ions. This improves the reliability of automated cross-link identification. Different radical initiators have been screened for the cross-linking reaction of DAU using the thiol-containing compounds cysteine and glutathione. Our concept has also been exemplified for the biologically relevant proteins bMunc13-2 and retinal guanylyl cyclase-activating protein-2. [Figure not available: see fulltext.

Disturbed Interhemispheric Functional Connectivity Rather than Structural Connectivity in Irritable Bowel Syndrome

Directory of Open Access Journals (Sweden)

Rongfeng Qi

2016-12-01

Full Text Available Neuroimaging studies have demonstrated that irritable bowel syndrome (IBS—a relapsing functional bowel disorder—presents with disrupted brain connections. However, little is known about the alterations of interhemispheric functional connectivity and underlying structural connectivity in IBS. This study combined resting-state functional magnetic resonance imaging (MRI and diffusion tensor imaging (DTI to investigate changes in interhemispheric coordination in IBS patients. Resting-state functional and structural magnetic resonance images were acquired from 65 IBS patients and 67 healthy controls (matched for age, sex and educational level. Interhemispheric voxel-mirrored homotopic connectivity (VMHC was calculated and compared between groups. Homotopic regions showing abnormal VMHC in patients were targeted as regions of interest for analysis of DTI tractography. The fractional anisotropy, fiber number, and fiber length were compared between groups. Statistical analysis was also performed by including anxiety and depression as covariates to evaluate their effect. A Pearson correlation analysis between abnormal interhemispheric connectivity and clinical indices of IBS patients was performed. Compared to healthy controls, IBS patients had higher interhemispheric functional connectivity between bilateral thalami, cuneus, posterior cingulate cortices, lingual gyri and inferior occipital/cerebellum lobes, as well as lower interhemispheric functional connectivity between bilateral ventral anterior cingulate cortices (vACC and inferior parietal lobules (IPL. The inclusion of anxiety and depression as covariates abolished VMHC difference in vACC. Microstructural features of white matter tracts connecting functionally abnormal regions did not reveal any differences between the groups. VMHC values in vACC negatively correlated with the quality of life scores of patients. In conclusion, this study provides preliminary evidence of the disrupted

Ab initio study of hydrogen adsorption on benzenoid linkers in metal-organic framework materials

International Nuclear Information System (INIS)

Gao Yi; Zeng, X C

2007-01-01

We have computed the energies of adsorption of molecular hydrogen on a number of molecular linkers in metal-organic framework solid materials using density functional theory (DFT) and ab initio molecular orbital methods. We find that the hybrid B3LYP (Becke three-parameter Lee-Yang-Parr) DFT method gives a qualitatively incorrect prediction of the hydrogen binding with benzenoid molecular linkers. Both local-density approximation (LDA) and generalized gradient approximation (GGA) DFT methods are inaccurate in predicting the values of hydrogen binding energies, but can give a qualitatively correct prediction of the hydrogen binding. When compared to the more accurate binding-energy results based on the ab initio Moeller-Plesset second-order perturbation (MP2) method, the LDA results may be viewed as an upper limit while the GGA results may be viewed as a lower limit. Since the MP2 calculation is impractical for realistic metal-organic framework systems, the combined LDA and GGA calculations provide a cost-effective way to assess the hydrogen binding capability of these systems

A Small Number of Residues Can Determine if Linker Histones Are Bound On or Off Dyad in the Chromatosome.

Science.gov (United States)

Zhou, Bing-Rui; Feng, Hanqiao; Ghirlando, Rodolfo; Li, Shipeng; Schwieters, Charles D; Bai, Yawen

2016-10-09

Linker histones bind to the nucleosome and regulate the structure and function of chromatin. We have previously shown that the globular domains of chicken H5 and Drosophila H1 linker histones bind to the nucleosome with on- or off-dyad modes, respectively. To explore the determinant for the distinct binding modes, we investigated the binding of a mutant globular domain of H5 to the nucleosome. This mutant, termed GH5_pMut, includes substitutions of five globular domain residues of H5 with the corresponding residues in the globular domain of Drosophila H1. The residues at these five positions play important roles in nucleosome binding by either H5 or Drosophila H1. NMR and spin-labeling experiments showed that GH5_pMut bound to the nucleosome off the dyad. We further found that the nucleosome array condensed by either the GH5_pMut or the globular domain of Drosophila H1 displayed a similar sedimentation coefficient, whereas the same nucleosome array condensed by the wild-type globular domain of H5 showed a much larger sedimentation coefficient. Moreover, NMR and spin-labeling results from the study of the nucleosome in complex with the full-length human linker histone H1.0, whose globular domain shares high sequence conservation with the corresponding globular domain of H5, are consistent with an on-dyad binding mode. Taken together, our results suggest that a small number of residues in the globular domain of a linker histone can control its binding location on the nucleosome and higher-order chromatin structure. Copyright © 2016. Published by Elsevier Ltd.

Using the "K[subscript 5]Connected Cognition Diagram" to Analyze Teachers' Communication and Understanding of Regions in Three-Dimensional Space

Science.gov (United States)

Moore-Russo, Deborah; Viglietti, Janine M.

2012-01-01

This paper reports on a study that introduces and applies the "K[subscript 5]Connected Cognition Diagram" as a lens to explore video data showing teachers' interactions related to the partitioning of regions by axes in a three-dimensional geometric space. The study considers "semiotic bundles" (Arzarello, 2006), introduces "semiotic connections,"…

Micromachined silicon acoustic delay line with 3D-printed micro linkers and tapered input for improved structural stability and acoustic directivity

International Nuclear Information System (INIS)

Cho, Y; Kumar, A; Xu, S; Zou, J

2016-01-01

Recent studies have shown that micromachined silicon acoustic delay lines can provide a promising solution to achieve real-time photoacoustic tomography without the need for complex transducer arrays and data acquisition electronics. To achieve deeper imaging depth and wider field of view, a longer delay time and therefore delay length are required. However, as the length of the delay line increases, it becomes more vulnerable to structural instability due to reduced mechanical stiffness. In this paper, we report the design, fabrication, and testing of a new silicon acoustic delay line enhanced with 3D printed polymer micro linker structures. First, mechanical deformation of the silicon acoustic delay line (with and without linker structures) under gravity was simulated by using finite element method. Second, the acoustic crosstalk and acoustic attenuation caused by the polymer micro linker structures were evaluated with both numerical simulation and ultrasound transmission testing. The result shows that the use of the polymer micro linker structures significantly improves the structural stability of the silicon acoustic delay lines without creating additional acoustic attenuation and crosstalk. In addition, the improvement of the acoustic acceptance angle of the silicon acoustic delay lines was also investigated to better suppress the reception of unwanted ultrasound signals outside of the imaging plane. These two improvements are expected to provide an effective solution to eliminate current limitations on the achievable acoustic delay time and out-of-plane imaging resolution of micromachined silicon acoustic delay line arrays. (paper)

Deforestation and rainfall recycling in Brazil: Is decreased forest cover connectivity associated with decreased rainfall connectivity?

Science.gov (United States)

Adera, S.; Larsen, L.; Levy, M. C.; Thompson, S. E.

2017-12-01

In the Brazilian rainforest-savanna transition zone, deforestation has the potential to significantly affect rainfall by disrupting rainfall recycling, the process by which regional evapotranspiration contributes to regional rainfall. Understanding rainfall recycling in this region is important not only for sustaining Amazon and Cerrado ecosystems, but also for cattle ranching, agriculture, hydropower generation, and drinking water management. Simulations in previous studies suggest complex, scale-dependent interactions between forest cover connectivity and rainfall. For example, the size and distribution of deforested patches has been found to affect rainfall quantity and spatial distribution. Here we take an empirical approach, using the spatial connectivity of rainfall as an indicator of rainfall recycling, to ask: as forest cover connectivity decreased from 1981 - 2015, how did the spatial connectivity of rainfall change in the Brazilian rainforest-savanna transition zone? We use satellite forest cover and rainfall data covering this period of intensive forest cover loss in the region (forest cover from the Hansen Global Forest Change dataset; rainfall from the Climate Hazards Infrared Precipitation with Stations dataset). Rainfall spatial connectivity is quantified using transfer entropy, a metric from information theory, and summarized using network statistics. Networks of connectivity are quantified for paired deforested and non-deforested regions before deforestation (1981-1995) and during/after deforestation (2001-2015). Analyses reveal a decline in spatial connectivity networks of rainfall following deforestation.

Gating mechanism of Kv11.1 (hERG) K+ channels without covalent connection between voltage sensor and pore domains.

Science.gov (United States)

de la Peña, Pilar; Domínguez, Pedro; Barros, Francisco

2018-03-01

Kv11.1 (hERG, KCNH2) is a voltage-gated potassium channel crucial in setting the cardiac rhythm and the electrical behaviour of several non-cardiac cell types. Voltage-dependent gating of Kv11.1 can be reconstructed from non-covalently linked voltage sensing and pore modules (split channels), challenging classical views of voltage-dependent channel activation based on a S4-S5 linker acting as a rigid mechanical lever to open the gate. Progressive displacement of the split position from the end to the beginning of the S4-S5 linker induces an increasing negative shift in activation voltage dependence, a reduced z g value and a more negative ΔG 0 for current activation, an almost complete abolition of the activation time course sigmoid shape and a slowing of the voltage-dependent deactivation. Channels disconnected at the S4-S5 linker near the S4 helix show a destabilization of the closed state(s). Furthermore, the isochronal ion current mode shift magnitude is clearly reduced in the different splits. Interestingly, the progressive modifications of voltage dependence activation gating by changing the split position are accompanied by a shift in the voltage-dependent availability to a methanethiosulfonate reagent of a Cys introduced at the upper S4 helix. Our data demonstrate for the first time that alterations in the covalent connection between the voltage sensor and the pore domains impact on the structural reorganizations of the voltage sensor domain. Also, they support the hypothesis that the S4-S5 linker integrates signals coming from other cytoplasmic domains that constitute either an important component or a crucial regulator of the gating machinery in Kv11.1 and other KCNH channels.

Temporal and spatial patterns of wetland extent influence variability of surface water connectivity in the Prairie Pothole Region, United States

Science.gov (United States)

Vanderhoof, Melanie; Alexander, Laurie C.; Todd, Jason

2016-01-01

Context. Quantifying variability in landscape-scale surface water connectivity can help improve our understanding of the multiple effects of wetlands on downstream waterways. Objectives. We examined how wetland merging and the coalescence of wetlands with streams varied both spatially (among ecoregions) and interannually (from drought to deluge) across parts of the Prairie Pothole Region. Methods. Wetland extent was derived over a time series (1990-2011) using Landsat imagery. Changes in landscape-scale connectivity, generated by the physical coalescence of wetlands with other surface water features, were quantified by fusing static wetland and stream datasets with Landsat-derived wetland extent maps, and related to multiple wetness indices. The usage of Landsat allows for decadal-scale analysis, but limits the types of surface water connections that can be detected. Results. Wetland extent correlated positively with the merging of wetlands and wetlands with streams. Wetness conditions, as defined by drought indices and runoff, were positively correlated with wetland extent, but less consistently correlated with measures of surface water connectivity. The degree of wetland-wetland merging was found to depend less on total wetland area or density, and more on climate conditions, as well as the threshold for how wetland/upland was defined. In contrast, the merging of wetlands with streams was positively correlated with stream density, and inversely related to wetland density. Conclusions. Characterizing the degree of surface water connectivity within the Prairie Pothole Region in North America requires consideration of 1) climate-driven variation in wetness conditions and 2) within-region variation in wetland and stream spatial arrangements.

Yeast linker histone Hho1p is required for efficient RNA polymerase I processivity and transcriptional silencing at the ribosomal DNA

OpenAIRE

Levy, Anat; Eyal, Miri; Hershkovits, Gitit; Salmon-Divon, Mali; Klutstein, Michael; Katcoff, Don Jay

2008-01-01

Nucleosome core particles in eukaryotes are linked by a stretch of DNA that is usually associated with a linker histone. Here, we show in yeast, that the presence of yeast linker histone Hho1p represses expression of a pol II transcribed gene (MET15) embedded in the rDNA. In vivo deletions of Hho1p sequences showed that the second globular domain is sufficient for that repression, whereas the presence of the N terminus is required for its derepression. In contrast, a run-on assay confirmed by...

Disrupted resting-state functional connectivity in minimally treated chronic schizophrenia.

Science.gov (United States)

Wang, Xijin; Xia, Mingrui; Lai, Yunyao; Dai, Zhengjia; Cao, Qingjiu; Cheng, Zhang; Han, Xue; Yang, Lei; Yuan, Yanbo; Zhang, Yong; Li, Keqing; Ma, Hong; Shi, Chuan; Hong, Nan; Szeszko, Philip; Yu, Xin; He, Yong

2014-07-01

The pathophysiology of chronic schizophrenia may reflect long term brain changes related to the disorder. The effect of chronicity on intrinsic functional connectivity patterns in schizophrenia without the potentially confounding effect of antipsychotic medications, however, remains largely unknown. We collected resting-state fMRI data in 21 minimally treated chronic schizophrenia patients and 20 healthy controls. We computed regional functional connectivity strength for each voxel in the brain, and further divided regional functional connectivity strength into short-range regional functional connectivity strength and long-range regional functional connectivity strength. General linear models were used to detect between-group differences in these regional functional connectivity strength metrics and to further systematically investigate the relationship between these differences and clinical/behavioral variables in the patients. Compared to healthy controls, the minimally treated chronic schizophrenia patients showed an overall reduced regional functional connectivity strength especially in bilateral sensorimotor cortex, right lateral prefrontal cortex, left insula and right lingual gyrus, and these regional functional connectivity strength decreases mainly resulted from disruption of short-range regional functional connectivity strength. The minimally treated chronic schizophrenia patients also showed reduced long-range regional functional connectivity strength in the bilateral posterior cingulate cortex/precuneus, and increased long-range regional functional connectivity strength in the right lateral prefrontal cortex and lingual gyrus. Notably, disrupted short-range regional functional connectivity strength mainly correlated with duration of illness and negative symptoms, whereas disrupted long-range regional functional connectivity strength correlated with neurocognitive performance. All of the results were corrected using Monte-Carlo simulation. This

The anatomy of the human medial forebrain bundle: Ventral tegmental area connections to reward-associated subcortical and frontal lobe regions

Directory of Open Access Journals (Sweden)

Volker Arnd Coenen

Full Text Available Introduction: Despite their importance in reward, motivation, and learning there is only sparse anatomical knowledge about the human medial forebrain bundle (MFB and the connectivity of the ventral tegmental area (VTA. A thorough anatomical and microstructural description of the reward related PFC/OFC regions and their connection to the VTA - the superolateral branch of the MFB (slMFB - is however mandatory to enable an interpretation of distinct therapeutic effects from different interventional treatment modalities in neuropsychiatric disorders (DBS, TMS etc.. This work aims at a normative description of the human MFB (and more detailed the slMFB anatomy with respect to distant prefrontal connections and microstructural features. Methods and material: Healthy subjects (n = 55; mean age ± SD, 40 ± 10 years; 32 females underwent high resolution anatomical magnetic resonance imaging including diffusion tensor imaging. Connectivity of the VTA and the resulting slMFB were investigated on the group level using a global tractography approach. The Desikan/Killiany parceling (8 segments of the prefrontal cortex was used to describe sub-segments of the MFB. A qualitative overlap with Brodmann areas was additionally described. Additionally, a pure visual analysis was performed comparing local and global tracking approaches for their ability to fully visualize the slMFB. Results: The MFB could be robustly described both in the present sample as well as in additional control analyses in data from the human connectome project. Most VTA- connections reached the superior frontal gyrus, the middel frontal gyrus and the lateral orbitofrontal region corresponding to Brodmann areas 10, 9, 8, 11, and 11m. The projections to these regions comprised 97% (right and 98% (left of the total relative fiber counts of the slMFB. Discussion: The anatomical description of the human MFB shows far reaching connectivity of VTA to reward-related subcortical and

Cloning of cDNAs coding for the heavy chain region and connecting region of human factor V, a blood coagulation factor with four types of internal repeats

International Nuclear Information System (INIS)

Kane, W.H.; Ichinose, A.; Hagen, F.S.; Davie, E.W.

1987-01-01

Human factor V is a high molecular weight plasma glycoprotein that participates as a cofactor in the conversion of prothrombin to thrombin by factor X/sub a/. Prior to its participation in the coagulation cascade, factor V is converted to factor V/sub a/ by thrombin generating a heavy chain and a light chain, and these two chains are held together by calcium ions. A connecting region originally located between the heavy and light chains is liberated during the activation reaction. In a previous study, a cDNA of 2970 nucleotides that codes for the carboxyl-terminal 938 amino acids of factor V was isolated and characterized from a Hep G2 cDNA library. This cDNA has been used to obtain additional clones from Hep G2 and human liver cDNA libraries. Furthermore, a Hep G2 cDNA library prepared with an oligonucleotide from the 5' end of these cDNAs was screened to obtain overlapping cDNA clones that code for the amino-terminal region of the molecule. The composite sequence of these clones spans 6911 nucleotides and is consistent with the size of the factor V message present in Hep G2 cells (approximately 7 kilobases). The cDNA codes for a leader sequence of 28 amino acids and a mature protein of 2196 amino acids. The amino acid sequence predicted from the cDNA was in complete agreement with 139 amino acid residues that were identified by Edman degradation of cyanogen bromide peptides isolated from the heavy chain region and connecting region of plasma factor V. The domain structure of human factor V is similar to that previously reported for human coagulation factor VIII. Two types of tandem repeats (17 and 9 amino acids) have also been identified in the connecting region of factor V. The present data indicate that the amino acid sequence in the heavy and light chain regions of factor V is ∼ 40% identical with the corresponding regions of factor VIII

Influential factors on debris flow events and hillslope-channel connectivity in Alpine regions: case studies from two Alpine regions in Styria, Austria

Science.gov (United States)

Traper, Sandra; Pöppl, Ronald; Rascher, Eric; Sass, Oliver

2016-04-01

In recent times different types of natural disasters like debris flow events have attracted increasing attention worldwide, since they can cause great damage and loss of infrastructure or even lives is not unusual when it comes to such an event. The engagement with debris flows is especially important in mountainous areas like Austria, since Alpine regions have proved to be particularly prone to the often harmful consequences of such events because of increasing settlement of previously uninhabited regions. Due to those frequently damaging effects of debris flows, research on this kind of natural disaster often focuses on mitigation and recovery measures after an event and on how to restore the initial situation. However, a view on the situation of an area, where severe debris flows recently occurred and are well documented, before the actual event can aid in discovering important preparatory factors that contribute to initiating debris flows and hillslope-channel connectivity in the first place. Valuable insights into the functioning and preconditions of debris flows and their potential connectivity to the main channel can be gained. The study focuses on two geologically different areas in the Austrian Alps, which are both prone to debris flows and have experienced rather severe events recently. Based on data from debris flow events in two regions in Styria (Austria), the Kleinsölk and the Johnsbach valleys, the aim of the study is to identify factors which influence the development of debris flows and the potential of such debris flows to reach the main channel potentially clogging up the river (hillslope-channel connectivity). The degree of hillslope-channel coupling was verified in extensive TLS and ALS surveys, resulting in DEMs of different resolution and spatial extension. Those factors are obtained, analyzed and evaluated with DEM-based GIS- and statistical analyses. These include factors that are attributed to catchment topography, such as slope angle

Exploring the Associations Between Intrinsic Brain Connectivity and Creative Ability Using Functional Connectivity Strength and Connectome Analysis.

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Gao, Zhenni; Zhang, Delong; Liang, Aiying; Liang, Bishan; Wang, Zengjian; Cai, Yuxuan; Li, Junchao; Gao, Mengxia; Liu, Xiaojin; Chang, Song; Jiao, Bingqing; Huang, Ruiwang; Liu, Ming

2017-11-01

The present study aimed to explore the association between resting-state functional connectivity and creativity ability. Toward this end, the figural Torrance Tests of Creative Thinking (TTCT) scores were collected from 180 participants. Based on the figural TTCT measures, we collected resting-state functional magnetic resonance imaging data for participants with two different levels of creativity ability (a high-creativity group [HG, n = 22] and a low-creativity group [LG, n = 20]). For the aspect of group difference, this study combined voxel-wise functional connectivity strength (FCS) and seed-based functional connectivity to identify brain regions with group-change functional connectivity. Furthermore, the connectome properties of the identified regions and their associations with creativity were investigated using the permutation test, discriminative analysis, and brain-behavior correlation analysis. The results indicated that there were 4 regions with group differences in FCS, and these regions were linked to 30 other regions, demonstrating different functional connectivity between the groups. Together, these regions form a creativity-related network, and we observed higher network efficiency in the HG compared with the LG. The regions involved in the creativity network were widely distributed across the modality-specific/supramodality cerebral cortex, subcortex, and cerebellum. Notably, properties of regions in the supramodality networks (i.e., the default mode network and attention network) carried creativity-level discriminative information and were significantly correlated with the creativity performance. Together, these findings demonstrate a link between intrinsic brain connectivity and creative ability, which should provide new insights into the neural basis of creativity.

Cerebro-cerebellar connectivity is increased in primary lateral sclerosis.

Science.gov (United States)

Meoded, Avner; Morrissette, Arthur E; Katipally, Rohan; Schanz, Olivia; Gotts, Stephen J; Floeter, Mary Kay

2015-01-01

Increased functional connectivity in resting state networks was found in several studies of patients with motor neuron disorders, although diffusion tensor imaging studies consistently show loss of white matter integrity. To understand the relationship between structural connectivity and functional connectivity, we examined the structural connections between regions with altered functional connectivity in patients with primary lateral sclerosis (PLS), a long-lived motor neuron disease. Connectivity matrices were constructed from resting state fMRI in 16 PLS patients to identify areas of differing connectivity between patients and healthy controls. Probabilistic fiber tracking was used to examine structural connections between regions of differing connectivity. PLS patients had 12 regions with increased functional connectivity compared to controls, with a predominance of cerebro-cerebellar connections. Increased functional connectivity was strongest between the cerebellum and cortical motor areas and between the cerebellum and frontal and temporal cortex. Fiber tracking detected no difference in connections between regions with increased functional connectivity. We conclude that functional connectivity changes are not strongly based in structural connectivity. Increased functional connectivity may be caused by common inputs, or by reduced selectivity of cortical activation, which could result from loss of intracortical inhibition when cortical afferents are intact.

Enhanced Charge Separation Efficiency in Pyridine-Anchored Phthalocyanine-Sensitized Solar Cells by Linker Elongation.

Science.gov (United States)

Ikeuchi, Takuro; Agrawal, Saurabh; Ezoe, Masayuki; Mori, Shogo; Kimura, Mutsumi

2015-11-01

A series of zinc phthalocyanine sensitizers (PcS22-24) having a pyridine anchoring group are designed and synthesized to investigate the structural dependence on performance in dye-sensitized solar cells. The pyridine-anchor zinc phthalocyanine sensitizer PcS23 shows 79 % incident-photon to current-conversion efficiency (IPCE) and 6.1 % energy conversion efficiency, which are comparable with similar phthalocyanine dyes having a carboxylic acid anchoring group. Based on DFT calculations, the high IPCE is attributed with the mixture of an excited-state molecular orbital of the sensitizer and the orbitals of TiO2 . Between pyridine and carboxylic acid anchor dyes, opposite trends are observed in the linker-length dependence of the IPCE. The red-absorbing PcS23 is applied for co-sensitization with a carboxyl-anchor organic dye D131 that has a complementary spectral response. The site-selective adsorption of PcS23 and D131 on the TiO2 surface results in a panchromatic photocurrent response for the whole visible-light region of sun light. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Identification of unique interactions between the flexible linker and the RecA-like domains of DEAD-box helicase Mss116

International Nuclear Information System (INIS)

Zhang, Yuan; Palla, Mirkó; Liao, Jung-Chi; Sun, Andrew

2013-01-01

DEAD-box RNA helicases are ATP-dependent proteins implicated in nearly all aspects of RNA metabolism. The yeast DEAD-box helicase Mss116 is unique in its functions of splicing group I and group II introns and activating mRNA translation, but the structural understanding of why it performs these unique functions remains unclear. Here we used sequence analysis and molecular dynamics simulation to identify residues in the flexible linker specific for yeast Mss116, potentially associated with its unique functions. We first identified residues that are 100% conserved in Mss116 of different species of the Saccharomycetaceae family. The amino acids of these conserved residues were then compared with the amino acids of the corresponding residue positions of other RNA helicases to identify residues that have distinct amino acids from other DEAD-box proteins. Four residues in the flexible linker, i.e. N334, E335, P336 and H339, are conserved and Mss116-specific. Molecular dynamics simulation was conducted for the wild-type Mss116 structure and mutant models to examine mutational effects of the linker on the conformational equilibrium. Relatively short MD simulation runs (within 20 ns) were enough for us to observe mutational effects, suggesting serious structural perturbations by these mutations. The mutation of E335 depletes the interactions between E335 and K95 in domain 1. The interactions between N334/P336 and N496/I497 of domain 2 are also abolished by mutation. Our results suggest that tight interactions between the Mss116-specific flexible linker and the two RecA-like domains may be mechanically required to crimp RNA for the unique RNA processes of yeast Mss116. (paper)

Identification of unique interactions between the flexible linker and the RecA-like domains of DEAD-box helicase Mss116

Science.gov (United States)

Zhang, Yuan; Palla, Mirkó; Sun, Andrew; Liao, Jung-Chi

2013-09-01

DEAD-box RNA helicases are ATP-dependent proteins implicated in nearly all aspects of RNA metabolism. The yeast DEAD-box helicase Mss116 is unique in its functions of splicing group I and group II introns and activating mRNA translation, but the structural understanding of why it performs these unique functions remains unclear. Here we used sequence analysis and molecular dynamics simulation to identify residues in the flexible linker specific for yeast Mss116, potentially associated with its unique functions. We first identified residues that are 100% conserved in Mss116 of different species of the Saccharomycetaceae family. The amino acids of these conserved residues were then compared with the amino acids of the corresponding residue positions of other RNA helicases to identify residues that have distinct amino acids from other DEAD-box proteins. Four residues in the flexible linker, i.e. N334, E335, P336 and H339, are conserved and Mss116-specific. Molecular dynamics simulation was conducted for the wild-type Mss116 structure and mutant models to examine mutational effects of the linker on the conformational equilibrium. Relatively short MD simulation runs (within 20 ns) were enough for us to observe mutational effects, suggesting serious structural perturbations by these mutations. The mutation of E335 depletes the interactions between E335 and K95 in domain 1. The interactions between N334/P336 and N496/I497 of domain 2 are also abolished by mutation. Our results suggest that tight interactions between the Mss116-specific flexible linker and the two RecA-like domains may be mechanically required to crimp RNA for the unique RNA processes of yeast Mss116.

Radioiodination of protein using 2,3,5,6-tetrafluorophenyl 3-(nido-carboranyl) propionate (TCP) as a potential bi-functional linker: Synthesis and biodistribution in mice

International Nuclear Information System (INIS)

Lin Rushan; Liu Ning; Yang Yuanyou; Li Bing; Liao Jiali; Jin Jiannan

2009-01-01

2,3,5,6-Tetrafluorophenyl 3-(nido-carboranyl) propionate (TCP), as a new potential bi-functional linker for radiohalogenation of proteins or peptides, was synthesized. With this bi-functional linker, the first attempt to conjugate bovine serum albumin (BSA) with 125 I was made and the biodistribution of the conjugated BSA ( 125 I-TCP-BSA) was investigated in NIH strain mice. By the use of TCP as the linker, BSA was conjugated with 125 I in a labeling yield of 58-75% and with radiochemical purity of 99.8% after purification by Sephadex TM G-50. Even after being kept at room temperature for 72 h, the radiochemical purity of 125 I-TCP-BSA was still more than 98%, much higher than that of the directly 125 I-labeled BSA ( 125 I-BSA). Meanwhile, biodistribution experiments in mice indicated that the uptake of 125 I with 125 I-TCP-BSA into thyroid was obviously less than that with 125 I-BSA post-injection. All the results implied that the 125 I-conjugated BSA ( 125 I-TCP-BSA) was considerably stable in vivo as well as in vitro, and TCP was regarded as a promising bi-functional linker for radiohalogenation of proteins

Hybrid Zeolitic Imidazolate Frameworks: Controlling Framework Porosity and Functionality by Mixed-Linker Synthesis

KAUST Repository

Thompson, Joshua A.

2012-05-22

Zeolitic imidazolate frameworks (ZIFs) are a subclass of nanoporous metal-organic frameworks (MOFs) that exhibit zeolite-like structural topologies and have interesting molecular recognition properties, such as molecular sieving and gate-opening effects associated with their pore apertures. The synthesis and characterization of hybrid ZIFs with mixed linkers in the framework are described in this work, producing materials with properties distinctly different from the parent frameworks (ZIF-8, ZIF-90, and ZIF-7). NMR spectroscopy is used to assess the relative amounts of the different linkers included in the frameworks, whereas nitrogen physisorption shows the evolution of the effective pore size distribution in materials resulting from the framework hybridization. X-ray diffraction shows these hybrid materials to be crystalline. In the case of ZIF-8-90 hybrids, the cubic space group of the parent frameworks is continuously maintained, whereas in the case of the ZIF-7-8 hybrids there is a transition from a cubic to a rhombohedral space group. Nitrogen physisorption data reveal that the hybrid materials exhibit substantial changes in gate-opening phenomena, either occurring at continuously tunable partial pressures of nitrogen (ZIF-8-90 hybrids) or loss of gate-opening effects to yield more rigid frameworks (ZIF-7-8 hybrids). With this synthetic approach, significant alterations in MOF properties may be realized to suit a desired separation or catalytic process. © 2012 American Chemical Society.

A Switchable Linker-Based Immunoassay for Ultrasensitive Visible Detection of Salmonella in Tomatoes.

Science.gov (United States)

Hahn, Jungwoo; Kim, Eunghee; You, Young Sang; Gunasekaran, Sundaram; Lim, Seokwon; Choi, Young Jin

2017-10-01

On-site detection for sensitive identification of foodborne pathogens on fresh produce with minimal use of specialized instrumentation is crucial to the food industry. A switchable linker (SL)-based immunoassay was designed for ultrasensitive on-site detection of Salmonella in tomato samples. The assay is based on large-scale aggregation of gold nanoparticles (GNPs), induced by a quantitative relationship among the biotinylated Salmonella polyclonal antibody (b-Ab) used as the SL, the functionalized GNPs, and Salmonella. Important factors such as the concentration of SLs, time required for large-scale aggregation, and selectivity of b-Ab were optimized to minimize the detection time (within 45 min with gentle agitation) and achieve the lowest limit of detection (LOD; 10 CFU/g in tomato samples) possible. This SL-based immunoassay with its relatively low LOD and short detection time may meet the need for rapid, simple, on-site analysis of pathogens in fresh produce. The novel switchable linker-based immunoassay is a rapid, specific, and sensitive method that has potential applications for routine diagnostics of Salmonella in tomato products. These advantages make it a practical approach for general use in the processing industry to detect Salmonella rapidly and to implement appropriate regulatory procedures. Furthermore, it could be applied to other fresh products including cantaloupe, strawberry, and cucumbers. © 2017 Institute of Food Technologists®.

About Connections

Directory of Open Access Journals (Sweden)

Kathleen S Rockland

2015-05-01

Full Text Available Despite the attention attracted by connectomics, one can lose sight of the very real questions concerning What are connections? In the neuroimaging community, structural connectivity is ground truth and underlying constraint on functional or effective connectivity. It is referenced to underlying anatomy; but, as increasingly remarked, there is a large gap between the wealth of human brain mapping and the relatively scant data on actual anatomical connectivity. Moreover, connections have typically been discussed as pairwise, point x projecting to point y (or: to points y and z, or more recently, in graph theoretical terms, as nodes or regions and the interconnecting edges. This is a convenient shorthand, but tends not to capture the richness and nuance of basic anatomical properties as identified in the classic tradition of tracer studies. The present short review accordingly revisits connectional weights, heterogeneity, reciprocity, topography, and hierarchical organization, drawing on concrete examples. The emphasis is on presynaptic long-distance connections, motivated by the intention to probe current assumptions and promote discussions about further progress and synthesis.

Integrity of the Linker of Nucleoskeleton and Cytoskeleton Is Required for Efficient Herpesvirus Nuclear Egress.

