Locating Temporal Functional Dynamics of Visual Short-Term Memory Binding using Graph Modular Dirichlet Energy

NASA Astrophysics Data System (ADS)

Smith, Keith; Ricaud, Benjamin; Shahid, Nauman; Rhodes, Stephen; Starr, John M.; Ibáñez, Augustin; Parra, Mario A.; Escudero, Javier; Vandergheynst, Pierre

2017-02-01

Visual short-term memory binding tasks are a promising early marker for Alzheimer’s disease (AD). To uncover functional deficits of AD in these tasks it is meaningful to first study unimpaired brain function. Electroencephalogram recordings were obtained from encoding and maintenance periods of tasks performed by healthy young volunteers. We probe the task’s transient physiological underpinnings by contrasting shape only (Shape) and shape-colour binding (Bind) conditions, displayed in the left and right sides of the screen, separately. Particularly, we introduce and implement a novel technique named Modular Dirichlet Energy (MDE) which allows robust and flexible analysis of the functional network with unprecedented temporal precision. We find that connectivity in the Bind condition is less integrated with the global network than in the Shape condition in occipital and frontal modules during the encoding period of the right screen condition. Using MDE we are able to discern driving effects in the occipital module between 100-140 ms, coinciding with the P100 visually evoked potential, followed by a driving effect in the frontal module between 140-180 ms, suggesting that the differences found constitute an information processing difference between these modules. This provides temporally precise information over a heterogeneous population in promising tasks for the detection of AD.

Leveraging non-binding instruments for global health governance: reflections from the Global AIDS Reporting Mechanism for WHO reform.

PubMed

Taylor, A L; Alfven, T; Hougendobler, D; Tanaka, S; Buse, K

2014-02-01

As countries contend with an increasingly complex global environment with direct implications for population health, the international community is seeking novel mechanisms to incentivize coordinated national and international action towards shared health goals. Binding legal instruments have garnered increasing attention since the World Health Organization adopted its first convention in 2003. This paper seeks to expand the discourse on future global health lawmaking by exploring the potential value of non-binding instruments in global health governance, drawing on the case of the 2001 United Nations General Assembly Special Session Declaration of Commitment on HIV/AIDS. In other realms of international concern ranging from the environment to human rights to arms control, non-binding instruments are increasingly used as effective instruments of international cooperation. The experience of the Global AIDS Reporting Mechanism, established pursuant to the Declaration, evidences that, at times, non-binding legal instruments can offer benefits over slower, more rigid binding legal approaches to governance. The global AIDS response has demonstrated that the use of a non-binding instrument can be remarkably effective in galvanizing increasingly deep commitments, action, reporting compliance and ultimately accountability for results. Based on this case, the authors argued that non-binding instruments deserve serious consideration by the international community for the future of global health governance, including in the context of WHO reform. Copyright © 2013 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.

Modeling chain folding in protein-constrained circular DNA.

PubMed Central

Martino, J A; Olson, W K

1998-01-01

An efficient method for sampling equilibrium configurations of DNA chains binding one or more DNA-bending proteins is presented. The technique is applied to obtain the tertiary structures of minimal bending energy for a selection of dinucleosomal minichromosomes that differ in degree of protein-DNA interaction, protein spacing along the DNA chain contour, and ring size. The protein-bound portions of the DNA chains are represented by tight, left-handed supercoils of fixed geometry. The protein-free regions are modeled individually as elastic rods. For each random spatial arrangement of the two nucleosomes assumed during a stochastic search for the global minimum, the paths of the flexible connecting DNA segments are determined through a numerical solution of the equations of equilibrium for torsionally relaxed elastic rods. The minimal energy forms reveal how protein binding and spacing and plasmid size differentially affect folding and offer new insights into experimental minichromosome systems. PMID:9591675

Global transformation of erythrocyte properties via engagement of an SH2-like sequence in band 3

PubMed Central

Turrini, Francesco M.; Li, Yen-Hsing; Low, Philip S.

2016-01-01

Src homology 2 (SH2) domains are composed of weakly conserved sequences of ∼100 aa that bind phosphotyrosines in signaling proteins and thereby mediate intra- and intermolecular protein–protein interactions. In exploring the mechanism whereby tyrosine phosphorylation of the erythrocyte anion transporter, band 3, triggers membrane destabilization, vesiculation, and fragmentation, we discovered a SH2 signature motif positioned between membrane-spanning helices 4 and 5. Evidence that this exposed cytoplasmic sequence contributes to a functional SH2-like domain is provided by observations that: (i) it contains the most conserved sequence of SH2 domains, GSFLVR; (ii) it binds the tyrosine phosphorylated cytoplasmic domain of band 3 (cdb3-PO4) with Kd = 14 nM; (iii) binding of cdb3-PO4 to erythrocyte membranes is inhibited both by antibodies against the SH2 signature sequence and dephosphorylation of cdb3-PO4; (iv) label transfer experiments demonstrate the covalent transfer of photoactivatable biotin from isolated cdb3-PO4 (but not cdb3) to band 3 in erythrocyte membranes; and (v) phosphorylation-induced binding of cdb3-PO4 to the membrane-spanning domain of band 3 in intact cells causes global changes in membrane properties, including (i) displacement of a glycolytic enzyme complex from the membrane, (ii) inhibition of anion transport, and (iii) rupture of the band 3–ankyrin bridge connecting the spectrin-based cytoskeleton to the membrane. Because SH2-like motifs are not retrieved by normal homology searches for SH2 domains, but can be found in many tyrosine kinase-regulated transport proteins using modified search programs, we suggest that related cases of membrane transport proteins containing similar motifs are widespread in nature where they participate in regulation of cell properties. PMID:27856737

Global transformation of erythrocyte properties via engagement of an SH2-like sequence in band 3.

PubMed

Puchulu-Campanella, Estela; Turrini, Francesco M; Li, Yen-Hsing; Low, Philip S

2016-11-29

Src homology 2 (SH2) domains are composed of weakly conserved sequences of ∼100 aa that bind phosphotyrosines in signaling proteins and thereby mediate intra- and intermolecular protein-protein interactions. In exploring the mechanism whereby tyrosine phosphorylation of the erythrocyte anion transporter, band 3, triggers membrane destabilization, vesiculation, and fragmentation, we discovered a SH2 signature motif positioned between membrane-spanning helices 4 and 5. Evidence that this exposed cytoplasmic sequence contributes to a functional SH2-like domain is provided by observations that: (i) it contains the most conserved sequence of SH2 domains, GSFLVR; (ii) it binds the tyrosine phosphorylated cytoplasmic domain of band 3 (cdb3-PO 4 ) with K d = 14 nM; (iii) binding of cdb3-PO 4 to erythrocyte membranes is inhibited both by antibodies against the SH2 signature sequence and dephosphorylation of cdb3-PO 4 ; (iv) label transfer experiments demonstrate the covalent transfer of photoactivatable biotin from isolated cdb3-PO 4 (but not cdb3) to band 3 in erythrocyte membranes; and (v) phosphorylation-induced binding of cdb3-PO 4 to the membrane-spanning domain of band 3 in intact cells causes global changes in membrane properties, including (i) displacement of a glycolytic enzyme complex from the membrane, (ii) inhibition of anion transport, and (iii) rupture of the band 3-ankyrin bridge connecting the spectrin-based cytoskeleton to the membrane. Because SH2-like motifs are not retrieved by normal homology searches for SH2 domains, but can be found in many tyrosine kinase-regulated transport proteins using modified search programs, we suggest that related cases of membrane transport proteins containing similar motifs are widespread in nature where they participate in regulation of cell properties.

The connection Between Plasma Protein Binding and Acute Toxicity as Determined by the LD50 Value.

PubMed

Svennebring, Andreas

2016-02-01

Preclinical Research A dataset of three drug classes (acids, bases, and neutrals) with LD50 values in mice was analysed to investigate a possible connection between high plasma protein binding and acute toxicity. Initially, it was found that high plasma protein binding was associated with toxicity for acids and neutrals, but after compensating for differences in lipophilicity, plasma protein binding was found not to be associated with toxicity. The therapeutic index established by the quotient between mouse LD50 and the defined daily dose was unaffected by both lipophilicity and plasma protein binding. © 2015 Wiley Periodicals, Inc.

Selection Shapes Transcriptional Logic and Regulatory Specialization in Genetic Networks.

PubMed

Fogelmark, Karl; Peterson, Carsten; Troein, Carl

2016-01-01

Living organisms need to regulate their gene expression in response to environmental signals and internal cues. This is a computational task where genes act as logic gates that connect to form transcriptional networks, which are shaped at all scales by evolution. Large-scale mutations such as gene duplications and deletions add and remove network components, whereas smaller mutations alter the connections between them. Selection determines what mutations are accepted, but its importance for shaping the resulting networks has been debated. To investigate the effects of selection in the shaping of transcriptional networks, we derive transcriptional logic from a combinatorially powerful yet tractable model of the binding between DNA and transcription factors. By evolving the resulting networks based on their ability to function as either a simple decision system or a circadian clock, we obtain information on the regulation and logic rules encoded in functional transcriptional networks. Comparisons are made between networks evolved for different functions, as well as with structurally equivalent but non-functional (neutrally evolved) networks, and predictions are validated against the transcriptional network of E. coli. We find that the logic rules governing gene expression depend on the function performed by the network. Unlike the decision systems, the circadian clocks show strong cooperative binding and negative regulation, which achieves tight temporal control of gene expression. Furthermore, we find that transcription factors act preferentially as either activators or repressors, both when binding multiple sites for a single target gene and globally in the transcriptional networks. This separation into positive and negative regulators requires gene duplications, which highlights the interplay between mutation and selection in shaping the transcriptional networks.

Lateral Prefrontal Cortex Contributes to Fluid Intelligence Through Multinetwork Connectivity.

PubMed

Cole, Michael W; Ito, Takuya; Braver, Todd S

2015-10-01

Our ability to effectively adapt to novel circumstances--as measured by general fluid intelligence--has recently been tied to the global connectivity of lateral prefrontal cortex (LPFC). Global connectivity is a broad measure that summarizes both within-network connectivity and across-network connectivity. We used additional graph theoretical measures to better characterize the nature of LPFC connectivity and its relationship with fluid intelligence. We specifically hypothesized that LPFC is a connector hub with an across-network connectivity that contributes to fluid intelligence independent of within-network connectivity. We verified that LPFC was in the top 10% of brain regions in terms of across-network connectivity, suggesting it is a strong connector hub. Importantly, we found that the LPFC across-network connectivity predicted individuals' fluid intelligence and this correlation remained statistically significant when controlling for global connectivity (which includes within-network connectivity). This supports the conclusion that across-network connectivity independently contributes to the relationship between LPFC connectivity and intelligence. These results suggest that LPFC contributes to fluid intelligence by being a connector hub with a truly global multisystem connectivity throughout the brain.

Locally excitatory, globally inhibitory oscillator networks: theory and application to scene segmentation

NASA Astrophysics Data System (ADS)

Wang, DeLiang; Terman, David

1995-01-01

A novel class of locally excitatory, globally inhibitory oscillator networks (LEGION) is proposed and investigated analytically and by computer simulation. The model of each oscillator corresponds to a standard relaxation oscillator with two time scales. The network exhibits a mechanism of selective gating, whereby an oscillator jumping up to its active phase rapidly recruits the oscillators stimulated by the same pattern, while preventing other oscillators from jumping up. We show analytically that with the selective gating mechanism the network rapidly achieves both synchronization within blocks of oscillators that are stimulated by connected regions and desynchronization between different blocks. Computer simulations demonstrate LEGION's promising ability for segmenting multiple input patterns in real time. This model lays a physical foundation for the oscillatory correlation theory of feature binding, and may provide an effective computational framework for scene segmentation and figure/ground segregation.

Autoradiographic localization of endothelin-1 binding sites in porcine skin

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

Zhao, Y.D.; Springall, D.R.; Wharton, J.

Autoradiographic techniques and {sup 125}I-labeled endothelin-1 were used to study the distribution of endothelin-1 binding sites in porcine skin. Specific endothelin-1 binding sites were localized to blood vessels (capillaries, deep cutaneous vascular plexus, arteries, and arterioles), the deep dermal and connective tissue sheath of hair follicles, sebaceous and sweat glands, and arrector pili muscle. Specific binding was inhibited by endothelin-2 and endothelin-3 as well as endothelin-1. Non-specific binding was found in the epidermis and the medulla of hair follicles. No binding was found in connective tissue or fat. These vascular binding sites may represent endothelin receptors, in keeping with themore » known cutaneous vasoconstrictor actions of the peptide. If all binding sites are receptors, the results suggest that endothelin could also regulate the function of sweat glands and may have trophic effects in the skin.« less

Global network centrality of university rankings

NASA Astrophysics Data System (ADS)

Guo, Weisi; Del Vecchio, Marco; Pogrebna, Ganna

2017-10-01

Universities and higher education institutions form an integral part of the national infrastructure and prestige. As academic research benefits increasingly from international exchange and cooperation, many universities have increased investment in improving and enabling their global connectivity. Yet, the relationship of university performance and its global physical connectedness has not been explored in detail. We conduct, to our knowledge, the first large-scale data-driven analysis into whether there is a correlation between university relative ranking performance and its global connectivity via the air transport network. The results show that local access to global hubs (as measured by air transport network betweenness) strongly and positively correlates with the ranking growth (statistical significance in different models ranges between 5% and 1% level). We also found that the local airport's aggregate flight paths (degree) and capacity (weighted degree) has no effect on university ranking, further showing that global connectivity distance is more important than the capacity of flight connections. We also examined the effect of local city economic development as a confounding variable and no effect was observed suggesting that access to global transportation hubs outweighs economic performance as a determinant of university ranking. The impact of this research is that we have determined the importance of the centrality of global connectivity and, hence, established initial evidence for further exploring potential connections between university ranking and regional investment policies on improving global connectivity.

Global network centrality of university rankings

PubMed Central

Del Vecchio, Marco; Pogrebna, Ganna

2017-01-01

Universities and higher education institutions form an integral part of the national infrastructure and prestige. As academic research benefits increasingly from international exchange and cooperation, many universities have increased investment in improving and enabling their global connectivity. Yet, the relationship of university performance and its global physical connectedness has not been explored in detail. We conduct, to our knowledge, the first large-scale data-driven analysis into whether there is a correlation between university relative ranking performance and its global connectivity via the air transport network. The results show that local access to global hubs (as measured by air transport network betweenness) strongly and positively correlates with the ranking growth (statistical significance in different models ranges between 5% and 1% level). We also found that the local airport’s aggregate flight paths (degree) and capacity (weighted degree) has no effect on university ranking, further showing that global connectivity distance is more important than the capacity of flight connections. We also examined the effect of local city economic development as a confounding variable and no effect was observed suggesting that access to global transportation hubs outweighs economic performance as a determinant of university ranking. The impact of this research is that we have determined the importance of the centrality of global connectivity and, hence, established initial evidence for further exploring potential connections between university ranking and regional investment policies on improving global connectivity. PMID:29134105

Increased GABA-A receptor binding and reduced connectivity at the motor cortex in children with hemiplegic cerebral palsy: a multimodal investigation using 18F-fluoroflumazenil PET, immunohistochemistry, and MR imaging.

PubMed

Park, Hae-Jeong; Kim, Chul Hoon; Park, Eun Sook; Park, Bumhee; Oh, So Ra; Oh, Maeng-Keun; Park, Chang Il; Lee, Jong Doo

2013-08-01

γ-aminobutyric acid (GABA)-A receptor-mediated neural transmission is important to promote practice-dependent plasticity after brain injury. This study investigated alterations in GABA-A receptor binding and functional and anatomic connectivity within the motor cortex in children with cerebral palsy (CP). We conducted (18)F-fluoroflumazenil PET on children with hemiplegic CP to investigate whether in vivo GABA-A receptor binding is altered in the ipsilateral or contralateral hemisphere of the lesion site. To evaluate changes in the GABA-A receptor subunit after prenatal brain injury, we performed GABA-A receptor immunohistochemistry using rat pups with a diffuse hypoxic ischemic insult. We also performed diffusion tensor MR imaging and resting-state functional MR imaging on the same children with hemiplegic CP to investigate alterations in anatomic and functional connectivity at the motor cortex with increased GABA-A receptor binding. In children with hemiplegic CP, the (18)F-fluoroflumazenil binding potential was increased within the ipsilateral motor cortex. GABA-A receptors with the α1 subunit were highly expressed exclusively within cortical layers III, IV, and VI of the motor cortex in rat pups. The motor cortex with increased GABA-A receptor binding in children with hemiplegic CP had reduced thalamocortical and corticocortical connectivity, which might be linked to increased GABA-A receptor distribution in cortical layers in rats. Increased expression of the GABA-A receptor α1 subunit within the ipsilateral motor cortex may be an important adaptive mechanism after prenatal brain injury in children with CP but may be associated with improper functional connectivity after birth and have adverse effects on the development of motor plasticity.

Global connectivity of prefrontal cortex predicts cognitive control and intelligence

PubMed Central

Cole, Michael W.; Yarkoni, Tal; Repovs, Grega; Anticevic, Alan; Braver, Todd S.

2012-01-01

Control of thought and behavior is fundamental to human intelligence. Evidence suggests a fronto-parietal brain network implements such cognitive control across diverse contexts. We identify a mechanism – global connectivity – by which components of this network might coordinate control of other networks. A lateral prefrontal cortex (LPFC) region’s activity was found to predict performance in a high control demand working memory task, and also to exhibit high global connectivity. Critically, global connectivity in this LPFC region, involving connections both within and outside the fronto-parietal network, showed a highly selective relationship with individual differences in fluid intelligence. These findings suggest LPFC is a global hub with a brain-wide influence that facilitates the ability to implement control processes central to human intelligence. PMID:22745498

Im/mobilities and dis/connectivities in medical globalisation: How global is Global Health?

PubMed

Dilger, Hansjörg; Mattes, Dominik

2018-03-01

The interdisciplinary, politically contested field of Global Health has often been described as a consequence of, and response to, an intensification of the mobilities of, and connectivities between, people, pathogens, ideas, and infrastructure across national borders and large distances. However, such global mobilities and connectivities are not as omnidirectional and unpatterned as the rhetoric of many Global Health actors suggests. Instead, we argue that they are suffused by a plethora of institutional, national, and global political agendas, and substantially shaped by transnational and postcolonial power relations. Furthermore, the configurations that are typically subsumed under the category of Global Health represent only a minor part of the range of im/mobilities and dis/connectivities that are essential for understanding transformations of epidemiological patterns, health care infrastructures, and the responses to health-related challenges in a globalising world. In order to broaden such a limiting analytical perspective, we propose to expand the analytical focus in studying Global Health phenomena by paying close attention to the myriad ways in which particular im/mobilities and dis/connectivities constitute medicine and well-being in global and transnational settings. Pursuing a conceptual shift from studies of 'Global Health' to studying 'medical globalization' may carve out new analytical ground for such an endeavour.

Protein dynamics and motions in relation to their functions: several case studies and the underlying mechanisms

PubMed Central

Yang, Li-Quan; Sang, Peng; Tao, Yan; Fu, Yun-Xin; Zhang, Ke-Qin; Xie, Yue-Hui; Liu, Shu-Qun

2013-01-01

Proteins are dynamic entities in cellular solution with functions governed essentially by their dynamic personalities. We review several dynamics studies on serine protease proteinase K and HIV-1 gp120 envelope glycoprotein to demonstrate the importance of investigating the dynamic behaviors and molecular motions for a complete understanding of their structure–function relationships. Using computer simulations and essential dynamic (ED) analysis approaches, the dynamics data obtained revealed that: (i) proteinase K has highly flexible substrate-binding site, thus supporting the induced-fit or conformational selection mechanism of substrate binding; (ii) Ca2+ removal from proteinase K increases the global conformational flexibility, decreases the local flexibility of substrate-binding region, and does not influence the thermal motion of catalytic triad, thus explaining the experimentally determined decreased thermal stability, reduced substrate affinity, and almost unchanged catalytic activity upon Ca2+ removal; (iii) substrate binding affects the large concerted motions of proteinase K, and the resulting dynamic pocket can be connected to substrate binding, orientation, and product release; (iv) amino acid mutations 375 S/W and 423 I/P of HIV-1 gp120 have distinct effects on molecular motions of gp120, facilitating 375 S/W mutant to assume the CD4-bound conformation, while 423 I/P mutant to prefer for CD4-unliganded state. The mechanisms underlying protein dynamics and protein–ligand binding, including the concept of the free energy landscape (FEL) of the protein–solvent system, how the ruggedness and variability of FEL determine protein's dynamics, and how the three ligand-binding models, the lock-and-key, induced-fit, and conformational selection are rationalized based on the FEL theory are discussed in depth. PMID:23527883

Protein dynamics and motions in relation to their functions: several case studies and the underlying mechanisms.

PubMed

Yang, Li-Quan; Sang, Peng; Tao, Yan; Fu, Yun-Xin; Zhang, Ke-Qin; Xie, Yue-Hui; Liu, Shu-Qun

2014-01-01

Proteins are dynamic entities in cellular solution with functions governed essentially by their dynamic personalities. We review several dynamics studies on serine protease proteinase K and HIV-1 gp120 envelope glycoprotein to demonstrate the importance of investigating the dynamic behaviors and molecular motions for a complete understanding of their structure-function relationships. Using computer simulations and essential dynamic (ED) analysis approaches, the dynamics data obtained revealed that: (i) proteinase K has highly flexible substrate-binding site, thus supporting the induced-fit or conformational selection mechanism of substrate binding; (ii) Ca(2+) removal from proteinase K increases the global conformational flexibility, decreases the local flexibility of substrate-binding region, and does not influence the thermal motion of catalytic triad, thus explaining the experimentally determined decreased thermal stability, reduced substrate affinity, and almost unchanged catalytic activity upon Ca(2+) removal; (iii) substrate binding affects the large concerted motions of proteinase K, and the resulting dynamic pocket can be connected to substrate binding, orientation, and product release; (iv) amino acid mutations 375 S/W and 423 I/P of HIV-1 gp120 have distinct effects on molecular motions of gp120, facilitating 375 S/W mutant to assume the CD4-bound conformation, while 423 I/P mutant to prefer for CD4-unliganded state. The mechanisms underlying protein dynamics and protein-ligand binding, including the concept of the free energy landscape (FEL) of the protein-solvent system, how the ruggedness and variability of FEL determine protein's dynamics, and how the three ligand-binding models, the lock-and-key, induced-fit, and conformational selection are rationalized based on the FEL theory are discussed in depth.

Selection Shapes Transcriptional Logic and Regulatory Specialization in Genetic Networks

PubMed Central

Fogelmark, Karl; Peterson, Carsten; Troein, Carl

2016-01-01

Background Living organisms need to regulate their gene expression in response to environmental signals and internal cues. This is a computational task where genes act as logic gates that connect to form transcriptional networks, which are shaped at all scales by evolution. Large-scale mutations such as gene duplications and deletions add and remove network components, whereas smaller mutations alter the connections between them. Selection determines what mutations are accepted, but its importance for shaping the resulting networks has been debated. Methodology To investigate the effects of selection in the shaping of transcriptional networks, we derive transcriptional logic from a combinatorially powerful yet tractable model of the binding between DNA and transcription factors. By evolving the resulting networks based on their ability to function as either a simple decision system or a circadian clock, we obtain information on the regulation and logic rules encoded in functional transcriptional networks. Comparisons are made between networks evolved for different functions, as well as with structurally equivalent but non-functional (neutrally evolved) networks, and predictions are validated against the transcriptional network of E. coli. Principal Findings We find that the logic rules governing gene expression depend on the function performed by the network. Unlike the decision systems, the circadian clocks show strong cooperative binding and negative regulation, which achieves tight temporal control of gene expression. Furthermore, we find that transcription factors act preferentially as either activators or repressors, both when binding multiple sites for a single target gene and globally in the transcriptional networks. This separation into positive and negative regulators requires gene duplications, which highlights the interplay between mutation and selection in shaping the transcriptional networks. PMID:26927540

Oxidative stress signaling to chromatin in health and disease

PubMed Central

Kreuz, Sarah; Fischle, Wolfgang

2016-01-01

Oxidative stress has a significant impact on the development and progression of common human pathologies, including cancer, diabetes, hypertension and neurodegenerative diseases. Increasing evidence suggests that oxidative stress globally influences chromatin structure, DNA methylation, enzymatic and non-enzymatic post-translational modifications of histones and DNA-binding proteins. The effects of oxidative stress on these chromatin alterations mediate a number of cellular changes, including modulation of gene expression, cell death, cell survival and mutagenesis, which are disease-driving mechanisms in human pathologies. Targeting oxidative stress-dependent pathways is thus a promising strategy for the prevention and treatment of these diseases. We summarize recent research developments connecting oxidative stress and chromatin regulation. PMID:27319358

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

Ratto, T V; Rudd, R E; Langry, K C

We present evidence of multivalent interactions between a single protein molecule and multiple carbohydrates at a pH where the protein can bind four ligands. The evidence is based not only on measurements of the force required to rupture the bonds formed between ConcanavalinA (ConA) and {alpha}-D-mannose, but also on an analysis of the polymer-extension force curves to infer the polymer architecture that binds the protein to the cantilever and the ligands to the substrate. We find that although the rupture forces for multiple carbohydrate connections to a single protein are larger than the rupture force for a single connection, theymore » do not scale additively with increasing number. Specifically, the most common rupture forces are approximately 46, 66, and 85 pN, which we argue corresponds to 1, 2, and 3 ligands being pulled simultaneously from a single protein as corroborated by an analysis of the linkage architecture. As in our previous work polymer tethers allow us to discriminate between specific and non-specific binding. We analyze the binding configuration (i.e. serial versus parallel connections) through fitting the polymer stretching data with modified Worm-Like Chain (WLC) models that predict how the effective stiffness of the tethers is affected by multiple connections. This analysis establishes that the forces we measure are due to single proteins interacting with multiple ligands, the first force spectroscopy study that establishes single-molecule multivalent binding unambiguously.« less

Clinical Research: A Globalized Network

PubMed Central

Richter, Trevor A.

2014-01-01

Clinical research has become increasingly globalized, but the extent of globalization has not been assessed. To describe the globalization of clinical research, we used all (n = 13,208) multinational trials registered at ClinicalTrials.gov to analyzed geographic connections among individual countries. Our findings indicate that 95% (n = 185) of all countries worldwide have participated in multinational clinical research. Growth in the globalization of clinical research peaked in 2009, suggesting that the global infrastructure that supports clinical research might have reached its maximum capacity. Growth in the globalization of clinical research is attributable to increased involvement of non-traditional markets, particularly in South America and Asia. Nevertheless, Europe is the most highly interconnected geographic region (60.64% of global connections), and collectively, Europe, North America, and Asia comprise more than 85% of all global connections. Therefore, while the expansion of clinical trials into non-traditional markets has increased over the last 20 years and connects countries across the globe, traditional markets still dominate multinational clinical research, which appears to have reached a maximum global capacity. PMID:25517976

On the Connectedness of Attractors for Dynamical Systems

NASA Astrophysics Data System (ADS)

Gobbino, Massimo; Sardella, Mirko

1997-01-01

For a dynamical system on a connected metric spaceX, the global attractor (when it exists) is connected provided that either the semigroup is time-continuous orXis locally connected. Moreover, there exists an example of a dynamical system on a connected metric space which admits a disconnected global attractor.

Ceramic tamper-revealing seals

DOEpatents

Kupperman, David S.; Raptis, Apostolos C.; Sheen, Shuh-Haw

1992-01-01

A flexible metal or ceramic cable with composite ceramic ends, or a u-shaped ceramic connecting element attached to a binding element plate or block cast from alumina or zirconium, and connected to the connecting element by shrink fitting.

Quantifying edge significance on maintaining global connectivity

PubMed Central

Qian, Yuhua; Li, Yebin; Zhang, Min; Ma, Guoshuai; Lu, Furong

2017-01-01

Global connectivity is a quite important issue for networks. The failures of some key edges may lead to breakdown of the whole system. How to find them will provide a better understanding on system robustness. Based on topological information, we propose an approach named LE (link entropy) to quantify the edge significance on maintaining global connectivity. Then we compare the LE with the other six acknowledged indices on the edge significance: the edge betweenness centrality, degree product, bridgeness, diffusion importance, topological overlap and k-path edge centrality. Experimental results show that the LE approach outperforms in quantifying edge significance on maintaining global connectivity. PMID:28349923

Globalization: Ecological consequences of global-scale connectivity in people, resources and information

USDA-ARS?s Scientific Manuscript database

Globalization is a phenomenon affecting all facets of the Earth System. Within the context of ecological systems, it is becoming increasingly apparent that global connectivity among terrestrial systems, the atmosphere, and oceans is driving many ecological dynamics at finer scales and pushing thresh...

Microarray study of single nucleotide polymorphisms and expression of ATP-binding cassette genes in breast tumors

NASA Astrophysics Data System (ADS)

Tsyganov, M. M.; Ibragimova, M. K.; Karabut, I. V.; Freydin, M. B.; Choinzonov, E. L.; Litvyakov, N. V.

2015-11-01

Our previous research establishes that changes of expression of the ATP-binding cassette genes family is connected with the neoadjuvant chemotherapy effect. However, the mechanism of regulation of resistance gene expression remains unclear. As many researchers believe, single nucleotide polymorphisms can be involved in this process. Thereupon, microarray analysis is used to study polymorphisms in ATP-binding cassette genes. It is thus found that MDR gene expression is connected with 5 polymorphisms, i.e. rs241432, rs241429, rs241430, rs3784867, rs59409230, which participate in the regulation of expression of own genes.

Mass-action equilibrium and non-specific interactions in protein binding networks

NASA Astrophysics Data System (ADS)

Maslov, Sergei

2009-03-01

Large-scale protein binding networks serve as a paradigm of complex properties of living cells. These networks are naturally weighted with edges characterized by binding strength and protein-nodes -- by their concentrations. However, the state-of-the-art high-throughput experimental techniques generate just a binary (yes or no) information about individual interactions. As a result, most of the previous research concentrated just on topology of these networks. In a series of recent publications [1-4] my collaborators and I went beyond purely topological studies and calculated the mass-action equilibrium of a genome-wide binding network using experimentally determined protein concentrations, localizations, and reliable binding interactions in baker's yeast. We then studied how this equilibrium responds to large perturbations [1-2] and noise [3] in concentrations of proteins. We demonstrated that the change in the equilibrium concentration of a protein exponentially decays (and sign-alternates) with its network distance away from the perturbed node. This explains why, despite a globally connected topology, individual functional modules in such networks are able to operate fairly independently. In a separate study [4] we quantified the interplay between specific and non-specific binding interactions under crowded conditions inside living cells. We show how the need to limit the waste of resources constrains the number of types and concentrations of proteins that are present at the same time and at the same place in yeast cells. [1] S Maslov, I. Ispolatov, PNAS 104:13655 (2007). [2] S. Maslov, K. Sneppen, I. Ispolatov, New J. of Phys. 9: 273 (2007). [3] K-K. Yan, D. Walker, S. Maslov, PRL accepted (2008). [4] J. Zhang, S. Maslov, and E. I. Shakhnovich, Mol Syst Biol 4, 210 (2008).

Ceramic tamper-revealing seals

DOEpatents

Kupperman, D.S.; Raptis, A.C.; Sheen, S.H.

1992-12-08

A flexible metal or ceramic cable is described with composite ceramic ends, or a U-shaped ceramic connecting element attached to a binding element plate or block cast from alumina or zirconium, and connected to the connecting element by shrink fitting. 7 figs.

Anisotropic energy flow and allosteric ligand binding in albumin

NASA Astrophysics Data System (ADS)

Li, Guifeng; Magana, Donny; Dyer, R. Brian

2014-01-01

Allosteric interactions in proteins generally involve propagation of local structural changes through the protein to a remote site. Anisotropic energy transport is thought to couple the remote sites, but the nature of this process is poorly understood. Here, we report the relationship between energy flow through the structure of bovine serum albumin and allosteric interactions between remote ligand binding sites of the protein. Ultrafast infrared spectroscopy is used to probe the flow of energy through the protein backbone following excitation of a heater dye, a metalloporphyrin or malachite green, bound to different binding sites in the protein. We observe ballistic and anisotropic energy flow through the protein structure following input of thermal energy into the flexible ligand binding sites, without local heating of the rigid helix bundles that connect these sites. This efficient energy transport mechanism enables the allosteric propagation of binding energy through the connecting helix structures.

Anisotropic energy flow and allosteric ligand binding in albumin.

PubMed

Li, Guifeng; Magana, Donny; Dyer, R Brian

2014-01-01

Allosteric interactions in proteins generally involve propagation of local structural changes through the protein to a remote site. Anisotropic energy transport is thought to couple the remote sites, but the nature of this process is poorly understood. Here, we report the relationship between energy flow through the structure of bovine serum albumin and allosteric interactions between remote ligand binding sites of the protein. Ultrafast infrared spectroscopy is used to probe the flow of energy through the protein backbone following excitation of a heater dye, a metalloporphyrin or malachite green, bound to different binding sites in the protein. We observe ballistic and anisotropic energy flow through the protein structure following input of thermal energy into the flexible ligand binding sites, without local heating of the rigid helix bundles that connect these sites. This efficient energy transport mechanism enables the allosteric propagation of binding energy through the connecting helix structures.

Anisotropic energy flow and allosteric ligand binding in albumin

PubMed Central

Li, Guifeng; Magana, Donny; Dyer, R. Brian

2014-01-01

Allosteric interactions in proteins generally involve propagation of local structural changes through the protein to a remote site. Anisotropic energy transport is thought to couple the remote sites, but the nature of this process is poorly understood. Here, we report the relationship between energy flow through the structure of bovine serum albumin and allosteric interactions between remote ligand binding sites of the protein. Ultrafast infrared spectroscopy is used to probe the flow of energy through the protein backbone following excitation of a heater dye, a metalloporphyrin or malachite green, bound to different binding sites in the protein. We observe ballistic and anisotropic energy flow through the protein structure following input of thermal energy into the flexible ligand binding sites, without local heating of the rigid helix bundles that connect these sites. This efficient energy transport mechanism enables the allosteric propagation of binding energy through the connecting helix structures. PMID:24445265

Binding ligand prediction for proteins using partial matching of local surface patches.

PubMed

Sael, Lee; Kihara, Daisuke

2010-01-01

Functional elucidation of uncharacterized protein structures is an important task in bioinformatics. We report our new approach for structure-based function prediction which captures local surface features of ligand binding pockets. Function of proteins, specifically, binding ligands of proteins, can be predicted by finding similar local surface regions of known proteins. To enable partial comparison of binding sites in proteins, a weighted bipartite matching algorithm is used to match pairs of surface patches. The surface patches are encoded with the 3D Zernike descriptors. Unlike the existing methods which compare global characteristics of the protein fold or the global pocket shape, the local surface patch method can find functional similarity between non-homologous proteins and binding pockets for flexible ligand molecules. The proposed method improves prediction results over global pocket shape-based method which was previously developed by our group.

Binding Ligand Prediction for Proteins Using Partial Matching of Local Surface Patches

PubMed Central

Sael, Lee; Kihara, Daisuke

2010-01-01

Functional elucidation of uncharacterized protein structures is an important task in bioinformatics. We report our new approach for structure-based function prediction which captures local surface features of ligand binding pockets. Function of proteins, specifically, binding ligands of proteins, can be predicted by finding similar local surface regions of known proteins. To enable partial comparison of binding sites in proteins, a weighted bipartite matching algorithm is used to match pairs of surface patches. The surface patches are encoded with the 3D Zernike descriptors. Unlike the existing methods which compare global characteristics of the protein fold or the global pocket shape, the local surface patch method can find functional similarity between non-homologous proteins and binding pockets for flexible ligand molecules. The proposed method improves prediction results over global pocket shape-based method which was previously developed by our group. PMID:21614188

Reduced Global Functional Connectivity of the Medial Prefrontal Cortex in Major Depressive Disorder

PubMed Central

Murrough, James W.; Abdallah, Chadi G.; Anticevic, Alan; Collins, Katherine A.; Geha, Paul; Averill, Lynnette A.; Schwartz, Jaclyn; DeWilde, Kaitlin E.; Averill, Christopher; Yang, Genevieve Jia-wei; Wong, Edmund; Tang, Cheuk Y.; Krystal, John H.; Iosifescu, Dan V.; Charney, Dennis S.

2016-01-01

Background Major depressive disorder is a disabling neuropsychiatric condition that is associated with disrupted functional connectivity across brain networks. The precise nature of altered connectivity, however, remains incompletely understood. The current study was designed to examine the coherence of large-scale connectivity in depression using a recently developed technique termed global brain connectivity. Methods A total of 82 subjects, including medication-free patients with major depression (n=57) and healthy volunteers (n=25) underwent functional magnetic resonance imaging with resting data acquisition for functional connectivity analysis. Global brain connectivity was computed as the mean of each voxel’s time series correlation with every other voxel and compared between study groups. Relationships between global connectivity and depressive symptom severity measured using the Montgomery-Åsberg Depression Rating Scale were examined by means of linear correlation. Results Relative to the healthy group, patients with depression evidenced reduced global connectivity bilaterally within multiple regions of medial and lateral prefrontal cortex. The largest between-group difference was observed within the right subgenual anterior cingulate cortex, extending into ventromedial prefrontal cortex bilaterally (Hedges’ g = −1.48, p<0.000001). Within the depressed group, patients with the lowest connectivity evidenced the highest symptom severity within ventromedial prefrontal cortex (r = −0.47, p=0.0005). Conclusions Patients with major depressive evidenced abnormal large-scale functional coherence in the brain that was centered within the subgenual cingulate cortex, and medial prefrontal cortex more broadly. These data extend prior studies of connectivity in depression and demonstrate that functional disconnection of the medial prefrontal cortex is a key pathological feature of the disorder. PMID:27144347

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

Lu, Deyu

A systematic route to go beyond the exact exchange plus random phase approximation (RPA) is to include a physical exchange-correlation kernel in the adiabatic-connection fluctuation-dissipation theorem. Previously, [D. Lu, J. Chem. Phys. 140, 18A520 (2014)], we found that non-local kernels with a screening length depending on the local Wigner-Seitz radius, r s(r), suffer an error associated with a spurious long-range repulsion in van der Waals bounded systems, which deteriorates the binding energy curve as compared to RPA. Here, we analyze the source of the error and propose to replace r s(r) by a global, average r s in the kernel.more » Exemplary studies with the Corradini, del Sole, Onida, and Palummo kernel show that while this change does not affect the already outstanding performance in crystalline solids, using an average r s significantly reduces the spurious long-range tail in the exchange-correlation kernel in van der Waals bounded systems. Finally, when this method is combined with further corrections using local dielectric response theory, the binding energy of the Kr dimer is improved three times as compared to RPA.« less

Global patterns of fragmentation and connectivity of mammalian carnivore habitat.

PubMed

Crooks, Kevin R; Burdett, Christopher L; Theobald, David M; Rondinini, Carlo; Boitani, Luigi

2011-09-27

Although mammalian carnivores are vulnerable to habitat fragmentation and require landscape connectivity, their global patterns of fragmentation and connectivity have not been examined. We use recently developed high-resolution habitat suitability models to conduct comparative analyses and to identify global hotspots of fragmentation and connectivity for the world's terrestrial carnivores. Species with less fragmentation (i.e. more interior high-quality habitat) had larger geographical ranges, a greater proportion of habitat within their range, greater habitat connectivity and a lower risk of extinction. Species with higher connectivity (i.e. less habitat isolation) also had a greater proportion of high-quality habitat, but had smaller, not larger, ranges, probably reflecting shorter distances between habitat patches for species with restricted distributions; such species were also more threatened, as would be expected given the negative relationship between range size and extinction risk. Fragmentation and connectivity did not differ among Carnivora families, and body mass was associated with connectivity but not fragmentation. On average, only 54.3 per cent of a species' geographical range comprised high-quality habitat, and more troubling, only 5.2 per cent of the range comprised such habitat within protected areas. Identification of global hotspots of fragmentation and connectivity will help guide strategic priorities for carnivore conservation.

Global patterns of fragmentation and connectivity of mammalian carnivore habitat

PubMed Central

Crooks, Kevin R.; Burdett, Christopher L.; Theobald, David M.; Rondinini, Carlo; Boitani, Luigi

2011-01-01

Although mammalian carnivores are vulnerable to habitat fragmentation and require landscape connectivity, their global patterns of fragmentation and connectivity have not been examined. We use recently developed high-resolution habitat suitability models to conduct comparative analyses and to identify global hotspots of fragmentation and connectivity for the world's terrestrial carnivores. Species with less fragmentation (i.e. more interior high-quality habitat) had larger geographical ranges, a greater proportion of habitat within their range, greater habitat connectivity and a lower risk of extinction. Species with higher connectivity (i.e. less habitat isolation) also had a greater proportion of high-quality habitat, but had smaller, not larger, ranges, probably reflecting shorter distances between habitat patches for species with restricted distributions; such species were also more threatened, as would be expected given the negative relationship between range size and extinction risk. Fragmentation and connectivity did not differ among Carnivora families, and body mass was associated with connectivity but not fragmentation. On average, only 54.3 per cent of a species' geographical range comprised high-quality habitat, and more troubling, only 5.2 per cent of the range comprised such habitat within protected areas. Identification of global hotspots of fragmentation and connectivity will help guide strategic priorities for carnivore conservation. PMID:21844043

Tracing neuronal circuits in transgenic animals by transneuronal control of transcription (TRACT)

PubMed Central

Huang, Ting-hao; Niesman, Peter; Arasu, Deepshika; Lee, Donghyung; De La Cruz, Aubrie L; Callejas, Antuca; Hong, Elizabeth J

2017-01-01

Understanding the computations that take place in brain circuits requires identifying how neurons in those circuits are connected to one another. We describe a technique called TRACT (TRAnsneuronal Control of Transcription) based on ligand-induced intramembrane proteolysis to reveal monosynaptic connections arising from genetically labeled neurons of interest. In this strategy, neurons expressing an artificial ligand (‘donor’ neurons) bind to and activate a genetically-engineered artificial receptor on their synaptic partners (‘receiver’ neurons). Upon ligand-receptor binding at synapses the receptor is cleaved in its transmembrane domain and releases a protein fragment that activates transcription in the synaptic partners. Using TRACT in Drosophila we have confirmed the connectivity between olfactory receptor neurons and their postsynaptic targets, and have discovered potential new connections between neurons in the circadian circuit. Our results demonstrate that the TRACT method can be used to investigate the connectivity of neuronal circuits in the brain. PMID:29231171

Ecopedagogy and Citizenship in the Age of Globalisation: Connections between Environmental and Global Citizenship Education to Save the Planet

ERIC Educational Resources Information Center

Misiaszek, Greg William

2015-01-01

Teaching the connections between environmentally-harmful acts and social conflict is essential but is often ignored in education. This article presents two ways in which these are not taught because of the policies of those who benefit from the ignorance of these connections: first, the avoidance of teaching global-local connectivity and second,…

Predicting RNA-protein binding sites and motifs through combining local and global deep convolutional neural networks.

PubMed

Pan, Xiaoyong; Shen, Hong-Bin

2018-05-02

RNA-binding proteins (RBPs) take over 5∼10% of the eukaryotic proteome and play key roles in many biological processes, e.g. gene regulation. Experimental detection of RBP binding sites is still time-intensive and high-costly. Instead, computational prediction of the RBP binding sites using pattern learned from existing annotation knowledge is a fast approach. From the biological point of view, the local structure context derived from local sequences will be recognized by specific RBPs. However, in computational modeling using deep learning, to our best knowledge, only global representations of entire RNA sequences are employed. So far, the local sequence information is ignored in the deep model construction process. In this study, we present a computational method iDeepE to predict RNA-protein binding sites from RNA sequences by combining global and local convolutional neural networks (CNNs). For the global CNN, we pad the RNA sequences into the same length. For the local CNN, we split a RNA sequence into multiple overlapping fixed-length subsequences, where each subsequence is a signal channel of the whole sequence. Next, we train deep CNNs for multiple subsequences and the padded sequences to learn high-level features, respectively. Finally, the outputs from local and global CNNs are combined to improve the prediction. iDeepE demonstrates a better performance over state-of-the-art methods on two large-scale datasets derived from CLIP-seq. We also find that the local CNN run 1.8 times faster than the global CNN with comparable performance when using GPUs. Our results show that iDeepE has captured experimentally verified binding motifs. https://github.com/xypan1232/iDeepE. xypan172436@gmail.com or hbshen@sjtu.edu.cn. Supplementary data are available at Bioinformatics online.

Energy levels of double triangular graphene quantum dots

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

Liang, F. X.; Jiang, Z. T., E-mail: ztjiang616@hotmail.com; Zhang, H. Y.

2014-09-28

We investigate theoretically the energy levels of the coupled double triangular graphene quantum dots (GQDs) based on the tight-binding Hamiltonian model. The double GQDs including the ZZ-type, ZA-type, and AA-type GQDs with the two GQDs having the zigzag or armchair boundaries can be coupled together via different interdot connections, such as the direct coupling, the chains of benzene rings, and those of carbon atoms. It is shown that the energy spectrum of the coupled double GQDs is the amalgamation of those spectra of the corresponding two isolated GQDs with the modification triggered by the interdot connections. The interdot connection ismore » inclined to lift up the degeneracies of the energy levels in different degree, and as the connection changes from the direct coupling to the long chains, the removal of energy degeneracies is suppressed in ZZ-type and AA-type double GQDs, which indicates that the two coupled GQDs are inclined to become decoupled. Then we consider the influences on the spectra of the coupled double GQDs induced by the electric fields applied on the GQDs or the connection, which manifests as the global spectrum redistribution or the local energy level shift. Finally, we study the symmetrical and asymmetrical energy spectra of the double GQDs caused by the substrates supporting the two GQDs, clearly demonstrating how the substrates affect the double GQDs' spectrum. This research elucidates the energy spectra of the coupled double GQDs, as well as the mechanics of manipulating them by the electric field and the substrates, which would be a significant reference for designing GQD-based devices.« less

Shifting Tides in Global Higher Education: Agency, Autonomy, and Governance in the Global Network. Global Studies in Education, Volume 9

ERIC Educational Resources Information Center

Witt, Mary Allison

2011-01-01

The increasing connection among higher education institutions worldwide is well documented. What is less understood is how this connectivity is enacted and manifested on specific levels of the global education network. This book details the planning process of a multi-institutional program in engineering between institutions in the US and…

Neuromorphic device architectures with global connectivity through electrolyte gating

NASA Astrophysics Data System (ADS)

Gkoupidenis, Paschalis; Koutsouras, Dimitrios A.; Malliaras, George G.

2017-05-01

Information processing in the brain takes place in a network of neurons that are connected with each other by an immense number of synapses. At the same time, neurons are immersed in a common electrochemical environment, and global parameters such as concentrations of various hormones regulate the overall network function. This computational paradigm of global regulation, also known as homeoplasticity, has important implications in the overall behaviour of large neural ensembles and is barely addressed in neuromorphic device architectures. Here, we demonstrate the global control of an array of organic devices based on poly(3,4ethylenedioxythiophene):poly(styrene sulf) that are immersed in an electrolyte, a behaviour that resembles homeoplasticity phenomena of the neural environment. We use this effect to produce behaviour that is reminiscent of the coupling between local activity and global oscillations in the biological neural networks. We further show that the electrolyte establishes complex connections between individual devices, and leverage these connections to implement coincidence detection. These results demonstrate that electrolyte gating offers significant advantages for the realization of networks of neuromorphic devices of higher complexity and with minimal hardwired connectivity.