Science.gov (United States)

Klupp, Barbara G; Hellberg, Teresa; Granzow, Harald; Franzke, Kati; Dominguez Gonzalez, Beatriz; Goodchild, Rose E; Mettenleiter, Thomas C

2017-10-01

Herpesvirus capsids assemble in the nucleus, while final virion maturation proceeds in the cytoplasm. This requires that newly formed nucleocapsids cross the nuclear envelope (NE), which occurs by budding at the inner nuclear membrane (INM), release of the primary enveloped virion into the perinuclear space (PNS), and subsequent rapid fusion with the outer nuclear membrane (ONM). During this process, the NE remains intact, even at late stages of infection. In addition, the spacing between the INM and ONM is maintained, as is that between the primary virion envelope and nuclear membranes. The linker of nucleoskeleton and cytoskeleton (LINC) complex consists of INM proteins with a luminal SUN (Sad1/UNC-84 homology) domain connected to ONM proteins with a KASH (Klarsicht, ANC-1, SYNE homology) domain and is thought to be responsible for spacing the nuclear membranes. To investigate the role of the LINC complex during herpesvirus infection, we generated cell lines constitutively expressing dominant negative (dn) forms of SUN1 and SUN2. Ultrastructural analyses revealed a significant expansion of the PNS and the contiguous intracytoplasmic lumen, most likely representing endoplasmic reticulum (ER), especially in cells expressing dn-SUN2. After infection, primary virions accumulated in these expanded luminal regions, also very distant from the nucleus. The importance of the LINC complex was also confirmed by reduced progeny virus titers in cells expressing dn-SUN2. These data show that the intact LINC complex is required for efficient nuclear egress of herpesviruses, likely acting to promote fusion of primary enveloped virions with the ONM. IMPORTANCE While the viral factors for primary envelopment of nucleocapsids at the inner nuclear membrane are known to the point of high-resolution structures, the roles of cellular components and regulators remain enigmatic. Furthermore, the machinery responsible for fusion with the outer nuclear membrane is unsolved. We show here

Altered intrinsic and extrinsic connectivity in schizophrenia.

Science.gov (United States)

Zhou, Yuan; Zeidman, Peter; Wu, Shihao; Razi, Adeel; Chen, Cheng; Yang, Liuqing; Zou, Jilin; Wang, Gaohua; Wang, Huiling; Friston, Karl J

2018-01-01

Schizophrenia is a disorder characterized by functional dysconnectivity among distributed brain regions. However, it is unclear how causal influences among large-scale brain networks are disrupted in schizophrenia. In this study, we used dynamic causal modeling (DCM) to assess the hypothesis that there is aberrant directed (effective) connectivity within and between three key large-scale brain networks (the dorsal attention network, the salience network and the default mode network) in schizophrenia during a working memory task. Functional MRI data during an n-back task from 40 patients with schizophrenia and 62 healthy controls were analyzed. Using hierarchical modeling of between-subject effects in DCM with Parametric Empirical Bayes, we found that intrinsic (within-region) and extrinsic (between-region) effective connectivity involving prefrontal regions were abnormal in schizophrenia. Specifically, in patients (i) inhibitory self-connections in prefrontal regions of the dorsal attention network were decreased across task conditions; (ii) extrinsic connectivity between regions of the default mode network was increased; specifically, from posterior cingulate cortex to the medial prefrontal cortex; (iii) between-network extrinsic connections involving the prefrontal cortex were altered; (iv) connections within networks and between networks were correlated with the severity of clinical symptoms and impaired cognition beyond working memory. In short, this study revealed the predominance of reduced synaptic efficacy of prefrontal efferents and afferents in the pathophysiology of schizophrenia.

Demonstration of Improved Charge Transfer in Graphene/Au Nanorods Plasmonic Hybrids Stabilized by Benzyl Thiol Linkers

Directory of Open Access Journals (Sweden)

Giuseppe Valerio Bianco

2016-01-01

Full Text Available Hybrids based on graphene decorated with plasmonic gold (Au nanostructures are being investigated as possible materials combination to add to graphene functionalities of tunable plasmon resonance and enhanced absorption at selected wavelength in the visible-near-infrared region of the spectrum. Here, we report a solution drop-casting approach for fabricating stable hybrids based on chemical vapor deposition (CVD graphene and Au nanorods, which are able to activate effective charge transfer from graphene. We demonstrate that CVD graphene functionalization by benzyl thiol (BZT provides the linker to strong anchoring, via S-Au bonds, Au nanorods to graphene. Optical measurements by spectroscopic ellipsometry give evidence of the introduction of plasmon resonances at 1.85 and 2.25 eV in the Au nanorods/BZT/graphene hybrids, which enable surface enhanced Raman scattering (SERS detection. Furthermore, an effective electron transfer from graphene to Au nanorods, resulting in an enhancement of p-type doping of graphene with a consequent decrease of its sheet resistance, is probed by Raman spectroscopy and corroborated by electrical measurements.

Perfiles Latinoamericanos: Regional sociology, connected sociologies

Directory of Open Access Journals (Sweden)

Nelson Arteaga Botello

2017-07-01

Full Text Available The landscape of sociology published in the 48 numbers of the Perfiles Latinoamericanos magazineis analyzed. The diversity of topics, perspectives, and methodologies of the articles define aseries of fields of reflection around civil society, collective action, subjectivities and social identities,cities, media, violence, and theory. The essay suggests how the sociology that is producedin Latin America is not isolated but connected with international debates. It converges forms ofdoing theory and research with resonances on a global scale.

CD6 and Linker of Activated T Cells are Potential Interaction Partners for T Cell-Specific Adaptor Protein.

Science.gov (United States)

Hem, C D; Ekornhol, M; Granum, S; Sundvold-Gjerstad, V; Spurkland, A

2017-02-01

The T cell-specific adaptor protein (TSAd) contains several protein interaction domains, and is merging as a modulator of T cell activation. Several interaction partners for the TSAd proline-rich region and phosphotyrosines have been identified, including the Src and Tec family kinases lymphocyte-specific protein tyrosine kinase and interleukin 2-inducible T cell kinase. Via its Src homology 2 (SH2) domain, TSAd may thus function as a link between these enzymes and other signalling molecules. However, few binding partners to the TSAd SH2 domain in T cells are hitherto known. Through the use of in silico ligand prediction, peptide spot arrays, pull-down and immunoprecipitation experiments, we here report novel interactions between the TSAd SH2 domain and CD6 phosphotyrosine (pTyr) 629 and linker of activated T cells (LAT) pTyr 171 , pTyr 191 and pTyr 226 . © 2016 The Foundation for the Scandinavian Journal of Immunology.

Dual-purpose linker for alpha helix stabilization and imaging agent conjugation to glucagon-like peptide-1 receptor ligands.

Science.gov (United States)

Zhang, Liang; Navaratna, Tejas; Liao, Jianshan; Thurber, Greg M

2015-02-18

Peptides display many characteristics of efficient imaging agents such as rapid targeting, fast background clearance, and low non-specific cellular uptake. However, poor stability, low affinity, and loss of binding after labeling often preclude their use in vivo. Using glucagon-like peptide-1 receptor (GLP-1R) ligands exendin and GLP-1 as a model system, we designed a novel α-helix-stabilizing linker to simultaneously address these limitations. The stabilized and labeled peptides showed an increase in helicity, improved protease resistance, negligible loss or an improvement in binding affinity, and excellent in vivo targeting. The ease of incorporating azidohomoalanine in peptides and efficient reaction with the dialkyne linker enable this technique to potentially be used as a general method for labeling α helices. This strategy should be useful for imaging beta cells in diabetes research and in developing and testing other peptide targeting agents.

Default network connectivity during a working memory task.

Science.gov (United States)

Bluhm, Robyn L; Clark, C Richard; McFarlane, Alexander C; Moores, Kathryn A; Shaw, Marnie E; Lanius, Ruth A

2011-07-01

The default network exhibits correlated activity at rest and has shown decreased activation during performance of cognitive tasks. There has been little investigation of changes in connectivity of this network during task performance. In this study, we examined task-related modulation of connectivity between two seed regions from the default network posterior cingulated cortex (PCC) and medial prefrontal cortex (mPFC) and the rest of the brain in 12 healthy adults. The purpose was to determine (1) whether connectivity within the default network differs between a resting state and performance of a cognitive (working memory) task and (2) whether connectivity differs between these nodes of the default network and other brain regions, particularly those implicated in cognitive tasks. There was little change in connectivity with the other main areas of the default network for either seed region, but moderate task-related changes in connectivity occurred between seed regions and regions outside the default network. For example, connectivity of the mPFC with the right insula and the right superior frontal gyrus decreased during task performance. Increased connectivity during the working memory task occurred between the PCC and bilateral inferior frontal gyri, and between the mPFC and the left inferior frontal gyrus, cuneus, superior parietal lobule, middle temporal gyrus and cerebellum. Overall, the areas showing greater correlation with the default network seed regions during task than at rest have been previously implicated in working memory tasks. These changes may reflect a decrease in the negative correlations occurring between the default and task-positive networks at rest. Copyright © 2010 Wiley-Liss, Inc.

Corticolimbic functional connectivity in adolescents with bipolar disorder.

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Fei Wang

Full Text Available Convergent evidence supports regional dysfunction within a corticolimbic neural system that subserves emotional processing and regulation in adolescents and adults with bipolar disorder (BD, with abnormalities prominent within the amygdala and its major anterior paralimbic cortical connection sites including ventral anterior cingulate, orbitofrontal, insular and temporopolar cortices. Recent studies of adults with BD demonstrate abnormalities in the functional connectivity between the amygdala and anterior paralimbic regions suggesting an important role for the connections between these regions in the development of the disorder. This study tests the hypothesis that these functional connectivity abnormalities are present in adolescents with BD. Fifty-seven adolescents, twenty-one with BD and thirty-six healthy comparison (HC adolescents, participated in functional magnetic resonance imaging while processing emotional face stimuli. The BD and HC groups were compared in the strength of functional connectivity from amygdala to the anterior paralimbic cortical regions, and explored in remaining brain regions. Functional connectivity was decreased in the BD group, compared to the HC group, during processing of emotional faces in ventral anterior cingulate (VACC, orbitofrontal, insular and temporopolar cortices (p<0.005. Orbitofrontal and VACC findings for the happy condition, and additionally right insula for the neutral condition, survived multiple comparison correction. Exploratory analyses did not reveal additional regions of group differences. This study provides evidence for decreased functional connectivity between the amygdala and anterior paralimbic cortices in adolescents with BD. This suggests that amygdala-anterior paralimbic connectivity abnormalities are early features of BD that emerge at least by adolescence in the disorder.

Decreased Cerebellar-Orbitofrontal Connectivity Correlates with Stuttering Severity: Whole-Brain Functional and Structural Connectivity Associations with Persistent Developmental Stuttering.

Science.gov (United States)

Sitek, Kevin R; Cai, Shanqing; Beal, Deryk S; Perkell, Joseph S; Guenther, Frank H; Ghosh, Satrajit S

2016-01-01

Persistent developmental stuttering is characterized by speech production disfluency and affects 1% of adults. The degree of impairment varies widely across individuals and the neural mechanisms underlying the disorder and this variability remain poorly understood. Here we elucidate compensatory mechanisms related to this variability in impairment using whole-brain functional and white matter connectivity analyses in persistent developmental stuttering. We found that people who stutter had stronger functional connectivity between cerebellum and thalamus than people with fluent speech, while stutterers with the least severe symptoms had greater functional connectivity between left cerebellum and left orbitofrontal cortex (OFC). Additionally, people who stutter had decreased functional and white matter connectivity among the perisylvian auditory, motor, and speech planning regions compared to typical speakers, but greater functional connectivity between the right basal ganglia and bilateral temporal auditory regions. Structurally, disfluency ratings were negatively correlated with white matter connections to left perisylvian regions and to the brain stem. Overall, we found increased connectivity among subcortical and reward network structures in people who stutter compared to controls. These connections were negatively correlated with stuttering severity, suggesting the involvement of cerebellum and OFC may underlie successful compensatory mechanisms by more fluent stutterers.

Decreased Cerebellar-Orbitofrontal Connectivity Correlates with Stuttering Severity: Whole-Brain Functional and Structural Connectivity Associations with Persistent Developmental Stuttering

Science.gov (United States)

Sitek, Kevin R.; Cai, Shanqing; Beal, Deryk S.; Perkell, Joseph S.; Guenther, Frank H.; Ghosh, Satrajit S.

2016-01-01

Persistent developmental stuttering is characterized by speech production disfluency and affects 1% of adults. The degree of impairment varies widely across individuals and the neural mechanisms underlying the disorder and this variability remain poorly understood. Here we elucidate compensatory mechanisms related to this variability in impairment using whole-brain functional and white matter connectivity analyses in persistent developmental stuttering. We found that people who stutter had stronger functional connectivity between cerebellum and thalamus than people with fluent speech, while stutterers with the least severe symptoms had greater functional connectivity between left cerebellum and left orbitofrontal cortex (OFC). Additionally, people who stutter had decreased functional and white matter connectivity among the perisylvian auditory, motor, and speech planning regions compared to typical speakers, but greater functional connectivity between the right basal ganglia and bilateral temporal auditory regions. Structurally, disfluency ratings were negatively correlated with white matter connections to left perisylvian regions and to the brain stem. Overall, we found increased connectivity among subcortical and reward network structures in people who stutter compared to controls. These connections were negatively correlated with stuttering severity, suggesting the involvement of cerebellum and OFC may underlie successful compensatory mechanisms by more fluent stutterers. PMID:27199712

Decreased cerebellar-orbitofrontal connectivity correlates with stuttering severity: Whole-brain functional and structural connectivity associations with persistent developmental stuttering

Directory of Open Access Journals (Sweden)

Kevin Richard Sitek

2016-05-01

Full Text Available Persistent developmental stuttering is characterized by speech production disfluency and affects 1% of adults. The degree of impairment varies widely across individuals and the neural mechanisms underlying the disorder and this variability remain poorly understood. Here, we elucidate compensatory mechanisms related to this variability in impairment using whole-brain functional and white matter connectivity analyses in persistent developmental stuttering. We found that people who stutter had stronger functional connectivity between cerebellum and thalamus than people with fluent speech, while stutterers with the least severe symptoms had greater functional connectivity between left cerebellum and left orbitofrontal cortex. Additionally, people who stutter had decreased functional and white matter connectivity among the perisylvian auditory, motor, and speech planning regions compared to typical speakers, but greater functional connectivity between the right basal ganglia and bilateral temporal auditory regions. Structurally, disfluency ratings were negatively correlated with white matter connections to left perisylvian regions and to the brain stem. Overall, we found increased connectivity among subcortical and reward network structures in people who stutter compared to controls. These connections were negatively correlated with stuttering severity, suggesting the involvement of cerebellum and orbitofrontal cortex may underlie successful compensatory mechanisms by more fluent stutterers.

Intrinsic Connections of the Core Auditory Cortical Regions and Rostral Supratemporal Plane in the Macaque Monkey.

Science.gov (United States)

Scott, Brian H; Leccese, Paul A; Saleem, Kadharbatcha S; Kikuchi, Yukiko; Mullarkey, Matthew P; Fukushima, Makoto; Mishkin, Mortimer; Saunders, Richard C

2017-01-01

In the ventral stream of the primate auditory cortex, cortico-cortical projections emanate from the primary auditory cortex (AI) along 2 principal axes: one mediolateral, the other caudorostral. Connections in the mediolateral direction from core, to belt, to parabelt, have been well described, but less is known about the flow of information along the supratemporal plane (STP) in the caudorostral dimension. Neuroanatomical tracers were injected throughout the caudorostral extent of the auditory core and rostral STP by direct visualization of the cortical surface. Auditory cortical areas were distinguished by SMI-32 immunostaining for neurofilament, in addition to established cytoarchitectonic criteria. The results describe a pathway comprising step-wise projections from AI through the rostral and rostrotemporal fields of the core (R and RT), continuing to the recently identified rostrotemporal polar field (RTp) and the dorsal temporal pole. Each area was strongly and reciprocally connected with the areas immediately caudal and rostral to it, though deviations from strictly serial connectivity were observed. In RTp, inputs converged from core, belt, parabelt, and the auditory thalamus, as well as higher order cortical regions. The results support a rostrally directed flow of auditory information with complex and recurrent connections, similar to the ventral stream of macaque visual cortex. Published by Oxford University Press 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US.

Regional scheme for the connection to the grid of renewable energies: for the Hauts-de-France region, for the Nord-Pas-de-Calais region, for the Picardy region, the Alsace region, the Aquitaine region, the Auvergne region, the Lower-Normandy region, the Burgundy region, the Brittany region, the Centre-Val-de-Loire region, the Champagne-Ardennes region, the Franche-Comte region, the Upper Normandy region, the Ile-de-France region, the Languedoc-Roussillon region, the Lorraine region, the Midi-Pyrenees region, the Provence-Alps-Cote d'Azur region, the Pays-de-la-Loire region, the Poitou-Charentes region, the Rhone-Alps region. Technical and financial status of the scheme implementation

International Nuclear Information System (INIS)

2017-01-01

This document gathers reports related to all French regions. Each one addresses the elaboration of the concerned regional scheme of connection of renewable energies to the distribution network (French acronym: S3REnR) which aims at anticipating and planning evolutions of electrical networks which are necessary for the integration of renewable energies. Illustrated by maps, tables and graphs, these reports propose indications of energy production locations, an identification of planned works, a presentation of the concerned region, of its existing grid and projects, an overview of the scheme content (initial status, results of consultations, adopted strategies, planned works), and an overview of the scheme implementation status

Improved diagnostic accuracy of Alzheimer's disease by combining regional cortical thickness and default mode network functional connectivity: Validated in the Alzheimer's disease neuroimaging initiative set

International Nuclear Information System (INIS)

Park, Ji Eun; Park, Bum Woo; Kim, Sang Joon; Kim, Ho Sung; Choi, Choong Gon; Jung, Seung Jung; Oh, Joo Young; Shim, Woo Hyun; Lee, Jae Hong; Roh, Jee Hoon

2017-01-01

To identify potential imaging biomarkers of Alzheimer's disease by combining brain cortical thickness (CThk) and functional connectivity and to validate this model's diagnostic accuracy in a validation set. Data from 98 subjects was retrospectively reviewed, including a study set (n = 63) and a validation set from the Alzheimer's Disease Neuroimaging Initiative (n = 35). From each subject, data for CThk and functional connectivity of the default mode network was extracted from structural T1-weighted and resting-state functional magnetic resonance imaging. Cortical regions with significant differences between patients and healthy controls in the correlation of CThk and functional connectivity were identified in the study set. The diagnostic accuracy of functional connectivity measures combined with CThk in the identified regions was evaluated against that in the medial temporal lobes using the validation set and application of a support vector machine. Group-wise differences in the correlation of CThk and default mode network functional connectivity were identified in the superior temporal (p < 0.001) and supramarginal gyrus (p = 0.007) of the left cerebral hemisphere. Default mode network functional connectivity combined with the CThk of those two regions were more accurate than that combined with the CThk of both medial temporal lobes (91.7% vs. 75%). Combining functional information with CThk of the superior temporal and supramarginal gyri in the left cerebral hemisphere improves diagnostic accuracy, making it a potential imaging biomarker for Alzheimer's disease

Fuzzy Control and Connected Region Marking Algorithm-Based SEM Nanomanipulation

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Dongjie Li

2012-01-01

Full Text Available The interactive nanomanipulation platform is established based on fuzzy control and connected region marking (CRM algorithm in SEM. The 3D virtual nanomanipulation model is developed to make up the insufficiency of the 2D SEM image information, which provides the operator with depth and real-time visual feedback information to guide the manipulation. The haptic device Omega3 is used as the master to control the 3D motion of the nanopositioner in master-slave mode and offer the force sensing to the operator controlled with fuzzy control algorithm. Aiming at sensing of force feedback during the nanomanipulation, the collision detection method of the virtual nanomanipulation model and the force rending model are studied to realize the force feedback of nanomanipulation. The CRM algorithm is introduced to process the SEM image which provides effective position data of the objects for updating the virtual environment (VE, and relevant issues such as calibration and update rate of VE are also discussed. Finally, the performance of the platform is validated by the ZnO nanowire manipulation experiments.

Effective generation of transgenic pigs and mice by linker based sperm-mediated gene transfer.

Directory of Open Access Journals (Sweden)

Shih Ping Yao

2002-04-01

Full Text Available Abstract Background Transgenic animals have become valuable tools for both research and applied purposes. The current method of gene transfer, microinjection, which is widely used in transgenic mouse production, has only had limited success in producing transgenic animals of larger or higher species. Here, we report a linker based sperm-mediated gene transfer method (LB-SMGT that greatly improves the production efficiency of large transgenic animals. Results The linker protein, a monoclonal antibody (mAb C, is reactive to a surface antigen on sperm of all tested species including pig, mouse, chicken, cow, goat, sheep, and human. mAb C is a basic protein that binds to DNA through ionic interaction allowing exogenous DNA to be linked specifically to sperm. After fertilization of the egg, the DNA is shown to be successfully integrated into the genome of viable pig and mouse offspring with germ-line transfer to the F1 generation at a highly efficient rate: 37.5% of pigs and 33% of mice. The integration is demonstrated again by FISH analysis and F2 transmission in pigs. Furthermore, expression of the transgene is demonstrated in 61% (35/57 of transgenic pigs (F0 generation. Conclusions Our data suggests that LB-SMGT could be used to generate transgenic animals efficiently in many different species.

A Dual-Purpose Linker for Alpha Helix Stabilization and Imaging Agent Conjugation to Glucagon-Like Peptide-1 Receptor Ligands

Science.gov (United States)

Zhang, Liang; Navaratna, Tejas; Liao, Jianshan; Thurber, Greg M.

2016-01-01

Peptides display many characteristics of efficient imaging agents such as rapid targeting, fast background clearance, and low non-specific cellular uptake. However, poor stability, low affinity, and loss of binding after labeling often preclude their use in vivo. Using the glucagon-like peptide-1 receptor (GLP-1R) ligands exendin and GLP-1 as a model system, we designed a novel alpha helix stabilizing linker to simultaneously address these limitations. The stabilized and labeled peptides showed an increase in helicity, improved protease resistance, negligible loss or an improvement in binding affinity, and excellent in vivo targeting. The ease of incorporating azidohomoalanine in peptides and efficient reaction with the dialkyne linker enables this technique to potentially be used as a general method for labeling alpha helices. This strategy should be useful for imaging beta cells in diabetes research and in developing and testing other peptide targeting agents. PMID:25594741

Mechanistic Evaluation of Motion in Redox-Driven Rotaxanes Reveals Longer Linkers Hasten Forward Escape's and Hinder Backward Translations

DEFF Research Database (Denmark)

Andersen, S. S.; Share, A. I.; Poulsen, B. L.

2014-01-01

temperatures to provide activation enthalpies (Delta H-double dagger) and entropies (Delta S-double dagger). Longer glycol linkers led to modest increases in the forward escape (t(1/2) = 60 to 69 s); though not because of a diffusive walk. The reduced rate of motion backward depended on folded structures...

Dynamic brain connectivity is a better predictor of PTSD than static connectivity.

Science.gov (United States)

Jin, Changfeng; Jia, Hao; Lanka, Pradyumna; Rangaprakash, D; Li, Lingjiang; Liu, Tianming; Hu, Xiaoping; Deshpande, Gopikrishna

2017-09-01

Using resting-state functional magnetic resonance imaging, we test the hypothesis that subjects with post-traumatic stress disorder (PTSD) are characterized by reduced temporal variability of brain connectivity compared to matched healthy controls. Specifically, we test whether PTSD is characterized by elevated static connectivity, coupled with decreased temporal variability of those connections, with the latter providing greater sensitivity toward the pathology than the former. Static functional connectivity (FC; nondirectional zero-lag correlation) and static effective connectivity (EC; directional time-lagged relationships) were obtained over the entire brain using conventional models. Dynamic FC and dynamic EC were estimated by letting the conventional models to vary as a function of time. Statistical separation and discriminability of these metrics between the groups and their ability to accurately predict the diagnostic label of a novel subject were ascertained using separate support vector machine classifiers. Our findings support our hypothesis that PTSD subjects have stronger static connectivity, but reduced temporal variability of connectivity. Further, machine learning classification accuracy obtained with dynamic FC and dynamic EC was significantly higher than that obtained with static FC and static EC, respectively. Furthermore, results also indicate that the ease with which brain regions engage or disengage with other regions may be more sensitive to underlying pathology than the strength with which they are engaged. Future studies must examine whether this is true only in the case of PTSD or is a general organizing principle in the human brain. Hum Brain Mapp 38:4479-4496, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Regulating repression: roles for the sir4 N-terminus in linker DNA protection and stabilization of epigenetic states.

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Stephanie Kueng

Full Text Available Silent information regulator proteins Sir2, Sir3, and Sir4 form a heterotrimeric complex that represses transcription at subtelomeric regions and homothallic mating type (HM loci in budding yeast. We have performed a detailed biochemical and genetic analysis of the largest Sir protein, Sir4. The N-terminal half of Sir4 is dispensable for SIR-mediated repression of HM loci in vivo, except in strains that lack Yku70 or have weak silencer elements. For HM silencing in these cells, the C-terminal domain (Sir4C, residues 747-1,358 must be complemented with an N-terminal domain (Sir4N; residues 1-270, expressed either independently or as a fusion with Sir4C. Nonetheless, recombinant Sir4C can form a complex with Sir2 and Sir3 in vitro, is catalytically active, and has sedimentation properties similar to a full-length Sir4-containing SIR complex. Sir4C-containing SIR complexes bind nucleosomal arrays and protect linker DNA from nucleolytic digestion, but less effectively than wild-type SIR complexes. Consistently, full-length Sir4 is required for the complete repression of subtelomeric genes. Supporting the notion that the Sir4 N-terminus is a regulatory domain, we find it extensively phosphorylated on cyclin-dependent kinase consensus sites, some being hyperphosphorylated during mitosis. Mutation of two major phosphoacceptor sites (S63 and S84 derepresses natural subtelomeric genes when combined with a serendipitous mutation (P2A, which alone can enhance the stability of either the repressed or active state. The triple mutation confers resistance to rapamycin-induced stress and a loss of subtelomeric repression. We conclude that the Sir4 N-terminus plays two roles in SIR-mediated silencing: it contributes to epigenetic repression by stabilizing the SIR-mediated protection of linker DNA; and, as a target of phosphorylation, it can destabilize silencing in a regulated manner.

Developmental Changes in Brain Network Hub Connectivity in Late Adolescence.

Science.gov (United States)

Baker, Simon T E; Lubman, Dan I; Yücel, Murat; Allen, Nicholas B; Whittle, Sarah; Fulcher, Ben D; Zalesky, Andrew; Fornito, Alex

2015-06-17

The human brain undergoes substantial development throughout adolescence and into early adulthood. This maturational process is thought to include the refinement of connectivity between putative connectivity hub regions of the brain, which collectively form a dense core that enhances the functional integration of anatomically distributed, and functionally specialized, neural systems. Here, we used longitudinal diffusion magnetic resonance imaging to characterize changes in connectivity between 80 cortical and subcortical anatomical regions over a 2 year period in 31 adolescents between the ages of 15 and 19 years. Connectome-wide analysis indicated that only a small subset of connections showed evidence of statistically significant developmental change over the study period, with 8% and 6% of connections demonstrating decreased and increased structural connectivity, respectively. Nonetheless, these connections linked 93% and 90% of the 80 regions, respectively, pointing to a selective, yet anatomically distributed pattern of developmental changes that involves most of the brain. Hub regions showed a distinct tendency to be highly connected to each other, indicating robust "rich-club" organization. Moreover, connectivity between hubs was disproportionately influenced by development, such that connectivity between subcortical hubs decreased over time, whereas frontal-subcortical and frontal-parietal hub-hub connectivity increased over time. These findings suggest that late adolescence is characterized by selective, yet significant remodeling of hub-hub connectivity, with the topological organization of hubs shifting emphasis from subcortical hubs in favor of an increasingly prominent role for frontal hub regions. Copyright © 2015 the authors 0270-6474/15/359078-10$15.00/0.

Altered thalamic functional connectivity in multiple sclerosis

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Liu, Yaou; Liang, Peipeng; Duan, Yunyun; Huang, Jing; Ren, Zhuoqiong; Jia, Xiuqin [Department of Radiology, Xuanwu Hospital, Capital Medical University, Beijing 100053 (China); Dong, Huiqing; Ye, Jing [Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing 100053 (China); Shi, Fu-Dong [Department of Neurology and Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin 300052 (China); Butzkueven, Helmut [Department of Medicine, University of Melbourne, Parkville 3010 (Australia); Li, Kuncheng, E-mail: kunchengli55@gmail.com [Department of Radiology, Xuanwu Hospital, Capital Medical University, Beijing 100053 (China)

2015-04-15

Highlights: •We demonstrated decreased connectivity between thalamus and cortical regions in MS. •Increased intra- and inter-thalamic connectivity was also observed in MS. •The increased functional connectivity is attenuated by increasing disease duration. -- Abstract: Objective: To compare thalamic functional connectivity (FC) in patients with multiple sclerosis (MS) and healthy controls (HC), and correlate these connectivity measures with other MRI and clinical variables. Methods: We employed resting-state functional MRI (fMRI) to examine changes in thalamic connectivity by comparing thirty-five patients with MS and 35 age- and sex-matched HC. Thalamic FC was investigated by correlating low frequency fMRI signal fluctuations in thalamic voxels with voxels in all other brain regions. Additionally thalamic volume fraction (TF), T2 lesion volume (T2LV), EDSS and disease duration were recorded and correlated with the FC changes. Results: MS patients were found to have a significantly lower TF than HC in bilateral thalami. Compared to HC, the MS group showed significantly decreased FC between thalamus and several brain regions including right middle frontal and parahippocampal gyri, and the left inferior parietal lobule. Increased intra- and inter-thalamic FC was observed in the MS group compared to HC. These FC alterations were not correlated with T2LV, thalamic volume or lesions. In the MS group, however, there was a negative correlation between disease duration and inter-thalamic connectivity (r = −0.59, p < 0.001). Conclusion: We demonstrated decreased FC between thalamus and several cortical regions, while increased intra- and inter-thalamic connectivity in MS patients. These complex functional changes reflect impairments and/or adaptations that are independent of T2LV, thalamic volume or presence of thalamic lesions. The negative correlation between disease duration and inter-thalamic connectivity could indicate an adaptive role of thalamus that is

Spatial connections in regional climate model rainfall outputs at different temporal scales: Application of network theory

Science.gov (United States)

Naufan, Ihsan; Sivakumar, Bellie; Woldemeskel, Fitsum M.; Raghavan, Srivatsan V.; Vu, Minh Tue; Liong, Shie-Yui

2018-01-01

Understanding the spatial and temporal variability of rainfall has always been a great challenge, and the impacts of climate change further complicate this issue. The present study employs the concepts of complex networks to study the spatial connections in rainfall, with emphasis on climate change and rainfall scaling. Rainfall outputs (during 1961-1990) from a regional climate model (i.e. Weather Research and Forecasting (WRF) model that downscaled the European Centre for Medium-range Weather Forecasts, ECMWF ERA-40 reanalyses) over Southeast Asia are studied, and data corresponding to eight different temporal scales (6-hr, 12-hr, daily, 2-day, 4-day, weekly, biweekly, and monthly) are analyzed. Two network-based methods are applied to examine the connections in rainfall: clustering coefficient (a measure of the network's local density) and degree distribution (a measure of the network's spread). The influence of rainfall correlation threshold (T) on spatial connections is also investigated by considering seven different threshold levels (ranging from 0.5 to 0.8). The results indicate that: (1) rainfall networks corresponding to much coarser temporal scales exhibit properties similar to that of small-world networks, regardless of the threshold; (2) rainfall networks corresponding to much finer temporal scales may be classified as either small-world networks or scale-free networks, depending upon the threshold; and (3) rainfall spatial connections exhibit a transition phase at intermediate temporal scales, especially at high thresholds. These results suggest that the most appropriate model for studying spatial connections may often be different at different temporal scales, and that a combination of small-world and scale-free network models might be more appropriate for rainfall upscaling/downscaling across all scales, in the strict sense of scale-invariance. The results also suggest that spatial connections in the studied rainfall networks in Southeast Asia are

Surface Water Connectivity, Flow Pathways and Water Level Fluctuation in a Cold Region Deltaic Ecosystem

Science.gov (United States)

Peters, D. L.; Niemann, O.; Skelly, R.; Monk, W. A.; Baird, D. J.

2017-12-01

The Peace-Athabasca Delta (PAD) is a 6000 km2 deltaic floodplain ecosystem of international importance (Wood Buffalo National Park, Ramsar Convention, UNESCO World Heritage, and SWOT satellite water level calibration/validation site). The low-relief floodplain formed at the confluence of the Peace, Athabasca and Birch rivers with Lake Athabasca. More than 1000 wetland and lake basins have varying degrees of connectivity to the main flow system. Hydroperiod and water storage is influenced by ice-jam and open-water inundations and prevailing semi-arid climate that control water drawdown. Prior studies have identified pathways of river-to-wetland floodwater connection and historical water level fluctuation/trends as a key knowledge gaps, limiting our knowledge of deltaic ecosystem status and potential hydroecological responses to climate change and upstream water alterations to flow contributions. To address this knowledge gap, surface elevation mapping of the PAD has been conducted since 2012 using aerial remote sensing Light Detection and Ranging (LiDAR), plus thousands of ground based surface and bathymetric survey points tied to Global Positioning System (GPS) were obtained. The elevation information was used to develop a high resolution digital terrain model to simulate and investigate surface water connectivity. Importantly, the surveyed areas contain a set of wetland monitoring sites where ground-based surface water connectivity, water level/depth, water quality, and aquatic ecology (eg, vegetation, macroinvertebrate and muskrat) have been examined. The goal of this presentation is to present an assessment of: i) surface water fluctuation and connectivity for PAD wetland sites; ii) 40+ year inter-annual hydroperiod reconstruction for a perched basin using a combination of field measurements, remote sensing estimates, and historical documents; and iii) outline an approach to integrate newly available hydro-bio-geophysical information into a novel, multi

Structural connectivity asymmetry in the neonatal brain.