Switch-connected HyperX network

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

Chen, Dong; Heidelberger, Philip

A network system includes a plurality of sub-network planes and global switches. The sub-network planes have a same network topology as each other. Each of the sub-network planes includes edge switches. Each of the edge switches has N ports. Each of the global switches is configured to connect a group of edge switches at a same location in the sub-network planes. In each of the sub-network planes, some of the N ports of each of the edge switches are connected to end nodes, and others of the N ports are connected to other edge switches in the same sub-network plane,more » other of the N ports are connected to at least one of the global switches.« less

Analysis of globally connected active rotators with excitatory and inhibitory connections using the Fokker-Planck equation

NASA Astrophysics Data System (ADS)

Kanamaru, Takashi; Sekine, Masatoshi

2003-03-01

The globally connected active rotators with excitatory and inhibitory connections are analyzed using the nonlinear Fokker-Planck equation. The bifurcation diagram of the system is obtained numerically, and both periodic solutions and chaotic solutions are found. By observing the interspike interval, the coefficient of variance, and the correlation coefficient of the system, the relationship of our model to the biological data is discussed.

Mechanism of the Association between Na+ Binding and Conformations at the Intracellular Gate in Neurotransmitter:Sodium Symporters*

PubMed Central

Stolzenberg, Sebastian; Quick, Matthias; Zhao, Chunfeng; Gotfryd, Kamil; Khelashvili, George; Gether, Ulrik; Loland, Claus J.; Javitch, Jonathan A.; Noskov, Sergei; Weinstein, Harel; Shi, Lei

2015-01-01

Neurotransmitter:sodium symporters (NSSs) terminate neurotransmission by Na+-dependent reuptake of released neurotransmitters. Previous studies suggested that Na+-binding reconfigures dynamically coupled structural elements in an allosteric interaction network (AIN) responsible for function-related conformational changes, but the intramolecular pathway of this mechanism has remained uncharted. We describe a new approach for the modeling and analysis of intramolecular dynamics in the bacterial NSS homolog LeuT. From microsecond-scale molecular dynamics simulations and cognate experimental verifications in both LeuT and human dopamine transporter (hDAT), we apply the novel method to identify the composition and the dynamic properties of their conserved AIN. In LeuT, two different perturbations disrupting Na+ binding and transport (i.e. replacing Na+ with Li+ or the Y268A mutation at the intracellular gate) affect the AIN in strikingly similar ways. In contrast, other mutations that affect the intracellular gate (i.e. R5A and D369A) do not significantly impair Na+ cooperativity and transport. Our analysis shows these perturbations to have much lesser effects on the AIN, underscoring the sensitivity of this novel method to the mechanistic nature of the perturbation. Notably, this set of observations holds as well for hDAT, where the aligned Y335A, R60A, and D436A mutations also produce different impacts on Na+ dependence. Thus, the detailed AIN generated from our method is shown to connect Na+ binding with global conformational changes that are critical for the transport mechanism. That the AIN between the Na+ binding sites and the intracellular gate in bacterial LeuT resembles that in eukaryotic hDAT highlights the conservation of allosteric pathways underlying NSS function. PMID:25869126

Mechanism of the association between Na + binding and conformations at the intracellular gate in neurotransmitter:sodium symporters

DOE PAGES

Stolzenberg, Sebastian; Quick, Matthias; Zhao, Chunfeng; ...

2015-04-13

Neurotransmitter:sodium symporters (NSSs) terminate neurotransmission by Na +-dependent reuptake of released neurotransmitters. Previous studies suggested that Na +-binding reconfigures dynamically coupled structural elements in an allosteric interaction network (AIN) responsible for function-related conformational changes, but the intramolecular pathway of this mechanism has remained uncharted. Here we describe a new approach for the modeling and analysis of intramolecular dynamics in the bacterial NSS homolog LeuT. From microsecond-scale molecular dynamics simulations and cognate experimental verifications in both LeuT and human dopamine transporter (hDAT), we apply the novel method to identify the composition and the dynamic properties of their conserved AIN. In LeuT,more » two different perturbations disrupting Na+ binding and transport ( i.e. replacing Na + with Li + or the Y268A mutation at the intracellular gate) affect the AIN in strikingly similar ways. In contrast, other mutations that affect the intracellular gate (i.e. R5A and D369A) do not significantly impair Na + cooperativity and transport. Our analysis shows these perturbations to have much lesser effects on the AIN, underscoring the sensitivity of this novel method to the mechanistic nature of the perturbation. Notably, this set of observations holds as well for hDAT, where the aligned Y335A, R60A, and D436A mutations also produce different impacts on Na + dependence. Furthermore, the detailed AIN generated from our method is shown to connect Na + binding with global conformational changes that are critical for the transport mechanism. Lastly, that the AIN between the Na + binding sites and the intracellular gate in bacterial LeuT resembles that in eukaryotic hDAT highlights the conservation of allosteric pathways underlying NSS function.« less

Multiscaled exploration of coupled folding and binding of an intrinsically disordered molecular recognition element in measles virus nucleoprotein

PubMed Central

Wang, Yong; Chu, Xiakun; Longhi, Sonia; Roche, Philippe; Han, Wei; Wang, Erkang; Wang, Jin

2013-01-01

Numerous relatively short regions within intrinsically disordered proteins (IDPs) serve as molecular recognition elements (MoREs). They fold into ordered structures upon binding to their partner molecules. Currently, there is still a lack of in-depth understanding of how coupled binding and folding occurs in MoREs. Here, we quantified the unbound ensembles of the α-MoRE within the intrinsically disordered C-terminal domain of the measles virus nucleoprotein. We developed a multiscaled approach by combining a physics-based and an atomic hybrid model to decipher the mechanism by which the α-MoRE interacts with the X domain of the measles virus phosphoprotein. Our multiscaled approach led to remarkable qualitative and quantitative agreements between the theoretical predictions and experimental results (e.g., chemical shifts). We found that the free α-MoRE rapidly interconverts between multiple discrete partially helical conformations and the unfolded state, in accordance with the experimental observations. We quantified the underlying global folding–binding landscape. This leads to a synergistic mechanism in which the recognition event proceeds via (minor) conformational selection, followed by (major) induced folding. We also provided evidence that the α-MoRE is a compact molten globule-like IDP and behaves as a downhill folder in the induced folding process. We further provided a theoretical explanation for the inherent connections between “downhill folding,” “molten globule,” and “intrinsic disorder” in IDP-related systems. Particularly, we proposed that binding and unbinding of IDPs proceed in a stepwise way through a “kinetic divide-and-conquer” strategy that confers them high specificity without high affinity. PMID:24043820

Linear Response Path Following: A Molecular Dynamics Method To Simulate Global Conformational Changes of Protein upon Ligand Binding.

PubMed

Tamura, Koichi; Hayashi, Shigehiko

2015-07-14

Molecular functions of proteins are often fulfilled by global conformational changes that couple with local events such as the binding of ligand molecules. High molecular complexity of proteins has, however, been an obstacle to obtain an atomistic view of the global conformational transitions, imposing a limitation on the mechanistic understanding of the functional processes. In this study, we developed a new method of molecular dynamics (MD) simulation called the linear response path following (LRPF) to simulate a protein's global conformational changes upon ligand binding. The method introduces a biasing force based on a linear response theory, which determines a local reaction coordinate in the configuration space that represents linear coupling between local events of ligand binding and global conformational changes and thus provides one with fully atomistic models undergoing large conformational changes without knowledge of a target structure. The overall transition process involving nonlinear conformational changes is simulated through iterative cycles consisting of a biased MD simulation with an updated linear response force and a following unbiased MD simulation for relaxation. We applied the method to the simulation of global conformational changes of the yeast calmodulin N-terminal domain and successfully searched out the end conformation. The atomistically detailed trajectories revealed a sequence of molecular events that properly lead to the global conformational changes and identified key steps of local-global coupling that induce the conformational transitions. The LRPF method provides one with a powerful means to model conformational changes of proteins such as motors and transporters where local-global coupling plays a pivotal role in their functional processes.

Tissue types (image)

MedlinePlus

... are 4 basic types of tissue: connective tissue, epithelial tissue, muscle tissue, and nervous tissue. Connective tissue supports ... binds them together (bone, blood, and lymph tissues). Epithelial tissue provides a covering (skin, the linings of the ...

Connected motorcycle system performance.

DOT National Transportation Integrated Search

2016-01-15

This project characterized the performance of Connected Vehicle Systems (CVS) on motorcycles based on two key components: global positioning and wireless communication systems. Considering that Global Positioning System (GPS) and 5.9 GHz Dedicated Sh...

Allosteric Ligand Binding and Anisotropic Energy Flow in Albumin

NASA Astrophysics Data System (ADS)

Dyer, Brian

2014-03-01

Protein allostery usually involves propagation of local structural changes through the protein to a remote site. Coupling of structural changes at remote sites is thought to occur through anisotropic energy transport, but the nature of this process is poorly understood. We have studied the relationship between allosteric interactions of remote ligand binding sites of the protein and energy flow through the structure of bovine serum albumin (BSA). We applied ultrafast infrared spectroscopy to probe the flow of energy through the protein backbone following excitation of a heater dye, a metalloporphyrin or malachite green, bound to different binding sites in the protein. We observe ballistic flow through the protein structure following input of thermal energy into the flexible ligand binding sites. We also observe anisotropic heat flow through the structure, without local heating of the rigid helix bundles that connect these sites. We will discuss the implications of this efficient energy transport mechanism with regard to the allosteric propagation of binding energy through the connecting helix structures.

Global competition and local cooperation in a network of neural oscillators

NASA Astrophysics Data System (ADS)

Terman, David; Wang, DeLiang

An architecture of locally excitatory, globally inhibitory oscillator networks is proposed and investigated both analytically and by computer simulation. The model for each oscillator corresponds to a standard relaxation oscillator with two time scales. Oscillators are locally coupled by a scheme that resembles excitatory synaptic coupling, and each oscillator also inhibits other oscillators through a common inhibitor. Oscillators are driven to be oscillatory by external stimulation. The network exhibits a mechanism of selective gating, whereby an oscillator jumping up to its active phase rapidly recruits the oscillators stimulated by the same pattern, while preventing the other oscillators from jumping up. We show analytically that with the selective gating mechanism, the network rapidly achieves both synchronization within blocks of oscillators that are stimulated by connected regions and desynchronization between different blocks. Computer simulations demonstrate the model's promising ability for segmenting multiple input patterns in real time. This model lays a physical foundation for the oscillatory correlation theory of feature binding and may provide an effective computational framework for scene segmentation and figure/ ground segregation.

Not5-dependent co-translational assembly of Ada2 and Spt20 is essential for functional integrity of SAGA

PubMed Central

Kassem, Sari; Villanyi, Zoltan

2017-01-01

Abstract Acetylation of histones regulates gene expression in eukaryotes. In the yeast Saccharomyces cerevisiae it depends mainly upon the ADA and SAGA histone acetyltransferase complexes for which Gcn5 is the catalytic subunit. Previous screens have determined that global acetylation is reduced in cells lacking subunits of the Ccr4–Not complex, a global regulator of eukaryotic gene expression. In this study we have characterized the functional connection between the Ccr4–Not complex and SAGA. We show that SAGA mRNAs encoding a core set of SAGA subunits are tethered together for co-translational assembly of the encoded proteins. Ccr4–Not subunits bind SAGA mRNAs and promote the co-translational assembly of these subunits. This is needed for integrity of SAGA. In addition, we determine that a glycolytic enzyme, the glyceraldehyde-3-phosphate dehydrogenase Tdh3, a prototypical moonlighting protein, is tethered at this site of Ccr4–Not-dependent co-translational SAGA assembly and functions as a chaperone. PMID:28180299

Global malaria connectivity through air travel.

PubMed

Huang, Zhuojie; Tatem, Andrew J

2013-08-02

Air travel has expanded at an unprecedented rate and continues to do so. Its effects have been seen on malaria in rates of imported cases, local outbreaks in non-endemic areas and the global spread of drug resistance. With elimination and global eradication back on the agenda, changing levels and compositions of imported malaria in malaria-free countries, and the threat of artemisinin resistance spreading from Southeast Asia, there is a need to better understand how the modern flow of air passengers connects each Plasmodium falciparum- and Plasmodium vivax-endemic region to the rest of the world. Recently constructed global P. falciparum and P.vivax malaria risk maps, along with data on flight schedules and modelled passenger flows across the air network, were combined to describe and quantify global malaria connectivity through air travel. Network analysis approaches were then utilized to describe and quantify the patterns that exist in passenger flows weighted by malaria prevalence. Finally, the connectivity within and to the Southeast Asia region where the threat of imported artemisinin resistance arising is highest, was examined to highlight risk routes for its spread. The analyses demonstrate the substantial connectivity that now exists between and from malaria-endemic regions through air travel. While the air network provides connections to previously isolated malarious regions, it is clear that great variations exist, with significant regional communities of airports connected by higher rates of flow standing out. The structures of these communities are often not geographically coherent, with historical, economic and cultural ties evident, and variations between P. falciparum and P. vivax clear. Moreover, results highlight how well connected the malaria-endemic areas of Africa are now to Southeast Asia, illustrating the many possible routes that artemisinin-resistant strains could take. The continuing growth in air travel is playing an important role in the global epidemiology of malaria, with the endemic world becoming increasingly connected to both malaria-free areas and other endemic regions. The research presented here provides an initial effort to quantify and analyse the connectivity that exists across the malaria-endemic world through air travel, and provide a basic assessment of the risks it results in for movement of infections.

Global malaria connectivity through air travel

PubMed Central

2013-01-01

Background Air travel has expanded at an unprecedented rate and continues to do so. Its effects have been seen on malaria in rates of imported cases, local outbreaks in non-endemic areas and the global spread of drug resistance. With elimination and global eradication back on the agenda, changing levels and compositions of imported malaria in malaria-free countries, and the threat of artemisinin resistance spreading from Southeast Asia, there is a need to better understand how the modern flow of air passengers connects each Plasmodium falciparum- and Plasmodium vivax-endemic region to the rest of the world. Methods Recently constructed global P. falciparum and P.vivax malaria risk maps, along with data on flight schedules and modelled passenger flows across the air network, were combined to describe and quantify global malaria connectivity through air travel. Network analysis approaches were then utilized to describe and quantify the patterns that exist in passenger flows weighted by malaria prevalence. Finally, the connectivity within and to the Southeast Asia region where the threat of imported artemisinin resistance arising is highest, was examined to highlight risk routes for its spread. Results The analyses demonstrate the substantial connectivity that now exists between and from malaria-endemic regions through air travel. While the air network provides connections to previously isolated malarious regions, it is clear that great variations exist, with significant regional communities of airports connected by higher rates of flow standing out. The structures of these communities are often not geographically coherent, with historical, economic and cultural ties evident, and variations between P. falciparum and P. vivax clear. Moreover, results highlight how well connected the malaria-endemic areas of Africa are now to Southeast Asia, illustrating the many possible routes that artemisinin-resistant strains could take. Discussion The continuing growth in air travel is playing an important role in the global epidemiology of malaria, with the endemic world becoming increasingly connected to both malaria-free areas and other endemic regions. The research presented here provides an initial effort to quantify and analyse the connectivity that exists across the malaria-endemic world through air travel, and provide a basic assessment of the risks it results in for movement of infections. PMID:23914776

Students without Borders: Global Collaborative Learning Connects School to the Real World

ERIC Educational Resources Information Center

Bickley, Mali; Carleton, Jim

2009-01-01

Kids can't help but get engaged when they're collaborating with peers across the globe to solve real-life problems. Global collaborative learning is about connecting students in communities of learners around the world so they can work together on projects that make a difference locally and globally. It is about building relationships and…

Global Network Connectivity Assessment via Local Data Exchange for Underwater Acoustic Sensor Networks

DTIC Science & Technology

2014-03-31

Network Connectivity Assessment via Local Data Exchange for Underwater Acoustic Sensor Networks M.M. Asadi H. Mahboubi A...2014 Global Network Connectivity Assessment via Local Data Exchange for Underwater Acoustic Sensor Networks Contract Report # AMBUSH.1.1 Contract...pi j /= 0. The sensor network considered in this work is composed of underwater sensors , which use acoustic waves for

Mapping internal connectivity through human migration in malaria endemic countries.

PubMed

Sorichetta, Alessandro; Bird, Tom J; Ruktanonchai, Nick W; Zu Erbach-Schoenberg, Elisabeth; Pezzulo, Carla; Tejedor, Natalia; Waldock, Ian C; Sadler, Jason D; Garcia, Andres J; Sedda, Luigi; Tatem, Andrew J

2016-08-16

Human mobility continues to increase in terms of volumes and reach, producing growing global connectivity. This connectivity hampers efforts to eliminate infectious diseases such as malaria through reintroductions of pathogens, and thus accounting for it becomes important in designing global, continental, regional, and national strategies. Recent works have shown that census-derived migration data provides a good proxy for internal connectivity, in terms of relative strengths of movement between administrative units, across temporal scales. To support global malaria eradication strategy efforts, here we describe the construction of an open access archive of estimated internal migration flows in endemic countries built through pooling of census microdata. These connectivity datasets, described here along with the approaches and methods used to create and validate them, are available both through the WorldPop website and the WorldPop Dataverse Repository.

Mapping internal connectivity through human migration in malaria endemic countries

PubMed Central

Sorichetta, Alessandro; Bird, Tom J.; Ruktanonchai, Nick W.; zu Erbach-Schoenberg, Elisabeth; Pezzulo, Carla; Tejedor, Natalia; Waldock, Ian C.; Sadler, Jason D.; Garcia, Andres J.; Sedda, Luigi; Tatem, Andrew J.

2016-01-01

Human mobility continues to increase in terms of volumes and reach, producing growing global connectivity. This connectivity hampers efforts to eliminate infectious diseases such as malaria through reintroductions of pathogens, and thus accounting for it becomes important in designing global, continental, regional, and national strategies. Recent works have shown that census-derived migration data provides a good proxy for internal connectivity, in terms of relative strengths of movement between administrative units, across temporal scales. To support global malaria eradication strategy efforts, here we describe the construction of an open access archive of estimated internal migration flows in endemic countries built through pooling of census microdata. These connectivity datasets, described here along with the approaches and methods used to create and validate them, are available both through the WorldPop website and the WorldPop Dataverse Repository. PMID:27529469

Brain regions with abnormal network properties in severe epilepsy of Lennox-Gastaut phenotype: Multivariate analysis of task-free fMRI.

PubMed

Pedersen, Mangor; Curwood, Evan K; Archer, John S; Abbott, David F; Jackson, Graeme D

2015-11-01

Lennox-Gastaut syndrome, and the similar but less tightly defined Lennox-Gastaut phenotype, describe patients with severe epilepsy, generalized epileptic discharges, and variable intellectual disability. Our previous functional neuroimaging studies suggest that abnormal diffuse association network activity underlies the epileptic discharges of this clinical phenotype. Herein we use a data-driven multivariate approach to determine the spatial changes in local and global networks of patients with severe epilepsy of the Lennox-Gastaut phenotype. We studied 9 adult patients and 14 controls. In 20 min of task-free blood oxygen level-dependent functional magnetic resonance imaging data, two metrics of functional connectivity were studied: Regional homogeneity or local connectivity, a measure of concordance between each voxel to a focal cluster of adjacent voxels; and eigenvector centrality, a global connectivity estimate designed to detect important neural hubs. Multivariate pattern analysis of these data in a machine-learning framework was used to identify spatial features that classified disease subjects. Multivariate pattern analysis was 95.7% accurate in classifying subjects for both local and global connectivity measures (22/23 subjects correctly classified). Maximal discriminating features were the following: increased local connectivity in frontoinsular and intraparietal areas; increased global connectivity in posterior association areas; decreased local connectivity in sensory (visual and auditory) and medial frontal cortices; and decreased global connectivity in the cingulate cortex, striatum, hippocampus, and pons. Using a data-driven analysis method in task-free functional magnetic resonance imaging, we show increased connectivity in critical areas of association cortex and decreased connectivity in primary cortex. This supports previous findings of a critical role for these association cortical regions as a final common pathway in generating the Lennox-Gastaut phenotype. Abnormal function of these areas is likely to be important in explaining the intellectual problems characteristic of this disorder. Wiley Periodicals, Inc. © 2015 International League Against Epilepsy.

Distributed Data-aggregation Consensus for Sensor Networks: Global Connectivity Assessment through Local Data Exchange

DTIC Science & Technology

2014-08-01

Distributed data-aggregation consensus for sensor networks Global connectivity assessment through local data exchange A. Ajorlou Concordia...k − i) i = 1, 2, ..., k − 1 3 Acoustic Channel Characterization *! f

Specific excitatory connectivity for feature integration in mouse primary visual cortex

PubMed Central

Molina-Luna, Patricia; Roth, Morgane M.

2017-01-01

Local excitatory connections in mouse primary visual cortex (V1) are stronger and more prevalent between neurons that share similar functional response features. However, the details of how functional rules for local connectivity shape neuronal responses in V1 remain unknown. We hypothesised that complex responses to visual stimuli may arise as a consequence of rules for selective excitatory connectivity within the local network in the superficial layers of mouse V1. In mouse V1 many neurons respond to overlapping grating stimuli (plaid stimuli) with highly selective and facilitatory responses, which are not simply predicted by responses to single gratings presented alone. This complexity is surprising, since excitatory neurons in V1 are considered to be mainly tuned to single preferred orientations. Here we examined the consequences for visual processing of two alternative connectivity schemes: in the first case, local connections are aligned with visual properties inherited from feedforward input (a ‘like-to-like’ scheme specifically connecting neurons that share similar preferred orientations); in the second case, local connections group neurons into excitatory subnetworks that combine and amplify multiple feedforward visual properties (a ‘feature binding’ scheme). By comparing predictions from large scale computational models with in vivo recordings of visual representations in mouse V1, we found that responses to plaid stimuli were best explained by assuming feature binding connectivity. Unlike under the like-to-like scheme, selective amplification within feature-binding excitatory subnetworks replicated experimentally observed facilitatory responses to plaid stimuli; explained selective plaid responses not predicted by grating selectivity; and was consistent with broad anatomical selectivity observed in mouse V1. Our results show that visual feature binding can occur through local recurrent mechanisms without requiring feedforward convergence, and that such a mechanism is consistent with visual responses and cortical anatomy in mouse V1. PMID:29240769

DRD2 genotype-based variation of default mode network activity and of its relationship with striatal DAT binding.

PubMed

Sambataro, Fabio; Fazio, Leonardo; Taurisano, Paolo; Gelao, Barbara; Porcelli, Annamaria; Mancini, Marina; Sinibaldi, Lorenzo; Ursini, Gianluca; Masellis, Rita; Caforio, Grazia; Di Giorgio, Annabella; Niccoli-Asabella, Artor; Popolizio, Teresa; Blasi, Giuseppe; Bertolino, Alessandro

2013-01-01

The default mode network (DMN) comprises a set of brain regions with "increased" activity during rest relative to cognitive processing. Activity in the DMN is associated with functional connections with the striatum and dopamine (DA) levels in this brain region. A functional single-nucleotide polymorphism within the dopamine D2 receptor gene (DRD2, rs1076560 G > T) shifts splicing of the 2 D2 isoforms, D2 short and D2 long, and has been associated with striatal DA signaling as well as with cognitive processing. However, the effects of this polymorphism on DMN have not been explored. The aim of this study was to evaluate the effects of rs1076560 on DMN and striatal connectivity and on their relationship with striatal DA signaling. Twenty-eight subjects genotyped for rs1076560 underwent functional magnetic resonance imaging during a working memory task and 123 55 I-Fluoropropyl-2-beta-carbomethoxy-3-beta(4-iodophenyl) nortropan Single Photon Emission Computed Tomography ([(123)I]-FP-CIT SPECT) imaging (a measure of dopamine transporter [DAT] binding). Spatial group-independent component (IC) analysis was used to identify DMN and striatal ICs. Within the anterior DMN IC, GG subjects had relatively greater connectivity in medial prefrontal cortex (MPFC), which was directly correlated with striatal DAT binding. Within the posterior DMN IC, GG subjects had reduced connectivity in posterior cingulate relative to T carriers. Additionally, rs1076560 genotype predicted connectivity differences within a striatal network, and these changes were correlated with connectivity in MPFC and posterior cingulate within the DMN. These results suggest that genetically determined D2 receptor signaling is associated with DMN connectivity and that these changes are correlated with striatal function and presynaptic DA signaling.

DRD2 Genotype-Based Variation of Default Mode Network Activity and of Its Relationship With Striatal DAT Binding

PubMed Central

Sambataro, Fabio; Fazio, Leonardo; Taurisano, Paolo; Gelao, Barbara; Porcelli, Annamaria; Mancini, Marina; Sinibaldi, Lorenzo; Ursini, Gianluca; Masellis, Rita; Caforio, Grazia; Di Giorgio, Annabella; Niccoli-Asabella, Artor; Popolizio, Teresa; Blasi, Giuseppe; Bertolino, Alessandro

2013-01-01

The default mode network (DMN) comprises a set of brain regions with “increased” activity during rest relative to cognitive processing. Activity in the DMN is associated with functional connections with the striatum and dopamine (DA) levels in this brain region. A functional single-nucleotide polymorphism within the dopamine D2 receptor gene (DRD2, rs1076560 G > T) shifts splicing of the 2 D2 isoforms, D2 short and D2 long, and has been associated with striatal DA signaling as well as with cognitive processing. However, the effects of this polymorphism on DMN have not been explored. The aim of this study was to evaluate the effects of rs1076560 on DMN and striatal connectivity and on their relationship with striatal DA signaling. Twenty-eight subjects genotyped for rs1076560 underwent functional magnetic resonance imaging during a working memory task and 123 55 I-Fluoropropyl-2-beta-carbomethoxy-3-beta(4-iodophenyl) nortropan Single Photon Emission Computed Tomography ([123I]-FP-CIT SPECT) imaging (a measure of dopamine transporter [DAT] binding). Spatial group-independent component (IC) analysis was used to identify DMN and striatal ICs. Within the anterior DMN IC, GG subjects had relatively greater connectivity in medial prefrontal cortex (MPFC), which was directly correlated with striatal DAT binding. Within the posterior DMN IC, GG subjects had reduced connectivity in posterior cingulate relative to T carriers. Additionally, rs1076560 genotype predicted connectivity differences within a striatal network, and these changes were correlated with connectivity in MPFC and posterior cingulate within the DMN. These results suggest that genetically determined D2 receptor signaling is associated with DMN connectivity and that these changes are correlated with striatal function and presynaptic DA signaling. PMID:21976709

Increased Global Functional Connectivity Correlates with LSD-Induced Ego Dissolution.

PubMed

Tagliazucchi, Enzo; Roseman, Leor; Kaelen, Mendel; Orban, Csaba; Muthukumaraswamy, Suresh D; Murphy, Kevin; Laufs, Helmut; Leech, Robert; McGonigle, John; Crossley, Nicolas; Bullmore, Edward; Williams, Tim; Bolstridge, Mark; Feilding, Amanda; Nutt, David J; Carhart-Harris, Robin

2016-04-25

Lysergic acid diethylamide (LSD) is a non-selective serotonin-receptor agonist that was first synthesized in 1938 and identified as (potently) psychoactive in 1943. Psychedelics have been used by indigenous cultures for millennia [1]; however, because of LSD's unique potency and the timing of its discovery (coinciding with a period of major discovery in psychopharmacology), it is generally regarded as the quintessential contemporary psychedelic [2]. LSD has profound modulatory effects on consciousness and was used extensively in psychological research and psychiatric practice in the 1950s and 1960s [3]. In spite of this, however, there have been no modern human imaging studies of its acute effects on the brain. Here we studied the effects of LSD on intrinsic functional connectivity within the human brain using fMRI. High-level association cortices (partially overlapping with the default-mode, salience, and frontoparietal attention networks) and the thalamus showed increased global connectivity under the drug. The cortical areas showing increased global connectivity overlapped significantly with a map of serotonin 2A (5-HT2A) receptor densities (the key site of action of psychedelic drugs [4]). LSD also increased global integration by inflating the level of communication between normally distinct brain networks. The increase in global connectivity observed under LSD correlated with subjective reports of "ego dissolution." The present results provide the first evidence that LSD selectively expands global connectivity in the brain, compromising the brain's modular and "rich-club" organization and, simultaneously, the perceptual boundaries between the self and the environment. Copyright © 2016 Elsevier Ltd. All rights reserved.

Genome-Wide Motif Statistics are Shaped by DNA Binding Proteins over Evolutionary Time Scales

NASA Astrophysics Data System (ADS)

Qian, Long; Kussell, Edo

The composition of genomes with respect to short DNA motifs impacts the ability of DNA binding proteins to locate and bind their target sites. Since nonfunctional DNA binding can be detrimental to cellular functions and ultimately to organismal fitness, organisms could benefit from reducing the number of nonfunctional binding sites genome wide. Using in vitro measurements of binding affinities for a large collection of DNA binding proteins, in multiple species, we detect a significant global avoidance of weak binding sites in genomes. The underlying evolutionary process leaves a distinct genomic hallmark in that similar words have correlated frequencies, which we detect in all species across domains of life. We hypothesize that natural selection against weak binding sites contributes to this process, and using an evolutionary model we show that the strength of selection needed to maintain global word compositions is on the order of point mutation rates. Alternative contributions may come from interference of protein-DNA binding with replication and mutational repair processes, which operates with similar rates. We conclude that genome-wide word compositions have been molded by DNA binding proteins through tiny evolutionary steps over timescales spanning millions of generations.

Global environmental crisis: is there a connection with place-based, ecosociocultural education in rural Spain?

NASA Astrophysics Data System (ADS)

Glasson, George E.

2011-06-01

Environmental educators are challenged by how to teach children about global environmental crisis such as the Gulf oil spill, which only serves to engender children's fears and apprehensions about the negative impact of humans on ecosystems. Eduardo Dopico and Eva Garcia-Vazquez's article presents an interesting context from which to analyze and reflect on the connections between local and global environmental education issues. The authors' study involves student researchers in actively learning about place-based, sustainable agricultural practices in rural Spain that are passed down through generations. These ecofriendly, culturally mediated farming practices, referred to as "traditional" by the farmers, were contrasted to "modern" practices that are used throughout market-based globalized economy. The connection between local (traditional) and global (modern) practices became very important in the reflections and learning of the student participants about sustainability and ecojustice issues associated with traditional farming. Students learned from the local farmers a positive, non-dualistic approach to sustainable agriculture in which human activity and culture is connected to ecological sustainability. Further, the students' active research of sustainable and culturally medicated agricultural practices at the local level provided a frame of reference to understand global environmental crises.

A global interaction network maps a wiring diagram of cellular function

PubMed Central

Costanzo, Michael; VanderSluis, Benjamin; Koch, Elizabeth N.; Baryshnikova, Anastasia; Pons, Carles; Tan, Guihong; Wang, Wen; Usaj, Matej; Hanchard, Julia; Lee, Susan D.; Pelechano, Vicent; Styles, Erin B.; Billmann, Maximilian; van Leeuwen, Jolanda; van Dyk, Nydia; Lin, Zhen-Yuan; Kuzmin, Elena; Nelson, Justin; Piotrowski, Jeff S.; Srikumar, Tharan; Bahr, Sondra; Chen, Yiqun; Deshpande, Raamesh; Kurat, Christoph F.; Li, Sheena C.; Li, Zhijian; Usaj, Mojca Mattiazzi; Okada, Hiroki; Pascoe, Natasha; Luis, Bryan-Joseph San; Sharifpoor, Sara; Shuteriqi, Emira; Simpkins, Scott W.; Snider, Jamie; Suresh, Harsha Garadi; Tan, Yizhao; Zhu, Hongwei; Malod-Dognin, Noel; Janjic, Vuk; Przulj, Natasa; Troyanskaya, Olga G.; Stagljar, Igor; Xia, Tian; Ohya, Yoshikazu; Gingras, Anne-Claude; Raught, Brian; Boutros, Michael; Steinmetz, Lars M.; Moore, Claire L.; Rosebrock, Adam P.; Caudy, Amy A.; Myers, Chad L.; Andrews, Brenda; Boone, Charles

2017-01-01

We generated a global genetic interaction network for Saccharomyces cerevisiae, constructing over 23 million double mutants, identifying ~550,000 negative and ~350,000 positive genetic interactions. This comprehensive network maps genetic interactions for essential gene pairs, highlighting essential genes as densely connected hubs. Genetic interaction profiles enabled assembly of a hierarchical model of cell function, including modules corresponding to protein complexes and pathways, biological processes, and cellular compartments. Negative interactions connected functionally related genes, mapped core bioprocesses, and identified pleiotropic genes, whereas positive interactions often mapped general regulatory connections among gene pairs, rather than shared functionality. The global network illustrates how coherent sets of genetic interactions connect protein complex and pathway modules to map a functional wiring diagram of the cell. PMID:27708008

Solvated dissipative electro-elastic network model of hydrated proteins

NASA Astrophysics Data System (ADS)

Martin, Daniel

2013-03-01

Elastic network models coarse grain proteins into a network of residue beads connected by springs. We add dissipative dynamics to this mechanical system by applying overdamped Langevin equations of motion to normal-mode vibrations of the network. In addition, the network is made heterogeneous and softened at the protein surface by accounting for hydration of the ionized residues. Solvation changes the network Hessian in two ways. Diagonal solvation terms soften the spring constants and off-diagonal dipole-dipole terms correlate displacements of the ionized residues. The model is used to formulate the response functions of the electrostatic potential and electric field appearing in theories of redox reactions and spectroscopy. We also formulate the dielectric response of the protein and find that solvation of the surface ionized residues leads to a slow relaxation peak in the dielectric loss spectrum, about two orders of magnitude slower than the main peak of protein relaxation. Finally, the solvated network is used to formulate the allosteric response of the protein to ion binding. The global thermodynamics of ion binding is not strongly affected by the network solvation, but it dramatically enhances conformational changes in response to placing a charge at the a the active site.

Solvated dissipative electro-elastic network model of hydrated proteins

NASA Astrophysics Data System (ADS)

Martin, Daniel R.; Matyushov, Dmitry V.

2012-10-01

Elastic network models coarse grain proteins into a network of residue beads connected by springs. We add dissipative dynamics to this mechanical system by applying overdamped Langevin equations of motion to normal-mode vibrations of the network. In addition, the network is made heterogeneous and softened at the protein surface by accounting for hydration of the ionized residues. Solvation changes the network Hessian in two ways. Diagonal solvation terms soften the spring constants and off-diagonal dipole-dipole terms correlate displacements of the ionized residues. The model is used to formulate the response functions of the electrostatic potential and electric field appearing in theories of redox reactions and spectroscopy. We also formulate the dielectric response of the protein and find that solvation of the surface ionized residues leads to a slow relaxation peak in the dielectric loss spectrum, about two orders of magnitude slower than the main peak of protein relaxation. Finally, the solvated network is used to formulate the allosteric response of the protein to ion binding. The global thermodynamics of ion binding is not strongly affected by the network solvation, but it dramatically enhances conformational changes in response to placing a charge at the active site of the protein.

Insights into the spurious long-range nature of local rs-dependent non-local exchange-correlation kernels

DOE PAGES

Lu, Deyu

2016-08-05

A systematic route to go beyond the exact exchange plus random phase approximation (RPA) is to include a physical exchange-correlation kernel in the adiabatic-connection fluctuation-dissipation theorem. Previously, [D. Lu, J. Chem. Phys. 140, 18A520 (2014)], we found that non-local kernels with a screening length depending on the local Wigner-Seitz radius, r s(r), suffer an error associated with a spurious long-range repulsion in van der Waals bounded systems, which deteriorates the binding energy curve as compared to RPA. Here, we analyze the source of the error and propose to replace r s(r) by a global, average r s in the kernel.more » Exemplary studies with the Corradini, del Sole, Onida, and Palummo kernel show that while this change does not affect the already outstanding performance in crystalline solids, using an average r s significantly reduces the spurious long-range tail in the exchange-correlation kernel in van der Waals bounded systems. Finally, when this method is combined with further corrections using local dielectric response theory, the binding energy of the Kr dimer is improved three times as compared to RPA.« less

Global imprint of historical connectivity on freshwater fish biodiversity.

PubMed

Dias, Murilo S; Oberdorff, Thierry; Hugueny, Bernard; Leprieur, Fabien; Jézéquel, Céline; Cornu, Jean-François; Brosse, Sébastien; Grenouillet, Gael; Tedesco, Pablo A

2014-09-01

The relative importance of contemporary and historical processes is central for understanding biodiversity patterns. While several studies show that past conditions can partly explain the current biodiversity patterns, the role of history remains elusive. We reconstructed palaeo-drainage basins under lower sea level conditions (Last Glacial Maximum) to test whether the historical connectivity between basins left an imprint on the global patterns of freshwater fish biodiversity. After controlling for contemporary and past environmental conditions, we found that palaeo-connected basins displayed greater species richness but lower levels of endemism and beta diversity than did palaeo-disconnected basins. Palaeo-connected basins exhibited shallower distance decay of compositional similarity, suggesting that palaeo-river connections favoured the exchange of fish species. Finally, we found that a longer period of palaeo-connection resulted in lower levels of beta diversity. These findings reveal the first unambiguous results of the role played by history in explaining the global contemporary patterns of biodiversity. © 2014 John Wiley & Sons Ltd/CNRS.

Binding of aldolase and glyceraldehyde-3-phosphate dehydrogenase to the cytoplasmic tails of Plasmodium falciparum merozoite duffy binding-like and reticulocyte homology ligands.

PubMed

Pal-Bhowmick, Ipsita; Andersen, John; Srinivasan, Prakash; Narum, David L; Bosch, Jürgen; Miller, Louis H

2012-01-01

Invasion of erythrocytes by Plasmodium falciparum requires a connection between the cytoplasmic tail of the parasite's ligands for its erythrocyte receptors and the actin-myosin motor of the parasite. For the thromobospondin-related anonymous protein (TRAP) ligand on Plasmodium sporozoites, aldolase forms this connection and requires tryptophan and negatively charged amino acids in the ligand's cytoplasmic tail. Because of the importance of the Duffy binding-like (DBL) and the reticulocyte homology (RH) ligand families in erythrocyte binding and merozoite invasion, we characterized the ability of their cytoplasmic tails to bind aldolase and glyceraldehyde-3-phosphate dehydrogenase (GAPDH), both of which bind actin. We tested the binding of the cytoplasmic peptides of the two ligand families to aldolase and GAPDH. Only the cytoplasmic peptides of some RH ligands showed strong binding to aldolase, and the binding depended on the presence of an aromatic amino acid (phenylalanine or tyrosine), rather than tryptophan, in the context of negatively charged amino acids. The binding was confirmed by surface plasmon resonance analysis and was found to represent affinity similar to that seen with TRAP. An X-ray crystal structure of aldolase at 2.5 Å in the presence of RH2b peptide suggested that the binding site location was near the TRAP-binding site. GAPDH bound to some of the cytoplasmic tails of certain RH and DBL ligands in an aromatic amino acid-dependent manner. Thus, the connection between Plasmodium merozoite ligands and erythrocyte receptors and the actin motor can be achieved through the activity of either aldolase or GAPDH by mechanisms that do not require tryptophan but, rather, other aromatic amino acids. IMPORTANCE The invasion of the Plasmodium merozoite into erythrocytes is a critical element in malaria pathogenesis. It is important to understand the molecular details of this process, as this machinery can be a target for both vaccine and drug development. In Plasmodium sporozoites and Toxoplasma tachyzoites, invasion involves a glycolytic enzyme aldolase, linking the cytoplasmic tail domains of the parasite ligands to the actin-myosin motor that drives invasion. This binding requires a tryptophan that cannot be replaced by other aromatic residues. Here we show that aldolase binds the cytoplasmic tails of some P. falciparum merozoite erythrocyte-binding ligands but that the binding involves aromatic residues other than tryptophan. The biological relevance of aldolase binding to cytoplasmic tails of parasite ligands in invasion is demonstrated by our observation that RH2b but not RH2a binds to aldolase and, as previously shown, that RH2b but not RH2a is required for P. falciparum invasion of erythrocytes.

Interferon-α acutely impairs whole-brain functional connectivity network architecture - A preliminary study.

PubMed

Dipasquale, Ottavia; Cooper, Ella A; Tibble, Jeremy; Voon, Valerie; Baglio, Francesca; Baselli, Giuseppe; Cercignani, Mara; Harrison, Neil A

2016-11-01

Interferon-alpha (IFN-α) is a key mediator of antiviral immune responses used to treat Hepatitis C infection. Though clinically effective, IFN-α rapidly impairs mood, motivation and cognition, effects that can appear indistinguishable from major depression and provide powerful empirical support for the inflammation theory of depression. Though inflammation has been shown to modulate activity within discrete brain regions, how it affects distributed information processing and the architecture of whole brain functional connectivity networks have not previously been investigated. Here we use a graph theoretic analysis of resting state functional magnetic resonance imaging (rfMRI) to investigate acute effects of systemic interferon-alpha (IFN-α) on whole brain functional connectivity architecture and its relationship to IFN-α-induced mood change. Twenty-two patients with Hepatitis-C infection, initiating IFN-α-based therapy were scanned at baseline and 4h after their first IFN-α dose. The whole brain network was parcellated into 110 cortical and sub-cortical nodes based on the Oxford-Harvard Atlas and effects assessed on higher-level graph metrics, including node degree, betweenness centrality, global and local efficiency. IFN-α was associated with a significant reduction in global network connectivity (node degree) (p=0.033) and efficiency (p=0.013), indicating a global reduction of information transfer among the nodes forming the whole brain network. Effects were similar for highly connected (hub) and non-hub nodes, with no effect on betweenness centrality (p>0.1). At a local level, we identified regions with reduced efficiency of information exchange and a sub-network with decreased functional connectivity after IFN-α. Changes in local and particularly global functional connectivity correlated with associated changes in mood measured on the Profile of Mood States (POMS) questionnaire. IFN-α rapidly induced a profound shift in whole brain network structure, impairing global functional connectivity and the efficiency of parallel information exchange. Correlations with multiple indices of mood change support a role for global changes in brain functional connectivity architecture in coordinated behavioral responses to IFN-α. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Correcting for Blood Arrival Time in Global Mean Regression Enhances Functional Connectivity Analysis of Resting State fMRI-BOLD Signals.

PubMed

Erdoğan, Sinem B; Tong, Yunjie; Hocke, Lia M; Lindsey, Kimberly P; deB Frederick, Blaise

2016-01-01

Resting state functional connectivity analysis is a widely used method for mapping intrinsic functional organization of the brain. Global signal regression (GSR) is commonly employed for removing systemic global variance from resting state BOLD-fMRI data; however, recent studies have demonstrated that GSR may introduce spurious negative correlations within and between functional networks, calling into question the meaning of anticorrelations reported between some networks. In the present study, we propose that global signal from resting state fMRI is composed primarily of systemic low frequency oscillations (sLFOs) that propagate with cerebral blood circulation throughout the brain. We introduce a novel systemic noise removal strategy for resting state fMRI data, "dynamic global signal regression" (dGSR), which applies a voxel-specific optimal time delay to the global signal prior to regression from voxel-wise time series. We test our hypothesis on two functional systems that are suggested to be intrinsically organized into anticorrelated networks: the default mode network (DMN) and task positive network (TPN). We evaluate the efficacy of dGSR and compare its performance with the conventional "static" global regression (sGSR) method in terms of (i) explaining systemic variance in the data and (ii) enhancing specificity and sensitivity of functional connectivity measures. dGSR increases the amount of BOLD signal variance being modeled and removed relative to sGSR while reducing spurious negative correlations introduced in reference regions by sGSR, and attenuating inflated positive connectivity measures. We conclude that incorporating time delay information for sLFOs into global noise removal strategies is of crucial importance for optimal noise removal from resting state functional connectivity maps.

Disulfide connectivity and reduction in pheromone-binding proteins of the gypsy moth, Lymantria dispar

NASA Astrophysics Data System (ADS)

Honson, Nicolette S.; Plettner, Erika

2006-06-01

Males of the gypsy moth, Lymantria dispar, are attracted by a pheromone released by females. Pheromones are detected by olfactory neurons housed in specialized sensory hairs located on the antennae of the male moth. Once pheromone molecules enter the sensilla lymph, a highly abundant pheromone-binding protein (PBP) transports the molecule to the sensory neuron. The PBPs are members of the insect odorant-binding protein family, with six conserved cysteine residues. In this study, the disulfide bond connectivities of the pheromone-binding proteins PBP1 and PBP2 from the gypsy moth were found to be cysteines 19-54, 50-109, and 97-118 for PBP1, and cysteines 19-54, 50-110, and 97-119 for PBP2, as determined by cyanylation reactions and cyanogen bromide chemical cleavage. We have discovered that the second disulfide linkage is the most easily reduced of the three, and this same linkage is missing among four cysteine-containing insect odorant-binding proteins (OBPs). We are the first to identify the unique steric and electronic properties of this second disulfide linkage.

Global synthesis suggests that food web connectance correlates to invasion resistance.

PubMed

Smith-Ramesh, Lauren M; Moore, Alexandria C; Schmitz, Oswald J

2017-02-01

Biological invasions are a key component of global change, and understanding the drivers of global invasion patterns will aid in assessing and mitigating the impact of invasive species. While invasive species are most often studied in the context of one or two trophic levels, in reality species invade communities comprised of complex food webs. The complexity and integrity of the native food web may be a more important determinant of invasion success than the strength of interactions between a small subset of species within a larger food web. Previous efforts to understand the relationship between food web properties and species invasions have been primarily theoretical and have yielded mixed results. Here, we present a synthesis of empirical information on food web connectance and species invasion success gathered from different sources (estimates of food web connectance from the primary literature and estimates of invasion success from the Global Invasive Species Database as well as the primary literature). Our results suggest that higher-connectance food webs tend to host fewer invaders and exert stronger biotic resistance compared to low-connectance webs. We argue that while these correlations cannot be used to infer a causal link between food web connectance and habitat invasibility, the promising findings beg for further empirical research that deliberately tests for relationships between food web connectance and invasion. © 2016 John Wiley & Sons Ltd.

Nonbinding Legal Instruments in Governance for Global Health: Lessons from the Global AIDS Reporting Mechanism.

PubMed

Taylor, Allyn; Alfvén, Tobias; Hougendobler, Daniel; Buse, Kent

2014-01-01

Recent debate over World Health Organization reform has included unprecedented attention to international lawmaking as a future priority function of the Organization. However, the debate is largely focused on the codification of new binding legal instruments. Drawing upon lessons from the success of the Global AIDS Reporting Mechanism, established pursuant to the United Nations' Declaration of Commitment on HIV/AIDS, we argue that effective global health governance requires consideration of a broad range of instruments, both binding and nonbinding. A detailed examination of the Global AIDS Reporting Mechanism reveals that the choice of the nonbinding format makes an important contribution to its effectiveness. For instance, the flexibility and adaptability of the nonbinding format have allowed the global community to: (1) undertake commitments in a timely manner; (2) adapt and experiment in the face of a dynamic pandemic; and (3) grant civil society an unparalleled role in monitoring and reporting on state implementation of global commitments. UNAIDS' institutional support has also played a vital role in ensuring the continuing effectiveness of the Global AIDS Reporting Mechanism. Overall, the experience of the Global AIDS Reporting Mechanism evidences that, at times, nimbler nonbinding instruments can offer benefits over slower, more rigid binding legal approaches to governance, but depend critically, like all instruments, on the perceived legitimacy thereof. © 2014 American Society of Law, Medicine & Ethics, Inc.