Science.gov (United States)

Ratnarajah, Nagulan; Rifkin-Graboi, Anne; Fortier, Marielle V; Chong, Yap Seng; Kwek, Kenneth; Saw, Seang-Mei; Godfrey, Keith M; Gluckman, Peter D; Meaney, Michael J; Qiu, Anqi

2013-07-15

Asymmetry of the neonatal brain is not yet understood at the level of structural connectivity. We utilized DTI deterministic tractography and structural network analysis based on graph theory to determine the pattern of structural connectivity asymmetry in 124 normal neonates. We tracted white matter axonal pathways characterizing interregional connections among brain regions and inferred asymmetry in left and right anatomical network properties. Our findings revealed that in neonates, small-world characteristics were exhibited, but did not differ between the two hemispheres, suggesting that neighboring brain regions connect tightly with each other, and that one region is only a few paths away from any other region within each hemisphere. Moreover, the neonatal brain showed greater structural efficiency in the left hemisphere than that in the right. In neonates, brain regions involved in motor, language, and memory functions play crucial roles in efficient communication in the left hemisphere, while brain regions involved in emotional processes play crucial roles in efficient communication in the right hemisphere. These findings suggest that even at birth, the topology of each cerebral hemisphere is organized in an efficient and compact manner that maps onto asymmetric functional specializations seen in adults, implying lateralized brain functions in infancy. Copyright © 2013 Elsevier Inc. All rights reserved.

Aberrant brain regional homogeneity and functional connectivity in middle-aged T2DM patients: a resting-state functional MRI study

Directory of Open Access Journals (Sweden)

Daihong Liu

2016-09-01

Full Text Available Type 2 diabetes mellitus (T2DM has been associated with cognitive impairment. However, its neurological mechanism remains elusive. Combining regional homogeneity (ReHo and functional connectivity (FC analyses, the present study aimed to investigate brain functional alterations in middle-aged T2DM patients, which could provide complementary information for the neural substrates underlying T2DM-associated brain dysfunction. Twenty-five T2DM patients and 25 healthy controls were involved in neuropsychological testing and structural and resting-state functional magnetic resonance imaging data acquisition. ReHo analysis was conducted to determine the peak coordinates of brain regions with abnormal local brain activity synchronization. Then, the identified brain regions were considered as seeds, and FC between these brain regions and global voxels was computed. Finally, the potential correlations between the imaging indices and neuropsychological data were also explored. Compared with healthy controls, T2DM patients exhibited higher ReHo values in the anterior cingulate gyrus and lower ReHo in right fusiform gyrus, right precentral gyrus and right medial orbit of the superior frontal gyrus. Considering these areas as seed regions, T2DM patients displayed aberrant FC, mainly in the frontal and parietal lobes. The pattern of FC alterations in T2DM patients was characterized by decreased connectivity and positive to negative or negative to positive converted connectivity. Digital Span Test forward scores revealed significant correlations with the ReHo values of the right precentral gyrus (ρ = 0.527, p = 0.014 and FC between the right fusiform gyrus and middle temporal gyrus (ρ = -0.437, p = 0.048. Our findings suggest that T2DM patients suffer from cognitive dysfunction related to spatially local and remote brain activity synchronization impairment. The patterns of ReHo and FC alterations shed light on the mechanisms underlying T2DM-associated brain

ESTABLISHING A CONNECTION BETWEEN ACTIVE REGION OUTFLOWS AND THE SOLAR WIND: ABUNDANCE MEASUREMENTS WITH EIS/HINODE

International Nuclear Information System (INIS)

Brooks, David H.; Warren, Harry P.

2011-01-01

One of the most interesting discoveries from Hinode is the presence of persistent high-temperature high-speed outflows from the edges of active regions (ARs). EUV imaging spectrometer (EIS) measurements indicate that the outflows reach velocities of 50 km s -1 with spectral line asymmetries approaching 200 km s -1 . It has been suggested that these outflows may lie on open field lines that connect to the heliosphere, and that they could potentially be a significant source of the slow speed solar wind. A direct link has been difficult to establish, however. We use EIS measurements of spectral line intensities that are sensitive to changes in the relative abundance of Si and S as a result of the first ionization potential (FIP) effect, to measure the chemical composition in the outflow regions of AR 10978 over a 5 day period in 2007 December. We find that Si is always enhanced over S by a factor of 3-4. This is generally consistent with the enhancement factor of low FIP elements measured in situ in the slow solar wind by non-spectroscopic methods. Plasma with a slow wind-like composition was therefore flowing from the edge of the AR for at least 5 days. Furthermore, on December 10 and 11, when the outflow from the western side was favorably oriented in the Earth direction, the Si/S ratio was found to match the value measured a few days later by the Advanced Composition Explorer/Solar Wind Ion Composition Spectrometer. These results provide strong observational evidence for a direct connection between the solar wind, and the coronal plasma in the outflow regions.

Hyper-connectivity of functional networks for brain disease diagnosis.

Science.gov (United States)

Jie, Biao; Wee, Chong-Yaw; Shen, Dinggang; Zhang, Daoqiang

2016-08-01

Exploring structural and functional interactions among various brain regions enables better understanding of pathological underpinnings of neurological disorders. Brain connectivity network, as a simplified representation of those structural and functional interactions, has been widely used for diagnosis and classification of neurodegenerative diseases, especially for Alzheimer's disease (AD) and its early stage - mild cognitive impairment (MCI). However, the conventional functional connectivity network is usually constructed based on the pairwise correlation among different brain regions and thus ignores their higher-order relationships. Such loss of high-order information could be important for disease diagnosis, since neurologically a brain region predominantly interacts with more than one other brain regions. Accordingly, in this paper, we propose a novel framework for estimating the hyper-connectivity network of brain functions and then use this hyper-network for brain disease diagnosis. Here, the functional connectivity hyper-network denotes a network where each of its edges representing the interactions among multiple brain regions (i.e., an edge can connect with more than two brain regions), which can be naturally represented by a hyper-graph. Specifically, we first construct connectivity hyper-networks from the resting-state fMRI (R-fMRI) time series by using sparse representation. Then, we extract three sets of brain-region specific features from the connectivity hyper-networks, and further exploit a manifold regularized multi-task feature selection method to jointly select the most discriminative features. Finally, we use multi-kernel support vector machine (SVM) for classification. The experimental results on both MCI dataset and attention deficit hyperactivity disorder (ADHD) dataset demonstrate that, compared with the conventional connectivity network-based methods, the proposed method can not only improve the classification performance, but also help

Structural basis for activation of ZAP-70 by phosphorylation of the SH2-kinase linker.

Science.gov (United States)

Yan, Qingrong; Barros, Tiago; Visperas, Patrick R; Deindl, Sebastian; Kadlecek, Theresa A; Weiss, Arthur; Kuriyan, John

2013-06-01

Serial activation of the tyrosine kinases Lck and ZAP-70 initiates signaling downstream of the T cell receptor. We previously reported the structure of an autoinhibited ZAP-70 variant in which two regulatory tyrosine residues (315 and 319) in the SH2-kinase linker were replaced by phenylalanine. We now present a crystal structure of ZAP-70 in which Tyr 315 and Tyr 319 are not mutated, leading to the recognition of a five-residue sequence register error in the SH2-kinase linker of the original crystallographic model. The revised model identifies distinct roles for these two tyrosines. As seen in a recently reported structure of the related tyrosine kinase Syk, Tyr 315 of ZAP-70 is part of a hydrophobic interface between the regulatory apparatus and the kinase domain, and the integrity of this interface would be lost upon engagement of doubly phosphorylated peptides by the SH2 domains. Tyr 319 is not necessarily dislodged by SH2 engagement, which activates ZAP-70 only ∼5-fold in vitro. In contrast, phosphorylation by Lck activates ZAP-70 ∼100-fold. This difference is due to the ability of Tyr 319 to suppress ZAP-70 activity even when the SH2 domains are dislodged from the kinase domain, providing stringent control of ZAP-70 activity downstream of Lck.

Improving the performance of DomainDiscovery of protein domain boundary assignment using inter-domain linker index

Directory of Open Access Journals (Sweden)

Zomaya Albert Y

2006-12-01

Full Text Available Abstract Background Knowledge of protein domain boundaries is critical for the characterisation and understanding of protein function. The ability to identify domains without the knowledge of the structure – by using sequence information only – is an essential step in many types of protein analyses. In this present study, we demonstrate that the performance of DomainDiscovery is improved significantly by including the inter-domain linker index value for domain identification from sequence-based information. Improved DomainDiscovery uses a Support Vector Machine (SVM approach and a unique training dataset built on the principle of consensus among experts in defining domains in protein structure. The SVM was trained using a PSSM (Position Specific Scoring Matrix, secondary structure, solvent accessibility information and inter-domain linker index to detect possible domain boundaries for a target sequence. Results Improved DomainDiscovery is compared with other methods by benchmarking against a structurally non-redundant dataset and also CASP5 targets. Improved DomainDiscovery achieves 70% accuracy for domain boundary identification in multi-domains proteins. Conclusion Improved DomainDiscovery compares favourably to the performance of other methods and excels in the identification of domain boundaries for multi-domain proteins as a result of introducing support vector machine with benchmark_2 dataset.

Default network connectivity in medial temporal lobe amnesia.

Science.gov (United States)

Hayes, Scott M; Salat, David H; Verfaellie, Mieke

2012-10-17

There is substantial overlap between the brain regions supporting episodic memory and the default network. However, in humans, the impact of bilateral medial temporal lobe (MTL) damage on a large-scale neural network such as the default mode network is unknown. To examine this issue, resting fMRI was performed with amnesic patients and control participants. Seed-based functional connectivity analyses revealed robust default network connectivity in amnesia in cortical default network regions such as medial prefrontal cortex, posterior medial cortex, and lateral parietal cortex, as well as evidence of connectivity to residual MTL tissue. Relative to control participants, decreased posterior cingulate cortex connectivity to MTL and increased connectivity to cortical default network regions including lateral parietal and medial prefrontal cortex were observed in amnesic patients. In contrast, somatomotor network connectivity was intact in amnesic patients, indicating that bilateral MTL lesions may selectively impact the default network. Changes in default network connectivity in amnesia were largely restricted to the MTL subsystem, providing preliminary support from MTL amnesic patients that the default network can be fractionated into functionally and structurally distinct components. To our knowledge, this is the first examination of the default network in amnesia.

The functional connectivity landscape of the human brain.

Directory of Open Access Journals (Sweden)

Bratislav Mišić

Full Text Available Functional brain networks emerge and dissipate over a primarily static anatomical foundation. The dynamic basis of these networks is inter-regional communication involving local and distal regions. It is assumed that inter-regional distances play a pivotal role in modulating network dynamics. Using three different neuroimaging modalities, 6 datasets were evaluated to determine whether experimental manipulations asymmetrically affect functional relationships based on the distance between brain regions in human participants. Contrary to previous assumptions, here we show that short- and long-range connections are equally likely to strengthen or weaken in response to task demands. Additionally, connections between homotopic areas are the most stable and less likely to change compared to any other type of connection. Our results point to a functional connectivity landscape characterized by fluid transitions between local specialization and global integration. This ability to mediate functional properties irrespective of spatial distance may engender a diverse repertoire of cognitive processes when faced with a dynamic environment.

Transnational Connections and Multiple Belongings

DEFF Research Database (Denmark)

Galal, Lise Paulsen; Sparre, Sara Cathrine Lei

With the purpose of presenting DIMECCE key findings, we in this paper present different aspects, potentials and challenges related to the Middle Eastern Christians transnational connections and multiple belonging. We distinguish between individual transnational connections and practices, such as ......, such as family relations, churches as transnational – or global – institutions, and other organisations and associations established to support politically, socially or culturally connections and development in the country or region of origin....

Plankton community structure and connectivity in the Kimberley-Browse region of NW Australia

Science.gov (United States)

McKinnon, A. D.; Duggan, S.; Holliday, D.; Brinkman, R.

2015-02-01

We describe the zooplankton and ichthyoplankton communities of coastal waters of the Kimberley coast (North West Australia), sampled in macrotidal Camden Sound during both the wet and dry seasons of 2011, and compare these to six other Kimberley embayments during the wet season of 2013. Zooplankton abundance in Camden Sound was 7038 ± 3913 SD ind. m-3 in the wet season and 1892 ± 708 SD ind. m-3 in the dry season, with copepods accounting for 85% by number. In all, 78 species of copepods were recorded, with the families Paracalanidae and Oithonidae dominant. In Camden Sound, 48 families of larval fish occurred, with ichthyoplankton more abundant in the wet season than the dry season (1.16 ± 0.2 ind. m-3 cf 0.76 ± 0.2 ind. m-3). Larval gobiids (Subfamily Gobiinae) were most abundant, with other common families associated with either pelagic or soft-bottom habitats as adults. Multivariate analyses of both copepod and ichthyoplankton communities demonstrated strong seasonal contrasts, although an along-shelf gradient in copepod community composition was apparent along the embayments sampled in 2013. There was little spatial variation in plankton communities within Camden Sound as a result of the large tidal range (up to 11.7 m, with 2.5 m-1 velocities), although gradients in abundance and composition on cross-shelf transects occurred in the more northern embayments that had a lower tidal range, such as Napier Broome Bay. Copepod communities of the Kimberley-Browse region were placed in regional perspective by multivariate analyses of similar data collected in the eastern Indian Ocean at Scott Reef, in the Arafura Sea and on the southern North West (NW) shelf. The plankton communities of the NW shelf form a series of along-shore metacommunities linked by advection, with weaker cross-shelf connectivity. The presence of the larvae of mesopelagic fishes of the family Myctophidae in coastal waters confirms seasonal cross-shelf connectivity.

Lymphatic transport and lymph node targeting of methotrexate-conjugated PEGylated dendrimers are enhanced by reducing the length of the drug linker or masking interactions with the injection site.

Science.gov (United States)

Ryan, Gemma M; McLeod, Victoria M; Mehta, Dharmini; Kelly, Brian D; Stanislawski, Pauline C; Owen, David J; Kaminskas, Lisa M; Porter, Christopher J H

2017-11-01

Drug conjugation to dendrimer-based delivery systems has been shown to enhance delivery to the lymphatic system after subcutaneous administration. Dendrimer interaction with components of the interstitium at the injection site, however, may prevent drainage from the injection site. The current study sought to vary the length of a linker employed to conjugate methotrexate (MTX) to a PEGylated dendrimer, in an attempt to reduce MTX interaction with interstitial binding sites and enhance lymphatic drainage. Dendrimers with shorter linkers resulted in higher lymphatic drainage, presumably via shielding of interaction sites by the PEG mantle, but were not retained in lymph nodes. Improved drainage of dendrimers with longer linkers was achieved through coadministration with dextran to mask interactions at the injection site while maintaining retention within the node. Enhanced drug exposure to the lymph node has the potential to enhance the treatment of lymph-node resident cancer metastases. Copyright © 2017 Elsevier Inc. All rights reserved.

Auditory and visual connectivity gradients in frontoparietal cortex.

Science.gov (United States)

Braga, Rodrigo M; Hellyer, Peter J; Wise, Richard J S; Leech, Robert

2017-01-01

A frontoparietal network of brain regions is often implicated in both auditory and visual information processing. Although it is possible that the same set of multimodal regions subserves both modalities, there is increasing evidence that there is a differentiation of sensory function within frontoparietal cortex. Magnetic resonance imaging (MRI) in humans was used to investigate whether different frontoparietal regions showed intrinsic biases in connectivity with visual or auditory modalities. Structural connectivity was assessed with diffusion tractography and functional connectivity was tested using functional MRI. A dorsal-ventral gradient of function was observed, where connectivity with visual cortex dominates dorsal frontal and parietal connections, while connectivity with auditory cortex dominates ventral frontal and parietal regions. A gradient was also observed along the posterior-anterior axis, although in opposite directions in prefrontal and parietal cortices. The results suggest that the location of neural activity within frontoparietal cortex may be influenced by these intrinsic biases toward visual and auditory processing. Thus, the location of activity in frontoparietal cortex may be influenced as much by stimulus modality as the cognitive demands of a task. It was concluded that stimulus modality was spatially encoded throughout frontal and parietal cortices, and was speculated that such an arrangement allows for top-down modulation of modality-specific information to occur within higher-order cortex. This could provide a potentially faster and more efficient pathway by which top-down selection between sensory modalities could occur, by constraining modulations to within frontal and parietal regions, rather than long-range connections to sensory cortices. Hum Brain Mapp 38:255-270, 2017. © 2016 Wiley Periodicals, Inc. © 2016 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.

Defective functional connectivity between posterior hypothalamus and regions of the diencephalic-mesencephalic junction in chronic cluster headache.

Science.gov (United States)

Ferraro, Stefania; Nigri, Anna; Bruzzone, Maria Grazia; Brivio, Luca; Proietti Cecchini, Alberto; Verri, Mattia; Chiapparini, Luisa; Leone, Massimo

2018-01-01

Objective We tested the hypothesis of a defective functional connectivity between the posterior hypothalamus and diencephalic-mesencephalic regions in chronic cluster headache based on: a) clinical and neuro-endocrinological findings in cluster headache patients; b) neuroimaging findings during cluster headache attacks; c) neuroimaging findings in drug-refractory chronic cluster headache patients improved after successful deep brain stimulation. Methods Resting state functional magnetic resonance imaging, associated with a seed-based approach, was employed to investigate the functional connectivity of the posterior hypothalamus in chronic cluster headache patients (n = 17) compared to age and sex-matched healthy subjects (n = 16). Random-effect analyses were performed to study differences between patients and controls in ipsilateral and contralateral-to-the-pain posterior hypothalamus functional connectivity. Results Cluster headache patients showed an increased functional connectivity between the ipsilateral posterior hypothalamus and a number of diencephalic-mesencephalic structures, comprising ventral tegmental area, dorsal nuclei of raphe, and bilateral substantia nigra, sub-thalamic nucleus, and red nucleus ( p cluster headache patients mainly involves structures that are part of (i.e. ventral tegmental area, substantia nigra) or modulate (dorsal nuclei of raphe, sub-thalamic nucleus) the midbrain dopaminergic systems. The midbrain dopaminergic systems could play a role in cluster headache pathophysiology and in particular in the chronicization process. Future studies are needed to better clarify if this finding is specific to cluster headache or if it represents an unspecific response to chronic pain.

Microencapsulation of Epoxidized Linseed Oil Liquid Cross-Linker in Poly(N-vinyl-pyrrolidone): Optimization by a Design-of-Experiments Approach

NARCIS (Netherlands)

Senatore, D.; Laven, J.; Benthem, van R.A.T.M.; La Camera, D.; With, de G.

2010-01-01

A liquid cross-linker, epoxidized linseed oil (ELO), was encapsulated in a plastic with a high glass transition temperature (poly(N-vinyl-2-pyrrolidone); PVP). The process parameters of the spray-drying employed were optimized by a Design-of-Experiments (DoE) approach. Three factors concerning both

The ortho backbone amide linker (o-BAL) is an easily prepared and highly acid-labile handle for solid-phase synthesis

DEFF Research Database (Denmark)

Boas, Ulrik; Brask, Jesper; Christensen, J.B.

2002-01-01

The tris(alkoxy)benzyl backbone amide linker (BAL) has found widespread application in solid-phase synthesis. The key intermediate for preparation of para BAL (p-BAL) is 2,6-dimethoxy-4-hydroxybenzaldehyde; several reports on its synthesis have appeared. However, the ortho analogue of the handle (o...

Regional homogeneity, resting-state functional connectivity and amplitude of low frequency fluctuation associated with creativity measured by divergent thinking in a sex-specific manner.

Science.gov (United States)

Takeuchi, Hikaru; Taki, Yasuyuki; Nouchi, Rui; Yokoyama, Ryoichi; Kotozaki, Yuka; Nakagawa, Seishu; Sekiguchi, Atsushi; Iizuka, Kunio; Yamamoto, Yuki; Hanawa, Sugiko; Araki, Tsuyoshi; Makoto Miyauchi, Carlos; Shinada, Takamitsu; Sakaki, Kohei; Nozawa, Takayuki; Ikeda, Shigeyuki; Yokota, Susumu; Daniele, Magistro; Sassa, Yuko; Kawashima, Ryuta

2017-05-15

Brain connectivity is traditionally thought to be important for creativity. Here we investigated the associations of creativity measured by divergent thinking (CMDT) with resting-state functional magnetic imaging (fMRI) measures and their sex differences. We examined these relationships in the brains of 1277 healthy young adults. Whole-brain analyses revealed a significant interaction between verbal CMDT and sex on (a) regional homogeneity within an area from the left anterior temporal lobe (b) on the resting state functional connectivity (RSFC) between the mPFC and the left inferior frontal gyrus and (c) on fractional amplitude of low frequency fluctuations (fALFF) in several distinct areas, including the precuneus and middle cingulate gyrus, left middle temporal gyrus, right middle frontal gyrus, and cerebellum. These interactions were mediated by positive correlations in females and negative correlations in males. These findings suggest that greater CMDT in females is reflected by (a) regional coherence (regional homogeneity) of brain areas responsible for representing and combining concepts as well as (b) the efficient functional connection (RSFC) between the key areas for the default state of cognitive activity and speech production, and (c) greater spontaneous neural activity (fALFF) during the resting of brain areas involved in frontal lobe functions, default cognitive activities, and language functions. Furthermore, these findings suggest that the associations between creativity and resting state brain connectivity patterns are different between males and females. Copyright © 2017 Elsevier Inc. All rights reserved.

Network structure shapes spontaneous functional connectivity dynamics.

Science.gov (United States)

Shen, Kelly; Hutchison, R Matthew; Bezgin, Gleb; Everling, Stefan; McIntosh, Anthony R

2015-04-08

The structural organization of the brain constrains the range of interactions between different regions and shapes ongoing information processing. Therefore, it is expected that large-scale dynamic functional connectivity (FC) patterns, a surrogate measure of coordination between brain regions, will be closely tied to the fiber pathways that form the underlying structural network. Here, we empirically examined the influence of network structure on FC dynamics by comparing resting-state FC (rsFC) obtained using BOLD-fMRI in macaques (Macaca fascicularis) to structural connectivity derived from macaque axonal tract tracing studies. Consistent with predictions from simulation studies, the correspondence between rsFC and structural connectivity increased as the sample duration increased. Regions with reciprocal structural connections showed the most stable rsFC across time. The data suggest that the transient nature of FC is in part dependent on direct underlying structural connections, but also that dynamic coordination can occur via polysynaptic pathways. Temporal stability was found to be dependent on structural topology, with functional connections within the rich-club core exhibiting the greatest stability over time. We discuss these findings in light of highly variable functional hubs. The results further elucidate how large-scale dynamic functional coordination exists within a fixed structural architecture. Copyright © 2015 the authors 0270-6474/15/355579-10$15.00/0.

Probing the Influence of Linker Length and Flexibility in the Design and Synthesis of New Trehalase Inhibitors

Directory of Open Access Journals (Sweden)

Giampiero D’Adamio

2018-02-01

Full Text Available This work aims to synthesize new trehalase inhibitors selective towards the insect trehalase versus the porcine trehalase, in view of their application as potentially non-toxic insecticides and fungicides. The synthesis of a new pseudodisaccharide mimetic 8, by means of a stereoselective α-glucosylation of the key pyrrolizidine intermediate 13, was accomplished. The activity of compound 8 as trehalase inhibitor towards C. riparius trehalase was evaluated and the results showed that 8 was active in the μM range and showed a good selectivity towards the insect trehalase. To reduce the overall number of synthetic steps, simpler and more flexible disaccharide mimetics 9–11 bearing a pyrrolidine nucleus instead of the pyrrolizidine core were synthesized. The biological data showed the key role of the linker chain’s length in inducing inhibitory properties, since only compounds 9 (α,β-mixture, bearing a two-carbon atom linker chain, maintained activity as trehalase inhibitors. A proper change in the glucosyl donor-protecting groups allowed the stereoselective synthesis of the β-glucoside 9β, which was active in the low micromolar range (IC50 = 0.78 μM and 12-fold more potent (and more selective than 9α towards the insect trehalase.

Parsing the roles of neck-linker docking and tethered head diffusion in the stepping dynamics of kinesin.

Science.gov (United States)

Zhang, Zhechun; Goldtzvik, Yonathan; Thirumalai, D

2017-11-14

Kinesin walks processively on microtubules (MTs) in an asymmetric hand-over-hand manner consuming one ATP molecule per 16-nm step. The individual contributions due to docking of the approximately 13-residue neck linker to the leading head (deemed to be the power stroke) and diffusion of the trailing head (TH) that contributes in propelling the motor by 16 nm have not been quantified. We use molecular simulations by creating a coarse-grained model of the MT-kinesin complex, which reproduces the measured stall force as well as the force required to dislodge the motor head from the MT, to show that nearly three-quarters of the step occurs by bidirectional stochastic motion of the TH. However, docking of the neck linker to the leading head constrains the extent of diffusion and minimizes the probability that kinesin takes side steps, implying that both the events are necessary in the motility of kinesin and for the maintenance of processivity. Surprisingly, we find that during a single step, the TH stochastically hops multiple times between the geometrically accessible neighboring sites on the MT before forming a stable interaction with the target binding site with correct orientation between the motor head and the [Formula: see text] tubulin dimer.

Crystal Structure of the FERM Domain of Focal Adhesion Kinase

International Nuclear Information System (INIS)

Ceccarelli, D.; Song, H.; Poy, F.; Schaller, M.; Eck, M.

2006-01-01

Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that localizes to focal adhesions in adherent cells. Through phosphorylation of proteins assembled at the cytoplasmic tails of integrins, FAK promotes signaling events that modulate cellular growth, survival, and migration. The amino-terminal region of FAK contains a region of sequence homology with band 4.1 and ezrin/radixin/moesin (ERM) proteins termed a FERM domain. FERM domains are found in a variety of signaling and cytoskeletal proteins and are thought to mediate intermolecular interactions with partner proteins and phospholipids at the plasma membrane and intramolecular regulatory interactions. Here we report two crystal structures of an NH2-terminal fragment of avian FAK containing the FERM domain and a portion of the regulatory linker that connects the FERM and kinase domains. The tertiary folds of the three subdomains (F1, F2, and F3) are similar to those of known FERM structures despite low sequence conservation. Differences in the sequence and relative orientation of the F3 subdomain alters the nature of the interdomain interface, and the phosphoinositide binding site found in ERM family FERM domains is not present in FAK. A putative protein interaction site on the F3 lobe is masked by the proximal region of the linker. Additionally, in one structure the adjacent Src SH3 and SH2 binding sites in the linker associate with the surfaces of the F3 and F1 lobes, respectively. These structural features suggest the possibility that protein interactions of the FAK FERM domain can be regulated by binding of Src kinases to the linker segment

Low resolution crystal structure of Arenicola erythrocruorin: influence of coiled coils on the architecture of a megadalton respiratory protein.

Science.gov (United States)

Royer, William E; Omartian, Michael N; Knapp, James E

2007-01-05

Annelid erythrocruorins are extracellular respiratory complexes assembled from 180 subunits into hexagonal bilayers. Cryo-electron microscopic experiments have identified two different architectural classes. In one, designated type I, the vertices of the two hexagonal layers are partially staggered, with one hexagonal layer rotated by about 16 degrees relative to the other layer, whereas in the other class, termed type II, the vertices are essentially eclipsed. We report here the first crystal structure of a type II erythrocruorin, that from Arenicola marina, at 6.2 A resolution. The structure reveals the presence of long continuous triple-stranded coiled-coil "spokes" projecting towards the molecular center from each one-twelfth unit; interdigitation of these spokes provides the only contacts between the two hexagonal layers of the complex. This arrangement contrasts with that of a type I erythrocruorin from Lumbricus terrestris in which the spokes are broken into two triple-stranded coiled coils with a disjointed connection. The disjointed connection allows formation of a more compact structure in the type I architecture, with the two hexagonal layers closer together and additional extensive contacts between the layers. Comparison of sequences of the coiled-coil regions of various linker subunits shows that the linker subunits from type II erythrocruorins possess continuous heptad repeats, whereas a sequence gap places these repeats out of register in the type I linker subunits, consistent with a disjointed coiled-coil arrangement.

Simulating Coral Reef Connectivity in the Southern Red Sea

KAUST Repository

Wang, Yixin

2018-05-01

Connectivity is an important component of coral reef studies for its role in the enhancement of ecosystem resilience. Previous genetic structure and physical circulation studies in the Red Sea reveal a homogeneity within the coral reef complexes in the central and northern parts of the basin. Yet, genetic isolation and relatively low connectivity has been observed in the southern Red Sea. Raitsos et al. (2017) recently hypothesized that coral reefs in the southern Red Sea are more connected with regions outside the basin, rather than with the central and northern Red Sea. Using a physical circulation approach based on a 3-D backward particle tracking simulation, we further investigate this hypothesis. A long-term (> 10 years), very high resolution (1km) MITgcm simulation is used to provide detailed information on velocity in the complex coastal regions of the Red Sea and the adjacent narrow Bab-El-Mandeb Strait. The particle tracking simulation results support the initial hypothesis that the coastal regions in the southern Red Sea exhibit a consistently higher connectivity with the regions outside the Bab-El-Mandeb Strait, than with the central and northern Red Sea. Substantially high levels of connectivity, facilitated by the circulation and eddies, is observed with the coastal regions in the Gulf of Aden. A strong seasonality in connectivity, related to the monsoon-driven circulation, is also evident with the regions outside of the Red Sea. The winter surface intrusion plays a leading role in transporting the particles from the Gulf of Aden and the Indian Ocean into the Red Sea, while the summer subsurface intrusion also supports the transport of particles into the Red Sea in the intermediate layer. In addition, the connectivity with the central and northern Red Sea is more affected by the intensity of the eddies. Evidence also suggests that potential connectivity exists between the coastal southern Red Sea and the coasts of Oman, Socotra, Somalia, Kenya

Traceless Azido Linker for the Solid-Phase Synthesis of NH-1,2,3-Triazoles via Cu-Catalyzed Azide-Alkyne Cycloaddition Reactions

DEFF Research Database (Denmark)

Cohrt, Anders Emil; Jensen, Jakob Feldthusen; Nielsen, Thomas Eiland

2010-01-01

A broadly useful acid-labile traceless azido linker for the solid-phase synthesis of NH-1,2,3-triazoles is presented. A variety of alkynes were efficiently immobilized on a range of polymeric supports by Cu(I)-mediated azide-alkyne cycloadditions. Supported triazoles showed excellent compatibility...

Synthesis and catalytic evaluation in the Heck reaction of deposited palladium catalysts immobilized via amide linkers and their molecular analogues

Czech Academy of Sciences Publication Activity Database

Semler, M.; Čejka, Jiří; Štěpnička, P.

2014-01-01

Roč. 227, MAY 2014 (2014), s. 207-214 ISSN 0920-5861 R&D Projects: GA ČR GA104/09/0561; GA ČR(CZ) GA13-08944S Institutional support: RVO:61388955 Keywords : deposited catalysts * palladium * amide linkers Subject RIV: CF - Physical ; Theoretical Chemistry Impact factor: 3.893, year: 2014

Power take-off analysis for diagonally connected MHD channels

International Nuclear Information System (INIS)

Pan, Y.C.; Doss, E.D.

1980-01-01

The electrical loading of the power take-off region of diagonally connected MHD channels is investigated by a two-dimensional model. The study examines the loading schemes typical of those proposed for the U-25 and U-25 Bypass channels. The model is applicable for the following four cases: (1) connection with diodes only, (2) connection with diodes and equal resistors, (3) connection with diodes and variable resistances to obtain a given current distribution, and (4) connection with diodes and variable resistors under changing load. The analysis is applicable for the power take-off regions of single or multiple-output systems. The general behaviors of the current and the potential distributions in all four cases are discussed. The analytical results are in good agreement with the experimental data. It is found possible to design the electrical circuit of the channel in the take-off region so as to achieve a fairly even load current output under changing total load current

Multivalent cyclic RGD ligands: influence of linker lengths on receptor binding

Energy Technology Data Exchange (ETDEWEB)

Kubas, Holger; Schaefer, Martin; Bauder-Wuest, Ulrike; Eder, Matthias; Oltmanns, Doerte [Department of Radiopharmaceutical Chemistry, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg (Germany); Haberkorn, Uwe; Mier, Walter [Department of Nuclear Medicine, University Hospital Heidelberg, Im Neuenheimer Feld 400, 69120 Heidelberg (Germany); Eisenhut, Michael, E-mail: m.eisenhut@dkfz.d [Department of Radiopharmaceutical Chemistry, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg (Germany)

2010-11-15

Peptides involving the RGD motive (arginine-glycine-aspartic acid) recognize members of the integrin receptor family. Since the receptors are located mainly on the surface of endothelial cells, structural modifications including multimers of c(RGDfE) were recently found to improve the binding avidity for {alpha}{sub v{beta}3} integrin significantly. The multivalent RGD peptides exhibited rather loose linkages partly including oligo(ethylene glycol) spacers (EG{sub n}) with different chain lengths. Therefore, the dependence of multivalent RGD systems with and without EG{sub n} linkers were investigated on their binding properties to cultured {alpha}{sub v{beta}3} integrin-expressing U87MG cells. Methods: We synthesized a series of di-, tri- and tetravalent rigid scaffolds (terephthalic acid, trimesic acid and adamantane-1,3,5,7-tetracarboxylic acid) conjugated to c(RGDyK) ligands, which were linked contiguously or separated by the oligo(ethylene glycol) spacers. The inhibition constants of these c(RGDyK) derivatives were determined by competition assays with {sup 125}I-labeled echistatin. Results: While c(RGDyK) function is a relative weak competitor against [{sup 125}I]echistatin (K{sub i}, 329{+-}18 nM) for {alpha}{sub v{beta}3} integrin-expressing U87MG cells, RGD dimers improved the competition potency considerably (K{sub i}, 64{+-}23 nM). This effect was even more pronounced with the RGD trimers (K{sub i}, 40{+-}7 nM) and tetramers (K{sub i}, 26{+-}9 nM). The introduction of EG{sub n} spacers and the increase of linker lengths proved to be detrimental since more competitors were needed to compete with [{sup 125}I]echistatin. The EG{sub 6} group, for example, reduced the inhibition constants by 29% (dimer), 57% (trimer) and 97% (tetramer). Conclusion: The binding experiments performed with the three forms of multivalent RGD ligands indicate the weakening of competitive potency against [{sup 125}I]echistatin with the introduction of EG{sub n} spacers. This effect

Empirical validation of directed functional connectivity.

Science.gov (United States)

Mill, Ravi D; Bagic, Anto; Bostan, Andreea; Schneider, Walter; Cole, Michael W

2017-02-01

Mapping directions of influence in the human brain connectome represents the next phase in understanding its functional architecture. However, a host of methodological uncertainties have impeded the application of directed connectivity methods, which have primarily been validated via "ground truth" connectivity patterns embedded in simulated functional MRI (fMRI) and magneto-/electro-encephalography (MEG/EEG) datasets. Such simulations rely on many generative assumptions, and we hence utilized a different strategy involving empirical data in which a ground truth directed connectivity pattern could be anticipated with confidence. Specifically, we exploited the established "sensory reactivation" effect in episodic memory, in which retrieval of sensory information reactivates regions involved in perceiving that sensory modality. Subjects performed a paired associate task in separate fMRI and MEG sessions, in which a ground truth reversal in directed connectivity between auditory and visual sensory regions was instantiated across task conditions. This directed connectivity reversal was successfully recovered across different algorithms, including Granger causality and Bayes network (IMAGES) approaches, and across fMRI ("raw" and deconvolved) and source-modeled MEG. These results extend simulation studies of directed connectivity, and offer practical guidelines for the use of such methods in clarifying causal mechanisms of neural processing. Copyright © 2016 Elsevier Inc. All rights reserved.

Improved diagnostic accuracy of Alzheimer's disease by combining regional cortical thickness and default mode network functional connectivity: Validated in the Alzheimer's disease neuroimaging initiative set

Energy Technology Data Exchange (ETDEWEB)

Park, Ji Eun; Park, Bum Woo; Kim, Sang Joon; Kim, Ho Sung; Choi, Choong Gon; Jung, Seung Jung; Oh, Joo Young; Shim, Woo Hyun [Dept. of Radiology and Research Institute of Radiology, University of Ulsan College of Medicine, Asan Medical Center, Seoul (Korea, Republic of); Lee, Jae Hong; Roh, Jee Hoon [University of Ulsan College of Medicine, Asan Medical Center, Seoul (Korea, Republic of)

2017-11-15

To identify potential imaging biomarkers of Alzheimer's disease by combining brain cortical thickness (CThk) and functional connectivity and to validate this model's diagnostic accuracy in a validation set. Data from 98 subjects was retrospectively reviewed, including a study set (n = 63) and a validation set from the Alzheimer's Disease Neuroimaging Initiative (n = 35). From each subject, data for CThk and functional connectivity of the default mode network was extracted from structural T1-weighted and resting-state functional magnetic resonance imaging. Cortical regions with significant differences between patients and healthy controls in the correlation of CThk and functional connectivity were identified in the study set. The diagnostic accuracy of functional connectivity measures combined with CThk in the identified regions was evaluated against that in the medial temporal lobes using the validation set and application of a support vector machine. Group-wise differences in the correlation of CThk and default mode network functional connectivity were identified in the superior temporal (p < 0.001) and supramarginal gyrus (p = 0.007) of the left cerebral hemisphere. Default mode network functional connectivity combined with the CThk of those two regions were more accurate than that combined with the CThk of both medial temporal lobes (91.7% vs. 75%). Combining functional information with CThk of the superior temporal and supramarginal gyri in the left cerebral hemisphere improves diagnostic accuracy, making it a potential imaging biomarker for Alzheimer's disease.

Regional exploration of pulmonary function using xenon 133. Value of the gamma camera connected to a computer

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Moyses, B; Gerard, G; Methlin, G [Centre Paul-Strauss, 67 - Strasbourg (France); Weitzenblum, E [Centre Hospitalier Universitaire, 67 - Strasbourg (France)

1978-06-17

Regional isotopic exploration of ventilation and pulmonary perfusion is not yet widely applied in clinical practice, by virtue of the complexity of the equipment required, but also because of the complicated and lengthy analysis of the results. In this respect, connection of the scintillation camera to a computer represents a major advance which other authors have already emphasized. Our own experience in this area and our method of exploration in a group of 43 cases of chronic obstructive lung disease (33 patients of the chronic bronchitis type, 10 patients with emphysema) are analysed and discussed. The results indicate the following: in chronic bronchitis, a very marked fall in ventilation of the bases with inversion of the normal vertical ventilation gradient, and a fall in the ventilation/perfusion ratio of the bases; in emphysema, a fall in ventilation, but also and above all in regional perfusion of all territories with preservation of normal or even increased regional ventilation/perfusion ratios. Regional exploration may also be of value in the detection of early stages of obstructive lung disease, and in pre-operative assessment in thoracic surgery.

Metabolic connectivity by interregional correlation analysis using statistical parametric mapping (SPM) and FDG brain PET; methodological development and patterns of metabolic connectivity in adults

International Nuclear Information System (INIS)

Lee, Dong Soo; Oh, Jungsu S.; Lee, Jae Sung; Lee, Myung Chul; Kang, Hyejin; Kim, Heejung; Park, Hyojin

2008-01-01

Regionally connected areas of the resting brain can be detected by fluorodeoxyglucose-positron emission tomography (FDG-PET). Voxel-wise metabolic connectivity was examined, and normative data were established by performing interregional correlation analysis on statistical parametric mapping of FDG-PET data. Characteristics of seed volumes of interest (VOIs) as functional brain units were represented by their locations, sizes, and the independent methods of their determination. Seed brain areas were identified as population-based gyral VOIs (n=70) or as population-based cytoarchitectonic Brodmann areas (BA; n=28). FDG uptakes in these areas were used as independent variables in a general linear model to search for voxels correlated with average seed VOI counts. Positive correlations were searched in entire brain areas. In normal adults, one third of gyral VOIs yielded correlations that were confined to themselves, but in the others, correlated voxels extended to adjacent areas and/or contralateral homologous regions. In tens of these latter areas with extensive connectivity, correlated voxels were found across midline, and asymmetry was observed in the patterns of connectivity of left and right homologous seed VOIs. Most of the available BAs yielded correlations reaching contralateral homologous regions and/or neighboring areas. Extents of metabolic connectivity were not found to be related to seed VOI size or to the methods used to define seed VOIs. These findings indicate that patterns of metabolic connectivity of functional brain units depend on their regional locations. We propose that interregional correlation analysis of FDG-PET data offers a means of examining voxel-wise regional metabolic connectivity of the resting human brain. (orig.)

Metabolic connectivity by interregional correlation analysis using statistical parametric mapping (SPM) and FDG brain PET; methodological development and patterns of metabolic connectivity in adults

Energy Technology Data Exchange (ETDEWEB)

Lee, Dong Soo; Oh, Jungsu S.; Lee, Jae Sung; Lee, Myung Chul [Seoul National University, College of Medicine, Department of Nuclear Medicine, Jongno-gu, Seoul (Korea); Kang, Hyejin [Seoul National University, College of Medicine, Department of Nuclear Medicine, Jongno-gu, Seoul (Korea); Seoul National University, Programs in Brain and Neuroscience, Seoul (Korea); Kim, Heejung; Park, Hyojin [Seoul National University, College of Medicine, Department of Nuclear Medicine, Jongno-gu, Seoul (Korea); Seoul National University, Interdisciplinary Program in Cognitive Science, Seoul (Korea)

2008-09-15

Regionally connected areas of the resting brain can be detected by fluorodeoxyglucose-positron emission tomography (FDG-PET). Voxel-wise metabolic connectivity was examined, and normative data were established by performing interregional correlation analysis on statistical parametric mapping of FDG-PET data. Characteristics of seed volumes of interest (VOIs) as functional brain units were represented by their locations, sizes, and the independent methods of their determination. Seed brain areas were identified as population-based gyral VOIs (n=70) or as population-based cytoarchitectonic Brodmann areas (BA; n=28). FDG uptakes in these areas were used as independent variables in a general linear model to search for voxels correlated with average seed VOI counts. Positive correlations were searched in entire brain areas. In normal adults, one third of gyral VOIs yielded correlations that were confined to themselves, but in the others, correlated voxels extended to adjacent areas and/or contralateral homologous regions. In tens of these latter areas with extensive connectivity, correlated voxels were found across midline, and asymmetry was observed in the patterns of connectivity of left and right homologous seed VOIs. Most of the available BAs yielded correlations reaching contralateral homologous regions and/or neighboring areas. Extents of metabolic connectivity were not found to be related to seed VOI size or to the methods used to define seed VOIs. These findings indicate that patterns of metabolic connectivity of functional brain units depend on their regional locations. We propose that interregional correlation analysis of FDG-PET data offers a means of examining voxel-wise regional metabolic connectivity of the resting human brain. (orig.)

Rootletin interacts with C-Nap1 and may function as a physical linker between the pair of centrioles/basal bodies in cells.

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Yang, Jun; Adamian, Michael; Li, Tiansen

2006-02-01

Rootletin, a major structural component of the ciliary rootlet, is located at the basal bodies and centrosomes in ciliated and nonciliated cells, respectively. Here we investigated its potential role in the linkage of basal bodies/centrioles and the mechanism involved in such linkages. We show that rootletin interacts with C-Nap1, a protein restricted at the ends of centrioles and functioning in centrosome cohesion in interphase cells. Their interaction in vivo is supported by their colocalization at the basal bodies/centrioles and coordinated association with the centrioles during the cell cycle. Ultrastructural examinations demonstrate that rootletin fibers connect the basal bodies in ciliated cells and are present both at the ends of and in between the pair of centrioles in nonciliated cells. The latter finding stands in contrast with C-Nap1, which is present only at the ends of the centrioles. Transient expression of C-Nap1 fragments dissociated rootletin fibers from the centrioles, resulting in centrosome separation in interphase. Overexpression of rootletin in cells caused multinucleation, micronucleation, and irregularity of nuclear shape and size, indicative of defects in chromosome separation. These data suggest that rootletin may function as a physical linker between the pair of basal bodies/centrioles by binding to C-Nap1.

Functional Connectivity Parcellation of the Human Thalamus by Independent Component Analysis.

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Zhang, Sheng; Li, Chiang-Shan R

2017-11-01

As a key structure to relay and integrate information, the thalamus supports multiple cognitive and affective functions through the connectivity between its subnuclei and cortical and subcortical regions. Although extant studies have largely described thalamic regional functions in anatomical terms, evidence accumulates to suggest a more complex picture of subareal activities and connectivities of the thalamus. In this study, we aimed to parcellate the thalamus and examine whole-brain connectivity of its functional clusters. With resting state functional magnetic resonance imaging data from 96 adults, we used independent component analysis (ICA) to parcellate the thalamus into 10 components. On the basis of the independence assumption, ICA helps to identify how subclusters overlap spatially. Whole brain functional connectivity of each subdivision was computed for independent component's time course (ICtc), which is a unique time series to represent an IC. For comparison, we computed seed-region-based functional connectivity using the averaged time course across all voxels within a thalamic subdivision. The results showed that, at p analysis, ICtc analysis revealed patterns of connectivity that were more distinguished between thalamic clusters. ICtc analysis demonstrated thalamic connectivity to the primary motor cortex, which has eluded the analysis as well as previous studies based on averaged time series, and clarified thalamic connectivity to the hippocampus, caudate nucleus, and precuneus. The new findings elucidate functional organization of the thalamus and suggest that ICA clustering in combination with ICtc rather than seed-region analysis better distinguishes whole-brain connectivities among functional clusters of a brain region.

Structural Polymorphism of the Actin-Espin System: A Prototypical System of Filaments and Linkers in Stereocilia

International Nuclear Information System (INIS)

Purdy, Kirstin R.; Wong, Gerard C. L.; Bartles, James R.

2007-01-01

We examine the interaction between cytoskeletal F-actin and espin 3A, a prototypical actin bundling protein found in sensory cell microvilli, including ear cell stereocilia. Espin induces twist distortions in F-actin as well as facilitates bundle formation. Mutations in one of the two F-actin binding sites of espin, which have been implicated in deafness, can tune espin-actin interactions and radically transform the system's phase behavior. These results are compared to recent theoretical work on the general phase behavior linker-rod systems

The role of H1 linker histone subtypes in preserving the fidelity of elaboration of mesendodermal and neuroectodermal lineages during embryonic development.

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Giang D Nguyen

Full Text Available H1 linker histone proteins are essential for the structural and functional integrity of chromatin and for the fidelity of additional epigenetic modifications. Deletion of H1c, H1d and H1e in mice leads to embryonic lethality by mid-gestation with a broad spectrum of developmental alterations. To elucidate the cellular and molecular mechanisms underlying H1 linker histone developmental functions, we analyzed embryonic stem cells (ESCs depleted of H1c, H1d and H1e subtypes (H1-KO ESCs by utilizing established ESC differentiation paradigms. Our study revealed that although H1-KO ESCs continued to express core pluripotency genes and the embryonic stem cell markers, alkaline phosphatase and SSEA1, they exhibited enhanced cell death during embryoid body formation and during specification of mesendoderm and neuroectoderm. In addition, we demonstrated deregulation in the developmental programs of cardiomyocyte, hepatic and pancreatic lineage elaboration. Moreover, ectopic neurogenesis and cardiomyogenesis occurred during endoderm-derived pancreatic but not hepatic differentiation. Furthermore, neural differentiation paradigms revealed selective impairments in the specification and maturation of glutamatergic and dopaminergic neurons with accelerated maturation of glial lineages. These impairments were associated with deregulation in the expression profiles of pro-neural genes in dorsal and ventral forebrain-derived neural stem cell species. Taken together, these experimental observations suggest that H1 linker histone proteins are critical for the specification, maturation and fidelity of organ-specific cellular lineages derived from the three cardinal germ layers.

Epigenetics and autism spectrum disorder: A report of an autism case with mutation in H1 linker histone HIST1H1e and literature review.

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Duffney, Lara J; Valdez, Purnima; Tremblay, Martine W; Cao, Xinyu; Montgomery, Sarah; McConkie-Rosell, Allyn; Jiang, Yong-Hui

2018-04-27

Genetic mutations in genes encoding proteins involved in epigenetic machinery have been reported in individuals with autism spectrum disorder (ASD), intellectual disability, congenital heart disease, and other disorders. H1 histone linker protein, the basic component in nucleosome packaging and chromatin organization, has not been implicated in human disease until recently. We report a de novo deleterious mutation of histone cluster 1 H1 family member e (HIST1H1E; c.435dupC; p.Thr146Hisfs*50), encoding H1 histone linker protein H1.4, in a 10-year-old boy with autism and intellectual disability diagnosed through clinical whole exome sequencing. The c.435dupC at the 3' end of the mRNA leads to a frameshift and truncation of the positive charge in the carboxy-terminus of the protein. An expression study demonstrates the mutation leads to reduced protein expression, supporting haploinsufficiency of HIST1H1E protein and loss of function as an underlying mechanism of dysfunction in the brain. Taken together with other recent cases with mutations of HIST1H1E in intellectual disability, the evidence supporting the link to causality in disease is strong. Our finding implicates the deficiency of H1 linker histone protein in autism. The systematic review of candidate genes implicated in ASD revealed that 42 of 215 (19.5%) genes are directly involved in epigenetic regulations and the majority of these genes belong to histone writers, readers, and erasers. While the mechanism of how haploinsufficiency of HIST1H1E causes autism is entirely unknown, our report underscores the importance of further study of the function of this protein and other histone linker proteins in brain development. © 2018 Wiley Periodicals, Inc.

Connectivity-based parcellation of the human orbitofrontal cortex.

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Kahnt, Thorsten; Chang, Luke J; Park, Soyoung Q; Heinzle, Jakob; Haynes, John-Dylan

2012-05-02

The primate orbitofrontal cortex (OFC) is involved in reward processing, learning, and decision making. Research in monkeys has shown that this region is densely connected with higher sensory, limbic, and subcortical regions. Moreover, a parcellation of the monkey OFC into two subdivisions has been suggested based on its intrinsic anatomical connections. However, in humans, little is known about any functional subdivisions of the OFC except for a rather coarse medial/lateral distinction. Here, we used resting-state fMRI in combination with unsupervised clustering techniques to investigate whether OFC subdivisions can be revealed based on their functional connectivity profiles with other brain regions. Examination of different cluster solutions provided support for a parcellation into two parts as observed in monkeys, but it also highlighted a much finer hierarchical clustering of the orbital surface. Specifically, we identified (1) a medial, (2) a posterior-central, (3) a central, and (4-6) three lateral clusters spanning the anterior-posterior gradient. Consistent with animal tracing studies, these OFC clusters were connected to other cortical regions such as prefrontal, temporal, and parietal cortices but also subcortical areas in the striatum and the midbrain. These connectivity patterns provide important implications for identifying specific functional roles of OFC subdivisions for reward processing, learning, and decision making. Moreover, this parcellation schema can provide guidance to report results in future studies.

Detecting Functional Connectivity During Audiovisual Integration with MEG: A Comparison of Connectivity Metrics.

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Ard, Tyler; Carver, Frederick W; Holroyd, Tom; Horwitz, Barry; Coppola, Richard

2015-08-01

In typical magnetoencephalography and/or electroencephalography functional connectivity analysis, researchers select one of several methods that measure a relationship between regions to determine connectivity, such as coherence, power correlations, and others. However, it is largely unknown if some are more suited than others for various types of investigations. In this study, the authors investigate seven connectivity metrics to evaluate which, if any, are sensitive to audiovisual integration by contrasting connectivity when tracking an audiovisual object versus connectivity when tracking a visual object uncorrelated with the auditory stimulus. The authors are able to assess the metrics' performances at detecting audiovisual integration by investigating connectivity between auditory and visual areas. Critically, the authors perform their investigation on a whole-cortex all-to-all mapping, avoiding confounds introduced in seed selection. The authors find that amplitude-based connectivity measures in the beta band detect strong connections between visual and auditory areas during audiovisual integration, specifically between V4/V5 and auditory cortices in the right hemisphere. Conversely, phase-based connectivity measures in the beta band as well as phase and power measures in alpha, gamma, and theta do not show connectivity between audiovisual areas. The authors postulate that while beta power correlations detect audiovisual integration in the current experimental context, it may not always be the best measure to detect connectivity. Instead, it is likely that the brain utilizes a variety of mechanisms in neuronal communication that may produce differential types of temporal relationships.

Evidence for intact local connectivity but disrupted regional function in the occipital lobe in children and adolescents with schizophrenia.

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White, Tonya; Moeller, Steen; Schmidt, Marcus; Pardo, Jose V; Olman, Cheryl

2012-08-01

It has long been known that specific visual frequencies result in greater blood flow to the striate cortex. These peaks are thought to reflect synchrony of local neuronal firing that is reflective of local cortical networks. Since disrupted neural connectivity is a possible etiology for schizophrenia, our goal was to investigate whether localized connectivity, as measured by aberrant synchrony, is abnormal in children and adolescents with schizophrenia. Subjects included 25 children and adolescents with schizophrenia and 39 controls matched for age and gender. Subjects were scanned on a Siemens 3 Tesla Trio scanner while observing flashing checkerboard presented at either 1, 4, 8, or 12 Hz. Image processing included both a standard GLM model and a Fourier transform analysis. Patients had significantly smaller volume of activation in the occipital lobe compared to controls. There were no differences in the integral or percent signal change of the hemodynamic response function for each of the four frequencies. Occipital activation was stable during development between childhood and late adolescence. Finally, both patients and controls demonstrated an increased response between 4 and 8 Hz consistent with synchrony or entrainment in the neuronal response. Children and adolescents with schizophrenia had a significantly lower volume of activation in the occipital lobe in response to the flashing checkerboard task. However, features of intact local connectivity in patients, such as the hemodynamic response function and maximal response at 8 Hz, were normal. These results are consistent with abnormalities in regional connectivity with preserved local connectivity in early-onset schizophrenia. Copyright © 2011 Wiley Periodicals, Inc.

Reconsidering connectivity in the sub-Antarctic.

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Moon, Katherine L; Chown, Steven L; Fraser, Ceridwen I

2017-11-01

Extreme and remote environments provide useful settings to test ideas about the ecological and evolutionary drivers of biological diversity. In the sub-Antarctic, isolation by geographic, geological and glaciological processes has long been thought to underpin patterns in the region's terrestrial and marine diversity. Molecular studies using increasingly high-resolution data are, however, challenging this perspective, demonstrating that many taxa disperse among distant sub-Antarctic landmasses. Here, we reconsider connectivity in the sub-Antarctic region, identifying which taxa are relatively isolated, which are well connected, and the scales across which this connectivity occurs in both terrestrial and marine systems. Although many organisms show evidence of occasional long-distance, trans-oceanic dispersal, these events are often insufficient to maintain gene flow across the region. Species that do show evidence of connectivity across large distances include both active dispersers and more sedentary species. Overall, connectivity patterns in the sub-Antarctic at intra- and inter-island scales are highly complex, influenced by life-history traits and local dynamics such as relative dispersal capacity and propagule pressure, natal philopatry, feeding associations, the extent of human exploitation, past climate cycles, contemporary climate, and physical barriers to movement. An increasing use of molecular data - particularly genomic data sets that can reveal fine-scale patterns - and more effective international collaboration and communication that facilitates integration of data from across the sub-Antarctic, are providing fresh insights into the processes driving patterns of diversity in the region. These insights offer a platform for assessing the ways in which changing dispersal mechanisms, such as through increasing human activity and changes to wind and ocean circulation, may alter sub-Antarctic biodiversity patterns in the future. © 2017 Cambridge

Resting state functional connectivity differences between behavioral variant frontotemporal dementia and Alzheimer’s disease

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Anne eHafkemeijer

2015-09-01

Full Text Available Alzheimer’s disease (AD and behavioral variant frontotemporal dementia (bvFTD are the most common types of early-onset dementia. Here, we apply resting state functional magnetic resonance imaging (fMRI to study functional brain connectivity differences between AD and bvFTD.We used resting state fMRI data of 31 AD patients, 25 bvFTD patients, and 29 controls. We studied functional connectivity throughout the entire brain, applying two different analysis techniques, studying network-to-region and region-to-region connectivity. A general linear model approach was used to study group differences, while controlling for physiological noise, age, gender, study center, and regional gray matter volume. Given gray matter differences, we observed decreased network-to-region connectivity in bvFTD between a lateral visual cortical network and lateral occipital and cuneal cortex, and b auditory system network and angular gyrus. In AD, we found decreased network-to-region connectivity between the dorsal visual stream network and lateral occipital and parietal opercular cortex. Region-to-region connectivity was decreased in bvFTD between superior temporal gyrus and cuneal, supracalcarine, intracalcarine cortex, and lingual gyrus. We showed that the pathophysiology of functional brain connectivity is different between AD and bvFTD. However, the group differences in functional connectivity are less abundant than has been shown in previous studies.

Network-based analysis reveals functional connectivity related to internet addiction tendency

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Tanya eWen

2016-02-01

Full Text Available IntroductionPreoccupation and compulsive use of the internet can have negative psychological effects, such that it is increasingly being recognized as a mental disorder. The present study employed network-based statistics to explore how whole-brain functional connections at rest is related to the extent of individual’s level of internet addiction, indexed by a self-rated questionnaire. We identified two topologically significant networks, one with connections that are positively correlated with internet addiction tendency, and one with connections negatively correlated with internet addiction tendency. The two networks are interconnected mostly at frontal regions, which might reflect alterations in the frontal region for different aspects of cognitive control (i.e., for control of internet usage and gaming skills. Next, we categorized the brain into several large regional subgroupings, and found that the majority of proportions of connections in the two networks correspond to the cerebellar model of addiction which encompasses the four-circuit model. Lastly, we observed that the brain regions with the most inter-regional connections associated with internet addiction tendency replicate those often seen in addiction literature, and is corroborated by our meta-analysis of internet addiction studies. This research provides a better understanding of large-scale networks involved in internet addiction tendency and shows that pre-clinical levels of internet addiction are associated with similar regions and connections as clinical cases of addiction.

Structural and Functional Brain Connectivity of People with Obesity and Prediction of Body Mass Index Using Connectivity.

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Bo-yong Park

Full Text Available Obesity is a medical condition affecting billions of people. Various neuroimaging methods including magnetic resonance imaging (MRI have been used to obtain information about obesity. We adopted a multi-modal approach combining diffusion tensor imaging (DTI and resting state functional MRI (rs-fMRI to incorporate complementary information and thus better investigate the brains of non-healthy weight subjects. The objective of this study was to explore multi-modal neuroimaging and use it to predict a practical clinical score, body mass index (BMI. Connectivity analysis was applied to DTI and rs-fMRI. Significant regions and associated imaging features were identified based on group-wise differences between healthy weight and non-healthy weight subjects. Six DTI-driven connections and 10 rs-fMRI-driven connectivities were identified. DTI-driven connections better reflected group-wise differences than did rs-fMRI-driven connectivity. We predicted BMI values using multi-modal imaging features in a partial least-square regression framework (percent error 15.0%. Our study identified brain regions and imaging features that can adequately explain BMI. We identified potentially good imaging biomarker candidates for obesity-related diseases.

Preparation, structural analysis and bioactivity of ribonuclease A-albumin conjugate: tetra-conjugation or PEG as the linker.

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Li, Chunju; Lin, Qixun; Wang, Jun; Shen, Lijuan; Ma, Guanghui; Su, Zhiguo; Hu, Tao

2012-12-31

Ribonuclease A (RNase A) is a therapeutic enzyme with cytotoxic action against tumor cells. Its clinical application is limited by the short half-life and insufficient stability. Conjugation of albumin can overcome the limitation, whereas dramatically decrease the enzymatic activity of RNase A. Here, three strategies were proposed to prepare the RNase A-bovine serum albumin (BSA) conjugates. R-SMCC-B (a conjugate of four RNase A attached with one BSA) and R-PEG-B (a mono-conjugate) were prepared using Sulfo-SMCC (a short bifunctional linker) and mal-PEG-NHS (a bifunctional PEG), respectively. Mal-PEG-NHS and hexadecylamine (HDA) were used to prepare the mono-conjugate, R-HDA-B, where HDA was adopted to bind BSA. The PEG linker can elongate the proximity between RNase A and BSA. In contrast, four RNase A were closely located on BSA in R-SMCC-B. R-SMCC-B showed the lowest K(m) and the highest relative enzymatic activity and k(cat)/K(m) in the three conjugates. Presumably, the tetravalent interaction of RNase A in R-SMCC-B can increase the binding affinity to its substrate. In addition, the slow release of BSA from R-HDA-B may increase the enzymatic activity of R-HDA-B. Our study is expected to provide strategies to develop protein-albumin conjugate with high therapeutic potential. Copyright © 2012 Elsevier B.V. All rights reserved.

Altered resting-state functional connectivity of the frontal-striatal reward system in social anxiety disorder.

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Manning, Joshua; Reynolds, Gretchen; Saygin, Zeynep M; Hofmann, Stefan G; Pollack, Mark; Gabrieli, John D E; Whitfield-Gabrieli, Susan

2015-01-01

We investigated differences in the intrinsic functional brain organization (functional connectivity) of the human reward system between healthy control participants and patients with social anxiety disorder. Functional connectivity was measured in the resting-state via functional magnetic resonance imaging (fMRI). 53 patients with social anxiety disorder and 33 healthy control participants underwent a 6-minute resting-state fMRI scan. Functional connectivity of the reward system was analyzed by calculating whole-brain temporal correlations with a bilateral nucleus accumbens seed and a ventromedial prefrontal cortex seed. Patients with social anxiety disorder, relative to the control group, had (1) decreased functional connectivity between the nucleus accumbens seed and other regions associated with reward, including ventromedial prefrontal cortex; (2) decreased functional connectivity between the ventromedial prefrontal cortex seed and lateral prefrontal regions, including the anterior and dorsolateral prefrontal cortices; and (3) increased functional connectivity between both the nucleus accumbens seed and the ventromedial prefrontal cortex seed with more posterior brain regions, including anterior cingulate cortex. Social anxiety disorder appears to be associated with widespread differences in the functional connectivity of the reward system, including markedly decreased functional connectivity between reward regions and between reward regions and lateral prefrontal cortices, and markedly increased functional connectivity between reward regions and posterior brain regions.

Experimental and Numerical Assessment of a New Alternative of RBS Moment Connection

International Nuclear Information System (INIS)

Mirghaderi, Rasoul; Imanpour, Ali; Keshavarzi, Farhad; Torabian, Shahab

2008-01-01

Reduced beam section (RBS) connection has been known as a famous connection for steel moment-resisting seismic frames in high-rise buildings, because of their economical advantages and seismic ductility. In the ordinary RBS connection, often portions of the beam flanges are selectively trimmed in the region adjacent to the beam-to-column connection, and beam section is weakened in the plastic hinge region; section weakening concept in the plastic hinge region of beam cause to reduction of beam plastic section modulus in this region, and force plastic hinge to occur within the reduced section.This paper presents a new alternative of RBS connection that has been used aforesaid weakening concept in it, with this difference that corrugated steel plate webs instead of beam flange cutting has been used in limited specific length near the column face. Corrugated steel plates because of their accordion effect don't have bending rigidity, then using of these plates in plastic hinge region reduces the beam plastic section modulus and plastic hinge is formed in corrugated region. For investigating the seismic behavior and performance of new RBS moment connection, experimental specimen of new RBS connection were subjected to cyclic load, and finite element analysis were executed. The result of cyclic test and numerical analysis specified that the corrugated webs improved the plastic stability and provided capability of large plastic rotation at the plastic hinge location without any appreciable buckling and brittle fractures in this region. The test observations also showed that the specimens' plastic rotations exceeded 0.04 rad without any local and global buckling. All of the analytical results for proposed connection are generally in good agreement with the test observations

Effects of the Amino Acid Linkers on the Melanoma-Targeting and Pharmacokinetic Properties of Indium-111-labeled Lactam Bridge-Cyclized α-MSH Peptides

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Guo, Haixun; Yang, Jianquan; Gallazzi, Fabio; Miao, Yubin

2011-01-01

The purpose of this study was to examine the profound effects of the amino acid linkers on the melanoma targeting and pharmacokinetic properties of novel 111In-labeled lactam bridge-cyclized DOTA-[X]-CycMSHhex {1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid-[X]-c[Asp-His-dPhe-Arg-Trp-Lys]-CONH2, X=GlyGlyNle, GlyGluNle or NleGlyGlu} peptides. Methods Three novel DOTA-GGNle-CycMSHhex, DOTA-GENle-CycMSHhex and DOTA-NleGE-CycMSHhex peptides were designed and synthesized. The melanocortin-1 (MC1) receptor binding affinities of the peptides were determined in B16/F1 melanoma cells. The melanoma targeting and pharmacokinetic properties of 111In-DOTA-GGNle-CycMSHhex and 111In-DOTA-GENle-CycMSHhex were determined in B16/F1 melanoma-bearing C57 mice. Results DOTA-GGNle-CycMSHhex and DOTA-GENle-CycMSHhex displayed 2.1 and 11.5 nM MC1 receptor binding affinities, whereas DOTA-NleGE-CycMSHhex showed 873.4 nM MC1 receptor binding affinity. The introduction of the -GlyGly- linker maintained high melanoma uptake while decreased the renal and liver uptakes of 111In-DOTA-GlyGlyNle-CycMSHhex. The tumor uptake values of 111In-DOTA-GGNle-CycMSHhex were 19.05 ± 5.04 and 18.6 ± 3.56 % injected dose/gram (%ID/g) at 2 and 4 h post-injection. 111In-DOTA-GGNle-CycMSHhex exhibited 28, 32 and 42% less renal uptake values than 111In-DOTA-Nle-CycMSHhex we reported previously, and 61, 65 and 68% less liver uptake values than 111In-DOTA-Nle-CycMSHhex at 2, 4 and 24 h post-injection, respectively. Conclusion The amino acid linkers exhibited the profound effects on the melanoma targeting and pharmacokinetic properties of the 111In-labeled lactam bridge-cyclized α-MSH peptides. Introduction of the -GlyGly- linker maintained high melanoma uptake while reducing the renal and liver uptakes of 111In-DOTA-GlyGlyNle-CycMSHhex, highlighting its potential as an effective imaging probe for melanoma detection, as well as a therapeutic peptide for melanoma treatment when labeled with a therapeutic

Changes in thalamus connectivity in mild cognitive impairment: Evidence from resting state fMRI

International Nuclear Information System (INIS)

Wang Zhiqun; Jia Xiuqin; Liang Peipeng; Qi Zhigang; Yang Yanhui; Zhou Weidong; Li Kuncheng

2012-01-01

Purpose: The subcortical region such as thalamus was believed to have close relationship with many cerebral cortexes which made it especially interesting in the study of functional connectivity. Here, we used resting state functional MRI (fMRI) to examine changes in thalamus connectivity in mild cognitive impairment (MCI), which presented a neuro-disconnection syndrome. Materials and methods: Data from 14 patients and 14 healthy age-matched controls were analyzed. Thalamus connectivity was investigated by examination of the correlation between low frequency fMRI signal fluctuations in the thalamus and those in all other brain regions. Results: We found that functional connectivity between the left thalamus and a set of regions was decreased in MCI; these regions are: bilateral cuneus, middle occipital gyrus (MOG), superior frontal gyrus (SFG), medial prefrontal cortex (MPFC), precuneus, inferior frontal gyrus (IFG) and precentral gyrus (PreCG). There are also some regions showed reduced connectivity to right thalamus; these regions are bilateral cuneus, MOG, fusiform gyrus (FG), MPFC, paracentral lobe (PCL), precuneus, superior parietal lobe (SPL) and IFG. We also found increased functional connectivity between the left thalamus and the right thalamus in MCI. Conclusion: The decreased connectivity between the thalamus and the other brain regions might indicate reduced integrity of thalamus-related cortical networks in MCI. Furthermore, the increased connectivity between the left and right thalamus suggest compensation for the loss of cognitive function. Briefly, impairment and compensation of thalamus connectivity coexist in the MCI patients.