Extracting physical chemistry from mechanics: a new approach to investigate DNA interactions with drugs and proteins in single molecule experiments.

PubMed

Rocha, M S

2015-09-01

In this review we focus on the idea of establishing connections between the mechanical properties of DNA-ligand complexes and the physical chemistry of DNA-ligand interactions. This type of connection is interesting because it opens the possibility of performing a robust characterization of such interactions by using only one experimental technique: single molecule stretching. Furthermore, it also opens new possibilities in comparing results obtained by very different approaches, in particular when comparing single molecule techniques to ensemble-averaging techniques. We start the manuscript reviewing important concepts of DNA mechanics, from the basic mechanical properties to the Worm-Like Chain model. Next we review the basic concepts of the physical chemistry of DNA-ligand interactions, revisiting the most important models used to analyze the binding data and discussing their binding isotherms. Then, we discuss the basic features of the single molecule techniques most used to stretch DNA-ligand complexes and to obtain "force × extension" data, from which the mechanical properties of the complexes can be determined. We also discuss the characteristics of the main types of interactions that can occur between DNA and ligands, from covalent binding to simple electrostatic driven interactions. Finally, we present a historical survey of the attempts to connect mechanics to physical chemistry for DNA-ligand systems, emphasizing a recently developed fitting approach useful to connect the persistence length of DNA-ligand complexes to the physicochemical properties of the interaction. Such an approach in principle can be used for any type of ligand, from drugs to proteins, even if multiple binding modes are present.

Quantification of the epitope diversity of HIV-1-specific binding antibodies by peptide microarrays for global HIV-1 vaccine development

DOE PAGES

Stephenson, Kathryn E.; Neubauer, George H.; Reimer, Ulf; ...

2014-11-14

An effective vaccine against human immunodeficiency virus type 1 (HIV-1) will have to provide protection against a vast array of different HIV-1 strains. Current methods to measure HIV-1-specific binding antibodies following immunization typically focus on determining the magnitude of antibody responses, but the epitope diversity of antibody responses has remained largely unexplored. Here we describe the development of a global HIV-1 peptide microarray that contains 6564 peptides from across the HIV-1 proteome and covers the majority of HIV-1 sequences in the Los Alamos National Laboratory global HIV-1 sequence database. Using this microarray, we quantified the magnitude, breadth, and depth ofmore » IgG binding to linear HIV-1 sequences in HIV-1-infected humans and HIV-1-vaccinated humans, rhesus monkeys and guinea pigs. The microarray measured potentially important differences in antibody epitope diversity, particularly regarding the depth of epitope variants recognized at each binding site. Our data suggest that the global HIV-1 peptide microarray may be a useful tool for both preclinical and clinical HIV-1 research.« less

Quantification of the epitope diversity of HIV-1-specific binding antibodies by peptide microarrays for global HIV-1 vaccine development

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

Stephenson, Kathryn E.; Neubauer, George H.; Reimer, Ulf

An effective vaccine against human immunodeficiency virus type 1 (HIV-1) will have to provide protection against a vast array of different HIV-1 strains. Current methods to measure HIV-1-specific binding antibodies following immunization typically focus on determining the magnitude of antibody responses, but the epitope diversity of antibody responses has remained largely unexplored. Here we describe the development of a global HIV-1 peptide microarray that contains 6564 peptides from across the HIV-1 proteome and covers the majority of HIV-1 sequences in the Los Alamos National Laboratory global HIV-1 sequence database. Using this microarray, we quantified the magnitude, breadth, and depth ofmore » IgG binding to linear HIV-1 sequences in HIV-1-infected humans and HIV-1-vaccinated humans, rhesus monkeys and guinea pigs. The microarray measured potentially important differences in antibody epitope diversity, particularly regarding the depth of epitope variants recognized at each binding site. Our data suggest that the global HIV-1 peptide microarray may be a useful tool for both preclinical and clinical HIV-1 research.« less

Different alterations in brain functional networks according to direct and indirect topological connections in patients with schizophrenia.

PubMed

Park, Chang-Hyun; Lee, Seungyup; Kim, Taewon; Won, Wang Yeon; Lee, Kyoung-Uk

2017-10-01

Schizophrenia displays connectivity deficits in the brain, but the literature has shown inconsistent findings about alterations in global efficiency of brain functional networks. We supposed that such inconsistency at the whole brain level may be due to a mixture of different portions of global efficiency at sub-brain levels. Accordingly, we considered measuring portions of global efficiency in two aspects: spatial portions by considering sub-brain networks and topological portions by considering contributions to global efficiency according to direct and indirect topological connections. We proposed adjacency and indirect adjacency as new network parameters attributable to direct and indirect topological connections, respectively, and applied them to graph-theoretical analysis of brain functional networks constructed from resting state fMRI data of 22 patients with schizophrenia and 22 healthy controls. Group differences in the network parameters were observed not for whole brain and hemispheric networks, but for regional networks. Alterations in adjacency and indirect adjacency were in opposite directions, such that adjacency increased, but indirect adjacency decreased in patients with schizophrenia. Furthermore, over connections in frontal and parietal regions, increased adjacency was associated with more severe negative symptoms, while decreased adjacency was associated with more severe positive symptoms of schizophrenia. This finding indicates that connectivity deficits associated with positive and negative symptoms of schizophrenia may involve topologically different paths in the brain. In patients with schizophrenia, although changes in global efficiency may not be clearly shown, different alterations in brain functional networks according to direct and indirect topological connections could be revealed at the regional level. Copyright © 2017 Elsevier B.V. All rights reserved.

Hydrodynamic modelling and global datasets: Flow connectivity and SRTM data, a Bangkok case study.

NASA Astrophysics Data System (ADS)

Trigg, M. A.; Bates, P. B.; Michaelides, K.

2012-04-01

The rise in the global interconnected manufacturing supply chains requires an understanding and consistent quantification of flood risk at a global scale. Flood risk is often better quantified (or at least more precisely defined) in regions where there has been an investment in comprehensive topographical data collection such as LiDAR coupled with detailed hydrodynamic modelling. Yet in regions where these data and modelling are unavailable, the implications of flooding and the knock on effects for global industries can be dramatic, as evidenced by the recent floods in Bangkok, Thailand. There is a growing momentum in terms of global modelling initiatives to address this lack of a consistent understanding of flood risk and they will rely heavily on the application of available global datasets relevant to hydrodynamic modelling, such as Shuttle Radar Topography Mission (SRTM) data and its derivatives. These global datasets bring opportunities to apply consistent methodologies on an automated basis in all regions, while the use of coarser scale datasets also brings many challenges such as sub-grid process representation and downscaled hydrology data from global climate models. There are significant opportunities for hydrological science in helping define new, realistic and physically based methodologies that can be applied globally as well as the possibility of gaining new insights into flood risk through analysis of the many large datasets that will be derived from this work. We use Bangkok as a case study to explore some of the issues related to using these available global datasets for hydrodynamic modelling, with particular focus on using SRTM data to represent topography. Research has shown that flow connectivity on the floodplain is an important component in the dynamics of flood flows on to and off the floodplain, and indeed within different areas of the floodplain. A lack of representation of flow connectivity, often due to data resolution limitations, means that important subgrid processes are missing from hydrodynamic models leading to poor model predictive capabilities. Specifically here, the issue of flow connectivity during flood events is explored using geostatistical techniques to quantify the change of flow connectivity on floodplains due to grid rescaling methods. We also test whether this method of assessing connectivity can be used as new tool in the quantification of flood risk that moves beyond the simple flood extent approach, encapsulating threshold changes and data limitations.

Cosmopolitan Sensitivities, Vulnerability, and Global Englishes

ERIC Educational Resources Information Center

Jacobsen, Ushma Chauhan

2015-01-01

This paper is the outcome of an afterthought that assembles connections between three elements: the ambitions of cultivating cosmopolitan sensitivities that circulate vibrantly in connection with the internationalization of higher education, a course on Global Englishes at a Danish university and the sensation of vulnerability. It discusses the…

Learning Global Citizenship?: Exploring Connections between the Local and the Global

ERIC Educational Resources Information Center

Mayo, Marjorie; Gaventa, John; Rooke, Alison

2009-01-01

This article identifies historical connections between adult learning, popular education and the emergence of the public sphere in Europe, exploring potential implications for adult learning and community development, drawing upon research evaluating programmes to promote community-based learning "for" active citizenship in UK. The…

Portal Pedagogy: From Interdisciplinarity and Internationalization to Transdisciplinarity and Transnationalization

ERIC Educational Resources Information Center

Monk, Nicholas

2015-01-01

Education in the twenty-first century is characterized by narratives of global connectivity. Opportunities offered by digital technologies, connectivity through mobile platforms, and social media, reinforced by changing expectations of students and parents, have put pressure on universities to reimagine global learning and flexible delivery…

Global and regional functional connectivity maps of neural oscillations in focal epilepsy

PubMed Central

Englot, Dario J.; Hinkley, Leighton B.; Kort, Naomi S.; Imber, Brandon S.; Mizuiri, Danielle; Honma, Susanne M.; Findlay, Anne M.; Garrett, Coleman; Cheung, Paige L.; Mantle, Mary; Tarapore, Phiroz E.; Knowlton, Robert C.; Chang, Edward F.; Nagarajan, Srikantan S.

2015-01-01

Intractable focal epilepsy is a devastating disorder with profound effects on cognition and quality of life. Epilepsy surgery can lead to seizure freedom in patients with focal epilepsy; however, sometimes it fails due to an incomplete delineation of the epileptogenic zone. Brain networks in epilepsy can be studied with resting-state functional connectivity analysis, yet previous investigations using functional magnetic resonance imaging or electrocorticography have produced inconsistent results. Magnetoencephalography allows non-invasive whole-brain recordings, and can be used to study both long-range network disturbances in focal epilepsy and regional connectivity at the epileptogenic zone. In magnetoencephalography recordings from presurgical epilepsy patients, we examined: (i) global functional connectivity maps in patients versus controls; and (ii) regional functional connectivity maps at the region of resection, compared to the homotopic non-epileptogenic region in the contralateral hemisphere. Sixty-one patients were studied, including 30 with mesial temporal lobe epilepsy and 31 with focal neocortical epilepsy. Compared with a group of 31 controls, patients with epilepsy had decreased resting-state functional connectivity in widespread regions, including perisylvian, posterior temporo-parietal, and orbitofrontal cortices (P < 0.01, t-test). Decreased mean global connectivity was related to longer duration of epilepsy and higher frequency of consciousness-impairing seizures (P < 0.01, linear regression). Furthermore, patients with increased regional connectivity within the resection site (n = 24) were more likely to achieve seizure postoperative seizure freedom (87.5% with Engel I outcome) than those with neutral (n = 15, 64.3% seizure free) or decreased (n = 23, 47.8% seizure free) regional connectivity (P < 0.02, chi-square). Widespread global decreases in functional connectivity are observed in patients with focal epilepsy, and may reflect deleterious long-term effects of recurrent seizures. Furthermore, enhanced regional functional connectivity at the area of resection may help predict seizure outcome and aid surgical planning. PMID:25981965

Chlorophyll-Derivative Modulation of Rhodopsin Signaling Properties through Evolutionarily Conserved Interaction Pathways

PubMed Central

Woods, Kristina N.; Pfeffer, Jürgen; Klein-Seetharaman, Judith

2017-01-01

Retinal is the light-absorbing chromophore that is responsible for the activation of visual pigments and light-driven ion pumps. Evolutionary changes in the intermolecular interactions of the retinal with specific amino acids allow for adaptation of the spectral characteristics, referred to as spectral tuning. However, it has been proposed that a specific species of dragon fish has bypassed the adaptive evolutionary process of spectral tuning and replaced it with a single evolutionary event: photosensitization of rhodopsin by chlorophyll derivatives. Here, by using a combination of experimental measurements and computational modeling to probe retinal-receptor interactions in rhodopsin, we show how the binding of the chlorophyll derivative, chlorin-e6 (Ce6) in the intracellular domain (ICD) of the receptor allosterically excites G-protein coupled receptor class A (GPCR-A) conserved long-range correlated fluctuations that connect distant parts of the receptor. These long-range correlated motions are associated with regulating the dynamics and intermolecular interactions of specific amino acids in the retinal ligand-binding pocket that have been associated with shifts in the absorbance peak maximum (λmax) and hence, spectral sensitivity of the visual system. Moreover, the binding of Ce6 affects the overall global properties of the receptor. Specifically, we find that Ce6-induced dynamics alter the thermal stability of rhodopsin by adjusting hydrogen-bonding interactions near the receptor active-site that consequently also influences the intrinsic conformational equilibrium of the receptor. Due to the conservation of the ICD residues amongst different receptors in this class and the fact that all GPCR-A receptors share a common mechanism of activation, it is possible that the allosteric associations excited in rhodopsin with Ce6 binding are a common feature in all class A GPCRs. PMID:29312953

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

Stolzenberg, Sebastian; Quick, Matthias; Zhao, Chunfeng

Neurotransmitter:sodium symporters (NSSs) terminate neurotransmission by Na +-dependent reuptake of released neurotransmitters. Previous studies suggested that Na +-binding reconfigures dynamically coupled structural elements in an allosteric interaction network (AIN) responsible for function-related conformational changes, but the intramolecular pathway of this mechanism has remained uncharted. Here we describe a new approach for the modeling and analysis of intramolecular dynamics in the bacterial NSS homolog LeuT. From microsecond-scale molecular dynamics simulations and cognate experimental verifications in both LeuT and human dopamine transporter (hDAT), we apply the novel method to identify the composition and the dynamic properties of their conserved AIN. In LeuT,more » two different perturbations disrupting Na+ binding and transport ( i.e. replacing Na + with Li + or the Y268A mutation at the intracellular gate) affect the AIN in strikingly similar ways. In contrast, other mutations that affect the intracellular gate (i.e. R5A and D369A) do not significantly impair Na + cooperativity and transport. Our analysis shows these perturbations to have much lesser effects on the AIN, underscoring the sensitivity of this novel method to the mechanistic nature of the perturbation. Notably, this set of observations holds as well for hDAT, where the aligned Y335A, R60A, and D436A mutations also produce different impacts on Na + dependence. Furthermore, the detailed AIN generated from our method is shown to connect Na + binding with global conformational changes that are critical for the transport mechanism. Lastly, that the AIN between the Na + binding sites and the intracellular gate in bacterial LeuT resembles that in eukaryotic hDAT highlights the conservation of allosteric pathways underlying NSS function.« less

Assessing the evolving fragility of the global food system

NASA Astrophysics Data System (ADS)

Puma, Michael J.; Bose, Satyajit; Chon, So Young; Cook, Benjamin I.

2015-02-01

The world food crisis in 2008 highlighted the susceptibility of the global food system to price shocks. Here we use annual staple food production and trade data from 1992-2009 to analyse the changing properties of the global food system. Over the 18 year study period, we show that the global food system is relatively homogeneous (85% of countries have low or marginal food self-sufficiency) and increases in complexity, with the number of global wheat and rice trade connections doubling and trade flows increasing by 42 and 90%, respectively. The increased connectivity and flows within these global trade networks suggest that the global food system is vulnerable to systemic disruptions, especially considering the tendency for exporting countries to switch to non-exporting states during times of food scarcity in the global markets. To test this hypothesis, we superimpose continental-scale disruptions on the wheat and rice trade networks. We find greater absolute reductions in global wheat and rice exports along with larger losses in network connectivity as the networks evolve due to disruptions in European wheat and Asian rice production. Importantly, our findings indicate that least developed countries suffer greater import losses in more connected networks through their increased dependence on imports for staple foods (due to these large-scale disturbances): mean (median) wheat losses as percentages of staple food supply are 8.9% (3.8%) for 1992-1996, increasing to 11% (5.7%) for 2005-2009. Over the same intervals, rice losses increase from 8.2% (2.2%) to 14% (5.2%). Our work indicates that policy efforts should focus on balancing the efficiency of international trade (and its associated specialization) with increased resilience of domestic production and global demand diversity.

Assessing the Evolving Fragility of the Global Food System

NASA Technical Reports Server (NTRS)

Puma, Michael Joseph; Bose, Satyajit; Chon, So Young; Cook, Benjamin I.

2015-01-01

The world food crisis in 2008 highlighted the susceptibility of the global food system to price shocks. Here we use annual staple food production and trade data from 1992-2009 to analyse the changing properties of the global food system. Over the 18-year study period, we show that the global food system is relatively homogeneous (85 of countries have low or marginal food self-sufficiency) and increases in complexity, with the number of global wheat and rice trade connections doubling and trade flows increasing by 42 and 90, respectively. The increased connectivity and flows within these global trade networks suggest that the global food system is vulnerable to systemic disruptions, especially considering the tendency for exporting countries to switch to non-exporting states during times of food scarcity in the global markets. To test this hypothesis, we superimpose continental-scale disruptions on the wheat and rice trade networks. We find greater absolute reductions in global wheat and rice exports along with larger losses in network connectivity as the networks evolve due to disruptions in European wheat and Asian rice production. Importantly, our findings indicate that least developed countries suffer greater import losses in more connected networks through their increased dependence on imports for staple foods (due to these large-scale disturbances): mean (median) wheat losses as percentages of staple food supply are 8.9 (3.8) for 1992-1996, increasing to 11 (5.7) for 20052009. Over the same intervals, rice losses increase from 8.2 (2.2) to 14 (5.2). Our work indicates that policy efforts should focus on balancing the efficiency of international trade (and its associated specialization) with increased resilience of domestic production and global demand diversity.

1-3-A Resolution Structure of Human Glutathione S-Transferase With S-Hexyl Glutathione Bound Reveals Possible Extended Ligandin Binding Site

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

Trong, I.Le; Stenkamp, R.E.; Ibarra, C.

2005-08-22

Cytosolic glutathione S-transferases (GSTs) play a critical role in xenobiotic binding and metabolism, as well as in modulation of oxidative stress. Here, the high-resolution X-ray crystal structures of homodimeric human GSTA1-1 in the apo form and in complex with S-hexyl glutathione (two data sets) are reported at 1.8, 1.5, and 1.3A respectively. At this level of resolution, distinct conformations of the alkyl chain of S-hexyl glutathione are observed, reflecting the nonspecific nature of the hydrophobic substrate binding site (H-site). Also, an extensive network of ordered water, including 75 discrete solvent molecules, traverses the open subunit-subunit interface and connects the glutathionemore » binding sites in each subunit. In the highest-resolution structure, three glycerol moieties lie within this network and directly connect the amino termini of the glutathione molecules. A search for ligand binding sites with the docking program Molecular Operating Environment identified the ordered water network binding site, lined mainly with hydrophobic residues, suggesting an extended ligand binding surface for nonsubstrate ligands, the so-called ligandin site. Finally, detailed comparison of the structures reported here with previously published X-ray structures reveal a possible reaction coordinate for ligand-dependent conformational changes in the active site and the C-terminus.« less

Three-dimensional structure of NADPH–cytochrome P450 reductase: Prototype for FMN- and FAD-containing enzymes

PubMed Central

Wang, Ming; Roberts, David L.; Paschke, Rosemary; Shea, Thomas M.; Masters, Bettie Sue Siler; Kim, Jung-Ja P.

1997-01-01

Microsomal NADPH–cytochrome P450 reductase (CPR) is one of only two mammalian enzymes known to contain both FAD and FMN, the other being nitric-oxide synthase. CPR is a membrane-bound protein and catalyzes electron transfer from NADPH to all known microsomal cytochromes P450. The structure of rat liver CPR, expressed in Escherichia coli and solubilized by limited trypsinolysis, has been determined by x-ray crystallography at 2.6 Å resolution. The molecule is composed of four structural domains: (from the N- to C- termini) the FMN-binding domain, the connecting domain, and the FAD- and NADPH-binding domains. The FMN-binding domain is similar to the structure of flavodoxin, whereas the two C-terminal dinucleotide-binding domains are similar to those of ferredoxin–NADP+ reductase (FNR). The connecting domain, situated between the FMN-binding and FNR-like domains, is responsible for the relative orientation of the other domains, ensuring the proper alignment of the two flavins necessary for efficient electron transfer. The two flavin isoalloxazine rings are juxtaposed, with the closest distance between them being about 4 Å. The bowl-shaped surface near the FMN-binding site is likely the docking site of cytochrome c and the physiological redox partners, including cytochromes P450 and b5 and heme oxygenase. PMID:9237990

Social justice and the global economy: new challenges for social work in the 21st century.

PubMed

Polack, Robert J

2004-04-01

The globalization of the economy creates new challenges for social work in the arenas of social and economic justice. This article outlines social justice issues related to the debt crisis of the Global South and sweatshops. A presentation of colonial precursors is followed by a detailed examination of these global institutions with an emphasis on the vulnerability, disempowered status, and exploitation of poor people of the Global South. Connections with global inequities in wealth, income, and the distribution of resources are made explicit. The article explores domestic social justice problems as possible points of connection with these issues. Finally, the authors give recommendations for social work education, advocacy, and activism.

Intrinsic gray-matter connectivity of the brain in adults with autism spectrum disorder.

PubMed

Ecker, Christine; Ronan, Lisa; Feng, Yue; Daly, Eileen; Murphy, Clodagh; Ginestet, Cedric E; Brammer, Michael; Fletcher, Paul C; Bullmore, Edward T; Suckling, John; Baron-Cohen, Simon; Williams, Steve; Loth, Eva; Murphy, Declan G M

2013-08-06

Autism spectrum disorders (ASD) are a group of neurodevelopmental conditions that are accompanied by atypical brain connectivity. So far, in vivo evidence for atypical structural brain connectivity in ASD has mainly been based on neuroimaging studies of cortical white matter. However, genetic studies suggest that abnormal connectivity in ASD may also affect neural connections within the cortical gray matter. Such intrinsic gray-matter connections are inherently more difficult to describe in vivo but may be inferred from a variety of surface-based geometric features that can be measured using magnetic resonance imaging. Here, we present a neuroimaging study that examines the intrinsic cortico-cortical connectivity of the brain in ASD using measures of "cortical separation distances" to assess the global and local intrinsic "wiring costs" of the cortex (i.e., estimated length of horizontal connections required to wire the cortex within the cortical sheet). In a sample of 68 adults with ASD and matched controls, we observed significantly reduced intrinsic wiring costs of cortex in ASD, both globally and locally. Differences in global and local wiring cost were predominantly observed in fronto-temporal regions and also significantly predicted the severity of social and repetitive symptoms (respectively). Our study confirms that atypical cortico-cortical "connectivity" in ASD is not restricted to the development of white-matter connections but may also affect the intrinsic gray-matter architecture (and connectivity) within the cortical sheet. Thus, the atypical connectivity of the brain in ASD is complex, affecting both gray and white matter, and forms part of the core neural substrates underlying autistic symptoms.