Geophysical Observatory in Kamchatka region for monitoring of phenomena connected with seismic activity

Science.gov (United States)

Uyeda, S.; Nagao, T.; Hattori, K.; Hayakawa, M.; Miyaki, K.; Molchanov, O.; Gladychev, V.; Baransky, L.; Chtchekotov, A.; Fedorov, E.; Pokhotelov, O.; Andreevsky, S.; Rozhnoi, A.; Khabazin, Y.; Gorbatikov, A.; Gordeev, E.; Chebrov, V.; Sinitzin, V.; Lutikov, A.; Yunga, S.; Kosarev, G.; Surkov, V.; Belyaev, G.

Regular monitoring of some geophysical parameters in association with seismicity has been carried out since last year at the Japan-Russian Complex Geophysical Observatory in the Kamchatka region. This observatory was organized in connection with the ISTC project in Russia and was motivated by the results of the FRONTIER/RIKEN and FRONTIER/NASDA research projects in Japan. The main purpose of the observations is to investigate the electromagnetic and acoustic phenomena induced by the lithosphere processes (especially by seismic activity). The seismicity of the Kamchatka area is analyzed and a description of the observatory equipment is presented. At present, the activity of the observatory includes the seismic (frequency range ∆F = 0.5 - 40 Hz) and meteorological recordings, together with seismo-acoustic (∆F = 30 - 1000 Hz) and electromagnetic observations: three-component magnetic ULF variations ( ∆F = 0.003 - 30 Hz), three-component electric potential variations ( ∆F < 1.0 Hz), and VLF transmitter's signal perturbations ( ∆F ~ 10 - 40 kHz).

Structural Graphical Lasso for Learning Mouse Brain Connectivity

KAUST Repository

Yang, Sen; Sun, Qian; Ji, Shuiwang; Wonka, Peter; Davidson, Ian; Ye, Jieping

2015-01-01

Investigations into brain connectivity aim to recover networks of brain regions connected by anatomical tracts or by functional associations. The inference of brain networks has recently attracted much interest due to the increasing availability

Hydrological connectivity of perched aquifers and regional aquifers in semi-arid environments: a case study from Namibia

Science.gov (United States)

Hamutoko, J. T.; Wanke, H.

2017-12-01

Integrated isotopic and hydrological tracers along with standard hydrological data are used to understand complex dry land hydrological processes on different spatial and temporal scales. The objective of this study is to analyse the relationship between the perched aquifers and the regional aquifer using hydrochemical data and isotopic composition in the Cuvelai-Etosha Basin in Namibia. This relation between the aquifers will aid in understanding groundwater recharge processes and flow dynamics. Perched aquifers are discontinuous shallow aquifers with water level ranging from 0 to 30 meters below ground level. The regional aquifer occurs in semi-consolidated sandstone at depths between about 60 and 160 meters below ground level. Water samples were collected from both aquifers in 10 villages and were analysed for major ions and stable isotopes. The results show overlapping hydrochemistry and isotopic compositions of both aquifers in 8 villages which suggest the possibility of perched aquifer water infiltrating into the regional aquifer. In two villages the hydrochemistry and isotopic composition of the aquifers are totally different and this suggests that there is no interaction between this aquifers. Areas where perched aquifers are connected to regional aquifers maybe recharge zones. These finding have important implications for groundwater resource management.

White matter structural connectivity and episodic memory in early childhood.

Science.gov (United States)

Ngo, Chi T; Alm, Kylie H; Metoki, Athanasia; Hampton, William; Riggins, Tracy; Newcombe, Nora S; Olson, Ingrid R

2017-12-01

Episodic memory undergoes dramatic improvement in early childhood; the reason for this is poorly understood. In adults, episodic memory relies on a distributed neural network. Key brain regions that supporting these processes include the hippocampus, portions of the parietal cortex, and portions of prefrontal cortex, each of which shows different developmental profiles. Here we asked whether developmental differences in the axonal pathways connecting these regions may account for the robust gains in episodic memory in young children. Using diffusion weighted imaging, we examined whether white matter connectivity between brain regions implicated in episodic memory differed with age, and were associated with memory performance differences in 4- and 6-year-old children. Results revealed that white matter connecting the hippocampus to the inferior parietal lobule significantly predicted children's performance on episodic memory tasks. In contrast, variation in the white matter connecting the hippocampus to the medial prefrontal cortex did not relate to memory performance. These findings suggest that structural connectivity between the hippocampus and lateral parietal regions is relevant to the development of episodic memory. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

White matter structural connectivity and episodic memory in early childhood

Directory of Open Access Journals (Sweden)

Chi T. Ngo

2017-12-01

Full Text Available Episodic memory undergoes dramatic improvement in early childhood; the reason for this is poorly understood. In adults, episodic memory relies on a distributed neural network. Key brain regions that supporting these processes include the hippocampus, portions of the parietal cortex, and portions of prefrontal cortex, each of which shows different developmental profiles. Here we asked whether developmental differences in the axonal pathways connecting these regions may account for the robust gains in episodic memory in young children. Using diffusion weighted imaging, we examined whether white matter connectivity between brain regions implicated in episodic memory differed with age, and were associated with memory performance differences in 4- and 6-year-old children. Results revealed that white matter connecting the hippocampus to the inferior parietal lobule significantly predicted children’s performance on episodic memory tasks. In contrast, variation in the white matter connecting the hippocampus to the medial prefrontal cortex did not relate to memory performance. These findings suggest that structural connectivity between the hippocampus and lateral parietal regions is relevant to the development of episodic memory. Keywords: White matter, Memory development, Episodic memory, Diffusion weighted imaging

Structural Connectivity Asymmetry in the Neonatal Brain

OpenAIRE

Ratnarajah, Nagulan; Rifkin-Graboi, Anne; Fortier, Marielle V.; Chong, Yap Seng; Kwek, Kenneth; Saw, Seang-Mei; Godfrey, Keith M; Gluckman, Peter D.; Meaney, Michael J.; Qiu, Anqi

2013-01-01

Asymmetry of the neonatal brain is not yet understood at the level of structural connectivity. We utilized DTI deterministic tractography and structural network analysis based on graph theory to determine the pattern of structural connectivity asymmetry in 124 normal neonates. We tracted white matter axonal pathways characterizing interregional connections among brain regions and inferred asymmetry in left and right anatomical network properties. Our findings revealed that in neonates, small-...

Patterns of deep-sea genetic connectivity in the New Zealand region: implications for management of benthic ecosystems.

Directory of Open Access Journals (Sweden)

Eleanor K Bors

Full Text Available Patterns of genetic connectivity are increasingly considered in the design of marine protected areas (MPAs in both shallow and deep water. In the New Zealand Exclusive Economic Zone (EEZ, deep-sea communities at upper bathyal depths (<2000 m are vulnerable to anthropogenic disturbance from fishing and potential mining operations. Currently, patterns of genetic connectivity among deep-sea populations throughout New Zealand's EEZ are not well understood. Using the mitochondrial Cytochrome Oxidase I and 16S rRNA genes as genetic markers, this study aimed to elucidate patterns of genetic connectivity among populations of two common benthic invertebrates with contrasting life history strategies. Populations of the squat lobster Munida gracilis and the polychaete Hyalinoecia longibranchiata were sampled from continental slope, seamount, and offshore rise habitats on the Chatham Rise, Hikurangi Margin, and Challenger Plateau. For the polychaete, significant population structure was detected among distinct populations on the Chatham Rise, the Hikurangi Margin, and the Challenger Plateau. Significant genetic differences existed between slope and seamount populations on the Hikurangi Margin, as did evidence of population differentiation between the northeast and southwest parts of the Chatham Rise. In contrast, no significant population structure was detected across the study area for the squat lobster. Patterns of genetic connectivity in Hyalinoecia longibranchiata are likely influenced by a number of factors including current regimes that operate on varying spatial and temporal scales to produce potential barriers to dispersal. The striking difference in population structure between species can be attributed to differences in life history strategies. The results of this study are discussed in the context of existing conservation areas that are intended to manage anthropogenic threats to deep-sea benthic communities in the New Zealand region.

Impairments of thalamic resting-state functional connectivity in patients with chronic tinnitus

Energy Technology Data Exchange (ETDEWEB)

Zhang, Jian [Jiangsu Key Laboratory of Molecular and Functional Imaging, Department of Radiology, Zhongda Hospital, Medical School, Southeast University, Nanjing (China); Chen, Yu-Chen [Jiangsu Key Laboratory of Molecular and Functional Imaging, Department of Radiology, Zhongda Hospital, Medical School, Southeast University, Nanjing (China); Center for Hearing and Deafness, University at Buffalo, State University of New York, Buffalo, NY (United States); Feng, Xu [Department of Otolaryngology, Zhongda Hospital, Medical School, Southeast University, Nanjing (China); Yang, Ming; Liu, Bin; Qian, Cheng [Jiangsu Key Laboratory of Molecular and Functional Imaging, Department of Radiology, Zhongda Hospital, Medical School, Southeast University, Nanjing (China); Wang, Jian [Department of Physiology, Southeast University, Nanjing (China); School of Human Communication Disorders, Dalhousie University, Halifax, NS (Canada); Salvi, Richard [Center for Hearing and Deafness, University at Buffalo, State University of New York, Buffalo, NY (United States); Teng, Gao-Jun, E-mail: gjteng@vip.sina.com [Jiangsu Key Laboratory of Molecular and Functional Imaging, Department of Radiology, Zhongda Hospital, Medical School, Southeast University, Nanjing (China)

2015-07-15

Highlights: • Tinnitus patients have aberrant thalamic connectivity to many brain regions. • Decreased thalamic connectivity is linked with tinnitus characteristics. • Thalamocortical connectivity disturbances can reflect tinnitus-related networks. - Abstract: Purpose: The phantom sound of tinnitus is believed to arise from abnormal functional coupling between the thalamus and cerebral cortex. To explore this hypothesis, we used resting-state functional magnetic resonance imaging (fMRI) to compare the degree of thalamocortical functional connectivity in chronic tinnitus patients and controls. Materials and methods: Resting-state fMRI scans were obtained from 31 chronic tinnitus patients and 33 well-matched healthy controls. Thalamocortical functional connectivity was characterized using a seed-based whole-brain correlation method. The resulting thalamic functional connectivity measures were correlated with other clinical data. Results: We found decreased functional connectivity between the seed region in left thalamus and right middle temporal gyrus (MTG), right middle orbitofrontal cortex, left middle frontal gyrus, right precentral gyrus, and bilateral calcarine cortex. Decreased functional connectivity was detected between the seed in the right thalamus and the left superior temporal gyrus (STG), left amygdala, right superior frontal gyrus, left precentral gyrus, and left middle occipital gyrus. Tinnitus distress correlated negatively with thalamic functional connectivity in right MTG; tinnitus duration correlated negatively with thalamic functional connectivity in left STG. Increased functional connectivity between the bilateral thalamus and a set of regions were also observed. Conclusions: Chronic tinnitus patients have disrupted thalamocortical functional connectivity to selected brain regions which is associated with specific tinnitus characteristics. Resting-state thalamic functional connectivity disturbances may play an important role in

Impairments of thalamic resting-state functional connectivity in patients with chronic tinnitus

International Nuclear Information System (INIS)

Zhang, Jian; Chen, Yu-Chen; Feng, Xu; Yang, Ming; Liu, Bin; Qian, Cheng; Wang, Jian; Salvi, Richard; Teng, Gao-Jun

2015-01-01

Highlights: • Tinnitus patients have aberrant thalamic connectivity to many brain regions. • Decreased thalamic connectivity is linked with tinnitus characteristics. • Thalamocortical connectivity disturbances can reflect tinnitus-related networks. - Abstract: Purpose: The phantom sound of tinnitus is believed to arise from abnormal functional coupling between the thalamus and cerebral cortex. To explore this hypothesis, we used resting-state functional magnetic resonance imaging (fMRI) to compare the degree of thalamocortical functional connectivity in chronic tinnitus patients and controls. Materials and methods: Resting-state fMRI scans were obtained from 31 chronic tinnitus patients and 33 well-matched healthy controls. Thalamocortical functional connectivity was characterized using a seed-based whole-brain correlation method. The resulting thalamic functional connectivity measures were correlated with other clinical data. Results: We found decreased functional connectivity between the seed region in left thalamus and right middle temporal gyrus (MTG), right middle orbitofrontal cortex, left middle frontal gyrus, right precentral gyrus, and bilateral calcarine cortex. Decreased functional connectivity was detected between the seed in the right thalamus and the left superior temporal gyrus (STG), left amygdala, right superior frontal gyrus, left precentral gyrus, and left middle occipital gyrus. Tinnitus distress correlated negatively with thalamic functional connectivity in right MTG; tinnitus duration correlated negatively with thalamic functional connectivity in left STG. Increased functional connectivity between the bilateral thalamus and a set of regions were also observed. Conclusions: Chronic tinnitus patients have disrupted thalamocortical functional connectivity to selected brain regions which is associated with specific tinnitus characteristics. Resting-state thalamic functional connectivity disturbances may play an important role in

Protein Connectivity in Chemotaxis Receptor Complexes.

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Stephan Eismann

2015-12-01

Full Text Available The chemotaxis sensory system allows bacteria such as Escherichia coli to swim towards nutrients and away from repellents. The underlying pathway is remarkably sensitive in detecting chemical gradients over a wide range of ambient concentrations. Interactions among receptors, which are predominantly clustered at the cell poles, are crucial to this sensitivity. Although it has been suggested that the kinase CheA and the adapter protein CheW are integral for receptor connectivity, the exact coupling mechanism remains unclear. Here, we present a statistical-mechanics approach to model the receptor linkage mechanism itself, building on nanodisc and electron cryotomography experiments. Specifically, we investigate how the sensing behavior of mixed receptor clusters is affected by variations in the expression levels of CheA and CheW at a constant receptor density in the membrane. Our model compares favorably with dose-response curves from in vivo Förster resonance energy transfer (FRET measurements, demonstrating that the receptor-methylation level has only minor effects on receptor cooperativity. Importantly, our model provides an explanation for the non-intuitive conclusion that the receptor cooperativity decreases with increasing levels of CheA, a core signaling protein associated with the receptors, whereas the receptor cooperativity increases with increasing levels of CheW, a key adapter protein. Finally, we propose an evolutionary advantage as explanation for the recently suggested CheW-only linker structures.

Dynamics differentiate between active and inactive inteins.

Science.gov (United States)

Cronin, Melissa; Coolbaugh, Michael J; Nellis, David; Zhu, Jianwei; Wood, David W; Nussinov, Ruth; Ma, Buyong

2015-02-16

The balance between stability and dynamics for active enzymes can be somewhat quantified by studies of intein splicing and cleaving reactions. Inteins catalyze the ligation of flanking host exteins while excising themselves. The potential for applications led to engineering of a mini-intein splicing domain, where the homing endonuclease domain of the Mycobacterium tuberculosis RecA (Mtu recA) intein was removed. The remaining domains were linked by several short peptides, but splicing activity in all was substantially lower than the full-length intein. Native splicing activity was restored in some cases by a V67L mutation. Using computations and experiments, we examine the impact of this mutation on the stability and conformational dynamics of the mini-intein splicing domain. Molecular dynamics simulations were used to delineate the factors that determine the active state, including the V67L mini-intein mutant, and peptide linker. We found that (1) the V67L mutation lowers the global fluctuations in all modeled mini-inteins, stabilizing the mini-intein constructs; (2) the connecting linker length affects intein dynamics; and (3) the flexibilities of the linker and intein core are higher in the active structure. We have observed that the interaction of the linker region and a turn region around residues 35-41 provides the pathway for the allostery interaction. Our experiments reveal that intein catalysis is characterized by non-linear Arrhenius plot, confirming the significant contribution of protein conformational dynamics to intein function. We conclude that while the V67L mutation stabilizes the global structure, cooperative dynamics of all intein regions appear more important for intein function than high stability. Our studies suggest that effectively quenching the conformational dynamics of an intein through engineered allosteric interactions could deactivate intein splicing or cleaving. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Generalized stability regions of current control for LCL-filtered grid-connected converters without passive or active damping

DEFF Research Database (Denmark)

Tang, Yi; Yoon, Changwoo; Zhu, Rongwu

2015-01-01

This paper investigates the stability regions of current control for LCL-filtered grid-connected converters, where no active or passive damping is required to stabilize the closed-loop control system. It is already identified in the literature that if the LCL resonance frequency is placed within 1....../6 to 1/2 of the system sampling frequency, the grid current control can be directly used without damping. If the resonance frequency is smaller than 1/6 of the sampling frequency, the converter current control should then be adopted. This paper further extends the analysis to the cases where...... the resonance frequency could be larger than 1/2 of the sampling frequency, and derives the complete stability regions for both grid and converter current control. Interestingly, it is found that for any given LCL-filter design, there will always be one stable current control design without any damping, which...

Advanced Connectivity Analysis (ACA): a Large Scale Functional Connectivity Data Mining Environment.

Science.gov (United States)

Chen, Rong; Nixon, Erika; Herskovits, Edward

2016-04-01

Using resting-state functional magnetic resonance imaging (rs-fMRI) to study functional connectivity is of great importance to understand normal development and function as well as a host of neurological and psychiatric disorders. Seed-based analysis is one of the most widely used rs-fMRI analysis methods. Here we describe a freely available large scale functional connectivity data mining software package called Advanced Connectivity Analysis (ACA). ACA enables large-scale seed-based analysis and brain-behavior analysis. It can seamlessly examine a large number of seed regions with minimal user input. ACA has a brain-behavior analysis component to delineate associations among imaging biomarkers and one or more behavioral variables. We demonstrate applications of ACA to rs-fMRI data sets from a study of autism.

The regional exploration of pulmonary function using xenon 133. Value of the gamma camera connected to a computer

International Nuclear Information System (INIS)

Moyses, B.; Gerard, G.; Methlin, G.; Weitzenblum, E.

1978-01-01

Regional isotopic exploration of ventilation and pulmonary perfusion is not yet widely applied in clinical practice, by virtue of the complexity of the equipment required, but also because of the complicated and lengthy analysis of the results. In this respect, connection of the scintillation camera to a computer represents a major advance which other authors have already emphasized. Our own experience in this area and our method of exploration in a group of 43 cases of chronic obstructive lung disease (33 patients of the chronic bronchitis type, 10 patients with emphysema) are analysed and discussed. The results indicate the following: in chronic bronchitis, a very marked fall in ventilation of the bases with inversion of the normal vertical ventilation gradient, and a fall in the ventilation/perfusion ratio of the bases; in emphysema, a fall in ventilation, but also and above all in regional perfusion of all territories with preservation of normal or even increased regional ventilation/perfusion ratios. Regional exploration may also be of value in the detection of early stages of obstructive lung disease, and in pre-operative assessment in thoracic surgery [fr

Sensing coral reef connectivity pathways from space

KAUST Repository

Raitsos, Dionysios E.; Brewin, Robert J. W.; Zhan, Peng; Dreano, Denis; Pradhan, Yaswant; Nanninga, Gerrit B.; Hoteit, Ibrahim

2017-01-01

Coral reefs rely on inter-habitat connectivity to maintain gene flow, biodiversity and ecosystem resilience. Coral reef communities of the Red Sea exhibit remarkable genetic homogeneity across most of the Arabian Peninsula coastline, with a genetic break towards the southern part of the basin. While previous studies have attributed these patterns to environmental heterogeneity, we hypothesize that they may also emerge as a result of dynamic circulation flow; yet, such linkages remain undemonstrated. Here, we integrate satellite-derived biophysical observations, particle dispersion model simulations, genetic population data and ship-borne in situ profiles to assess reef connectivity in the Red Sea. We simulated long-term (>20 yrs.) connectivity patterns driven by remotely-sensed sea surface height and evaluated results against estimates of genetic distance among populations of anemonefish, Amphiprion bicinctus, along the eastern Red Sea coastline. Predicted connectivity was remarkably consistent with genetic population data, demonstrating that circulation features (eddies, surface currents) formulate physical pathways for gene flow. The southern basin has lower physical connectivity than elsewhere, agreeing with known genetic structure of coral reef organisms. The central Red Sea provides key source regions, meriting conservation priority. Our analysis demonstrates a cost-effective tool to estimate biophysical connectivity remotely, supporting coastal management in data-limited regions.

Sensing coral reef connectivity pathways from space

KAUST Repository

Raitsos, Dionysios E.

2017-08-18

Coral reefs rely on inter-habitat connectivity to maintain gene flow, biodiversity and ecosystem resilience. Coral reef communities of the Red Sea exhibit remarkable genetic homogeneity across most of the Arabian Peninsula coastline, with a genetic break towards the southern part of the basin. While previous studies have attributed these patterns to environmental heterogeneity, we hypothesize that they may also emerge as a result of dynamic circulation flow; yet, such linkages remain undemonstrated. Here, we integrate satellite-derived biophysical observations, particle dispersion model simulations, genetic population data and ship-borne in situ profiles to assess reef connectivity in the Red Sea. We simulated long-term (>20 yrs.) connectivity patterns driven by remotely-sensed sea surface height and evaluated results against estimates of genetic distance among populations of anemonefish, Amphiprion bicinctus, along the eastern Red Sea coastline. Predicted connectivity was remarkably consistent with genetic population data, demonstrating that circulation features (eddies, surface currents) formulate physical pathways for gene flow. The southern basin has lower physical connectivity than elsewhere, agreeing with known genetic structure of coral reef organisms. The central Red Sea provides key source regions, meriting conservation priority. Our analysis demonstrates a cost-effective tool to estimate biophysical connectivity remotely, supporting coastal management in data-limited regions.

The First Extracellular Linker Is Important for Several Aspects of the Gating Mechanism of Human TRPA1 Channel

Czech Academy of Sciences Publication Activity Database

Maršáková, Lenka; Barvík, I.; Zíma, V.; Zímová, Lucie; Vlachová, Viktorie

2017-01-01

Roč. 10, Jan 31 (2017), č. článku 16. ISSN 1662-5099 R&D Projects: GA ČR(CZ) GA15-15839S; GA ČR(CZ) GBP304/12/G069; GA MŠk(CZ) EE2.3.30.0025 Institutional support: RVO:67985823 Keywords : TRP channel * S1-S2 linker * allyl isothiocynate * sensor module Subject RIV: FH - Neurology OBOR OECD: Neuroscience s (including psychophysiology Impact factor: 5.076, year: 2016

Metabolic connectivity mapping reveals effective connectivity in the resting human brain.

Science.gov (United States)

Riedl, Valentin; Utz, Lukas; Castrillón, Gabriel; Grimmer, Timo; Rauschecker, Josef P; Ploner, Markus; Friston, Karl J; Drzezga, Alexander; Sorg, Christian

2016-01-12

Directionality of signaling among brain regions provides essential information about human cognition and disease states. Assessing such effective connectivity (EC) across brain states using functional magnetic resonance imaging (fMRI) alone has proven difficult, however. We propose a novel measure of EC, termed metabolic connectivity mapping (MCM), that integrates undirected functional connectivity (FC) with local energy metabolism from fMRI and positron emission tomography (PET) data acquired simultaneously. This method is based on the concept that most energy required for neuronal communication is consumed postsynaptically, i.e., at the target neurons. We investigated MCM and possible changes in EC within the physiological range using "eyes open" versus "eyes closed" conditions in healthy subjects. Independent of condition, MCM reliably detected stable and bidirectional communication between early and higher visual regions. Moreover, we found stable top-down signaling from a frontoparietal network including frontal eye fields. In contrast, we found additional top-down signaling from all major clusters of the salience network to early visual cortex only in the eyes open condition. MCM revealed consistent bidirectional and unidirectional signaling across the entire cortex, along with prominent changes in network interactions across two simple brain states. We propose MCM as a novel approach for inferring EC from neuronal energy metabolism that is ideally suited to study signaling hierarchies in the brain and their defects in brain disorders.

Age Differences in the Intrinsic Functional Connectivity of Default Network Subsystems

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Karen eCampbell

2013-11-01

Full Text Available Recent work suggests that the default mode network (DMN includes two core regions, the ventromedial prefrontal cortex (vmPFC and posterior cingulate cortex (PCC, and several unique subsystems that are functionally distinct. These include a medial temporal lobe (MTL subsystem, active during remembering and future projection, and a dorsomedial PFC (dmPFC subsystem, active during self-reference. The PCC has been further subdivided into ventral (vPCC and dorsal (dPCC regions that are more strongly connected with the DMN and cognitive control networks, respectively. The goal of this study was to examine age differences in resting state functional connectivity within these subsystems. After applying a rigorous procedure to reduce the effects of head motion, we used a multivariate technique to identify both common and unique patterns of functional connectivity in the MTL vs. the dmPFC, and in vPCC vs. dPCC. All four areas had robust functional connectivity with other DMN regions, and each also showed distinct connectivity patterns in both age groups. Young and older adults had equivalent functional connectivity in the MTL subsystem. Older adults showed weaker connectivity in the vPCC and dmPFC subsystems, particularly with other DMN areas, but stronger connectivity than younger adults in the dPCC subsystem, which included areas involved in cognitive control. Our data provide evidence for distinct subsystems involving DMN nodes, which are maintained with age. Nevertheless, there are age differences in the strength of functional connectivity within these subsystems, supporting prior evidence that DMN connectivity is particularly vulnerable to age, whereas connectivity involving cognitive control regions is relatively maintained. These results suggest an age difference in the integrated activity among brain networks that can have implications for cognition in older adults.

The Cortical Connectivity of the Prefrontal Cortex in the Monkey Brain

Science.gov (United States)

Yeterian, Edward H.; Pandya, Deepak N.; Tomaiuolo, Francesco; Petrides, Michael

2011-01-01

One dimension of understanding the functions of the prefrontal cortex is knowledge of cortical connectivity. We have surveyed three aspects of prefrontal cortical connections: local projections (within the frontal lobe), the termination patterns of long association (post-Rolandic) projections, and the trajectories of major fiber pathways. The local connections appear to be organized in relation to dorsal (hippocampal origin) and ventral (paleocortical origin) architectonic trends. According to the proposal of a dual origin of the cerebral cortex, cortical areas can be traced as originating from archicortex (hippocampus) on the one hand, and paleocortex, on the other hand, in a stepwise manner (e.g., Sanides, 1969; Pandya and Yeterian, 1985). Prefrontal areas within each trend are connected with less architectonically differentiated areas, and, on the other hand, with more differentiated areas. Such organization may allow for the systematic exchange of information within each architectonic trend. The long connections of the prefrontal cortex with post-Rolandic regions seem to be organized preferentially in relation to dorsal and ventral prefrontal architectonic trends. Prefrontal areas are connected with post-Rolandic auditory, visual and somatosensory association areas, and with multimodal and paralimbic regions. This long connectivity likely works in conjunction with local connections to serve prefrontal cortical functions. The afferent and efferent connections of the prefrontal cortex with post-Rolandic regions are conveyed by specific long association pathways. These pathways as well appear to be organized in relation to dorsal and ventral prefrontal architectonic trends. Finally, although prefrontal areas have preferential connections in relation to dual architectonic trends, it is clear that there are interconnections between and among areas in each trend, which may provide a substrate for the overall integrative function of the prefrontal cortex. Prefrontal

Pramipexole Modulates Interregional Connectivity Within the Sensorimotor Network.

Science.gov (United States)

Ye, Zheng; Hammer, Anke; Münte, Thomas F

2017-05-01

Pramipexole is widely prescribed to treat Parkinson's disease but has been reported to cause impulse control disorders such as pathological gambling. Recent neurocomputational models suggested that D2 agonists may distort functional connections between the striatum and the motor cortex, resulting in impaired reinforcement learning and pathological gambling. To examine how D2 agonists modulate the striatal-motor connectivity, we carried out a pharmacological resting-state functional magnetic resonance imaging study with a double-blind randomized within-subject crossover design. We analyzed the medication-induced changes of network connectivity and topology with two approaches, an independent component analysis (ICA) and a graph theoretical analysis (GTA). The ICA identified the sensorimotor network (SMN) as well as other classical resting-state networks. Within the SMN, the connectivity between the right caudate nucleus and other cortical regions was weaker under pramipexole than under placebo. The GTA measured the topological properties of the whole-brain network at global and regional levels. Both the whole-brain network under placebo and that under pramipexole were identified as small-world networks. The two whole-brain networks were similar in global efficiency, clustering coefficient, small-world index, and modularity. However, the degree of the right caudate nucleus decreased under pramipexole mainly due to the loss of the connectivity with the supplementary motor area, paracentral lobule, and precentral and postcentral gyrus of the SMN. The two network analyses consistently revealed that pramipexole weakened the functional connectivity between the caudate nucleus and the SMN regions.

Extrinsic and Intrinsic Brain Network Connectivity Maintains Cognition across the Lifespan Despite Accelerated Decay of Regional Brain Activation.

Science.gov (United States)

Tsvetanov, Kamen A; Henson, Richard N A; Tyler, Lorraine K; Razi, Adeel; Geerligs, Linda; Ham, Timothy E; Rowe, James B

2016-03-16

-based cohort (n = 602, 18-88 years), separating neural connectivity from vascular components of fMRI signals. Cognitive ability was influenced by the strength of connection within and between functional brain networks, and this positive relationship increased with age. In older adults, there was more rapid decay of intrinsic neuronal activity in multiple regions of the brain networks, which related to cognitive performance. Our data demonstrate increased reliance on network flexibility to maintain cognitive function, in the presence of more rapid decay of neural activity. These insights will facilitate the development of new strategies to maintain cognitive ability. Copyright © 2016 Tsvetanov et al.

Intrinsic brain connectivity related to age in young and middle aged adults.

Directory of Open Access Journals (Sweden)

Michelle Hampson

Full Text Available Age-related variations in resting state connectivity of the human brain were examined from young adulthood through middle age. A voxel-based network measure, degree, was used to assess age-related differences in tissue connectivity throughout the brain. Increases in connectivity with age were found in paralimbic cortical and subcortical regions. Decreases in connectivity were found in cortical regions, including visual areas and the default mode network. These findings differ from those of recent developmental studies examining earlier growth trajectories, and are consistent with known changes in cognitive function and emotional processing during mature aging. The results support and extend previous findings that relied on a priori definitions of regions of interest for their analyses. This approach of applying a voxel-based measure to examine the functional connectivity of individual tissue elements over time, without the need for a priori region of interest definitions, provides an important new tool in brain science.

The specificity of Av3 sea anemone toxin for arthropods is determined at linker DI/SS2-S6 in the pore module of target sodium channels.

Science.gov (United States)

Gur Barzilai, Maya; Kahn, Roy; Regev, Noa; Gordon, Dalia; Moran, Yehu; Gurevitz, Michael

2014-10-15

Av3 is a peptide neurotoxin from the sea anemone Anemonia viridis that shows specificity for arthropod voltage-gated sodium channels (Navs). Interestingly, Av3 competes with a scorpion α-toxin on binding to insect Navs and similarly inhibits the inactivation process, and thus has been classified as 'receptor site-3 toxin', although the two peptides are structurally unrelated. This raises questions as to commonalities and differences in the way both toxins interact with Navs. Recently, site-3 was partly resolved for scorpion α-toxins highlighting S1-S2 and S3-S4 external linkers at the DIV voltage-sensor module and the juxtaposed external linkers at the DI pore module. To uncover channel determinants involved in Av3 specificity for arthropods, the toxin was examined on channel chimaeras constructed with the external linkers of the mammalian brain Nav1.2a, which is insensitive to Av3, in the background of the Drosophila DmNav1. This approach highlighted the role of linker DI/SS2-S6, adjacent to the channel pore, in determining Av3 specificity. Point mutagenesis at DI/SS2-S6 accompanied by functional assays highlighted Trp404 and His405 as a putative point of Av3 interaction with DmNav1. His405 conservation in arthropod Navs compared with tyrosine in vertebrate Navs may represent an ancient substitution that explains the contemporary selectivity of Av3. Trp404 and His405 localization near the membrane surface and the hydrophobic bioactive surface of Av3 suggest that the toxin possibly binds at a cleft by DI/S6. A partial overlap in receptor site-3 of both toxins nearby DI/S6 may explain their binding competition capabilities.

Sex-related differences in amygdala functional connectivity during resting conditions.

Science.gov (United States)

Kilpatrick, L A; Zald, D H; Pardo, J V; Cahill, L F

2006-04-01

Recent neuroimaging studies have established a sex-related hemispheric lateralization of amygdala involvement in memory for emotionally arousing material. Here, we examine the possibility that sex-related differences in amygdala involvement in memory for emotional material develop from differential patterns of amygdala functional connectivity evident in the resting brain. Seed voxel partial least square analyses of regional cerebral blood flow data revealed significant sex-related differences in amygdala functional connectivity during resting conditions. The right amygdala was associated with greater functional connectivity in men than in women. In contrast, the left amygdala was associated with greater functional connectivity in women than in men. Furthermore, the regions displaying stronger functional connectivity with the right amygdala in males (sensorimotor cortex, striatum, pulvinar) differed from those displaying stronger functional connectivity with the left amygdala in females (subgenual cortex, hypothalamus). These differences in functional connectivity at rest may link to sex-related differences in medical and psychiatric disorders.

Medial vestibular connections with the hypocretin (orexin) system

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Horowitz, Seth S.; Blanchard, Jane; Morin, Lawrence P.

2005-01-01

The mammalian medial vestibular nucleus (MVe) receives input from all vestibular endorgans and provides extensive projections to the central nervous system. Recent studies have demonstrated projections from the MVe to the circadian rhythm system. In addition, there are known projections from the MVe to regions considered to be involved in sleep and arousal. In this study, afferent and efferent subcortical connectivity of the medial vestibular nucleus of the golden hamster (Mesocricetus auratus) was evaluated using cholera toxin subunit-B (retrograde), Phaseolus vulgaris leucoagglutinin (anterograde), and pseudorabies virus (transneuronal retrograde) tract-tracing techniques. The results demonstrate MVe connections with regions mediating visuomotor and postural control, as previously observed in other mammals. The data also identify extensive projections from the MVe to regions mediating arousal and sleep-related functions, most of which receive immunohistochemically identified projections from the lateral hypothalamic hypocretin (orexin) neurons. These include the locus coeruleus, dorsal and pedunculopontine tegmental nuclei, dorsal raphe, and lateral preoptic area. The MVe itself receives a projection from hypocretin cells. CTB tracing demonstrated reciprocal connections between the MVe and most brain areas receiving MVe efferents. Virus tracing confirmed and extended the MVe afferent connections identified with CTB and additionally demonstrated transneuronal connectivity with the suprachiasmatic nucleus and the medial habenular nucleus. These anatomical data indicate that the vestibular system has access to a broad array of neural functions not typically associated with visuomotor, balance, or equilibrium, and that the MVe is likely to receive information from many of the same regions to which it projects.

Random Interchange of Magnetic Connectivity

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Matthaeus, W. H.; Ruffolo, D. J.; Servidio, S.; Wan, M.; Rappazzo, A. F.

2015-12-01

Magnetic connectivity, the connection between two points along a magnetic field line, has a stochastic character associated with field lines random walking in space due to magnetic fluctuations, but connectivity can also change in time due to dynamical activity [1]. For fluctuations transverse to a strong mean field, this connectivity change be caused by stochastic interchange due to component reconnection. The process may be understood approximately by formulating a diffusion-like Fokker-Planck coefficient [2] that is asymptotically related to standard field line random walk. Quantitative estimates are provided, for transverse magnetic field models and anisotropic models such as reduced magnetohydrodynamics. In heliospheric applications, these estimates may be useful for understanding mixing between open and close field line regions near coronal hole boundaries, and large latitude excursions of connectivity associated with turbulence. [1] A. F. Rappazzo, W. H. Matthaeus, D. Ruffolo, S. Servidio & M. Velli, ApJL, 758, L14 (2012) [2] D. Ruffolo & W. Matthaeus, ApJ, 806, 233 (2015)

Direct Modulation Of Aberrant Brain Network Connectivity Through Real-Time NeuroFeedback

OpenAIRE

White, Emily; Popal, Haroon; Roopchansingh, Vinai; Gonzalez-Castillo, Javier; Kimmich, Sara; Ramot, Michal; Martin Ph.D., Alex; Gotts, Stephen

2017-01-01

eLife digest Even when we are at rest, our brains are always active. For example, areas of the brain involved in vision remain active in complete darkness. Different brain regions that connect together to perform a given task often show coordinated activity at rest. Past studies have shown that these resting connections are different in people with conditions such as autism. Some brain regions are more weakly connected while others are more strongly connected in people with autism spectrum di...

Effect of the Linker in Terephthalate-Functionalized Conducting Redox Polymers

International Nuclear Information System (INIS)

Yang, Li; Huang, Xiao; Gogoll, Adolf; Strømme, Maria; Sjödin, Martin

2016-01-01

The combination of high capacity redox active pendent groups and conducting polymers, realized in conducting redox polymers (CRPs), provides materials with high charge storage capacity that are electronically conducting which makes CRPs attractive for electrical energy storage applications. In this report, six polythiophene and poly(3,4-ethylenedioxythiophene)(PEDOT)-based CRPs with a diethyl terephthalate unit covalently bound to the polymer chain by various linkers have been synthesized and characterized electrochemically. The effects of the choice of polymer backbone and of the nature of the link on the electrochemistry, and in particular the cycling stability of these polymers, are discussed. All CRPs show both the doping of the polymer backbone as well as the redox behavior of the pendent groups and the redox potential of the pendent groups in the CRPs is close to that of corresponding monomer, indicating insignificant interaction between the pendant and the polymer backbone. While all CRPs show various degrees of charge decay upon electrochemical redox conversion, the PEDOT-based CRPs show significantly improved stability compared to the polythiophene counterparts. Moreover, we show that by the right choice of link the cycling stability of diethyl terephthalate substituted PEDOT-based CRPs can be significantly improved.

Dissociation Behavior of a TEMPO-Active Ester Cross-Linker for Peptide Structure Analysis by Free Radical Initiated Peptide Sequencing (FRIPS) in Negative ESI-MS.

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Hage, Christoph; Ihling, Christian H; Götze, Michael; Schäfer, Mathias; Sinz, Andrea

2017-01-01

We have synthesized a homobifunctional amine-reactive cross-linking reagent, containing a TEMPO (2,2,6,6-tetramethylpiperidine-1-oxy) and a benzyl group (Bz), termed TEMPO-Bz-linker, to derive three-dimensional structural information of proteins. The aim for designing this novel cross-linker was to facilitate the mass spectrometric analysis of cross-linked products by free radical initiated peptide sequencing (FRIPS). In an initial study, we had investigated the fragmentation behavior of TEMPO-Bz-derivatized peptides upon collision activation in (+)-electrospray ionization collision-induced dissociation tandem mass spectrometry (ESI-CID-MS/MS) experiments. In addition to the homolytic NO-C bond cleavage FRIPS pathway delivering the desired odd-electron product ions, an alternative heterolytic NO-C bond cleavage, resulting in even-electron product ions mechanism was found to be relevant. The latter fragmentation route clearly depends on the protonation of the TEMPO-Bz-moiety itself, which motivated us to conduct (-)-ESI-MS, CID-MS/MS, and MS 3 experiments of TEMPO-Bz-cross-linked peptides to further clarify the fragmentation behavior of TEMPO-Bz-peptide molecular ions. We show that the TEMPO-Bz-linker is highly beneficial for conducting FRIPS in negative ionization mode as the desired homolytic cleavage of the NO-C bond is the major fragmentation pathway. Based on characteristic fragments, the isomeric amino acids leucine and isoleucine could be discriminated. Interestingly, we observed pronounced amino acid side chain losses in cross-linked peptides if the cross-linked peptides contain a high number of acidic amino acids. Graphical Abstract ᅟ.

Hyperthermia-induced disruption of functional connectivity in the human brain network.

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Gang Sun

Full Text Available BACKGROUND: Passive hyperthermia is a potential risk factor to human cognitive performance and work behavior in many extreme work environments. Previous studies have demonstrated significant effects of passive hyperthermia on human cognitive performance and work behavior. However, there is a lack of a clear understanding of the exact affected brain regions and inter-regional connectivities. METHODOLOGY AND PRINCIPAL FINDINGS: We simulated 1 hour environmental heat exposure to thirty-six participants under two environmental temperature conditions (25 °C and 50 °C, and collected resting-state functional brain activity. The functional connectivities with a preselected region of interest (ROI in the posterior cingulate cortex and precuneus (PCC/PCu, furthermore, inter-regional connectivities throughout the entire brain using a prior Anatomical Automatic Labeling (AAL atlas were calculated. We identified decreased correlations of a set of regions with the PCC/PCu, including the medial orbitofrontal cortex (mOFC and bilateral medial temporal cortex, as well as increased correlations with the partial orbitofrontal cortex particularly in the bilateral orbital superior frontal gyrus. Compared with the normal control (NC group, the hyperthermia (HT group showed 65 disturbed functional connectivities with 50 of them being decreased and 15 of them being increased. While the decreased correlations mainly involved with the mOFC, temporal lobe and occipital lobe, increased correlations were mainly located within the limbic system. In consideration of physiological system changes, we explored the correlations of the number of significantly altered inter-regional connectivities with differential rectal temperatures and weight loss, but failed to obtain significant correlations. More importantly, during the attention network test (ANT we found that the number of significantly altered functional connectivities was positively correlated with an increase in

Connectivity and functional profiling of abnormal brain structures in pedophilia.

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Poeppl, Timm B; Eickhoff, Simon B; Fox, Peter T; Laird, Angela R; Rupprecht, Rainer; Langguth, Berthold; Bzdok, Danilo

2015-06-01

Despite its 0.5-1% lifetime prevalence in men and its general societal relevance, neuroimaging investigations in pedophilia are scarce. Preliminary findings indicate abnormal brain structure and function. However, no study has yet linked structural alterations in pedophiles to both connectional and functional properties of the aberrant hotspots. The relationship between morphological alterations and brain function in pedophilia as well as their contribution to its psychopathology thus remain unclear. First, we assessed bimodal connectivity of structurally altered candidate regions using meta-analytic connectivity modeling (MACM) and resting-state correlations employing openly accessible data. We compared the ensuing connectivity maps to the activation likelihood estimation (ALE) maps of a recent quantitative meta-analysis of brain activity during processing of sexual stimuli. Second, we functionally characterized the structurally altered regions employing meta-data of a large-scale neuroimaging database. Candidate regions were functionally connected to key areas for processing of sexual stimuli. Moreover, we found that the functional role of structurally altered brain regions in pedophilia relates to nonsexual emotional as well as neurocognitive and executive functions, previously reported to be impaired in pedophiles. Our results suggest that structural brain alterations affect neural networks for sexual processing by way of disrupted functional connectivity, which may entail abnormal sexual arousal patterns. The findings moreover indicate that structural alterations account for common affective and neurocognitive impairments in pedophilia. The present multimodal integration of brain structure and function analyses links sexual and nonsexual psychopathology in pedophilia. © 2015 Wiley Periodicals, Inc.

Atypical functional connectivity in autism spectrum disorder is associated with disrupted white matter microstructural organisation

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Jane eMcGrath

2013-09-01

Full Text Available Disruption of structural and functional neural connectivity has been widely reported in Autism Spectrum Disorder (ASD but there is a striking lack of research attempting to integrate analysis of functional and structural connectivity in the same study population, an approach that may provide key insights into the specific neurobiological underpinnings of altered functional connectivity in autism. The aims of this study were 1. to determine whether functional connectivity abnormalities were associated with structural abnormalities of white matter (WM in ASD and 2. to examine the relationships between aberrant neural connectivity and behaviour in ASD. 22 individuals with ASD and 22 age, IQ-matched controls completed a high-angular-resolution diffusion MRI scan. Structural connectivity was analysed using constrained spherical deconvolution based tractography. Regions for tractography were generated from the results of a previous study, in which 10 pairs of brain regions showed abnormal functional connectivity during visuospatial processing in ASD. WM tracts directly connected 5 of the 10 region pairs that showed abnormal functional connectivity; linking a region in the left occipital lobe (left BA19 and five paired regions: left caudate head, left caudate body, left uncus, left thalamus and left cuneus. Measures of WM microstructural organisation were extracted from these tracts. Fractional anisotropy reductions in the ASD group relative to controls were significant for WM connecting left BA19 to left caudate head and left BA19 to left thalamus. Using a multimodal imaging approach, this study has revealed aberrant white matter microstructure in tracts that directly connect brain regions that are abnormally functionally connected in ASD. These results provide novel evidence to suggest that structural brain pathology may contribute 1. to abnormal functional connectivity and 2. to atypical visuospatial processing in ASD.

Assessment of the landscape connectivity of the Puuc-Chenes region, Mexico, based on the habitat requirements of jaguar (Panthera onca

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Eduardo Salazar

2017-03-01

Full Text Available The Yucatan Peninsula is included as part of the initiative for the Mesoamerican Biological Corridor. In its central area, are located three Protected Natural Areas (PNA: the Biocultural Puuc Reserve (RBP, by its Spanish acronym, the Bala’an K’aax flora and fauna protected area (APB, by its Spanish acronym, Quintana Roo, and the Calakmul Biosphere Reserve (RBC, by its Spanish acronym, Campeche. The Puuc-Chenes region is located in the center of the Yucatan Peninsula - among these PNAs - which included important fragments of vegetation that in the past formed a continuum through the forests of the Yucatan Peninsula, constituting an important link to keep the connectivity of the Mayan forest. However, the expansion of the agricultural frontier is causing the fragmentation of the habitat. In the present study, the structural and functional connectivity of the Puuc-Chenes region is analyzed, based on habitat requirements of the Panthera onca (jaguar by sex. Both, male and female, prefer tropical forest, however, P. onca males dare to transit in secondary vegetation and inclusively in agricultural areas. Males make inroads to villages more often than females, coming close to, and even crossing roads. P. onca males have a home range of 60 km2. In the present study, the ArcMap, FRAGSTATS and IDRISI software were used to analyses the structural and functional connectivity of the landscape, based on the known differences of habitat requirements for P. onca males and females. A vegetation and land use map of the studied area was elaborated, based on Landsat 7 ETM+ images, with 30 m size pixels. The following cover classes were differentiated: tropical forest, secondary forest, agriculture, urban, and water polls, which were validated in the fields. The Puuc-Chenes has an extension of 972 578 ha. Tropical forest was the dominant vegetation cover (49.8% with the largest patch index covering 19.7% of the total landscape. The landscape had 2 509 fragments

Functional Connectivity of Human Chewing

Science.gov (United States)

Quintero, A.; Ichesco, E.; Schutt, R.; Myers, C.; Peltier, S.; Gerstner, G.E.

2013-01-01

Mastication is one of the most important orofacial functions. The neurobiological mechanisms of masticatory control have been investigated in animal models, but less so in humans. This project used functional connectivity magnetic resonance imaging (fcMRI) to assess the positive temporal correlations among activated brain areas during a gum-chewing task. Twenty-nine healthy young-adults underwent an fcMRI scanning protocol while they chewed gum. Seed-based fcMRI analyses were performed with the motor cortex and cerebellum as regions of interest. Both left and right motor cortices were reciprocally functionally connected and functionally connected with the post-central gyrus, cerebellum, cingulate cortex, and precuneus. The cerebellar seeds showed functional connections with the contralateral cerebellar hemispheres, bilateral sensorimotor cortices, left superior temporal gyrus, and left cingulate cortex. These results are the first to identify functional central networks engaged during mastication. PMID:23355525

Default Mode Network Connectivity in Stroke Patients.

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Tuladhar, Anil Man; Snaphaan, Liselore; Shumskaya, Elena; Rijpkema, Mark; Fernandez, Guillén; Norris, David G; de Leeuw, Frank-Erik

2013-01-01

The pathophysiology of episodic memory dysfunction after infarction is not completely understood. It has been suggested that infarctions located anywhere in the brain can induce widespread effects causing disruption of functional networks of the cortical regions. The default mode network, which includes the medial temporal lobe, is a functional network that is associated with episodic memory processing. We investigated whether the default mode network activity is reduced in stroke patients compared to healthy control subjects in the resting state condition. We assessed the whole brain network properties during resting state functional MRI in 21 control subjects and 20 'first-ever' stroke patients. Patients were scanned 9-12 weeks after stroke onset. Stroke lesions were located in various parts of the brain. Independent component analyses were conducted to identify the default mode network and to compare the group differences of the default mode network. Furthermore, region-of-interest based analysis was performed to explore the functional connectivity between the regions of the default mode network. Stroke patients performed significantly worse than control subjects on the delayed recall score on California verbal learning test. We found decreased functional connectivity in the left medial temporal lobe, posterior cingulate and medial prefrontal cortical areas within the default mode network and reduced functional connectivity between these regions in stroke patients compared with controls. There were no significant volumetric differences between the groups. These results demonstrate that connectivity within the default mode network is reduced in 'first-ever' stroke patients compared to control subjects. This phenomenon might explain the occurrence of post-stroke cognitive dysfunction in stroke patients.

Effects of the amino acid linkers on the melanoma-targeting and pharmacokinetic properties of 111In-labeled lactam bridge-cyclized alpha-MSH peptides.

Science.gov (United States)

Guo, Haixun; Yang, Jianquan; Gallazzi, Fabio; Miao, Yubin

2011-04-01

The purpose of this study was to examine the profound effects of the amino acid linkers on the melanoma-targeting and pharmacokinetic properties of (111)In-labeled lactam bridge-cyclized DOTA-[X]-CycMSH(hex) {1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-[X]-c[Asp-His-dPhe-Arg-Trp-Lys]-CONH(2); X = GGNle, GENle, or NleGE; GG = -Gly-Gly- and GE = -Gly-Glu-} peptides. Three novel peptides (DOTA-GGNle-CycMSH(hex), DOTA-GENle-CycMSH(hex), and DOTA-NleGE-CycMSH(hex)) were designed and synthesized. The melanocortin-1 (MC1) receptor-binding affinities of the peptides were determined in B16/F1 melanoma cells. The melanoma-targeting and pharmacokinetic properties of (111)In-DOTA-GGNle-CycMSH(hex) and (111)In-DOTA-GENle-CycMSH(hex) were determined in B16/F1 melanoma-bearing C57 mice. DOTA-GGNle-CycMSH(hex) and DOTA-GENle-CycMSH(hex) displayed 2.1 and 11.5 nM MC1 receptor-binding affinities, whereas DOTA-NleGE-CycMSH(hex) showed 873.4 nM MC1 receptor-binding affinity. The introduction of the -GG- linker maintained high melanoma uptake while decreasing kidney and liver uptake of (111)In-DOTA-GGNle-CycMSH(hex). The tumor uptake of (111)In-DOTA-GGNle-CycMSH(hex) was 19.05 ± 5.04 and 18.6 ± 3.56 percentage injected dose per gram at 2 and 4 h after injection, respectively. (111)In-DOTA-GGNle-CycMSH(hex) exhibited 28%, 32%, and 42% less kidney uptake than (111)In-DOTA-Nle-CycMSH(hex) we reported previously, and 61%, 65%, and 68% less liver uptake than (111)In-DOTA-Nle-CycMSH(hex) at 2, 4, and 24 h after injection, respectively. The amino acid linkers exhibited profound effects on the melanoma-targeting and pharmacokinetic properties of the (111)In-labeled lactam bridge-cyclized α-melanocyte-stimulating hormone peptides. Introduction of the -GG- linker maintained high melanoma uptake while reducing kidney and liver uptake of (111)In-DOTA-GGNle-CycMSH(hex), highlighting its potential as an effective imaging probe for melanoma detection, as well as a therapeutic peptide

Geophysical Observatory in Kamchatka region for monitoring of phenomena connected with seismic activity

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S. Uyeda

2001-01-01

Full Text Available Regular monitoring of some geophysical parameters in association with seismicity has been carried out since last year at the Japan-Russian Complex Geophysical Observatory in the Kamchatka region. This observatory was organized in connection with the ISTC project in Russia and was motivated by the results of the FRONTIER/RIKEN and FRONTIER/NASDA research projects in Japan. The main purpose of the observations is to investigate the electromagnetic and acoustic phenomena induced by the lithosphere processes (especially by seismic activity. The seismicity of the Kamchatka area is analyzed and a description of the observatory equipment is presented. At present, the activity of the observatory includes the seismic (frequency range ∆F = 0.5 – 40 Hz and meteorological recordings, together with seismo-acoustic (∆F = 30 – 1000 Hz and electromagnetic observations: three-component magnetic ULF variations ( ∆F = 0.003 – 30 Hz, three-component electric potential variations ( ∆F 1.0 Hz, and VLF transmitter’s signal perturbations ( ∆F ~ 10 – 40 kHz.

A Multimodal Approach for Determining Brain Networks by Jointly Modeling Functional and Structural Connectivity

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Wenqiong eXue

2015-02-01

Full Text Available Recent innovations in neuroimaging technology have provided opportunities for researchers to investigate connectivity in the human brain by examining the anatomical circuitry as well as functional relationships between brain regions. Existing statistical approaches for connectivity generally examine resting-state or task-related functional connectivity (FC between brain regions or separately examine structural linkages. As a means to determine brain networks, we present a unified Bayesian framework for analyzing FC utilizing the knowledge of associated structural connections, which extends an approach by Patel et al.(2006a that considers only functional data. We introduce an FC measure that rests upon assessments of functional coherence between regional brain activity identified from functional magnetic resonance imaging (fMRI data. Our structural connectivity (SC information is drawn from diffusion tensor imaging (DTI data, which is used to quantify probabilities of SC between brain regions. We formulate a prior distribution for FC that depends upon the probability of SC between brain regions, with this dependence adhering to structural-functional links revealed by our fMRI and DTI data. We further characterize the functional hierarchy of functionally connected brain regions by defining an ascendancy measure that compares the marginal probabilities of elevated activity between regions. In addition, we describe topological properties of the network, which is composed of connected region pairs, by performing graph theoretic analyses. We demonstrate the use of our Bayesian model using fMRI and DTI data from a study of auditory processing. We further illustrate the advantages of our method by comparisons to methods that only incorporate functional information.

Interhemispheric functional connectivity in anorexia and bulimia nervosa.

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Canna, Antonietta; Prinster, Anna; Monteleone, Alessio Maria; Cantone, Elena; Monteleone, Palmiero; Volpe, Umberto; Maj, Mario; Di Salle, Francesco; Esposito, Fabrizio

2017-05-01

The functional interplay between hemispheres is fundamental for behavioral, cognitive, and emotional control. Anorexia nervosa (AN) and bulimia nervosa (BN) have been largely studied with brain magnetic resonance imaging (MRI) in relation to the functional mechanisms of high-level processing, but not in terms of possible inter-hemispheric functional connectivity anomalies. Using resting-state functional MRI (fMRI), voxel-mirrored homotopic connectivity (VMHC) and regional inter-hemispheric spectral coherence (IHSC) were studied in 15 AN and 13 BN patients and 16 healthy controls (HC). Using T1-weighted and diffusion tensor imaging MRI scans, regional VMHC values were correlated with the left-right asymmetry of corresponding homotopic gray matter volumes and with the white matter callosal fractional anisotropy (FA). Compared to HC, AN patients exhibited reduced VMHC in cerebellum, insula, and precuneus, while BN patients showed reduced VMHC in dorso-lateral prefrontal and orbito-frontal cortices. The regional IHSC analysis highlighted that the inter-hemispheric functional connectivity was higher in the 'Slow-5' band in all regions except the insula. No group differences in left-right structural asymmetries and in VMHC vs. callosal FA correlations were significant in the comparisons between cohorts. These anomalies, not explained by structural changes, indicate that AN and BN, at least in their acute phase, are associated with a loss of inter-hemispheric connectivity in regions implicated in self-referential, cognitive control and reward processing. These findings may thus gather novel functional markers to explore aberrant features of these eating disorders. © 2016 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Analytical Study of Common Rigid Steel Connections under the Effect of Heat

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Rohola Rahnavard

2014-01-01

Full Text Available One of the most important members of steel structure’s connection region is beam-to-column connection. Rigid connection in steel moment frame has special role in the behavior of these structures and the fire resistance of these connections can be important. In this paper the behaviors of three common types of rigid connections in Iran under the effect of heat were studied by the use of numerical finite element methods through ABAQUS software. The models were verified by the use of an experimental model through elastic and plastic amplitudes up to collapse and during numerical results, and the effect of large deformation in the nonlinear region has also been considered. The results show that the connection with the end plate had a better performance against heat than other connections. Also reduced stiffness and lateral buckling in this connection were less than other connections.

Neural intrinsic connectivity networks associated with risk aversion in old age.

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Han, S Duke; Boyle, Patricia A; Arfanakis, Konstantinos; Fleischman, Debra A; Yu, Lei; Edmonds, Emily C; Bennett, David A

2012-02-01

Risk aversion is associated with several important real world outcomes. Although the neurobiological correlates of risk aversion have been studied in young persons, little is known of the neurobiological correlates of risk aversion among older persons. Resting-state functional MRI data were collected on 134 non-demented participants of the Rush Memory and Aging Project, a community-based cohort study of aging. Risk aversion was measured using a series of standard questions in which participants were asked to choose between a certain monetary payment ($15) versus a gamble in which they could gain more than $15 or gain nothing, with potential gains varied across questions. Participants determined to be "high" (n=27) and "low" (n=27) in risk aversion were grouped accordingly. Using a spherical seed region of interest in the anterior cingulate cortex, voxel-wise functional connectivity network similarities were observed in bilateral frontal, anterior and posterior cingulate, insula, basal ganglia, temporal, parietal, and thalamic regions. Differences in functional connectivity were observed such that those low in risk aversion had greater connectivity to clusters in the superior, middle, and medial frontal regions, as well as cerebellar, parietal, occipital, and inferior temporal regions. Those high in risk aversion had greater connectivity to clusters in the inferior and orbital frontal, parahippocampal, and insula regions, as well as thalamic, parietal, precentral gyrus, postcentral gyrus, and middle temporal regions. Similarities and differences in functional connectivity patterns may reflect the historical recruitment of specific brain regions as a network in the active processing of risk in older adults. Copyright © 2011 Elsevier B.V. All rights reserved.

Prefrontal-limbic Functional Connectivity during Acquisition and Extinction of Conditioned Fear.

Science.gov (United States)

Barrett, Douglas W; Gonzalez-Lima, F

2018-04-15

This study is a new analysis to obtain novel metabolic data on the functional connectivity of prefrontal-limbic regions in Pavlovian fear acquisition and extinction of tone-footshock conditioning. Mice were analyzed with the fluorodeoxyglucose (FDG) autoradiographic method to metabolically map regional brain activity. New FDG data were sampled from the nuclei of the habenula and other regions implicated in aversive conditioning, such as infralimbic cortex, amygdala and periaqueductal gray regions. The activity patterns among these regions were inter-correlated during acquisition, extinction or pseudorandom training to develop a functional connectivity model. Two subdivisions of the habenular complex showed increased activity after acquisition relative to extinction, with the pseudorandom group intermediate between the other two groups. Significant acquisition activation effects were also found in centromedial amygdala, dorsomedial and ventrolateral periaqueductal gray. FDG uptake increases during extinction were found only in dorsal and ventral infralimbic cortex. The overall pattern of activity correlations between these regions revealed extensive but differential functional connectivity during acquisition and extinction training, with less functional connectivity found after pseudorandom training. Interestingly, habenula nuclei showed a distinct pattern of inter-correlations with amygdala nuclei during extinction. The functional connectivity model revealed changing interactions among infralimbic cortex, amygdala, habenula and periaqueductal gray regions through the stages of Pavlovian fear acquisition and extinction. This study provided new data on the contributions of the habenula to fear conditioning, and revealed previously unreported infralimbic-amygdala-habenula-periaqueductal gray interactions implicated in acquisition and extinction of conditioned fear. Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.

Two Distinct Scene-Processing Networks Connecting Vision and Memory.

Science.gov (United States)

Baldassano, Christopher; Esteva, Andre; Fei-Fei, Li; Beck, Diane M

2016-01-01

A number of regions in the human brain are known to be involved in processing natural scenes, but the field has lacked a unifying framework for understanding how these different regions are organized and interact. We provide evidence from functional connectivity and meta-analyses for a new organizational principle, in which scene processing relies upon two distinct networks that split the classically defined parahippocampal place area (PPA). The first network of strongly connected regions consists of the occipital place area/transverse occipital sulcus and posterior PPA, which contain retinotopic maps and are not strongly coupled to the hippocampus at rest. The second network consists of the caudal inferior parietal lobule, retrosplenial complex, and anterior PPA, which connect to the hippocampus (especially anterior hippocampus), and are implicated in both visual and nonvisual tasks, including episodic memory and navigation. We propose that these two distinct networks capture the primary functional division among scene-processing regions, between those that process visual features from the current view of a scene and those that connect information from a current scene view with a much broader temporal and spatial context. This new framework for understanding the neural substrates of scene-processing bridges results from many lines of research, and makes specific functional predictions.

Sex differences in the relationship between white matter connectivity and creativity.

Science.gov (United States)

Ryman, Sephira G; van den Heuvel, Martijn P; Yeo, Ronald A; Caprihan, Arvind; Carrasco, Jessica; Vakhtin, Andrei A; Flores, Ranee A; Wertz, Christopher; Jung, Rex E

2014-11-01

Creative cognition emerges from a complex network of interacting brain regions. This study investigated the relationship between the structural organization of the human brain and aspects of creative cognition tapped by divergent thinking tasks. Diffusion weighted imaging (DWI) was used to obtain fiber tracts from 83 segmented cortical regions. This information was represented as a network and metrics of connectivity organization, including connectivity strength, clustering and communication efficiency were computed, and their relationship to individual levels of creativity was examined. Permutation testing identified significant sex differences in the relationship between global connectivity and creativity as measured by divergent thinking tests. Females demonstrated significant inverse relationships between global connectivity and creative cognition, whereas there were no significant relationships observed in males. Node specific analyses revealed inverse relationships across measures of connectivity, efficiency, clustering and creative cognition in widespread regions in females. Our findings suggest that females involve more regions of the brain in processing to produce novel ideas to solutions, perhaps at the expense of efficiency (greater path lengths). Males, in contrast, exhibited few, relatively weak positive relationships across these measures. Extending recent observations of sex differences in connectome structure, our findings of sexually dimorphic relationships suggest a unique topological organization of connectivity underlying the generation of novel ideas in males and females. Published by Elsevier Inc.

Eviction of linker histone H1 by NAP-family histone chaperones enhances activated transcription.