Intramolecular activation of a Ca(2+)-dependent protein kinase is disrupted by insertions in the tether that connects the calmodulin-like domain to the kinase

NASA Technical Reports Server (NTRS)

Vitart, V.; Christodoulou, J.; Huang, J. F.; Chazin, W. J.; Harper, J. F.; Evans, M. L. (Principal Investigator)

2000-01-01

Ca(2+)-dependent protein kinases (CDPK) have a calmodulin-like domain (CaM-LD) tethered to the C-terminal end of the kinase. Activation is proposed to involve intramolecular binding of the CaM-LD to a junction sequence that connects the CaM-LD to the kinase domain. Consistent with this model, a truncated CDPK (DeltaNC) in which the CaM-LD has been deleted can be activated in a bimolecular interaction with an isolated CaM-LD or calmodulin, similar to the activation of a calmodulin-dependent protein kinase (CaMK) by calmodulin. Here we provide genetic evidence that this bimolecular activation requires a nine-residue binding segment from F436 to I444 (numbers correspond to CPK-1 accession number L14771). Two mutations at either end of this core segment (F436/A and VI444/AA) severely disrupted bimolecular activation, whereas flanking mutations had only minor effects. Intramolecular activation of a full-length kinase was also disrupted by a VI444/AA mutation, but surprisingly not by a F436/A mutation (at the N-terminal end of the binding site). Interestingly, intramolecular but not bimolecular activation was disrupted by insertion mutations placed immediately downstream of I444. To show that mutant enzymes were not misfolded, latent kinase activity was stimulated through binding of an antijunction antibody. Results here support a model of intramolecular activation in which the tether (A445 to G455) that connects the CaM-LD to the kinase provides an important structural constraint and is not just a simple flexible connection.

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.

PubMed

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

2005-03-01

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.

A Small World of Neuronal Synchrony

PubMed Central

Yu, Shan; Huang, Debin; Singer, Wolf

2008-01-01

A small-world network has been suggested to be an efficient solution for achieving both modular and global processing—a property highly desirable for brain computations. Here, we investigated functional networks of cortical neurons using correlation analysis to identify functional connectivity. To reconstruct the interaction network, we applied the Ising model based on the principle of maximum entropy. This allowed us to assess the interactions by measuring pairwise correlations and to assess the strength of coupling from the degree of synchrony. Visual responses were recorded in visual cortex of anesthetized cats, simultaneously from up to 24 neurons. First, pairwise correlations captured most of the patterns in the population's activity and, therefore, provided a reliable basis for the reconstruction of the interaction networks. Second, and most importantly, the resulting networks had small-world properties; the average path lengths were as short as in simulated random networks, but the clustering coefficients were larger. Neurons differed considerably with respect to the number and strength of interactions, suggesting the existence of “hubs” in the network. Notably, there was no evidence for scale-free properties. These results suggest that cortical networks are optimized for the coexistence of local and global computations: feature detection and feature integration or binding. PMID:18400792

Local and Global Gestalt Laws: A Neurally Based Spectral Approach.

PubMed

Favali, Marta; Citti, Giovanna; Sarti, Alessandro

2017-02-01

This letter presents a mathematical model of figure-ground articulation that takes into account both local and global gestalt laws and is compatible with the functional architecture of the primary visual cortex (V1). The local gestalt law of good continuation is described by means of suitable connectivity kernels that are derived from Lie group theory and quantitatively compared with long-range connectivity in V1. Global gestalt constraints are then introduced in terms of spectral analysis of a connectivity matrix derived from these kernels. This analysis performs grouping of local features and individuates perceptual units with the highest salience. Numerical simulations are performed, and results are obtained by applying the technique to a number of stimuli.

N-glycan based ER molecular chaperone and protein quality control system: the calnexin binding cycle

PubMed Central

Lamriben, Lydia; Graham, Jill B.; Adams, Benjamin M.; Hebert, Daniel N.

2015-01-01

Helenius and colleagues proposed over twenty-years ago a paradigm-shifting model for how chaperone binding in the endoplasmic reticulum was mediated and controlled for a new type of molecular chaperone- the carbohydrate binding chaperones, calnexin and calreticulin. While the originally established basics for this lectin chaperone binding cycle holds true today, there has been a number of important advances that have expanded our understanding of its mechanisms of action, role in protein homeostasis, and its connection to disease states that are highlighted in this review. PMID:26676362

Genome-Wide Motif Statistics are Shaped by DNA Binding Proteins over Evolutionary Time Scales

NASA Astrophysics Data System (ADS)

Qian, Long; Kussell, Edo

2016-10-01

The composition of a genome with respect to all possible short DNA motifs impacts the ability of DNA binding proteins to locate and bind their target sites. Since nonfunctional DNA binding can be detrimental to cellular functions and ultimately to organismal fitness, organisms could benefit from reducing the number of nonfunctional DNA binding sites genome wide. Using in vitro measurements of binding affinities for a large collection of DNA binding proteins, in multiple species, we detect a significant global avoidance of weak binding sites in genomes. We demonstrate that the underlying evolutionary process leaves a distinct genomic hallmark in that similar words have correlated frequencies, a signal that we detect in all species across domains of life. We consider the possibility that natural selection against weak binding sites contributes to this process, and using an evolutionary model we show that the strength of selection needed to maintain global word compositions is on the order of point mutation rates. Likewise, we show that evolutionary mechanisms based on interference of protein-DNA binding with replication and mutational repair processes could yield similar results and operate with similar rates. On the basis of these modeling and bioinformatic results, we conclude that genome-wide word compositions have been molded by DNA binding proteins acting through tiny evolutionary steps over time scales spanning millions of generations.

Electric-field-stimulated protein mechanics

PubMed Central

Hekstra, Doeke R.; White, K. Ian; Socolich, Michael A.; Henning, Robert W.; Šrajer, Vukica; Ranganathan, Rama

2017-01-01

The internal mechanics of proteins—the coordinated motions of amino acids and the pattern of forces constraining these motions—connects protein structure to function. Here we describe a new method combining the application of strong electric field pulses to protein crystals with time-resolved X-ray crystallography to observe conformational changes in spatial and temporal detail. Using a human PDZ domain (LNX2PDZ2) as a model system, we show that protein crystals tolerate electric field pulses strong enough to drive concerted motions on the sub-microsecond timescale. The induced motions are subtle, involve diverse physical mechanisms, and occur throughout the protein structure. The global pattern of electric-field-induced motions is consistent with both local and allosteric conformational changes naturally induced by ligand binding, including at conserved functional sites in the PDZ domain family. This work lays the foundation for comprehensive experimental study of the mechanical basis of protein function. PMID:27926732

Intrinsic gray-matter connectivity of the brain in adults with autism spectrum disorder

PubMed Central

Ecker, Christine; Ronan, Lisa; Feng, Yue; Daly, Eileen; Murphy, Clodagh; Ginestet, Cedric E.; Brammer, Michael; Fletcher, Paul C.; Bullmore, Edward T.; Suckling, John; Baron-Cohen, Simon; Williams, Steve; Loth, Eva; Murphy, Declan G. M.; Bailey, A. J.; Baron-Cohen, S.; Bolton, P. F.; Bullmore, E. T.; Carrington, S.; Chakrabarti, B.; Daly, E. M.; Deoni, S. C.; Ecker, C.; Happe, F.; Henty, J.; Jezzard, P.; Johnston, P.; Jones, D. K.; Lai, M. C.; Lombardo, M. V.; Madden, A.; Mullins, D.; Murphy, C. M.; Murphy, D. G.; Pasco, G.; Sadek, S.; Spain, D.; Steward, R.; Suckling, J.; Wheelwright, S.; Williams, S. C.

2013-01-01

Autism spectrum disorders (ASD) are a group of neurodevelopmental conditions that are accompanied by atypical brain connectivity. So far, in vivo evidence for atypical structural brain connectivity in ASD has mainly been based on neuroimaging studies of cortical white matter. However, genetic studies suggest that abnormal connectivity in ASD may also affect neural connections within the cortical gray matter. Such intrinsic gray-matter connections are inherently more difficult to describe in vivo but may be inferred from a variety of surface-based geometric features that can be measured using magnetic resonance imaging. Here, we present a neuroimaging study that examines the intrinsic cortico-cortical connectivity of the brain in ASD using measures of “cortical separation distances” to assess the global and local intrinsic “wiring costs” of the cortex (i.e., estimated length of horizontal connections required to wire the cortex within the cortical sheet). In a sample of 68 adults with ASD and matched controls, we observed significantly reduced intrinsic wiring costs of cortex in ASD, both globally and locally. Differences in global and local wiring cost were predominantly observed in fronto-temporal regions and also significantly predicted the severity of social and repetitive symptoms (respectively). Our study confirms that atypical cortico-cortical “connectivity” in ASD is not restricted to the development of white-matter connections but may also affect the intrinsic gray-matter architecture (and connectivity) within the cortical sheet. Thus, the atypical connectivity of the brain in ASD is complex, affecting both gray and white matter, and forms part of the core neural substrates underlying autistic symptoms. PMID:23878213

Evaluation of Denoising Strategies to Address Motion-Correlated Artifacts in Resting-State Functional Magnetic Resonance Imaging Data from the Human Connectome Project

PubMed Central

Kandala, Sridhar; Nolan, Dan; Laumann, Timothy O.; Power, Jonathan D.; Adeyemo, Babatunde; Harms, Michael P.; Petersen, Steven E.; Barch, Deanna M.

2016-01-01

Abstract Like all resting-state functional connectivity data, the data from the Human Connectome Project (HCP) are adversely affected by structured noise artifacts arising from head motion and physiological processes. Functional connectivity estimates (Pearson's correlation coefficients) were inflated for high-motion time points and for high-motion participants. This inflation occurred across the brain, suggesting the presence of globally distributed artifacts. The degree of inflation was further increased for connections between nearby regions compared with distant regions, suggesting the presence of distance-dependent spatially specific artifacts. We evaluated several denoising methods: censoring high-motion time points, motion regression, the FMRIB independent component analysis-based X-noiseifier (FIX), and mean grayordinate time series regression (MGTR; as a proxy for global signal regression). The results suggest that FIX denoising reduced both types of artifacts, but left substantial global artifacts behind. MGTR significantly reduced global artifacts, but left substantial spatially specific artifacts behind. Censoring high-motion time points resulted in a small reduction of distance-dependent and global artifacts, eliminating neither type. All denoising strategies left differences between high- and low-motion participants, but only MGTR substantially reduced those differences. Ultimately, functional connectivity estimates from HCP data showed spatially specific and globally distributed artifacts, and the most effective approach to address both types of motion-correlated artifacts was a combination of FIX and MGTR. PMID:27571276

75 FR 11976 - Bureau of Educational and Cultural Affairs (ECA) Request for Grant Proposals: Global Connections...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-03-12

... United States. The Global Connections and Exchange (GCE) program utilizes technology to create an... throughout the world. Social media such as Facebook, YouTube, mobile technology and blogs offer young people.... In order to harness these powerful technology tools to remove stereotypes and impel change, youth...

Anti-correlated Networks, Global Signal Regression, and the Effects of Caffeine in Resting-State Functional MRI

PubMed Central

Wong, Chi Wah; Olafsson, Valur; Tal, Omer; Liu, Thomas T.

2012-01-01

Resting-state functional connectivity magnetic resonance imaging is proving to be an essential tool for the characterization of functional networks in the brain. Two of the major networks that have been identified are the default mode network (DMN) and the task positive network (TPN). Although prior work indicates that these two networks are anti-correlated, the findings are controversial because the anti-correlations are often found only after the application of a pre-processing step, known as global signal regression, that can produce artifactual anti-correlations. In this paper, we show that, for subjects studied in an eyes-closed rest state, caffeine can significantly enhance the detection of anti-correlations between the DMN and TPN without the need for global signal regression. In line with these findings, we find that caffeine also leads to widespread decreases in connectivity and global signal amplitude. Using a recently introduced geometric model of global signal effects, we demonstrate that these decreases are consistent with the removal of an additive global signal confound. In contrast to the effects observed in the eyes-closed rest state, caffeine did not lead to significant changes in global functional connectivity in the eyes-open rest state. PMID:22743194

NEAT1 Scaffolds RNA Binding Proteins and the Microprocessor to Globally Enhance Pri-miRNA Processing

PubMed Central

Jiang, Li; Shao, Changwei; Wu, Qi-Jia; Chen, Geng; Zhou, Jie; Yang, Bo; Li, Hairi; Gou, Lan-Tao; Zhang, Yi; Wang, Yangming; Yeo, Gene W.; Zhou, Yu; Fu, Xiang-Dong

2018-01-01

Summary MicroRNA biogenesis is known to be modulated by a variety of RNA binding proteins (RBPs), but in most cases, individual RBPs appear to influence the processing of a small subset of target miRNAs. We herein report that the RNA binding NONO/PSF heterodimer binds a large number of expressed pri-miRNAs in HeLa cells to globally enhance pri-miRNA processing by the Drosha/DGCR8 Microprocessor. Because NONO/PSF are key components of paraspeckles organized by the lncRNA NEAT1, we further demonstrate that NEAT1 also has a profound effect on global pri-miRNA processing. Mechanistic dissection reveals that NEAT1 broadly interacts with NONO/PSF as well as many other RBPs, and that multiple RNA segments in NEAT1, including a “pseudo pri-miRNA” near its 3′ end, help attract the Microprocessor. These findings suggest a bird nest model for a large non-coding RNA to orchestrate efficient processing of almost an entire class of small non-coding RNAs in the nucleus. PMID:28846091

NEAT1 scaffolds RNA-binding proteins and the Microprocessor to globally enhance pri-miRNA processing.

PubMed

Jiang, Li; Shao, Changwei; Wu, Qi-Jia; Chen, Geng; Zhou, Jie; Yang, Bo; Li, Hairi; Gou, Lan-Tao; Zhang, Yi; Wang, Yangming; Yeo, Gene W; Zhou, Yu; Fu, Xiang-Dong

2017-10-01

MicroRNA (miRNA) biogenesis is known to be modulated by a variety of RNA-binding proteins (RBPs), but in most cases, individual RBPs appear to influence the processing of a small subset of target miRNAs. Here, we report that the RNA-binding NONO-PSF heterodimer binds a large number of expressed pri-miRNAs in HeLa cells to globally enhance pri-miRNA processing by the Drosha-DGCR8 Microprocessor. NONO and PSF are key components of paraspeckles organized by the long noncoding RNA (lncRNA) NEAT1. We further demonstrate that NEAT1 also has a profound effect on global pri-miRNA processing. Mechanistic dissection reveals that NEAT1 broadly interacts with the NONO-PSF heterodimer as well as many other RBPs and that multiple RNA segments in NEAT1, including a 'pseudo pri-miRNA' near its 3' end, help attract the Microprocessor. These findings suggest a 'bird nest' model in which an lncRNA orchestrates efficient processing of potentially an entire class of small noncoding RNAs in the nucleus.

Structure of Rot, a global regulator of virulence genes in Staphylococcus aureus.

PubMed

Zhu, Yuwei; Fan, Xiaojiao; Zhang, Xu; Jiang, Xuguang; Niu, Liwen; Teng, Maikun; Li, Xu

2014-09-01

Staphylococcus aureus is a highly versatile pathogen that can infect human tissue by producing a large arsenal of virulence factors that are tightly regulated by a complex regulatory network. Rot, which shares sequence similarity with SarA homologues, is a global regulator that regulates numerous virulence genes. However, the recognition model of Rot for the promoter region of target genes and the putative regulation mechanism remain elusive. In this study, the 1.77 Å resolution X-ray crystal structure of Rot is reported. The structure reveals that two Rot molecules form a compact homodimer, each of which contains a typical helix-turn-helix module and a β-hairpin motif connected by a flexible loop. Fluorescence polarization results indicate that Rot preferentially recognizes AT-rich dsDNA with ~30-base-pair nucleotides and that the conserved positively charged residues on the winged-helix motif are vital for binding to the AT-rich dsDNA. It is proposed that the DNA-recognition model of Rot may be similar to that of SarA, SarR and SarS, in which the helix-turn-helix motifs of each monomer interact with the major grooves of target dsDNA and the winged motifs contact the minor grooves. Interestingly, the structure shows that Rot adopts a novel dimerization model that differs from that of other SarA homologues. As expected, perturbation of the dimer interface abolishes the dsDNA-binding ability of Rot, suggesting that Rot functions as a dimer. In addition, the results have been further confirmed in vivo by measuring the transcriptional regulation of α-toxin, a major virulence factor produced by most S. aureus strains.

Leaders Seeking Resonance: Managing the Connectors that Bind Schools

ERIC Educational Resources Information Center

Walker, Allan

2012-01-01

This commentary focuses on school leadership as connective activity. Leadership is essentially about designing, managing and energizing the right connections, and untying the wrong ones, in order to make schools successful, equitable, happier places. The author's basic proposition is that school leaders who influence students and their communities…

Stable configurations in social networks

NASA Astrophysics Data System (ADS)

Bronski, Jared C.; DeVille, Lee; Ferguson, Timothy; Livesay, Michael

2018-06-01

We present and analyze a model of opinion formation on an arbitrary network whose dynamics comes from a global energy function. We study the global and local minimizers of this energy, which we call stable opinion configurations, and describe the global minimizers under certain assumptions on the friendship graph. We show a surprising result that the number of stable configurations is not necessarily monotone in the strength of connection in the social network, i.e. the model sometimes supports more stable configurations when the interpersonal connections are made stronger.

Identification of a Region in the Stalk Domain of the Nipah Virus Receptor Binding Protein That Is Critical for Fusion Activation

PubMed Central

Talekar, Aparna; DeVito, Ilaria; Salah, Zuhair; Palmer, Samantha G.; Chattopadhyay, Anasuya; Rose, John K.; Xu, Rui; Wilson, Ian A.; Moscona, Anne

2013-01-01

Paramyxoviruses, including the emerging lethal human Nipah virus (NiV) and the avian Newcastle disease virus (NDV), enter host cells through fusion of the viral and target cell membranes. For paramyxoviruses, membrane fusion is the result of the concerted action of two viral envelope glycoproteins: a receptor binding protein and a fusion protein (F). The NiV receptor binding protein (G) attaches to ephrin B2 or B3 on host cells, whereas the corresponding hemagglutinin-neuraminidase (HN) attachment protein of NDV interacts with sialic acid moieties on target cells through two regions of its globular domain. Receptor-bound G or HN via its stalk domain triggers F to undergo the conformational changes that render it competent to mediate fusion of the viral and cellular membranes. We show that chimeric proteins containing the NDV HN receptor binding regions and the NiV G stalk domain require a specific sequence at the connection between the head and the stalk to activate NiV F for fusion. Our findings are consistent with a general mechanism of paramyxovirus fusion activation in which the stalk domain of the receptor binding protein is responsible for F activation and a specific connecting region between the receptor binding globular head and the fusion-activating stalk domain is required for transmitting the fusion signal. PMID:23903846

Globalization and pollution: tele-connecting local primary PM2.5 emissions to global consumption.

PubMed

Meng, Jing; Liu, Junfeng; Xu, Yuan; Guan, Dabo; Liu, Zhu; Huang, Ye; Tao, Shu

2016-11-01

Globalization pushes production and consumption to geographically diverse locations and generates a variety of sizeable opportunities and challenges. The distribution and associated effects of short-lived primary fine particulate matter (PM 2.5 ), a representative of local pollution, are significantly affected by the consumption through global supply chain. Tele-connection is used here to represent the link between production and consumption activity at large distances. In this study, we develop a global consumption-based primary PM 2.5 emission inventory to track primary PM 2.5 emissions embodied in the supply chain and evaluate the extent to which local PM 2.5 emissions are triggered by international trade. We further adopt consumption-based accounting and identify the global original source that produced the emissions. We find that anthropogenic PM 2.5 emissions from industrial sectors accounted for 24 Tg globally in 2007; approximately 30% (7.2 Tg) of these emissions were embodied in export of products principally from Brazil, South Africa, India and China (3.8 Tg) to developed countries. Large differences (up to 10 times) in the embodied emissions intensity between net importers and exporters greatly increased total global PM 2.5 emissions. Tele-connecting production and consumption activity provides valuable insights with respect to mitigating long-range transboundary air pollution and prompts concerted efforts aiming at more environmentally conscious globalization.

Globalization and pollution: tele-connecting local primary PM2.5 emissions to global consumption

NASA Astrophysics Data System (ADS)

Meng, Jing; Liu, Junfeng; Xu, Yuan; Guan, Dabo; Liu, Zhu; Huang, Ye; Tao, Shu

2016-11-01

Globalization pushes production and consumption to geographically diverse locations and generates a variety of sizeable opportunities and challenges. The distribution and associated effects of short-lived primary fine particulate matter (PM2.5), a representative of local pollution, are significantly affected by the consumption through global supply chain. Tele-connection is used here to represent the link between production and consumption activity at large distances. In this study, we develop a global consumption-based primary PM2.5 emission inventory to track primary PM2.5 emissions embodied in the supply chain and evaluate the extent to which local PM2.5 emissions are triggered by international trade. We further adopt consumption-based accounting and identify the global original source that produced the emissions. We find that anthropogenic PM2.5 emissions from industrial sectors accounted for 24 Tg globally in 2007; approximately 30% (7.2 Tg) of these emissions were embodied in export of products principally from Brazil, South Africa, India and China (3.8 Tg) to developed countries. Large differences (up to 10 times) in the embodied emissions intensity between net importers and exporters greatly increased total global PM2.5 emissions. Tele-connecting production and consumption activity provides valuable insights with respect to mitigating long-range transboundary air pollution and prompts concerted efforts aiming at more environmentally conscious globalization.

Globalization and pollution: tele-connecting local primary PM2.5 emissions to global consumption

PubMed Central

Meng, Jing; Xu, Yuan; Guan, Dabo; Liu, Zhu; Huang, Ye; Tao, Shu

2016-01-01

Globalization pushes production and consumption to geographically diverse locations and generates a variety of sizeable opportunities and challenges. The distribution and associated effects of short-lived primary fine particulate matter (PM2.5), a representative of local pollution, are significantly affected by the consumption through global supply chain. Tele-connection is used here to represent the link between production and consumption activity at large distances. In this study, we develop a global consumption-based primary PM2.5 emission inventory to track primary PM2.5 emissions embodied in the supply chain and evaluate the extent to which local PM2.5 emissions are triggered by international trade. We further adopt consumption-based accounting and identify the global original source that produced the emissions. We find that anthropogenic PM2.5 emissions from industrial sectors accounted for 24 Tg globally in 2007; approximately 30% (7.2 Tg) of these emissions were embodied in export of products principally from Brazil, South Africa, India and China (3.8 Tg) to developed countries. Large differences (up to 10 times) in the embodied emissions intensity between net importers and exporters greatly increased total global PM2.5 emissions. Tele-connecting production and consumption activity provides valuable insights with respect to mitigating long-range transboundary air pollution and prompts concerted efforts aiming at more environmentally conscious globalization. PMID:27956874

Global Views, Personal Perspectives: Connecting to Self as Scholar

ERIC Educational Resources Information Center

Simmons, Nicola

2009-01-01

A global view requires not only a broader perspective, but also greater depth to anchor it firmly. In increasingly changing contexts, are we connected to ourselves in a way that feeds our spirits and nourishes our work? A professional sphere based only on research and practice risks being unbalanced and may jeopardize our well-being as academics.…

Applying Geography Course Projects to Issues in City Resilience and Global Connectivity

ERIC Educational Resources Information Center

Kalafsky, Ronald V.; Rosko, Helen M.

2017-01-01

Globalization would appear to be a subject that easily could be addressed in geography classrooms, yet this is not always the case. In terms of pedagogy, many geographers are concerned whether the field has been adequately engaging various components of this topic (e.g., connectivity, core-periphery), especially in terms of making the subject…

"Making Connections" at the University of North Carolina: Moving toward a Global Curriculum at a Flagship Research University

ERIC Educational Resources Information Center

Smith, Jay M.; Kruse, Julia

2009-01-01

The University of North Carolina at Chapel Hill has reformed its undergraduate curriculum to create connections across disciplines and advance efforts to internationalize its campus. As a result, global issues, experiential learning, study abroad, and international course clusters have become an integral part of a curriculum that emphasizes…

Teaching and Learning in the Global Village: Connect, Create, Collaborate, and Communicate

ERIC Educational Resources Information Center

Dwyer, Bernadette

2016-01-01

The world is increasingly interconnected through technology. In order to live and work in a global village our students need to develop global literacy. Global literacy incorporates a range of overlapping concepts including an advocacy dimension, global citizenship responsibility, and cultural and linguistic awareness. Further, global literacy…

Low-Symmetry Gap Functions of Organic Superconductors

NASA Astrophysics Data System (ADS)

Mori, Takehiko

2018-04-01

Superconducting gap functions of various low-symmetry organic superconductors are investigated starting from the tight-binding energy band and the random phase approximation by numerically solving Eliashberg's equation. The obtained singlet gap function is approximately represented by an asymmetrical dx2 - y2 form, where two cosine functions are mixed in an appropriate ratio. This is usually called d + s wave, where the ratio of the two cosine functions varies from 1:1 in the two-dimensional limit to 1:0 in the one-dimensional limit. A single cosine function does not make a superconducting gap in an ideal one-dimensional conductor, but works as a relevant gap function in quasi-one-dimensional conductors with slight interchain transfer integrals. Even when the Fermi surface is composed of small pockets, the gap function is obtained supposing a globally connected elliptical Fermi surface. In such a case, we have to connect the second energy band in the second Brillouin zone. The periodicity of the resulting gap function is larger than the first Brillouin zone. This is because the susceptibility has peaks at 2kF, where the periodicity has to be twice the size of the global Fermi surface. In general, periodicity of gap function corresponds to one electron or two molecules in the real space. In the κ-phase, two axes are nonequivalent, but the exact dx2 - y2 symmetry is maintained because the diagonal transfer integral introduced to a square lattice is oriented to the node direction of the dx2 - y2 wave. By contrast, the θ-phase gap function shows considerable anisotropy because a quarter-filled square lattice has a different dxy symmetry.

Correlations Between Extreme Atmospheric Hazards and Global Teleconnections: Implications for Multihazard Resilience

NASA Astrophysics Data System (ADS)

Steptoe, H.; Jones, S. E. O.; Fox, H.

2018-03-01

Occurrences of concurrent extreme atmospheric hazards represent a significant area of uncertainty for organizations involved in disaster mitigation and risk management. Understanding risks posed by natural disasters and their relationship with global climate drivers is crucial in preparing for extreme events. In this review we quantify the strength of the physical mechanisms linking hazards and atmosphere-ocean processes. We demonstrate how research from the science community may be used to support disaster risk reduction and global sustainable development efforts. We examine peer-reviewed literature connecting 16 regions affected by extreme atmospheric hazards and eight key global drivers of weather and climate. We summarize current understanding of multihazard disaster risk in each of these regions and identify aspects of the global climate system that require further investigation to strengthen our resilience in these areas. We show that some drivers can increase the risk of concurrent hazards across different regions. Organizations that support disaster risk reduction, or underwrite exposure, in multiple regions may have a heightened risk of facing multihazard losses. We find that 15 regional hazards share connections via the El Niño-Southern Oscillation, with the Indian Ocean Dipole, North Atlantic Oscillation, and the Southern Annular Mode being secondary sources of significant regional interconnectivity. From a hazard perspective, rainfall over China shares the most connections with global drivers and has links to both Northern and Southern Hemisphere modes of variability. We use these connections to assess the global likelihood of concurrent hazard occurrence in support of multihazard resilience and disaster risk reduction goals.

Resting-State Connectivity of the Left Frontal Cortex to the Default Mode and Dorsal Attention Network Supports Reserve in Mild Cognitive Impairment.

PubMed

Franzmeier, Nicolai; Göttler, Jens; Grimmer, Timo; Drzezga, Alexander; Áraque-Caballero, Miguel A; Simon-Vermot, Lee; Taylor, Alexander N W; Bürger, Katharina; Catak, Cihan; Janowitz, Daniel; Müller, Claudia; Duering, Marco; Sorg, Christian; Ewers, Michael

2017-01-01

Reserve refers to the phenomenon of relatively preserved cognition in disproportion to the extent of neuropathology, e.g., in Alzheimer's disease. A putative functional neural substrate underlying reserve is global functional connectivity of the left lateral frontal cortex (LFC, Brodmann Area 6/44). Resting-state fMRI-assessed global LFC-connectivity is associated with protective factors (education) and better maintenance of memory in mild cognitive impairment (MCI). Since the LFC is a hub of the fronto-parietal control network that regulates the activity of other networks, the question arises whether LFC-connectivity to specific networks rather than the whole-brain may underlie reserve. We assessed resting-state fMRI in 24 MCI and 16 healthy controls (HC) and in an independent validation sample (23 MCI/32 HC). Seed-based LFC-connectivity to seven major resting-state networks (i.e., fronto-parietal, limbic, dorsal-attention, somatomotor, default-mode, ventral-attention, visual) was computed, reserve was quantified as residualized memory performance after accounting for age and hippocampal atrophy. In both samples of MCI, LFC-activity was anti-correlated with the default-mode network (DMN), but positively correlated with the dorsal-attention network (DAN). Greater education predicted stronger LFC-DMN-connectivity (anti-correlation) and LFC-DAN-connectivity. Stronger LFC-DMN and LFC-DAN-connectivity each predicted higher reserve, consistently in both MCI samples. No associations were detected for LFC-connectivity to other networks. These novel results extend our previous findings on global functional connectivity of the LFC, showing that LFC-connectivity specifically to the DAN and DMN, two core memory networks, enhances reserve in the memory domain in MCI.

Designing connected marine reserves in the face of global warming.

PubMed

Álvarez-Romero, Jorge G; Munguía-Vega, Adrián; Beger, Maria; Del Mar Mancha-Cisneros, Maria; Suárez-Castillo, Alvin N; Gurney, Georgina G; Pressey, Robert L; Gerber, Leah R; Morzaria-Luna, Hem Nalini; Reyes-Bonilla, Héctor; Adams, Vanessa M; Kolb, Melanie; Graham, Erin M; VanDerWal, Jeremy; Castillo-López, Alejandro; Hinojosa-Arango, Gustavo; Petatán-Ramírez, David; Moreno-Baez, Marcia; Godínez-Reyes, Carlos R; Torre, Jorge

2018-02-01

Marine reserves are widely used to protect species important for conservation and fisheries and to help maintain ecological processes that sustain their populations, including recruitment and dispersal. Achieving these goals requires well-connected networks of marine reserves that maximize larval connectivity, thus allowing exchanges between populations and recolonization after local disturbances. However, global warming can disrupt connectivity by shortening potential dispersal pathways through changes in larval physiology. These changes can compromise the performance of marine reserve networks, thus requiring adjusting their design to account for ocean warming. To date, empirical approaches to marine prioritization have not considered larval connectivity as affected by global warming. Here, we develop a framework for designing marine reserve networks that integrates graph theory and changes in larval connectivity due to potential reductions in planktonic larval duration (PLD) associated with ocean warming, given current socioeconomic constraints. Using the Gulf of California as case study, we assess the benefits and costs of adjusting networks to account for connectivity, with and without ocean warming. We compare reserve networks designed to achieve representation of species and ecosystems with networks designed to also maximize connectivity under current and future ocean-warming scenarios. Our results indicate that current larval connectivity could be reduced significantly under ocean warming because of shortened PLDs. Given the potential changes in connectivity, we show that our graph-theoretical approach based on centrality (eigenvector and distance-weighted fragmentation) of habitat patches can help design better-connected marine reserve networks for the future with equivalent costs. We found that maintaining dispersal connectivity incidentally through representation-only reserve design is unlikely, particularly in regions with strong asymmetric patterns of dispersal connectivity. Our results support previous studies suggesting that, given potential reductions in PLD due to ocean warming, future marine reserve networks would require more and/or larger reserves in closer proximity to maintain larval connectivity. © 2017 John Wiley & Sons Ltd.

Riboswitches: emerging themes in RNA structure and function.

PubMed

Montange, Rebecca K; Batey, Robert T

2008-01-01

Riboswitches are RNAs capable of binding cellular metabolites using a diverse array of secondary and tertiary structures to modulate gene expression. The recent determination of the three-dimensional structures of parts of six different riboswitches illuminates common features that allow riboswitches to be grouped into one of two types. Type I riboswitches, as exemplified by the purine riboswitch, are characterized by a single, localized binding pocket supported by a largely pre-established global fold. This arrangement limits ligand-induced conformational changes in the RNA to a small region. In contrast, Type II riboswitches, such as the thiamine pyrophosphate riboswitch, contain binding pockets split into at least two spatially distinct sites. As a result, binding induces both local changes to the binding pocket and global architecture. Similar organizational themes are found in other noncoding RNAs, making it possible to begin to build a hierarchical classification of RNA structure based on the spatial organization of their active sites and associated secondary structural elements.

Structural Analysis of the Redesigned Ice/Frost Ramp Bracket

NASA Technical Reports Server (NTRS)

Phillips, D. R.; Dawicke, D. S.; Gentz, S. J.; Roberts, P. W.; Raju, I. S.

2007-01-01

This paper describes the interim structural analysis of a redesigned Ice/Frost Ramp bracket for the Space Shuttle External Tank (ET). The proposed redesigned bracket consists of mounts for attachment to the ET wall, supports for the electronic/instrument cables and propellant repressurization lines that run along the ET, an upper plate, a lower plate, and complex bolted connections. The eight nominal bolted connections are considered critical in the summarized structural analysis. Each bolted connection contains a bolt, a nut, four washers, and a non-metallic spacer and block that are designed for thermal insulation. A three-dimensional (3D) finite element model of the bracket is developed using solid 10-node tetrahedral elements. The loading provided by the ET Project is used in the analysis. Because of the complexities associated with accurately modeling the bolted connections in the bracket, the analysis is performed using a global/local analysis procedure. The finite element analysis of the bracket identifies one of the eight bolted connections as having high stress concentrations. A local area of the bracket surrounding this bolted connection is extracted from the global model and used as a local model. Within the local model, the various components of the bolted connection are refined, and contact is introduced along the appropriate interfaces determined by the analysts. The deformations from the global model are applied as boundary conditions to the local model. The results from the global/local analysis show that while the stresses in the bolts are well within yield, the spacers fail due to compression. The primary objective of the interim structural analysis is to show concept viability for static thermal testing. The proposed design concept would undergo continued design optimization to address the identified analytical assumptions and concept shortcomings, assuming successful thermal testing.

Study on the Connecting Length of CFRP

NASA Astrophysics Data System (ADS)

Liu, Xiongfei; Li, Yue; Li, Zhanguo

2018-05-01

The paper studied the varying mode of shear stress in the connecting zone of CFRP. Using epoxy resin (EP) as bond material, performance of specimens with different connecting length of CFRP was tested to obtain the conclusion. CFRP-confined concrete column was tested subsequently to verify the conclusion. The results show that: (1) The binding properties of modified epoxy resin with CFRP is good; (2) As the connecting length increased, the ultimate tensile strength of CFRP increased as well in the range of the experiment parameters; (3) Tensile strength of CFRP can reach the ultimate strength when the connecting length is 90mm;(4) The connecting length of 90mm of CFRP meet the reinforcement requirements.

β-Lactam Antibiotics with a High Affinity for PBP2 Act Synergistically with the FtsZ-Targeting Agent TXA707 against Methicillin-Resistant Staphylococcus aureus

PubMed Central

Ferrer-González, Edgar; Kaul, Malvika; Parhi, Ajit K.; LaVoie, Edmond J.

2017-01-01

ABSTRACT Methicillin-resistant Staphylococcus aureus (MRSA) is a multidrug-resistant pathogen that poses a significant risk to global health today. We have developed a promising new FtsZ-targeting agent (TXA707) with potent activity against MRSA isolates resistant to current standard-of-care antibiotics. We present here results that demonstrate differing extents of synergy between TXA707 and a broad range of β-lactam antibiotics (including six cephalosporins, two penicillins, and two carbapenems) against MRSA. To explore whether there is a correlation between the extent of synergy and the preferential antibacterial target of each β-lactam, we determined the binding affinities of the β-lactam antibiotics for each of the four native penicillin-binding proteins (PBPs) of S. aureus using a fluorescence anisotropy competition assay. A comparison of the resulting PBP binding affinities with our corresponding synergy results reveals that β-lactams with a high affinity for PBP2 afford the greatest degree of synergy with TXA707 against MRSA. In addition, we present fluorescence and electron microscopy studies that suggest a potential mechanism underlying the synergy between TXA707 and the β-lactam antibiotics. In this connection, our microscopy results show a disruption of septum formation in TXA707-treated MRSA cells, with a concomitant mislocalization of the PBPs from midcell to nonproductive peripheral sites. Viewed as a whole, our results indicate that PBP2-targeting β-lactam antibiotics are optimal synergistic partners with FtsZ-targeting agents for use in combination therapy of MRSA infections. PMID:28630190

Toward an Experimental Quantum Chemistry: Exploring a New Energy Partitioning.

PubMed

Rahm, Martin; Hoffmann, Roald

2015-08-19

Following the work of L. C. Allen, this work begins by relating the central chemical concept of electronegativity with the average binding energy of electrons in a system. The average electron binding energy, χ̅, is in principle accessible from experiment, through photoelectron and X-ray spectroscopy. It can also be estimated theoretically. χ̅ has a rigorous and understandable connection to the total energy. That connection defines a new kind of energy decomposition scheme. The changing total energy in a reaction has three primary contributions to it: the average electron binding energy, the nuclear-nuclear repulsion, and multielectron interactions. This partitioning allows one to gain insight into the predominant factors behind a particular energetic preference. We can conclude whether an energy change in a transformation is favored or resisted by collective changes to the binding energy of electrons, the movement of nuclei, or multielectron interactions. For example, in the classical formation of H2 from atoms, orbital interactions dominate nearly canceling nuclear-nuclear repulsion and two-electron interactions. While in electron attachment to an H atom, the multielectron interactions drive the reaction. Looking at the balance of average electron binding energy, multielectron, and nuclear-nuclear contributions one can judge when more traditional electronegativity arguments can be justifiably invoked in the rationalization of a particular chemical event.

Globally altered structural brain network topology in grapheme-color synesthesia.

PubMed

Hänggi, Jürgen; Wotruba, Diana; Jäncke, Lutz

2011-04-13

Synesthesia is a perceptual phenomenon in which stimuli in one particular modality elicit a sensation within the same or another sensory modality (e.g., specific graphemes evoke the perception of particular colors). Grapheme-color synesthesia (GCS) has been proposed to arise from abnormal local cross-activation between grapheme and color areas because of their hyperconnectivity. Recently published studies did not confirm such a hyperconnectivity, although morphometric alterations were found in occipitotemporal, parietal, and frontal regions of synesthetes. We used magnetic resonance imaging surface-based morphometry and graph-theoretical network analyses to investigate the topology of structural brain networks in 24 synesthetes and 24 nonsynesthetes. Connectivity matrices were derived from region-wise cortical thickness correlations of 2366 different cortical parcellations across the whole cortex and from 154 more common brain divisions as well. Compared with nonsynesthetes, synesthetes revealed a globally altered structural network topology as reflected by reduced small-worldness, increased clustering, increased degree, and decreased betweenness centrality. Connectivity of the fusiform gyrus (FuG) and intraparietal sulcus (IPS) was changed as well. Hierarchical modularity analysis revealed increased intramodular and intermodular connectivity of the IPS in GCS. However, connectivity differences in the FuG and IPS showed a low specificity because of global changes. We provide first evidence that GCS is rooted in a reduced small-world network organization that is driven by increased clustering suggesting global hyperconnectivity within the synesthetes' brain. Connectivity alterations were widespread and not restricted to the FuG and IPS. Therefore, synesthetic experience might be only one phenotypic manifestation of the globally altered network architecture in GCS.

Anti-correlated networks, global signal regression, and the effects of caffeine in resting-state functional MRI.

PubMed

Wong, Chi Wah; Olafsson, Valur; Tal, Omer; Liu, Thomas T

2012-10-15

Resting-state functional connectivity magnetic resonance imaging is proving to be an essential tool for the characterization of functional networks in the brain. Two of the major networks that have been identified are the default mode network (DMN) and the task positive network (TPN). Although prior work indicates that these two networks are anti-correlated, the findings are controversial because the anti-correlations are often found only after the application of a pre-processing step, known as global signal regression, that can produce artifactual anti-correlations. In this paper, we show that, for subjects studied in an eyes-closed rest state, caffeine can significantly enhance the detection of anti-correlations between the DMN and TPN without the need for global signal regression. In line with these findings, we find that caffeine also leads to widespread decreases in connectivity and global signal amplitude. Using a recently introduced geometric model of global signal effects, we demonstrate that these decreases are consistent with the removal of an additive global signal confound. In contrast to the effects observed in the eyes-closed rest state, caffeine did not lead to significant changes in global functional connectivity in the eyes-open rest state. Copyright © 2012 Elsevier Inc. All rights reserved.

Optimizing and Interpreting Insular Functional Connectivity Maps Obtained During Acute Experimental Pain: The Effects of Global Signal and Task Paradigm Regression.

PubMed

Ibinson, James W; Vogt, Keith M; Taylor, Kevin B; Dua, Shiv B; Becker, Christopher J; Loggia, Marco; Wasan, Ajay D

2015-12-01

The insula is uniquely located between the temporal and parietal cortices, making it anatomically well-positioned to act as an integrating center between the sensory and affective domains for the processing of painful stimulation. This can be studied through resting-state functional connectivity (fcMRI) imaging; however, the lack of a clear methodology for the analysis of fcMRI complicates the interpretation of these data during acute pain. Detected connectivity changes may reflect actual alterations in low-frequency synchronous neuronal activity related to pain, may be due to changes in global cerebral blood flow or the superimposed task-induced neuronal activity. The primary goal of this study was to investigate the effects of global signal regression (GSR) and task paradigm regression (TPR) on the changes in functional connectivity of the left (contralateral) insula in healthy subjects at rest and during acute painful electric nerve stimulation of the right hand. The use of GSR reduced the size and statistical significance of connectivity clusters and created negative correlation coefficients for some connectivity clusters. TPR with cyclic stimulation gave task versus rest connectivity differences similar to those with a constant task, suggesting that analysis which includes TPR is more accurately reflective of low-frequency neuronal activity. Both GSR and TPR have been inconsistently applied to fcMRI analysis. Based on these results, investigators need to consider the impact GSR and TPR have on connectivity during task performance when attempting to synthesize the literature.

Structural Connectivity Relates to Perinatal Factors and Functional Impairment at 7 Years in Children Born Very Preterm

PubMed Central

Thompson, Deanne K.; Chen, Jian; Beare, Richard; Adamson, Christopher L.; Ellis, Rachel; Ahmadzai, Zohra M.; Kelly, Claire E.; Lee, Katherine J.; Zalesky, Andrew; Yang, Joseph Y.M.; Hunt, Rodney W.; Cheong, Jeanie L.Y.; Inder, Terrie E.; Doyle, Lex W.; Seal, Marc L.; Anderson, Peter J.

2016-01-01

Objective To use structural connectivity to (1) compare brain networks between typically and atypically developing (very preterm) children, (2) explore associations between potential perinatal developmental disturbances and brain networks, and (3) describe associations between brain networks and functional impairments in very preterm children. Methods 26 full-term and 107 very preterm 7-year-old children (born <30 weeks’ gestational age and/or <1250 g) underwent T1- and diffusion-weighted imaging. Global white matter fiber networks were produced using 80 cortical and subcortical nodes, and edges created using constrained spherical deconvolution-based tractography. Global graph theory metrics were analysed, and regional networks were identified using network-based statistics. Cognitive and motor function were assessed at 7 years of age. Results Compared with full-term children, very preterm children had reduced density, lower global efficiency and higher local efficiency. Those with lower gestational age at birth, infection or higher neonatal brain abnormality score had reduced connectivity. Reduced connectivity within a widespread network was predictive of impaired IQ, while reduced connectivity within the right parietal and temporal lobes was associated with motor impairment in very preterm children. Conclusions This study utilized an innovative structural connectivity pipeline to reveal that children born very preterm have less connected and less complex brain networks compared with typically developing term-born children. Adverse perinatal factors led to disturbances in white matter connectivity, which in turn are associated with impaired functional outcomes, highlighting novel structure-function relationships. PMID:27046108

Angular default mode network connectivity across working memory load.

PubMed

Vatansever, D; Manktelow, A E; Sahakian, B J; Menon, D K; Stamatakis, E A

2017-01-01

Initially identified during no-task, baseline conditions, it has now been suggested that the default mode network (DMN) engages during a variety of working memory paradigms through its flexible interactions with other large-scale brain networks. Nevertheless, its contribution to whole-brain connectivity dynamics across increasing working memory load has not been explicitly assessed. The aim of our study was to determine which DMN hubs relate to working memory task performance during an fMRI-based n-back paradigm with parametric increases in difficulty. Using a voxel-wise metric, termed the intrinsic connectivity contrast (ICC), we found that the bilateral angular gyri (core DMN hubs) displayed the greatest change in global connectivity across three levels of n-back task load. Subsequent seed-based functional connectivity analysis revealed that the angular DMN regions robustly interact with other large-scale brain networks, suggesting a potential involvement in the global integration of information. Further support for this hypothesis comes from the significant correlations we found between angular gyri connectivity and reaction times to correct responses. The implication from our study is that the DMN is actively involved during the n-back task and thus plays an important role related to working memory, with its core angular regions contributing to the changes in global brain connectivity in response to increasing environmental demands. Hum Brain Mapp 38:41-52, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Cooperative Allosteric Ligand Binding in Calmodulin

NASA Astrophysics Data System (ADS)

Nandigrami, Prithviraj

Conformational dynamics is often essential for a protein's function. For example, proteins are able to communicate the effect of binding at one site to a distal region of the molecule through changes in its conformational dynamics. This so called allosteric coupling fine tunes the sensitivity of ligand binding to changes in concentration. A conformational change between a "closed" (apo) and an "open" (holo) conformation upon ligation often produces this coupling between binding sites. Enhanced sensitivity between the unbound and bound ensembles leads to a sharper binding curve. There are two basic conceptual frameworks that guide our visualization about ligand binding mechanisms. First, a ligand can stabilize the unstable "open" state from a dynamic ensemble of conformations within the unbound basin. This binding mechanism is called conformational selection. Second, a ligand can weakly bind to the low-affinity "closed" state followed by a conformational transition to the "open" state. In this dissertation, I focus on molecular dynamics simulations to understand microscopic origins of ligand binding cooperativity. A minimal model of allosteric binding transitions must include ligand binding/unbinding events, while capturing the transition mechanism between two distinct meta-stable free energy basins. Due in part to computational timescales limitations, work in this dissertation describes large-scale conformational transitions through a simplified, coarse-grained model based on the energy basins defined by the open and closed conformations of the protein Calmodulin (CaM). CaM is a ubiquitous calcium-binding protein consisting of two structurally similar globular domains connected by a flexible linker. The two domains of CaM, N-terminal domain (nCaM) and C-terminal domain (cCaM) consists of two helix-loop-helix motifs (the EF-hands) connected by a flexible linker. Each domain of CaM consists of two binding loops and binds 2 calcium ions each. The intact domain binds up to 4 calcium ions. The simulations use a coupled molecular dynamics/monte carlo scheme where the protein dynamics is simulated explicitly, while ligand binding/unbinding are treated implicitly. In the model, ligand binding/unbinding events coupled with a conformational change of the protein within the grand canonical ensemble. Here, ligand concentration is controlled through the chemical potential (micro). This allows us to use a simple thermodynamic model to analyze the simulated data and quantify binding cooperativity. Simulated binding titration curves are calculated through equilibrium simulations at different values of micro. First, I study domain opening transitions of isolated nCaM and cCaM in the absence of calcium. This work is motivated by results from a recent analytic variational model that predicts distinct domain opening transition mechanism for the domains of CaM. This is a surprising result because the domains have the same folded state topology. In the simulations, I find the two domains of CaM have distinct transition mechanism over a broad range of temperature, in harmony with the analytic predictions. In particular, the simulated transition mechanism of nCaM follows a two-state behavior, while domain opening in cCaM involves global unfolding and refolding of the tertiary structure. The unfolded intermediate also appears in the landscape of nCaM, but at a higher temperature than it appears in cCaM's energy landscape. This is consistent with nCaM's higher thermal stability. Under approximate physiological conditions, majority of the sampled transitions in cCaM involves unfolding and refolding during conformational change. Kinetically, the transient unfolding and refolding in cCaM significantly slows the domain opening and closing rates in cCaM. Second, I investigate the structural origins of binding affinity and allosteric cooperativity of binding 2 calcium-ions to each domain of CaM. In my work, I predict the order of binding strength of CaM's loops. I analyze simulated binding curves within the framework of the classic Monod-Wyman-Changeux (MWC) model of allostery to extract the binding free energies to the closed and open ensembles. The simulations predict that cCaM binds calcium with higher affinity and greater cooperativity than nCaM. Where it is possible to compare, these predictions are in good agreement with experimental results. The analysis of the simulations offers a rationale for why the two domains differ in cooperativity: the higher cooperativity of cCaM is due to larger difference in affinity of its binding loops. Third, I extend the work to investigate structural origins of binding cooperativity of 4 calcium-ions to intact CaM. I characterize the microscopic cooperativities of each ligation state and provide a kinetic description of the binding mechanism. Due to the heterogeneous nature of CaM's loops, as predicted in our simulations of isolated domains, I focus on investigating the influence of this heterogeneity on the kinetic flux of binding pathways as a function of concentration. The formalism developed for Network Models of protein folding kinetics, is used to evaluate the directed flux of all possible pathways between unligated and fully loaded CaM. (Abstract shortened by ProQuest.).