Science.gov (United States)

Zhang, Qian; Giebler, Holli A; Isaacson, Marisa K; Nyborg, Jennifer K

2015-01-01

In the Metazoan nucleus, core histones assemble the genomic DNA to form nucleosome arrays, which are further compacted into dense chromatin structures by the linker histone H1. The extraordinary density of chromatin creates an obstacle for accessing the genetic information. Regulation of chromatin dynamics is therefore critical to cellular homeostasis, and histone chaperones serve as prominent players in these processes. In the current study, we examined the role of specific histone chaperones in negotiating the inherently repressive chromatin structure during transcriptional activation. Using a model promoter, we demonstrate that the human nucleosome assembly protein family members hNap1 and SET/Taf1β stimulate transcription in vitro during pre-initiation complex formation, prior to elongation. This stimulatory effect is dependent upon the presence of activators, p300, and Acetyl-CoA. We show that transcription from our chromatin template is strongly repressed by H1, and that both histone chaperones enhance RNA synthesis by overcoming H1-induced repression. Importantly, both hNap1 and SET/Taf1β directly bind H1, and function to enhance transcription by evicting the linker histone from chromatin reconstituted with H1. In vivo studies demonstrate that SET/Taf1β, but not hNap1, strongly stimulates activated transcription from the chromosomally-integrated model promoter, consistent with the observation that SET/Taf1β is nuclear, whereas hNap1 is primarily cytoplasmic. Together, these observations indicate that SET/Taf1β may serve as a critical regulator of H1 dynamics and gene activation in vivo. These studies uncover a novel function for SET that mechanistically couples transcriptional derepression with H1 dynamics. Furthermore, they underscore the significance of chaperone-dependent H1 displacement as an essential early step in the transition of a promoter from a dense chromatin state into one that is permissive to transcription factor binding and robust

Cytoskeletal Linker Protein Dystonin Is Not Critical to Terminal Oligodendrocyte Differentiation or CNS Myelination.

Directory of Open Access Journals (Sweden)

Samantha F Kornfeld

Full Text Available Oligodendrocyte differentiation and central nervous system myelination require massive reorganization of the oligodendrocyte cytoskeleton. Loss of specific actin- and tubulin-organizing factors can lead to impaired morphological and/or molecular differentiation of oligodendrocytes, resulting in a subsequent loss of myelination. Dystonin is a cytoskeletal linker protein with both actin- and tubulin-binding domains. Loss of function of this protein results in a sensory neuropathy called Hereditary Sensory Autonomic Neuropathy VI in humans and dystonia musculorum in mice. This disease presents with severe ataxia, dystonic muscle and is ultimately fatal early in life. While loss of the neuronal isoforms of dystonin primarily leads to sensory neuron degeneration, it has also been shown that peripheral myelination is compromised due to intrinsic Schwann cell differentiation abnormalities. The role of this cytoskeletal linker in oligodendrocytes, however, remains unclear. We sought to determine the effects of the loss of neuronal dystonin on oligodendrocyte differentiation and central myelination. To address this, primary oligodendrocytes were isolated from a severe model of dystonia musculorum, Dstdt-27J, and assessed for morphological and molecular differentiation capacity. No defects could be discerned in the differentiation of Dstdt-27J oligodendrocytes relative to oligodendrocytes from wild-type littermates. Survival was also compared between Dstdt-27J and wild-type oligodendrocytes, revealing no significant difference. Using a recently developed migration assay, we further analysed the ability of primary oligodendrocyte progenitor cell motility, and found that Dstdt-27J oligodendrocyte progenitor cells were able to migrate normally. Finally, in vivo analysis of oligodendrocyte myelination was done in phenotype-stage optic nerve, cerebral cortex and spinal cord. The density of myelinated axons and g-ratios of Dstdt-27J optic nerves was normal, as

BOLD signal and functional connectivity associated with loving kindness meditation

Science.gov (United States)

Garrison, Kathleen A; Scheinost, Dustin; Constable, R Todd; Brewer, Judson A

2014-01-01

Loving kindness is a form of meditation involving directed well-wishing, typically supported by the silent repetition of phrases such as “may all beings be happy,” to foster a feeling of selfless love. Here we used functional magnetic resonance imaging to assess the neural substrate of loving kindness meditation in experienced meditators and novices. We first assessed group differences in blood oxygen level-dependent (BOLD) signal during loving kindness meditation. We next used a relatively novel approach, the intrinsic connectivity distribution of functional connectivity, to identify regions that differ in intrinsic connectivity between groups, and then used a data-driven approach to seed-based connectivity analysis to identify which connections differ between groups. Our findings suggest group differences in brain regions involved in self-related processing and mind wandering, emotional processing, inner speech, and memory. Meditators showed overall reduced BOLD signal and intrinsic connectivity during loving kindness as compared to novices, more specifically in the posterior cingulate cortex/precuneus (PCC/PCu), a finding that is consistent with our prior work and other recent neuroimaging studies of meditation. Furthermore, meditators showed greater functional connectivity during loving kindness between the PCC/PCu and the left inferior frontal gyrus, whereas novices showed greater functional connectivity during loving kindness between the PCC/PCu and other cortical midline regions of the default mode network, the bilateral posterior insula lobe, and the bilateral parahippocampus/hippocampus. These novel findings suggest that loving kindness meditation involves a present-centered, selfless focus for meditators as compared to novices. PMID:24944863

Using TV white space spectrum to practise telemedicine: A promising technology to enhance broadband internet connectivity within healthcare facilities in rural regions of developing countries.

Science.gov (United States)

Chavez, Afton; Littman-Quinn, Ryan; Ndlovu, Kagiso; Kovarik, Carrie L

2016-06-01

The following correspondence provides an overview of TV White Space (TVWS) technology, regulations, and potential applications to the health care sector. This report also introduces "Project Kgolagano," a Botswana-based initiative representing the first endeavour to utilize TVWS internet connection for practising telemedicine. TV "white space" refers to the previously unused, wasted spectrum within TV radiofrequency channels that can now be leveraged to obtain broadband internet access. TVWS represents a less costly, faster, and farther-reaching internet connection that is a promising option for connecting the previously unconnected populations of remote and underserved areas. The Botswana-University of Pennsylvania Partnership, Microsoft, Botswana Innovation Hub, Vista Life Sciences, and Global Broadband Solutions have partnered together to bring TVWS wireless broadband access to healthcare facilities in poorly connected regions of Botswana (Lobatse, Francistown, Maun, Gaborone) in order to improve healthcare delivery and facilitate telemedicine in dermatology, cervical cancer screening, and family medicine (HIV/AIDS, TB, general adult and pediatric medicine). © The Author(s) 2015.

Probabilistic Tractography Recovers a Rostrocaudal Trajectory of Connectivity Variability in the Human Insular Cortex

Science.gov (United States)

Cerliani, Leonardo; Thomas, Rajat M; Jbabdi, Saad; Siero, Jeroen CW; Nanetti, Luca; Crippa, Alessandro; Gazzola, Valeria; D'Arceuil, Helen; Keysers, Christian

2012-01-01

The insular cortex of macaques has a wide spectrum of anatomical connections whose distribution is related to its heterogeneous cytoarchitecture. Although there is evidence of a similar cytoarchitectural arrangement in humans, the anatomical connectivity of the insula in the human brain has not yet been investigated in vivo. In the present work, we used in vivo probabilistic white-matter tractography and Laplacian eigenmaps (LE) to study the variation of connectivity patterns across insular territories in humans. In each subject and hemisphere, we recovered a rostrocaudal trajectory of connectivity variation ranging from the anterior dorsal and ventral insula to the dorsal caudal part of the long insular gyri. LE suggested that regional transitions among tractography patterns in the insula occur more gradually than in other brain regions. In particular, the change in tractography patterns was more gradual in the insula than in the medial premotor region, where a sharp transition between different tractography patterns was found. The recovered trajectory of connectivity variation in the insula suggests a relation between connectivity and cytoarchitecture in humans resembling that previously found in macaques: tractography seeds from the anterior insula were mainly found in limbic and paralimbic regions and in anterior parts of the inferior frontal gyrus, while seeds from caudal insular territories mostly reached parietal and posterior temporal cortices. Regions in the putative dysgranular insula displayed more heterogeneous connectivity patterns, with regional differences related to the proximity with either putative granular or agranular regions. Hum Brain Mapp 33:2005–2034, 2012. © 2011 Wiley Periodicals, Inc. PMID:21761507

Synthetic surfactant- and cross-linker-free preparation of highly stable lipid-polymer hybrid nanoparticles as potential oral delivery vehicles.

Science.gov (United States)

Wang, Taoran; Xue, Jingyi; Hu, Qiaobin; Zhou, Mingyong; Chang, Chao; Luo, Yangchao

2017-06-05

The toxicity associated with concentrated synthetic surfactants and the poor stability at gastrointestinal condition are two major constraints for practical applications of solid lipid nanoparticles (SLN) as oral delivery vehicles. In this study, a synthetic surfactant-free and cross-linker-free method was developed to fabricate effective, safe, and ultra-stable lipid-polymer hybrid nanoparticles (LPN). Bovine serum albumin (BSA) and dextran varying in molecular weights were first conjugated through Maillard reaction and the conjugates were exploited to emulsify solid lipid by a solvent diffusion and sonication method. The multilayer structure was formed by self-assembly of BSA-dextran micelles to envelope solid lipid via a pH- and heating-induced facile process with simultaneous surface deposition of pectin. The efficiency of different BSA-dextran conjugates was systematically studied to prepare LPN with the smallest size, the most homogeneous distribution and the greatest stability. The molecular interactions were characterized by Fourier transform infrared and fluorescence spectroscopies. Both nano spray drying and freeze-drying methods were tested to produce spherical and uniform pectin-coated LPN powders that were able to re-assemble nanoscale structure when redispersed in water. The results demonstrated the promise of a synthetic surfactant- and cross-linker-free technique to prepare highly stable pectin-coated LPN from all natural biomaterials as potential oral delivery vehicles.

Wall to membrane linkers, stretch activated channels, and the detection of tension, voltage, temperature, auxin, and pH

Science.gov (United States)

Pickard, B. G.

1992-01-01

Introduction. The higher plant is a heterogeneous, mechanically prestressed structure continually subject to shifting forces. When a cell grows in a plant at gravitropic equilibrium, it must create localized maxima of shear in walls of neighboring cells. Such mechanical stress and strain are likely detected in a variety of ways. However, tension-sensitive ion channels are of particular interest because it appears that they are elaborately evolved for sensory function. We hypothesize that 1) the patchy patterns of high shear are focused via wall-to-membrane linkers onto the plasma membrane, where 2) they are translated by mechanosensory cation channels into corresponding patterns of high cytosolic Ca2+, which 3) initiate local enhancement of wall expansion. Further, we hypothesize that the local promotion of enhancement is achieved at least in part by local intensification of auxin transport across the plasma membrane. By implication, when an organ is asymmetrically pressed, rubbed, or bent or when it is displaced in the gravitational field, the net asymmetry of shear stress occurring across the organ would lead to asymmetric redistribution of auxin and corrective asymmetric growth. We shall describe a representative mechanosensitive Ca(2+) -selective cation channel (MCaC) with susceptibilities to xenobiotics implicating it as a force transducer in thigmo- and gravitropism. Then, we shall consider whether a putative wall-to-membrane linker (WML) could be a key feature of the molecular architecture permitting the stress distributed in the wall system to be focused on the channels.

Altered Network Oscillations and Functional Connectivity Dynamics in Children Born Very Preterm.

Science.gov (United States)

Moiseev, Alexander; Doesburg, Sam M; Herdman, Anthony T; Ribary, Urs; Grunau, Ruth E

2015-09-01

Structural brain connections develop atypically in very preterm children, and altered functional connectivity is also evident in fMRI studies. Such alterations in brain network connectivity are associated with cognitive difficulties in this population. Little is known, however, about electrophysiological interactions among specific brain networks in children born very preterm. In the present study, we recorded magnetoencephalography while very preterm children and full-term controls performed a visual short-term memory task. Regions expressing task-dependent activity changes were identified using beamformer analysis, and inter-regional phase synchrony was calculated. Very preterm children expressed altered regional recruitment in distributed networks of brain areas, across standard physiological frequency ranges including the theta, alpha, beta and gamma bands. Reduced oscillatory synchrony was observed among task-activated brain regions in very preterm children, particularly for connections involving areas critical for executive abilities, including middle frontal gyrus. These findings suggest that inability to recruit neurophysiological activity and interactions in distributed networks including frontal regions may contribute to difficulties in cognitive development in children born very preterm.

A lipid-mediated conformational switch modulates the thermosensing activity of DesK.

Science.gov (United States)

Inda, María Eugenia; Vandenbranden, Michel; Fernández, Ariel; de Mendoza, Diego; Ruysschaert, Jean-Marie; Cybulski, Larisa Estefanía

2014-03-04

The thermosensor DesK is a multipass transmembrane histidine-kinase that allows the bacterium Bacillus subtilis to adjust the levels of unsaturated fatty acids required to optimize membrane lipid fluidity. The cytoplasmic catalytic domain of DesK behaves like a kinase at low temperature and like a phosphatase at high temperature. Temperature sensing involves a built-in instability caused by a group of hydrophilic residues located near the N terminus of the first transmembrane (TM) segment. These residues are buried in the lipid phase at low temperature and partially "buoy" to the aqueous phase at higher temperature with the thinning of the membrane, promoting the required conformational change. Nevertheless, the core question remains poorly understood: How is the information sensed by the transmembrane region converted into a rearrangement in the cytoplasmic catalytic domain to control DesK activity? Here, we identify a "linker region" (KSRKERERLEEK) that connects the TM sensor domain with the cytoplasmic catalytic domain involved in signal transmission. The linker adopts two conformational states in response to temperature-dependent membrane thickness changes: (i) random coiled and bound to the phospholipid head groups at the water-membrane interface, promoting the phosphatase state or (ii) unbound and forming a continuous helix spanning a region from the membrane to the cytoplasm, promoting the kinase state. Our results uphold the view that the linker is endowed with a helix/random coil conformational duality that enables it to behave like a transmission switch, with helix disruption decreasing the kinase/phosphatase activity ratio, as required to modulate the DesK output response.

A new ductile moment-resisting connection for precast concrete frames in seismic regions: An experimental investigation

OpenAIRE

Parastesh, H.; Hajirasouliha, I.; Ramezani, R.

2014-01-01

A new ductile moment-resisting beam–column connection is developed for precast reinforced concrete (RC) frames in high seismic zones. The proposed connection provides good structural integrity in the connections and can reduce construction time by eliminating the need for formworks and welding, and minimizing cast-in-place concrete volume. A series of cyclic loading tests were carried out on six full-scale interior and exterior precast connections and two monolithic connections, all designed ...

Ventral medial prefrontal functional connectivity and emotion regulation in chronic schizophrenia: A pilot study

Institute of Scientific and Technical Information of China (English)

Feng-Mei Fan; Shu-Ping Tan; Fu-De Yang; Yun-Long Tan; Yan-Li Zhao; Nan Chen; Bin-Bin Li

2013-01-01

People with schizophrenia exhibit impaired social cognitive functions,particularly emotion regulation.Abnormal activations of the ventral medial prefrontal cortex (vMPFC) during emotional tasks have been demonstrated in schizophrenia,suggesting its important role in emotion processing in patients.We used the resting-state functional connectivity approach,setting a functionally relevant region,the vMPFC,as a seed region to examine the intrinsic functional interactions and communication between the vMPFC and other brain regions in schizophrenic patients.We found hypo-connectivity between the vMPFC and the medial frontal cortex,right middle temporal lobe (MTL),right hippocampus,parahippocampal cortex (PHC) and amygdala.Further,there was a decreased strength of the negative connectivity (or anticorrelation) between the vMPFC and the bilateral dorsal lateral prefrontal cortex (DLPFC) and pre-supplementary motor areas.Among these connectivity alterations,reduced vMPFCDLPFC connectivity was positively correlated with positive symptoms on the Positive and Negative Syndrome Scale,while vMPFC-right MTL/PHC/amygdala functional connectivity was positively correlated with the performance of emotional regulation in patients.These findings imply that communication and coordination throughout the brain networks are disrupted in schizophrenia.The emotional correlates of vMPFC connectivity suggest a role of the hypo-connectivity between these regions in the neuropathology of abnormal social cognition in chronic schizophrenia.

Aberrant Intrinsic Activity and Connectivity in Cognitively Normal Parkinson's Disease.

Science.gov (United States)

Harrington, Deborah L; Shen, Qian; Castillo, Gabriel N; Filoteo, J Vincent; Litvan, Irene; Takahashi, Colleen; French, Chelsea

2017-01-01

Disturbances in intrinsic activity during resting-state functional MRI (rsfMRI) are common in Parkinson's disease (PD), but have largely been studied in a priori defined subnetworks. The cognitive significance of abnormal intrinsic activity is also poorly understood, as are abnormalities that precede the onset of mild cognitive impairment. To address these limitations, we leveraged three different analytic approaches to identify disturbances in rsfMRI metrics in 31 cognitively normal PD patients (PD-CN) and 30 healthy adults. Subjects were screened for mild cognitive impairment using the Movement Disorders Society Task Force Level II criteria. Whole-brain data-driven analytic approaches first analyzed the amplitude of low-frequency intrinsic fluctuations (ALFF) and regional homogeneity (ReHo), a measure of local connectivity amongst functionally similar regions. We then examined if regional disturbances in these metrics altered functional connectivity with other brain regions. We also investigated if abnormal rsfMRI metrics in PD-CN were related to brain atrophy and executive, visual organization, and episodic memory functioning. The results revealed abnormally increased and decreased ALFF and ReHo in PD-CN patients within the default mode network (posterior cingulate, inferior parietal cortex, parahippocampus, entorhinal cortex), sensorimotor cortex (primary motor, pre/post-central gyrus), basal ganglia (putamen, caudate), and posterior cerebellar lobule VII, which mediates cognition. For default mode network regions, we also observed a compound profile of altered ALFF and ReHo. Most regional disturbances in ALFF and ReHo were associated with strengthened long-range interactions in PD-CN, notably with regions in different networks. Stronger long-range functional connectivity in PD-CN was also partly expanded to connections that were outside the networks of the control group. Abnormally increased activity and functional connectivity appeared to have a pathological

Brain functional connectivity in stimulant drug dependence and obsessive-compulsive disorder.

Science.gov (United States)

Meunier, David; Ersche, Karen D; Craig, Kevin J; Fornito, Alex; Merlo-Pich, Emilio; Fineberg, Naomi A; Shabbir, Shaila S; Robbins, Trevor W; Bullmore, Edward T

2012-01-16

There are reasons for thinking that obsessive-compulsive disorder (OCD) and drug dependence, although conventionally distinct diagnostic categories, might share important cognitive and neurobiological substrates. We tested this hypothesis directly by comparing brain functional connectivity measures between patients with OCD, stimulant dependent individuals (SDIs; many of whom were non-dependent users of other recreational drugs) and healthy volunteers. We measured functional connectivity between each possible pair of 506 brain regional functional MRI time series representing low frequency (0.03-0.06 Hz) spontaneous brain hemodynamics in healthy volunteers (N=18), patients with OCD (N=18) and SDIs (N=18). We used permutation tests to identify i) brain regions where strength of connectivity was significantly different in both patient groups compared to healthy volunteers; and ii) brain regions and connections which had significantly different functional connectivity between patient groups. We found that functional connectivity of right inferior and superior orbitofrontal cortex (OFC) was abnormally reduced in both disorders. Whether diagnosed as OCD or SDI, patients with higher scores on measures of compulsive symptom severity showed greater reductions of right orbitofrontal connectivity. Functional connections specifically between OFC and dorsal medial pre-motor and cingulate cortex were attenuated in both patient groups. However, patients with OCD demonstrated more severe and extensive reductions of functional connectivity compared to SDIs. OCD and stimulant dependence are not identical at the level of brain functional systems but they have some important abnormalities in common compared with healthy volunteers. Orbitofrontal connectivity may serve as a human brain systems biomarker for compulsivity across diagnostic categories. Copyright © 2011 Elsevier Inc. All rights reserved.

A magnetic nanoparticle-clustering biosensor for blu-ray based optical detection of small-molecules

DEFF Research Database (Denmark)

Yang, Jaeyoung; Donolato, Marco; Antunes, Paula Soares Martins

2014-01-01

MNP-clustering facilitates high-resolution small-molecule assays. For experiments, aptamer-functionalized MNPs (Apt-MNPs) were first incubated with adenosine-5'-triphosphate (ATP) followed by adding MNPs with linker strands (linker-MNPs). The linker hybridizes with a region of aptamer sequences...

Crystallization and preliminary X-ray analysis of a U2AF65 variant in complex with a polypyrimidine-tract analogue by use of protein engineering

International Nuclear Information System (INIS)

Sickmier, E. Allen; Frato, Katherine E.; Kielkopf, Clara L.

2006-01-01

A complex of the essential splicing factor U2AF 65 and a deoxyuridine oligonucleotide has been crystallized by modification of an interdomain linker. The large subunit of the essential pre-mRNA splicing factor U2 auxiliary factor (U2AF 65 ) binds the polypyrimidine tract near the 3′ splice site of pre-mRNA introns and directs the association of the U2 small nuclear ribonucleoprotein particle (U2 snRNP) of the spliceosome with the pre-mRNA. Protein engineering, in which the flexible linker region connecting tandem RNA-recognition motifs (RRMs) within the U2AF 65 RNA-binding domain was partially deleted, allowed successful crystallization of the protein–nucleic acid complex. Cocrystals of a U2AF 65 variant with a deoxyuridine dodecamer diffract X-rays to 2.9 Å resolution and contain one complex per asymmetric unit

Understanding spatial connectivity of individuals with non-uniform population density.

Science.gov (United States)

Wang, Pu; González, Marta C

2009-08-28

We construct a two-dimensional geometric graph connecting individuals placed in space within a given contact distance. The individuals are distributed using a measured country's density of population. We observe that while large clusters (group of individuals connected) emerge within some regions, they are trapped in detached urban areas owing to the low population density of the regions bordering them. To understand the emergence of a giant cluster that connects the entire population, we compare the empirical geometric graph with the one generated by placing the same number of individuals randomly in space. We find that, for small contact distances, the empirical distribution of population dominates the growth of connected components, but no critical percolation transition is observed in contrast to the graph generated by a random distribution of population. Our results show that contact distances from real-world situations as for WIFI and Bluetooth connections drop in a zone where a fully connected cluster is not observed, hinting that human mobility must play a crucial role in contact-based diseases and wireless viruses' large-scale spreading.

Seychelles Fisheries Connectivity and Transport Pathways

Science.gov (United States)

2015-09-30

1 DISTRIBUTION STATEMENT A. Approved for public release; distribution is unlimited. Seychelles Fisheries Connectivity and Transport Pathways...overarching goal for the proposed work is to develop predictive capabilities for physical oceanography for the Seychelles region in support of locally...for ocean observations in the Seychelles region that will lead to long-term data collection efforts. In collaboration with local partnerships, we

Habenula functional resting-state connectivity in pediatric CRPS.

Science.gov (United States)

Erpelding, Nathalie; Sava, Simona; Simons, Laura E; Lebel, Alyssa; Serrano, Paul; Becerra, Lino; Borsook, David

2014-01-01

The habenula (Hb) is a small brain structure located in the posterior end of the medial dorsal thalamus and through medial (MHb) and lateral (LHb) Hb connections, it acts as a conduit of information between forebrain and brainstem structures. The role of the Hb in pain processing is well documented in animals and recently also in acute experimental pain in humans. However, its function remains unknown in chronic pain disorders. Here, we investigated Hb resting-state functional connectivity (rsFC) in patients with complex regional pain syndrome (CRPS) compared with healthy controls. Twelve pediatric patients with unilateral lower-extremity CRPS (9 females; 10-17 yr) and 12 age- and sex-matched healthy controls provided informed consent to participate in the study. In healthy controls, Hb functional connections largely overlapped with previously described anatomical connections in cortical, subcortical, and brainstem structures. Compared with controls, patients exhibited an overall Hb rsFC reduction with the rest of the brain and, specifically, with the anterior midcingulate cortex, dorsolateral prefrontal cortex, supplementary motor cortex, primary motor cortex, and premotor cortex. Our results suggest that Hb rsFC parallels anatomical Hb connections in the healthy state and that overall Hb rsFC is reduced in patients, particularly connections with forebrain areas. Patients' decreased Hb rsFC to brain regions implicated in motor, affective, cognitive, and pain inhibitory/modulatory processes may contribute to their symptomatology.

Short local descriptors from 2D connected pattern spectra

NARCIS (Netherlands)

Bosilj, Petra; Kijak, Ewa; Wilkinson, Michael H. F.; Lefèvre, Sebastien

2015-01-01

We propose a local region descriptor based on connected pattern spectra, and combined with normalized central moments. The descriptors are calculated for MSER regions of the image, and their performance compared against SIFT. The MSER regions were chosen because they can be efficiently selected by

Identification of critical regions in human SAMHD1 required for nuclear localization and Vpx-mediated degradation.

Science.gov (United States)

Guo, Haoran; Wei, Wei; Wei, Zhenhong; Liu, Xianjun; Evans, Sean L; Yang, Weiming; Wang, Hong; Guo, Ying; Zhao, Ke; Zhou, Jian-Ying; Yu, Xiao-Fang

2013-01-01

The sterile alpha motif (SAM) and HD domain-containing protein-1 (SAMHD1) inhibits the infection of resting CD4+ T cells and myeloid cells by human and related simian immunodeficiency viruses (HIV and SIV). Vpx inactivates SAMHD1 by promoting its proteasome-dependent degradation through an interaction with CRL4 (DCAF1) E3 ubiquitin ligase and the C-terminal region of SAMHD1. However, the determinants in SAMHD1 that are required for Vpx-mediated degradation have not been well characterized. SAMHD1 contains a classical nuclear localization signal (NLS), and NLS point mutants are cytoplasmic and resistant to Vpx-mediated degradation. Here, we demonstrate that NLS-mutant SAMHD1 K11A can be rescued by wild-type SAMHD1, restoring its nuclear localization; consequently, SAMHD1 K11A became sensitive to Vpx-mediated degradation in the presence of wild-type SAMHD1. Surprisingly, deletion of N-terminal regions of SAMHD1, including the classical NLS, generated mutant SAMHD1 proteins that were again sensitive to Vpx-mediated degradation. Unlike SAMHD1 K11A, these deletion mutants could be detected in the nucleus. Interestingly, NLS-defective SAMHD1 could still bind to karyopherin-β1 and other nuclear proteins. We also determined that the linker region between the SAM and HD domain and the HD domain itself is important for Vpx-mediated degradation but not Vpx interaction. Thus, SAMHD1 contains an additional nuclear targeting mechanism in addition to the classical NLS. Our data indicate that multiple regions in SAMHD1 are critical for Vpx-mediated nuclear degradation and that association with Vpx is not sufficient for Vpx-mediated degradation of SAMHD1. Since the linker region and HD domain may be involved in SAMHD1 multimerization, our results suggest that SAMHD1 multimerization may be required for Vpx-mediation degradation.

Connecting CO2. Feasibility study CO2 network Southwest Netherlands; Connecting CO2. Haalbaarheidsstudie CO2-netwerk Zuidwest-Nederland

Energy Technology Data Exchange (ETDEWEB)

Rutten, M.

2009-06-10

An overview is given of supply and demand of CO2 in the region Southwest Netherlands and the regions Antwerp and Gent in Belgium. Also attention is paid to possible connections between these regions [Dutch] Een inventarisatie wordt gegeven van vraag en aanbod van CO2 in de regio Zuidwest- Nederland en de regios Antwerpen en Gent in Belgie. Ook worden mogelijke koppelingen tussen de regios besproken.

Enhanced temporal variability of amygdala-frontal functional connectivity in patients with schizophrenia.

Science.gov (United States)

Yue, Jing-Li; Li, Peng; Shi, Le; Lin, Xiao; Sun, Hong-Qiang; Lu, Lin

2018-01-01

The "dysconnectivity hypothesis" was proposed 20 years ago. It characterized schizophrenia as a disorder with dysfunctional connectivity across a large range of distributed brain areas. Resting-state functional magnetic resonance imaging (rsfMRI) data have supported this theory. Previous studies revealed that the amygdala might be responsible for the emotion regulation-related symptoms of schizophrenia. However, conventional methods oversimplified brain activities by assuming that it remained static throughout the entire scan duration, which may explain why inconsistent results have been reported for the same brain region. An emerging technique is sliding time window analysis, which is used to describe functional connectivity based on the temporal variability of regions of interest (e.g., amygdala) in patients with schizophrenia. Conventional analysis of the static functional connectivity between the amygdala and whole brain was also conducted. Static functional connectivity between the amygdala and orbitofrontal region was impaired in patients with schizophrenia. The variability of connectivity between the amygdala and medial prefrontal cortex was enhanced (i.e., greater dynamics) in patients with schizophrenia. A negative relationship was found between the variability of connectivity and information processing efficiency. A positive correlation was found between the variability of connectivity and symptom severity. The findings suggest that schizophrenia was related to abnormal patterns of fluctuating communication among brain areas that are involved in emotion regulations. Unveiling the temporal properties of functional connectivity could disentangle the inconsistent results of previous functional connectivity studies.

High-resolution photoacoustic tomography of resting-state functional connectivity in the mouse brain

Science.gov (United States)

Nasiriavanaki, Mohammadreza; Xia, Jun; Wan, Hanlin; Bauer, Adam Quentin; Culver, Joseph P.; Wang, Lihong V.

2014-01-01

The increasing use of mouse models for human brain disease studies presents an emerging need for a new functional imaging modality. Using optical excitation and acoustic detection, we developed a functional connectivity photoacoustic tomography system, which allows noninvasive imaging of resting-state functional connectivity in the mouse brain, with a large field of view and a high spatial resolution. Bilateral correlations were observed in eight functional regions, including the olfactory bulb, limbic, parietal, somatosensory, retrosplenial, visual, motor, and temporal regions, as well as in several subregions. The borders and locations of these regions agreed well with the Paxinos mouse brain atlas. By subjecting the mouse to alternating hyperoxic and hypoxic conditions, strong and weak functional connectivities were observed, respectively. In addition to connectivity images, vascular images were simultaneously acquired. These studies show that functional connectivity photoacoustic tomography is a promising, noninvasive technique for functional imaging of the mouse brain. PMID:24367107

Repositioning through Culture: Testing Change in Connectivity Patterns

Directory of Open Access Journals (Sweden)

Beatriz Plaza

2016-12-01

Full Text Available Symbolic knowledge-driven innovations can play an important role in the economic development of cities and regions. Cultural events and infrastructures can act as powerful connectivity engines, generating new connections, rewiring links, and repositioning institutions/cities/regions on the Internet map. Within this framework, this paper aims to contribute to the analytical understanding of culture-led repositioning. For this purpose we perform regression analysis with cultural networks (observational cross-sectional network data from digital media for a specific cultural case study: the Basque Culinary Center (BCC, a higher education faculty of haute cuisine promoted by the University of Mondragon along with a group of Michelin-starred chefs. Results show that a cultural sector, such as haute cuisine, can contribute to structural changes in connectivity patterns, putting an institution/city/region on the media map. It is the connection (in the online press of the BCC to the influential Michelin-starred chefs that can fuel the accumulation of press articles (media items on the BCC; and it is precisely this accumulation of press articles that can impact BCC revenues. Put differently, the co-branding between the influential Michelin chefs and the BCC may have put the BCC on the press map, promoting new student registrations and fostering Basque haute cuisine. The main contribution of this article is a prototype of regression analysis to test repositioning with network data.

Functional Imaging and Migraine: New Connections?

Science.gov (United States)

Schwedt, Todd J.; Chong, Catherine D.

2015-01-01

Purpose of Review Over the last several years, a growing number of brain functional imaging studies have provided insights into mechanisms underlying migraine. This manuscript reviews the recent migraine functional neuroimaging literature and provides recommendations for future studies that will help fill knowledge gaps. Recent Findings Positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) studies have identified brain regions that might be responsible for mediating the onset of a migraine attack and those associated with migraine symptoms. Enhanced activation of brain regions that facilitate processing of sensory stimuli suggests a mechanism by which migraineurs are hypersensitive to visual, olfactory, and cutaneous stimuli. Resting state functional connectivity MRI studies have identified numerous brain regions and functional networks with atypical functional connectivity in migraineurs, suggesting that migraine is associated with aberrant brain functional organization. Summary fMRI and PET studies that have identified brain regions and brain networks that are atypical in migraine have helped to describe the neurofunctional basis for migraine symptoms. Future studies should compare functional imaging findings in migraine to other headache and pain disorders and should explore the utility of functional imaging data as biomarkers for diagnostic and treatment purposes. PMID:25887764

Revealing the importance of linkers in K-series oxime reactivators for tabun-inhibited AChE using quantum chemical, docking and SMD studies.

Science.gov (United States)

Ghosh, Shibaji; Chandar, Nellore Bhanu; Jana, Kalyanashis; Ganguly, Bishwajit

2017-08-01

Inhibition of acetylcholinesterase (AChE) with organophosphorus compounds has a detrimental effect on human life. Oxime K203 seems to be one of the promising reactivators for tabun-inhibited AChE than (K027, K127, and K628). These reactivators differ only in the linker units between the two pyridinium rings. The conformational analyses performed with quantum chemical RHF/6-31G* level for K027, K127, K203 and K628 showed that the minimum energy conformers have different orientations of the active and peripheral pyridinium rings for these reactivator molecules. K203 with (-CH 2 -CH=CH-CH 2 -) linker unit possesses more open conformation compared to the other reactivators. Such orientation of K203 experiences favorable interaction with the surrounding residues of catalytic anionic site (CAS) and peripheral anionic site (PAS) of tabun-inhibited AChE. From the steered molecular dynamics simulations, it has been observed that the oxygen atom of the oxime group of K203 reactivator approaches nearest to the P-atom of the SUN203 (3.75 Å) at lower time scales (less than ~1000 ps) as compared to the other reactivators. K203 experiences less number of hydrophobic interaction with the PAS residues which is suggested to be an important factor for the efficient reactivation process. In addition, K203 crates large number of H-bonding with CAS residues SUN203, Phe295, Tyr337, Phe338 and His447. K203 barely changes its conformation during the SMD simulation process and hence the energy penalty to adopt any other conformation is minimal in this case as compared to the other reactivators. The molecular mechanics and Poisson-Boltzmann surface area binding energies obtained for the interaction of K203 inside the gorge of tabun inhibited AChE is substantially higher (-290.2 kcal/mol) than the corresponding K628 reactivator (-260.4 kcal/mol), which also possess unsaturated aromatic linker unit.

Revealing the importance of linkers in K-series oxime reactivators for tabun-inhibited AChE using quantum chemical, docking and SMD studies

Science.gov (United States)

Ghosh, Shibaji; Chandar, Nellore Bhanu; Jana, Kalyanashis; Ganguly, Bishwajit

2017-08-01

Inhibition of acetylcholinesterase (AChE) with organophosphorus compounds has a detrimental effect on human life. Oxime K203 seems to be one of the promising reactivators for tabun-inhibited AChE than (K027, K127, and K628). These reactivators differ only in the linker units between the two pyridinium rings. The conformational analyses performed with quantum chemical RHF/6-31G* level for K027, K127, K203 and K628 showed that the minimum energy conformers have different orientations of the active and peripheral pyridinium rings for these reactivator molecules. K203 with (-CH2-CH=CH-CH2-) linker unit possesses more open conformation compared to the other reactivators. Such orientation of K203 experiences favorable interaction with the surrounding residues of catalytic anionic site (CAS) and peripheral anionic site (PAS) of tabun-inhibited AChE. From the steered molecular dynamics simulations, it has been observed that the oxygen atom of the oxime group of K203 reactivator approaches nearest to the P-atom of the SUN203 (3.75 Å) at lower time scales (less than 1000 ps) as compared to the other reactivators. K203 experiences less number of hydrophobic interaction with the PAS residues which is suggested to be an important factor for the efficient reactivation process. In addition, K203 crates large number of H-bonding with CAS residues SUN203, Phe295, Tyr337, Phe338 and His447. K203 barely changes its conformation during the SMD simulation process and hence the energy penalty to adopt any other conformation is minimal in this case as compared to the other reactivators. The molecular mechanics and Poisson-Boltzmann surface area binding energies obtained for the interaction of K203 inside the gorge of tabun inhibited AChE is substantially higher (-290.2 kcal/mol) than the corresponding K628 reactivator (-260.4 kcal/mol), which also possess unsaturated aromatic linker unit.

Mesial temporal lobe epilepsy diminishes functional connectivity during emotion perception.

Science.gov (United States)

Steiger, Bettina K; Muller, Angela M; Spirig, Esther; Toller, Gianina; Jokeit, Hennric

2017-08-01

Unilateral mesial temporal lobe epilepsy (MTLE) has been associated with impaired recognition of emotional facial expressions. Correspondingly, imaging studies showed decreased activity of the amygdala and cortical face processing regions in response to emotional faces. However, functional connectivity among regions involved in emotion perception has not been studied so far. To address this, we examined intrinsic functional connectivity (FC) modulated by the perception of dynamic fearful faces among the amygdala and limbic, frontal, temporal and brainstem regions. Regions of interest were identified in an activation analysis by presenting a block-design with dynamic fearful faces and dynamic landscapes to 15 healthy individuals. This led to 10 predominately right-hemispheric regions. Functional connectivity between these regions during the perception of fearful faces was examined in drug-refractory patients with left- (n=16) or right-sided (n=17) MTLE, epilepsy patients with extratemporal seizure onset (n=15) and a second group of 15 healthy controls. Healthy controls showed a widespread functional network modulated by the perception of fearful faces that encompassed bilateral amygdalae, limbic, cortical, subcortical and brainstem regions. In patients with left MTLE, a downsized network of frontal and temporal regions centered on the right amygdala was present. Patients with right MTLE showed almost no significant functional connectivity. A maintained network in the epilepsy control group indicates that findings in mesial temporal lobe epilepsy could not be explained by clinical factors such as seizures and antiepileptic medication. Functional networks underlying facial emotion perception are considerably changed in left and right MTLE. Alterations are present for both hemispheres in either MTLE group, but are more pronounced in right MTLE. Disruption of the functional network architecture possibly contributes to deficits in facial emotion recognition frequently

Structural brain connectivity and cognitive ability differences: A multivariate distance matrix regression analysis.

Science.gov (United States)

Ponsoda, Vicente; Martínez, Kenia; Pineda-Pardo, José A; Abad, Francisco J; Olea, Julio; Román, Francisco J; Barbey, Aron K; Colom, Roberto

2017-02-01

Neuroimaging research involves analyses of huge amounts of biological data that might or might not be related with cognition. This relationship is usually approached using univariate methods, and, therefore, correction methods are mandatory for reducing false positives. Nevertheless, the probability of false negatives is also increased. Multivariate frameworks have been proposed for helping to alleviate this balance. Here we apply multivariate distance matrix regression for the simultaneous analysis of biological and cognitive data, namely, structural connections among 82 brain regions and several latent factors estimating cognitive performance. We tested whether cognitive differences predict distances among individuals regarding their connectivity pattern. Beginning with 3,321 connections among regions, the 36 edges better predicted by the individuals' cognitive scores were selected. Cognitive scores were related to connectivity distances in both the full (3,321) and reduced (36) connectivity patterns. The selected edges connect regions distributed across the entire brain and the network defined by these edges supports high-order cognitive processes such as (a) (fluid) executive control, (b) (crystallized) recognition, learning, and language processing, and (c) visuospatial processing. This multivariate study suggests that one widespread, but limited number, of regions in the human brain, supports high-level cognitive ability differences. Hum Brain Mapp 38:803-816, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Efficient loading of primary alcohols onto a solid phase using a trityl bromide linker

DEFF Research Database (Denmark)

Crestey, François; Ottesen, Lars Korsgaard; Jaroszewski, Jerzy Witold

2008-01-01

The Letter describes an improved, rapid and mild strategy for the loading of primary alcohols onto a polystyrene trityl resin via a highly reactive trityl bromide linker. This protocol facilitates an efficient resin loading even of acid-sensitive or heat-labile alcohols, which otherwise require...... expensive or non-commercial resin types. Secondary alcohols were only attached in moderate to low yields, while attempts to load a tertiary alcohol expectedly failed. Importantly, selective attachment of diols via a primary alcohol group in the presence of more hindered alcohol groups proved possible....... The effects of activation time and reagent excess as well as alcohol structure were investigated. This improved method provides a convenient access to O-linked resin-bound N-Fmoc-protected amino alcohols that may be employed in SPS of peptides with C-terminal alcohol functionalities. In the case...

Increased precuneus connectivity during propofol sedation.

Science.gov (United States)

Liu, Xiaolin; Li, Shi-Jiang; Hudetz, Anthony G

2014-02-21

Using functional magnetic resonance imaging in human participants, we show that sedation by propofol to the point of lost overt responsiveness during the performance of an auditory verbal memory task unexpectedly increases functional connectivity of the precuneus with cortical regions, particularly the dorsal prefrontal and visual cortices. After recovery of consciousness, functional connectivity returns to a pattern similar to that observed during the wakeful baseline. In the context of a recent proposal that highlights the uncoupling of consciousness, connectedness, and responsiveness in general anesthesia, the increased precuneus functional connectivity under propofol sedation may reflect disconnected endogenous mentation or dreaming that continues at a reduced level of metabolic activity. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Engineering of a novel Ca2+-regulated kinesin molecular motor using a calmodulin dimer linker

International Nuclear Information System (INIS)

Shishido, Hideki; Maruta, Shinsaku

2012-01-01

Highlights: ► Engineered kinesin–M13 and calmodulin involving single cysteine were prepared. ► CaM mutant was cross-linked to dimer by bifunctional thiol reactive reagent. ► Kinesin–M13 was dimerized via CaM dimer in the presence of calcium. ► Function of the engineered kinesin was regulated by a Ca 2+ -calmodulin dimer linker. -- Abstract: The kinesin–microtubule system holds great promise as a molecular shuttle device within biochips. However, one current barrier is that such shuttles do not have “on–off” control of their movement. Here we report the development of a novel molecular motor powered by an accelerator and brake system, using a kinesin monomer and a calmodulin (CaM) dimer. The kinesin monomer, K355, was fused with a CaM target peptide (M13 peptide) at the C-terminal part of the neck region (K355–M13). We also prepared CaM dimers using CaM mutants (Q3C), (R86C), or (A147C) and crosslinkers that react with cysteine residues. Following induction of K355–M13 dimerization with CaM dimers, we measured K355–M13 motility and found that it can be reversibly regulated in a Ca 2+ -dependent manner. We also found that velocities of K355–M13 varied depending on the type and crosslink position of the CaM dimer used; crosslink length also had a moderate effect on motility. These results suggest Ca 2+ -dependent dimerization of K355–M13 could be used as a novel molecular shuttle, equipped with an accelerator and brake system, for biochip applications.

Effects of linker variation on the in vitro and in vivo characteristics of an 111In-labeled RGD peptide

International Nuclear Information System (INIS)

Dijkgraaf, Ingrid; Liu, Shuang; Kruijtzer, John A.W.; Soede, Annemieke C.; Oyen, Wim J.G.; Liskamp, Rob M.J.; Corstens, Frans H.M.; Boerman, Otto C.

2007-01-01

Introduction: Due to the selective expression of the α v β 3 integrin in tumors, radiolabeled arginine-glycine-aspartic acid (RGD) peptides are attractive candidates for tumor targeting. Minor modifications of these peptides could have a major impact on in vivo characteristics. In this study, we systematically investigated the effects of linker modification between two cyclic RGD sequences and DOTA (1,4,7,10-tetraazadodecane-N,N',N ' ,N'''-tetraacetic acid) on the in vitro and in vivo characteristics of the tracer. Methods: A dimeric RGD peptide was synthesized and conjugated either directly with DOTA or via different linkers: PEG 4 (polyethylene glycol), glutamic acid or lysine. The RGD peptides were radiolabeled with 111 In, and their in vitro and in vivo α v β 3 -binding characteristics were determined. Results: LogP values varied between -2.82±0.06 and -3.95±0.33. The IC 50 values for DOTA-E-[c(RGDfK)] 2 , DOTA-PEG 4 -E-[c(RGDfK)] 2 , DOTA-E-E-[c(RGDfK)] 2 and DOTA-K-E-[c(RGDfK)] 2 were comparable. Two hours after injection, the tumor uptakes of the 111 In-labeled compounds were not significantly different. The kidney accumulation of [ 111 In]-DOTA-K-E-[c(RGDfK)] 2 [4.05±0.20% of the injected dose per gram (ID/g)] was significantly higher as compared with that of [ 111 In]-DOTA-E-[c(RGDfK)] 2 (2.63±0.19% ID/g; P 111 In]-DOTA-E-E-[c(RGDfK)] 2 (2.16±0.21% ID/g; P 111 In]-DOTA-E-E-[c(RGDfK)] 2 (2.12±0.09% ID/g) was significantly higher as compared with that of [ 111 In]-DOTA-E-[c(RGDfK)] 2 (1.64±0.1% ID/g; P 111 In]-DOTA-K-E-[c(RGDfK)] 2 (1.52±0.04% ID/g; P v β 3 and tumor uptake. Insertion of lysine caused enhanced kidney retention; that of glutamic acid also resulted in enhanced retention in the kidneys. PEG 4 appeared to be the most suitable linker as compared with glutamic acid and lysine because it has the highest tumor-to-blood ratio and the lowest uptake in the kidney and liver

Assessing the adsorption selectivity of linker functionalized, moisture-stable metal-organic framework thin films by means of an environment-controlled quartz crystal microbalance.

Science.gov (United States)

Bétard, Angélique; Wannapaiboon, Suttipong; Fischer, Roland A

2012-11-04

The stepwise thin film deposition of the robust, hydrophobic [Zn(4)O(dmcapz)(3)](n) (dmcapz = 3,5-dimethyl-4-carboxy-pyrazolato) is reported. The adsorption of small organic probe molecules, including alkanols, toluene, aniline and xylenes, was monitored by an environment-controlled quartz crystal microbalance setup. The adsorption selectivity was tuned by introducing alkyl side chains in the dmcapz linker.

Successful Object Encoding Induces Increased Directed Connectivity in Presymptomatic Early-Onset Alzheimer’s Disease

Science.gov (United States)

Ochoa, John Fredy; Alonso, Joan Francesc; Duque, Jon Edinson; Tobón, Carlos Andrés; Mañanas, Miguel Angel; Lopera, Francisco; Hernández, Alher Mauricio

2016-01-01

Background: Recent studies report increases in neural activity in brain regions critical to episodic memory at preclinical stages of Alzheimer’s disease (AD). Although electroencephalography (EEG) is widely used in AD studies, given its non-invasiveness and low cost, there is a need to translate the findings in other neuroimaging methods to EEG. Objective: To examine how the previous findings using functional magnetic resonance imaging (fMRI) at preclinical stage in presenilin-1 E280A mutation carriers could be assessed and extended, using EEG and a connectivity approach. Methods: EEG signals were acquired during resting and encoding in 30 normal cognitive young subjects, from an autosomal dominant early-onset AD kindred from Antioquia, Colombia. Regions of the brain previously reported as hyperactive were used for connectivity analysis. Results: Mutation carriers exhibited increasing connectivity at analyzed regions. Among them, the right precuneus exhibited the highest changes in connectivity. Conclusion: Increased connectivity in hyperactive cerebral regions is seen in individuals, genetically-determined to develop AD, at preclinical stage. The use of a connectivity approach and a widely available neuroimaging technique opens the possibility to increase the use of EEG in early detection of preclinical AD. PMID:27792014

Funktionalisierte Linker für Metallorganische Gerüstverbindungen, deren postsynthetische Modifikation und polar markierte Schutzgruppen für terminale Alkine

OpenAIRE

Roy, Pascal

2011-01-01

Metal-organic frameworks (MOFs) form the class of porous materials with the highest surface areas. This characteristic property combined with the variability of both building blocks, the inorganic node and the organic linker, makes many scientists dream of materials with very special chemical, electronic, optic and/or magnetic properties. For individual applications both building blocks, but also possibly in the framework embedded guests, play a crucial role. This work describes the synthe...

Detecting altered connectivity patterns in HIV associated neurocognitive impairment using mutual connectivity analysis

Science.gov (United States)

Abidin, Anas Zainul; D'Souza, Adora M.; Nagarajan, Mahesh B.; Wismüller, Axel

2016-03-01

The use of functional Magnetic Resonance Imaging (fMRI) has provided interesting insights into our understanding of the brain. In clinical setups these scans have been used to detect and study changes in the brain network properties in various neurological disorders. A large percentage of subjects infected with HIV present cognitive deficits, which are known as HIV associated neurocognitive disorder (HAND). In this study we propose to use our novel technique named Mutual Connectivity Analysis (MCA) to detect differences in brain networks in subjects with and without HIV infection. Resting state functional MRI scans acquired from 10 subjects (5 HIV+ and 5 HIV-) were subject to standard preprocessing routines. Subsequently, the average time-series for each brain region of the Automated Anatomic Labeling (AAL) atlas are extracted and used with the MCA framework to obtain a graph characterizing the interactions between them. The network graphs obtained for different subjects are then compared using Network-Based Statistics (NBS), which is an approach to detect differences between graphs edges while controlling for the family-wise error rate when mass univariate testing is performed. Applying this approach on the graphs obtained yields a single network encompassing 42 nodes and 65 edges, which is significantly different between the two subject groups. Specifically connections to the regions in and around the basal ganglia are significantly decreased. Also some nodes corresponding to the posterior cingulate cortex are affected. These results are inline with our current understanding of pathophysiological mechanisms of HIV associated neurocognitive disease (HAND) and other HIV based fMRI connectivity studies. Hence, we illustrate the applicability of our novel approach with network-based statistics in a clinical case-control study to detect differences connectivity patterns.

Multimodal Hyper-connectivity Networks for MCI Classification.

Science.gov (United States)

Li, Yang; Gao, Xinqiang; Jie, Biao; Yap, Pew-Thian; Kim, Min-Jeong; Wee, Chong-Yaw; Shen, Dinggang

2017-09-01

Hyper-connectivity network is a network where every edge is connected to more than two nodes, and can be naturally denoted using a hyper-graph. Hyper-connectivity brain network, either based on structural or functional interactions among the brain regions, has been used for brain disease diagnosis. However, the conventional hyper-connectivity network is constructed solely based on single modality data, ignoring potential complementary information conveyed by other modalities. The integration of complementary information from multiple modalities has been shown to provide a more comprehensive representation about the brain disruptions. In this paper, a novel multimodal hyper-network modelling method was proposed for improving the diagnostic accuracy of mild cognitive impairment (MCI). Specifically, we first constructed a multimodal hyper-connectivity network by simultaneously considering information from diffusion tensor imaging and resting-state functional magnetic resonance imaging data. We then extracted different types of network features from the hyper-connectivity network, and further exploited a manifold regularized multi-task feature selection method to jointly select the most discriminative features. Our proposed multimodal hyper-connectivity network demonstrated a better MCI classification performance than the conventional single modality based hyper-connectivity networks.

Altered Functional Connectivity of Insular Subregions in Alzheimer’s Disease

Directory of Open Access Journals (Sweden)

Xingyun Liu

2018-04-01

Full Text Available Recent researches have demonstrated that the insula is the crucial hub of the human brain networks and most vulnerable region of Alzheimer’s disease (AD. However, little is known about the changes of functional connectivity of insular subregions in the AD patients. In this study, we collected resting-state functional magnetic resonance imaging (fMRI data including 32 AD patients and 38 healthy controls (HCs. By defining three subregions of insula, we mapped whole-brain resting-state functional connectivity (RSFC and identified several distinct RSFC patterns of the insular subregions: For positive connectivity, three cognitive-related RSFC patterns were identified within insula that suggest anterior-to-posterior functional subdivisions: (1 an dorsal anterior zone of the insula that exhibits RSFC with executive control network (ECN; (2 a ventral anterior zone of insula, exhibits functional connectivity with the salience network (SN; (3 a posterior zone along the insula exhibits functional connectivity with the sensorimotor network (SMN. In addition, we found significant negative connectivities between the each insular subregion and several special default mode network (DMN regions. Compared with controls, the AD patients demonstrated distinct disruption of positive RSFCs in the different network (ECN and SMN, suggesting the impairment of the functional integrity. There were no differences of the positive RSFCs in the SN between the two groups. On the other hand, several DMN regions showed increased negative RSFCs to the sub-region of insula in the AD patients, indicating compensatory plasticity. Furthermore, these abnormal insular subregions RSFCs are closely correlated with cognitive performances in the AD patients. Our findings suggested that different insular subregions presented distinct RSFC patterns with various functional networks, which are differently affected in the AD patients.

A highly conserved glycine within linker I and the extreme C terminus of G protein alpha subunits interact cooperatively in switching G protein-coupled receptor-to-effector specificity

DEFF Research Database (Denmark)

Kostenis, Evi; Martini, Lene; Ellis, James

2004-01-01

Numerous studies have attested to the importance of the extreme C terminus of G protein alpha subunits in determining their selectivity of receptor recognition. We have previously reported that a highly conserved glycine residue within linker I is important for constraining the fidelity of receptor...... recognition by Galpha(q) proteins. Herein, we explored whether both modules (linker I and extreme C terminus) interact cooperatively in switching G protein-coupled receptor (GPCR)-to-effector specificity and created as models mutant Galpha(q) proteins in which glycine was replaced with various amino acids...... and the C-terminal five Galpha(q) residues with the corresponding Galpha(i) or Galpha(s) sequence. Coupling properties of the mutated Galpha(q) proteins were determined after coexpression with a panel of 13 G(i)-and G(s) -selective receptors and compared with those of Galpha proteins modified in only one...

Structural changes and cellular localization of resuscitation-promoting factor in environmental isolates of Micrococcus luteus.

Science.gov (United States)

Koltunov, Viktoria; Greenblatt, Charles L; Goncharenko, Anna V; Demina, Galya R; Klein, Benjamin Y; Young, Michael; Kaprelyants, Arseny S

2010-02-01

Dormancy among nonsporulating actinobacteria is now a widely accepted phenomenon. In Micrococcus luteus, the resuscitation of dormant cells is caused by a small secreted protein (resuscitation-promoting factor, or Rpf) that is found in "spent culture medium." Rpf is encoded by a single essential gene in M. luteus. Homologs of Rpf are widespread among the high G + C Gram-positive bacteria, including mycobacteria and streptomycetes, and most organisms make several functionally redundant proteins. M. luteus Rpf comprises a lysozyme-like domain that is necessary and sufficient for activity connected through a short linker region to a LysM motif, which is present in a number of cell-wall-associated enzymes. Muralytic activity is responsible for resuscitation. In this report, we characterized a number of environmental isolates of M. luteus, including several recovered from amber. There was substantial variation in the predicted rpf gene product. While the lysozyme-like and LysM domains showed little variation, the linker region was elongated from ten amino acid residues in the laboratory strains to as many as 120 residues in one isolate. The genes encoding these Rpf proteins have been characterized, and a possible role for the Rpf linker in environmental adaptation is proposed. The environmental isolates show enhanced resistance to lysozyme as compared with the laboratory strains and this correlates with increased peptidoglycan acetylation. In strains that make a protein with an elongated linker, Rpf was bound to the cell wall, rather than being released to the growth medium, as occurs in reference strains. This rpf gene was introduced into a lysozyme-sensitive reference strain. Both rpf genes were expressed in transformants which showed a slight but statistically significant increase in lysozyme resistance.

Micropatterning of biomolecules on a glass substrate in fused silica microchannels by using photolabile linker-based surface activation

International Nuclear Information System (INIS)

Jang, K.; Mawatari, K.; Kitamori, T.; Xu, Y.; Sato, K.; Tanaka, Y.

2012-01-01

We report on a straightforward method for creating micropatterns of multiple biomolecules. The anti-fouling agent 2-methacryloyloxyethyl phosphorylcholine (MPC) polymer and a photolabile linker (PL) were covalently linked to an amino-terminated silane surface. Patterns were generated by selective removal of the MPC polymer via UV irradiation. Multiple micropatterns of fluorescein isothiocyanate (FITC)-labeled bovine serum albumin (BSA) and rhodamine-labeled goat fragment antigen-binding fragments (FAB) were deposited on a same glass substrate. We also employed micropatterning of multiple biomolecules in that Texas red-labeled BSA and FITC-labeled rabbit anti-mouse IgG were placed inside a microchannel. (author)

Directed connectivity of brain default networks in resting state using GCA and motif.

Science.gov (United States)

Jiao, Zhuqing; Wang, Huan; Ma, Kai; Zou, Ling; Xiang, Jianbo

2017-06-01

Nowadays, there is a lot of interest in assessing functional interactions between key brain regions. In this paper, Granger causality analysis (GCA) and motif structure are adopted to study directed connectivity of brain default mode networks (DMNs) in resting state. Firstly, the time series of functional magnetic resonance imaging (fMRI) data in resting state were extracted, and the causal relationship values of the nodes representing related brain regions are analyzed in time domain to construct a default network. Then, the network structures were searched from the default networks of controls and patients to determine the fixed connection mode in the networks. The important degree of motif structures in directed connectivity of default networks was judged according to p-value and Z-score. Both node degree and average distance were used to analyze the effect degree an information transfer rate of brain regions in motifs and default networks, and efficiency of the network. Finally, activity and functional connectivity strength of the default brain regions are researched according to the change of energy distributions between the normals and the patients' brain regions. Experimental results demonstrate that, both normal subjects and stroke patients have some corresponding fixed connection mode of three nodes, and the efficiency and power spectrum of the patient's default network is somewhat lower than that of the normal person. In particular, the Right Posterior Cingulate Gyrus (PCG.R) has a larger change in functional connectivity and its activity. The research results verify the feasibility of the application of GCA and motif structure to study the functional connectivity of default networks in resting state.

Prefrontal-Thalamic Anatomical Connectivity and Executive Cognitive Function in Schizophrenia.

Science.gov (United States)

Giraldo-Chica, Monica; Rogers, Baxter P; Damon, Stephen M; Landman, Bennett A; Woodward, Neil D

2018-03-15

Executive cognitive functions, including working memory, cognitive flexibility, and inhibition, are impaired in schizophrenia. Executive functions rely on coordinated information processing between the prefrontal cortex (PFC) and thalamus, particularly the mediodorsal nucleus. This raises the possibility that anatomical connectivity between the PFC and mediodorsal thalamus may be 1) reduced in schizophrenia and 2) related to deficits in executive function. The current investigation tested these hypotheses. Forty-five healthy subjects and 62 patients with a schizophrenia spectrum disorder completed a battery of tests of executive function and underwent diffusion-weighted imaging. Probabilistic tractography was used to quantify anatomical connectivity between six cortical regions, including PFC, and the thalamus. Thalamocortical anatomical connectivity was compared between healthy subjects and patients with schizophrenia using region-of-interest and voxelwise approaches, and the association between PFC-thalamic anatomical connectivity and severity of executive function impairment was examined in patients. Anatomical connectivity between the thalamus and PFC was reduced in schizophrenia. Voxelwise analysis localized the reduction to areas of the mediodorsal thalamus connected to lateral PFC. Reduced PFC-thalamic connectivity in schizophrenia correlated with impaired working memory but not cognitive flexibility and inhibition. In contrast to reduced PFC-thalamic connectivity, thalamic connectivity with somatosensory and occipital cortices was increased in schizophrenia. The results are consistent with models implicating disrupted PFC-thalamic connectivity in the pathophysiology of schizophrenia and mechanisms of cognitive impairment. PFC-thalamic anatomical connectivity may be an important target for procognitive interventions. Further work is needed to determine the implications of increased thalamic connectivity with sensory cortex. Copyright © 2017 Society of

Abnormal Functional Connectivity of Frontopolar Subregions in Treatment-Nonresponsive Major Depressive Disorder.

Science.gov (United States)

Fettes, Peter W; Moayedi, Massieh; Dunlop, Katharine; Mansouri, Farrokh; Vila-Rodriguez, Fidel; Giacobbe, Peter; Davis, Karen D; Lam, Raymond W; Kennedy, Sidney H; Daskalakis, Zafiris J; Blumberger, Daniel M; Downar, Jonathan

2018-04-01

Approximately 30% of patients with major depressive disorder develop treatment-nonresponsive depression (TNRD); novel interventions targeting the substrates of this illness population are desperately needed. Convergent evidence from lesion, stimulation, connectivity, and functional neuroimaging studies implicates the frontopolar cortex (FPC) as a particularly important region in TNRD pathophysiology; regions functionally connected to the FPC, once identified, could present favorable targets for novel brain stimulation treatments. We recently published a parcellation of the FPC based on diffusion tensor imaging data, identifying distinct medial and lateral subregions. Here, we applied this parcellation to resting-state functional magnetic resonance imaging scans obtained in 56 patients with TNRD and 56 matched healthy control subjects. In patients, the medial FPC showed reduced connectivity to the anterior midcingulate cortex and insula. The left lateral FPC showed reduced connectivity to the right lateral orbitofrontal cortex and increased connectivity to the fusiform gyri. In addition, TNRD symptom severity correlated significantly with connectivity of the left lateral FPC subregion to a medial orbitofrontal cortex region of the classical reward network. Taken together, these findings suggest that changes in FPC subregion connectivity may underlie several dimensions of TNRD pathology, including changes in reward/positive valence, nonreward/negative valence, and cognitive control domains. Nodes of functional networks showing abnormal connectivity to the FPC could be useful in generating novel candidates for therapeutic brain stimulation in TNRD. Copyright © 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Looking Deeper Into Hydrologic Connectivity and Streamflow Generation: A Groundwater Hydrologist's Perspective.

Science.gov (United States)

Gardner, W. P.

2016-12-01

In this presentation the definition of hydraulic connection will be explored with a focus on the role of deep groundwater in streamflow generation and its time and space limits. Regional groundwater flow paths can be important sources of baseflow and potentially event response in surface water systems. This deep groundwater discharge plays an important role in determining how the watershed responds to climatic forcing, whether watersheds are a carbon source or sink and can be significant for watershed geochemistry and nutrient loading. These flow paths potentially "connect" to surface water systems and saturated soil zones at large distances, and over long time scales. However, these flow paths are challenging to detect, especially with hydraulic techniques. Here we will discuss some of the basic physical processes that affect the hydraulic signal along a groundwater flow path and their implications for the definition of hydrologic connection. Methods of measuring hydraulic connection using groundwater head response and their application in detecting regional groundwater discharge will be discussed. Environmental tracers are also a powerful method for identifying connected flowpaths in groundwater systems, and are commonly used to determine flow connection and flow rates in groundwater studies. Isotopic tracer methods for detecting deep, regional flow paths in watersheds will be discussed, along with observations of deep groundwater discharge in shallow alluvial systems around the world. The goal of this talk is to discuss hydraulic and hydrologic connection from a groundwater hydrologist's perspective, spark conversation on the meaning of hydrologic connection, the processes which govern hydraulic response and methods to measure flow connections and flux.

Connectivity analysis is essential to understand neurological disorders

Directory of Open Access Journals (Sweden)

James Rowe

2010-09-01

Full Text Available Neurological and neuropsychiatric disorders are major causes of morbidity worldwide. A systems level analysis including functional and structural neuroimaging is particularly useful when the pathology leads to disorders of higher order cognitive functions in human patients. However, an analysis that is restricted to regional effects is impoverished and insensitive, compared to the analysis of distributed brain networks. We discuss the issues to consider when choosing an appropriate connectivity method, and compare the results from several different methods that are relevant to fMRI and PET data. These include psychophysiological interactions in general linear models, structural equation modeling, dynamic causal modeling and independent components analysis. The advantages of connectivity analysis are illustrated with a range of structural and neurodegenerative brain disorders. We illustrate the sensitivity of these methods to the presence or severity of disease and/or treatment, even where analyses of voxel-wise activations are insensitive. However, functional and structural connectivity methods should be seen as complementary to, not a substitute for, other imaging and behavioral approaches. The functional relevance of changes in connectivity, to motor or cognitive performance, are considered alongside the complex relationship between structural and functional changes with neuropathology. Finally some of the problems associated with connectivity analysis are discussed. We suggest that the analysis of brain connectivity is an essential complement to the analysis of regionally specific dysfunction, in order to understand neurological and neuropsychiatric disease, and to evaluate the mechanisms of effective therapies.

Aberrant Intrinsic Activity and Connectivity in Cognitively Normal Parkinson’s Disease

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Deborah L. Harrington

2017-06-01

Full Text Available Disturbances in intrinsic activity during resting-state functional MRI (rsfMRI are common in Parkinson’s disease (PD, but have largely been studied in a priori defined subnetworks. The cognitive significance of abnormal intrinsic activity is also poorly understood, as are abnormalities that precede the onset of mild cognitive impairment. To address these limitations, we leveraged three different analytic approaches to identify disturbances in rsfMRI metrics in 31 cognitively normal PD patients (PD-CN and 30 healthy adults. Subjects were screened for mild cognitive impairment using the Movement Disorders Society Task Force Level II criteria. Whole-brain data-driven analytic approaches first analyzed the amplitude of low-frequency intrinsic fluctuations (ALFF and regional homogeneity (ReHo, a measure of local connectivity amongst functionally similar regions. We then examined if regional disturbances in these metrics altered functional connectivity with other brain regions. We also investigated if abnormal rsfMRI metrics in PD-CN were related to brain atrophy and executive, visual organization, and episodic memory functioning. The results revealed abnormally increased and decreased ALFF and ReHo in PD-CN patients within the default mode network (posterior cingulate, inferior parietal cortex, parahippocampus, entorhinal cortex, sensorimotor cortex (primary motor, pre/post-central gyrus, basal ganglia (putamen, caudate, and posterior cerebellar lobule VII, which mediates cognition. For default mode network regions, we also observed a compound profile of altered ALFF and ReHo. Most regional disturbances in ALFF and ReHo were associated with strengthened long-range interactions in PD-CN, notably with regions in different networks. Stronger long-range functional connectivity in PD-CN was also partly expanded to connections that were outside the networks of the control group. Abnormally increased activity and functional connectivity appeared to have a

MUSCULOSKELETAL AND CONNECTIVE TISSUE DISEASES: DISABILITY IN THE IRKUTSK REGION IN 2013–2015

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I. L. Petrunko

2017-01-01