Global spatio-temporal patterns in human migration: a complex network perspective.

PubMed

Davis, Kyle F; D'Odorico, Paolo; Laio, Francesco; Ridolfi, Luca

2013-01-01

Migration is a powerful adaptive strategy for humans to navigate hardship and pursue a better quality of life. As a universal vehicle facilitating exchanges of ideas, culture, money and goods, international migration is a major contributor to globalization. Consisting of countries linked by multiple connections of human movements, global migration constitutes a network. Despite the important role of human migration in connecting various communities in different parts of the world, the topology and behavior of the international migration network and its changes through time remain poorly understood. Here we show that the global human migration network became more interconnected during the latter half of the twentieth century and that migrant destination choice partly reflects colonial and postcolonial histories, language, religion, and distances. From 1960 to 2000 we found a steady increase in network transitivity (i.e. connectivity between nodes connected to the same node), a decrease in average path length and an upward shift in degree distribution, all of which strengthened the 'small-world' behavior of the migration network. Furthermore, we found that distinct groups of countries preferentially interact to form migration communities based largely on historical, cultural and economic factors.

Planning for the Maintenance of Floristic Diversity in the Face of Land Cover and Climate Change.

PubMed

Jewitt, Debbie; Goodman, Peter S; Erasmus, Barend F N; O'Connor, Timothy G; Witkowski, Ed T F

2017-05-01

Habitat loss and climate change are primary drivers of global biodiversity loss. Species will need to track changing environmental conditions through fragmented and transformed landscapes such as KwaZulu-Natal, South Africa. Landscape connectivity is an important tool for maintaining resilience to global change. We develop a coarse-grained connectivity map between protected areas to aid decision-making for implementing corridors to maintain floristic diversity in the face of global change. The spatial location of corridors was prioritised using a biological underpinning of floristic composition that incorporated high beta diversity regions, important plant areas, climate refugia, and aligned to major climatic gradients driving floristic pattern. We used Linkage Mapper to develop the connectivity network. The resistance layer was based on land-cover categories with natural areas discounted according to their contribution towards meeting the biological objectives. Three corridor maps were developed; a conservative option for meeting minimum corridor requirements, an optimal option for meeting a target amount of 50% of the landscape and an option including linkages in highly transformed areas. The importance of various protected areas and critical linkages in maintaining landscape connectivity are discussed, disconnected protected areas and pinch points identified where the loss of small areas could compromise landscape connectivity. This framework is suggested as a way to conserve floristic diversity into the future and is recommended as an approach for other global connectivity initiatives. A lack of implementation of corridors will lead to further habitat loss and fragmentation, resulting in further risk to plant diversity.

Planning for the Maintenance of Floristic Diversity in the Face of Land Cover and Climate Change

NASA Astrophysics Data System (ADS)

Jewitt, Debbie; Goodman, Peter S.; Erasmus, Barend F. N.; O'Connor, Timothy G.; Witkowski, Ed T. F.

2017-05-01

Habitat loss and climate change are primary drivers of global biodiversity loss. Species will need to track changing environmental conditions through fragmented and transformed landscapes such as KwaZulu-Natal, South Africa. Landscape connectivity is an important tool for maintaining resilience to global change. We develop a coarse-grained connectivity map between protected areas to aid decision-making for implementing corridors to maintain floristic diversity in the face of global change. The spatial location of corridors was prioritised using a biological underpinning of floristic composition that incorporated high beta diversity regions, important plant areas, climate refugia, and aligned to major climatic gradients driving floristic pattern. We used Linkage Mapper to develop the connectivity network. The resistance layer was based on land-cover categories with natural areas discounted according to their contribution towards meeting the biological objectives. Three corridor maps were developed; a conservative option for meeting minimum corridor requirements, an optimal option for meeting a target amount of 50% of the landscape and an option including linkages in highly transformed areas. The importance of various protected areas and critical linkages in maintaining landscape connectivity are discussed, disconnected protected areas and pinch points identified where the loss of small areas could compromise landscape connectivity. This framework is suggested as a way to conserve floristic diversity into the future and is recommended as an approach for other global connectivity initiatives. A lack of implementation of corridors will lead to further habitat loss and fragmentation, resulting in further risk to plant diversity.

Global Terrestrial Water Storage Changes and Connections to ENSO Events

NASA Astrophysics Data System (ADS)

Ni, Shengnan; Chen, Jianli; Wilson, Clark R.; Li, Jin; Hu, Xiaogong; Fu, Rong

2018-01-01

Improved data quality of extended record of the Gravity Recovery and Climate Experiment (GRACE) satellite gravity solutions enables better understanding of terrestrial water storage (TWS) variations. Connections of TWS and climate change are critical to investigate regional and global water cycles. In this study, we provide a comprehensive analysis of global connections between interannual TWS changes and El Niño Southern Oscillation (ENSO) events, using multiple sources of data, including GRACE measurements, land surface model (LSM) predictions and precipitation observations. We use cross-correlation and coherence spectrum analysis to examine global connections between interannual TWS changes and the Niño 3.4 index, and select four river basins (Amazon, Orinoco, Colorado, and Lena) for more detailed analysis. The results indicate that interannual TWS changes are strongly correlated with ENSO over much of the globe, with maximum cross-correlation coefficients up to 0.70, well above the 95% significance level ( 0.29) derived by the Monte Carlo experiments. The strongest correlations are found in tropical and subtropical regions, especially in the Amazon, Orinoco, and La Plata basins. While both GRACE and LSM TWS estimates show reasonably good correlations with ENSO and generally consistent spatial correlation patterns, notably higher correlations are found between GRACE TWS and ENSO. The existence of significant correlations in middle-high latitudes shows the large-scale impact of ENSO on the global water cycle.

A global optimization algorithm for protein surface alignment

PubMed Central

2010-01-01

Background A relevant problem in drug design is the comparison and recognition of protein binding sites. Binding sites recognition is generally based on geometry often combined with physico-chemical properties of the site since the conformation, size and chemical composition of the protein surface are all relevant for the interaction with a specific ligand. Several matching strategies have been designed for the recognition of protein-ligand binding sites and of protein-protein interfaces but the problem cannot be considered solved. Results In this paper we propose a new method for local structural alignment of protein surfaces based on continuous global optimization techniques. Given the three-dimensional structures of two proteins, the method finds the isometric transformation (rotation plus translation) that best superimposes active regions of two structures. We draw our inspiration from the well-known Iterative Closest Point (ICP) method for three-dimensional (3D) shapes registration. Our main contribution is in the adoption of a controlled random search as a more efficient global optimization approach along with a new dissimilarity measure. The reported computational experience and comparison show viability of the proposed approach. Conclusions Our method performs well to detect similarity in binding sites when this in fact exists. In the future we plan to do a more comprehensive evaluation of the method by considering large datasets of non-redundant proteins and applying a clustering technique to the results of all comparisons to classify binding sites. PMID:20920230

Abnormal rich club organization and functional brain dynamics in schizophrenia.

PubMed

van den Heuvel, Martijn P; Sporns, Olaf; Collin, Guusje; Scheewe, Thomas; Mandl, René C W; Cahn, Wiepke; Goñi, Joaquín; Hulshoff Pol, Hilleke E; Kahn, René S

2013-08-01

The human brain forms a large-scale structural network of regions and interregional pathways. Recent studies have reported the existence of a selective set of highly central and interconnected hub regions that may play a crucial role in the brain's integrative processes, together forming a central backbone for global brain communication. Abnormal brain connectivity may have a key role in the pathophysiology of schizophrenia. To examine the structure of the rich club in schizophrenia and its role in global functional brain dynamics. Structural diffusion tensor imaging and resting-state functional magnetic resonance imaging were performed in patients with schizophrenia and matched healthy controls. Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, the Netherlands. Forty-eight patients and 45 healthy controls participated in the study. An independent replication data set of 41 patients and 51 healthy controls was included to replicate and validate significant findings. MAIN OUTCOME(S) AND MEASURES: Measures of rich club organization, connectivity density of rich club connections and connections linking peripheral regions to brain hubs, measures of global brain network efficiency, and measures of coupling between brain structure and functional dynamics. Rich club organization between high-degree hub nodes was significantly affected in patients, together with a reduced density of rich club connections predominantly comprising the white matter pathways that link the midline frontal, parietal, and insular hub regions. This reduction in rich club density was found to be associated with lower levels of global communication capacity, a relationship that was absent for other white matter pathways. In addition, patients had an increase in the strength of structural connectivity-functional connectivity coupling. Our findings provide novel biological evidence that schizophrenia is characterized by a selective disruption of brain connectivity among central hub regions of the brain, potentially leading to reduced communication capacity and altered functional brain dynamics.

Serial interactome capture of the human cell nucleus.

PubMed

Conrad, Thomas; Albrecht, Anne-Susann; de Melo Costa, Veronica Rodrigues; Sauer, Sascha; Meierhofer, David; Ørom, Ulf Andersson

2016-04-04

Novel RNA-guided cellular functions are paralleled by an increasing number of RNA-binding proteins (RBPs). Here we present 'serial RNA interactome capture' (serIC), a multiple purification procedure of ultraviolet-crosslinked poly(A)-RNA-protein complexes that enables global RBP detection with high specificity. We apply serIC to the nuclei of proliferating K562 cells to obtain the first human nuclear RNA interactome. The domain composition of the 382 identified nuclear RBPs markedly differs from previous IC experiments, including few factors without known RNA-binding domains that are in good agreement with computationally predicted RNA binding. serIC extends the number of DNA-RNA-binding proteins (DRBPs), and reveals a network of RBPs involved in p53 signalling and double-strand break repair. serIC is an effective tool to couple global RBP capture with additional selection or labelling steps for specific detection of highly purified RBPs.

Effects of local and global network connectivity on synergistic epidemics

NASA Astrophysics Data System (ADS)

Broder-Rodgers, David; Pérez-Reche, Francisco J.; Taraskin, Sergei N.

2015-12-01

Epidemics in networks can be affected by cooperation in transmission of infection and also connectivity between nodes. An interplay between these two properties and their influence on epidemic spread are addressed in the paper. A particular type of cooperative effects (called synergy effects) is considered, where the transmission rate between a pair of nodes depends on the number of infected neighbors. The connectivity effects are studied by constructing networks of different topology, starting with lattices with only local connectivity and then with networks that have both local and global connectivity obtained by random bond-rewiring to nodes within a certain distance. The susceptible-infected-removed epidemics were found to exhibit several interesting effects: (i) for epidemics with strong constructive synergy spreading in networks with high local connectivity, the bond rewiring has a negative role in epidemic spread, i.e., it reduces invasion probability; (ii) in contrast, for epidemics with destructive or weak constructive synergy spreading on networks of arbitrary local connectivity, rewiring helps epidemics to spread; (iii) and, finally, rewiring always enhances the spread of epidemics, independent of synergy, if the local connectivity is low.

Effects of local and global network connectivity on synergistic epidemics.

PubMed

Broder-Rodgers, David; Pérez-Reche, Francisco J; Taraskin, Sergei N

2015-12-01

Epidemics in networks can be affected by cooperation in transmission of infection and also connectivity between nodes. An interplay between these two properties and their influence on epidemic spread are addressed in the paper. A particular type of cooperative effects (called synergy effects) is considered, where the transmission rate between a pair of nodes depends on the number of infected neighbors. The connectivity effects are studied by constructing networks of different topology, starting with lattices with only local connectivity and then with networks that have both local and global connectivity obtained by random bond-rewiring to nodes within a certain distance. The susceptible-infected-removed epidemics were found to exhibit several interesting effects: (i) for epidemics with strong constructive synergy spreading in networks with high local connectivity, the bond rewiring has a negative role in epidemic spread, i.e., it reduces invasion probability; (ii) in contrast, for epidemics with destructive or weak constructive synergy spreading on networks of arbitrary local connectivity, rewiring helps epidemics to spread; (iii) and, finally, rewiring always enhances the spread of epidemics, independent of synergy, if the local connectivity is low.

PilN binding modulates the structure and binding partners of the Pseudomonas aeruginosa type IVa pilus protein PilM

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

McCallum, Matthew; Tammam, Stephanie; Little, Dustin J.

Pseudomonas aeruginosa is an opportunistic bacterial pathogen that expresses type IVa pili. The pilus assembly system, which promotes surface-associated twitching motility and virulence, is composed of inner and outer membrane subcomplexes, connected by an alignment subcomplex composed of PilMNOP. PilM binds to the N terminus of PilN, and we hypothesize that this interaction causes functionally significant structural changes in PilM. To characterize this interaction, we determined the crystal structures of PilM and a PilM chimera where PilM was fused to the first 12 residues of PilN (PilM·PilN(1–12)). Structural analysis, multiangle light scattering coupled with size exclusion chromatography, and bacterial two-hybridmore » data revealed that PilM forms dimers mediated by the binding of a novel conserved motif in the N terminus of PilM, and binding PilN abrogates this binding interface, resulting in PilM monomerization. Structural comparison of PilM with PilM·PilN(1–12) revealed that upon PilN binding, there is a large domain closure in PilM that alters its ATP binding site. Using biolayer interferometry, we found that the association rate of PilN with PilM is higher in the presence of ATP compared with ADP. Bacterial two-hybrid data suggested the connectivity of the cytoplasmic and inner membrane components of the type IVa pilus machinery in P. aeruginosa, with PilM binding to PilB, PilT, and PilC in addition to PilN. Pull-down experiments demonstrated direct interactions of PilM with PilB and PilT. As a result, we propose a working model in which dynamic binding of PilN facilitates functionally relevant structural changes in PilM.« less

PilN binding modulates the structure and binding partners of the Pseudomonas aeruginosa type IVa pilus protein PilM

DOE PAGES

McCallum, Matthew; Tammam, Stephanie; Little, Dustin J.; ...

2016-03-28

Pseudomonas aeruginosa is an opportunistic bacterial pathogen that expresses type IVa pili. The pilus assembly system, which promotes surface-associated twitching motility and virulence, is composed of inner and outer membrane subcomplexes, connected by an alignment subcomplex composed of PilMNOP. PilM binds to the N terminus of PilN, and we hypothesize that this interaction causes functionally significant structural changes in PilM. To characterize this interaction, we determined the crystal structures of PilM and a PilM chimera where PilM was fused to the first 12 residues of PilN (PilM·PilN(1–12)). Structural analysis, multiangle light scattering coupled with size exclusion chromatography, and bacterial two-hybridmore » data revealed that PilM forms dimers mediated by the binding of a novel conserved motif in the N terminus of PilM, and binding PilN abrogates this binding interface, resulting in PilM monomerization. Structural comparison of PilM with PilM·PilN(1–12) revealed that upon PilN binding, there is a large domain closure in PilM that alters its ATP binding site. Using biolayer interferometry, we found that the association rate of PilN with PilM is higher in the presence of ATP compared with ADP. Bacterial two-hybrid data suggested the connectivity of the cytoplasmic and inner membrane components of the type IVa pilus machinery in P. aeruginosa, with PilM binding to PilB, PilT, and PilC in addition to PilN. Pull-down experiments demonstrated direct interactions of PilM with PilB and PilT. As a result, we propose a working model in which dynamic binding of PilN facilitates functionally relevant structural changes in PilM.« less

Proteomic Study Related to Vascular Connections in Watermelon Scions Grafted onto Bottle-Gourd Rootstock under Different Light Intensities

PubMed Central

Muneer, Sowbiya; Ko, Chung Ho; Soundararajan, Prabhakaran; Manivnnan, Abinaya; Park, Yoo Gyeong; Jeong, Byoung Ryong

2015-01-01

Although grafting is broadly used in the production of crops, no information is available about the proteins involved in vascular connections between rootstock and scion. Similarly, proteome changes under the light intensities widely used for grafted seedlings are of practical use. The objective of this study was to determine the proteome of vascular connections using watermelon (Citrullus vulgaris Schrad.) ‘Sambok Honey’ and ‘Speed’ as the scion and bottle gourd (Lagenaria siceraria Stanld.) ‘RS Dongjanggun’ as the rootstock grown under different light intensities (25, 50, 75 and 100 μmol m−2 s−1). Our proteomic analysis revealed 24 and 27 differentially expressed proteins in ‘Sambok Honey’ and ‘Speed’, respectively, under different light intensities. The identified proteins were largely involved in ion binding, amino acid metabolism, transcriptional regulation and defense response. The enhancement of ion-binding, transcriptional regulation, amino acid metabolism, and defense response proteins suggests a strengthening of the connection between the rootstock and scion under high light intensity. Indeed, the accumulation of key enzymes in the biological processes described above appears to play an important role in the vascular connections of grafted seedlings. Moreover, it appears that 100 μmol m−2 s−1 results in better protein expression responses in grafted seedlings. PMID:25789769

Proteomic study related to vascular connections in watermelon scions grafted onto bottle-gourd rootstock under different light intensities.

PubMed

Muneer, Sowbiya; Ko, Chung Ho; Soundararajan, Prabhakaran; Manivnnan, Abinaya; Park, Yoo Gyeong; Jeong, Byoung Ryong

2015-01-01

Although grafting is broadly used in the production of crops, no information is available about the proteins involved in vascular connections between rootstock and scion. Similarly, proteome changes under the light intensities widely used for grafted seedlings are of practical use. The objective of this study was to determine the proteome of vascular connections using watermelon (Citrullus vulgaris Schrad.) 'Sambok Honey' and 'Speed' as the scion and bottle gourd (Lagenaria siceraria Stanld.) 'RS Dongjanggun' as the rootstock grown under different light intensities (25, 50, 75 and 100 μmol m-2 s-1). Our proteomic analysis revealed 24 and 27 differentially expressed proteins in 'Sambok Honey' and 'Speed', respectively, under different light intensities. The identified proteins were largely involved in ion binding, amino acid metabolism, transcriptional regulation and defense response. The enhancement of ion-binding, transcriptional regulation, amino acid metabolism, and defense response proteins suggests a strengthening of the connection between the rootstock and scion under high light intensity. Indeed, the accumulation of key enzymes in the biological processes described above appears to play an important role in the vascular connections of grafted seedlings. Moreover, it appears that 100 μmol m-2 s-1 results in better protein expression responses in grafted seedlings.

Brain network connectivity in women exposed to intimate partner violence: a graph theory analysis study.

PubMed

Roos, Annerine; Fouche, Jean-Paul; Stein, Dan J

2017-12-01

Evidence suggests that women who suffer from intimate partner violence (IPV) and posttraumatic stress disorder (PTSD) have structural and functional alterations in specific brain regions. Yet, little is known about how brain connectivity may be altered in individuals with IPV, but without PTSD. Women exposed to IPV (n = 18) and healthy controls (n = 18) underwent structural brain imaging using a Siemens 3T MRI. Global and regional brain network connectivity measures were determined, using graph theory analyses. Structural covariance networks were created using volumetric and cortical thickness data after controlling for intracranial volume, age and alcohol use. Nonparametric permutation tests were used to investigate group differences. Findings revealed altered connectivity on a global and regional level in the IPV group of regions involved in cognitive-emotional control, with principal involvement of the caudal anterior cingulate, the middle temporal gyrus, left amygdala and ventral diencephalon that includes the thalamus. To our knowledge, this is the first evidence showing different brain network connectivity in global and regional networks in women exposed to IPV, and without PTSD. Altered cognitive-emotional control in IPV may underlie adaptive neural mechanisms in environments characterized by potentially dangerous cues.

QuickVina: accelerating AutoDock Vina using gradient-based heuristics for global optimization.

PubMed

Handoko, Stephanus Daniel; Ouyang, Xuchang; Su, Chinh Tran To; Kwoh, Chee Keong; Ong, Yew Soon

2012-01-01

Predicting binding between macromolecule and small molecule is a crucial phase in the field of rational drug design. AutoDock Vina, one of the most widely used docking software released in 2009, uses an empirical scoring function to evaluate the binding affinity between the molecules and employs the iterated local search global optimizer for global optimization, achieving a significantly improved speed and better accuracy of the binding mode prediction compared its predecessor, AutoDock 4. In this paper, we propose further improvement in the local search algorithm of Vina by heuristically preventing some intermediate points from undergoing local search. Our improved version of Vina-dubbed QVina-achieved a maximum acceleration of about 25 times with the average speed-up of 8.34 times compared to the original Vina when tested on a set of 231 protein-ligand complexes while maintaining the optimal scores mostly identical. Using our heuristics, larger number of different ligands can be quickly screened against a given receptor within the same time frame.

Molecular modeling of fibronectin adsorption on topographically nanostructured rutile (110) surfaces

NASA Astrophysics Data System (ADS)

Guo, Chuangqiang; Wu, Chunya; Chen, Mingjun; Zheng, Ting; Chen, Ni; Cummings, Peter T.

2016-10-01

To investigate the topographical dependency of protein adsorption, molecular dynamics simulations were employed to describe the adsorption behavior of the tenth type-III module of fibronectin (FN-III10) on nanostructured rutile (110) surfaces. The results indicated that the residence time of adsorbed FN-III10 largely relied on its binding mode (direct or indirect) with the substrate and the region for protein migration on the periphery (protrusion) or in the interior (cavity or groove) of nanostructures. In the direct binding mode, FN-III10 molecules were found to be 'trapped' at the anchoring sites of rutile surface, or even penetrate deep into the interior of nanostructures, regardless of the presented geometrical features. In the indirect binding mode, FN-III10 molecules were indirectly connected to the substrate via a hydrogen-bond network (linking FN-III10 and interfacial hydrations). The facets created by nanostructures, which exerted restraints on protein migration, were suggested to play an important role in the stability of indirect FN-III10-rutile binding. However, a doubly unfavorable situation - indirect FN-III10-rutile connections bridged by a handful of mediating waters and few constraints on movement of protein provided by nanostructures - would result in an early desorption of protein.

Cooperative Adaptive Output Regulation for Second-Order Nonlinear Multiagent Systems With Jointly Connected Switching Networks.

PubMed

Liu, Wei; Huang, Jie

2018-03-01

This paper studies the cooperative global robust output regulation problem for a class of heterogeneous second-order nonlinear uncertain multiagent systems with jointly connected switching networks. The main contributions consist of the following three aspects. First, we generalize the result of the adaptive distributed observer from undirected jointly connected switching networks to directed jointly connected switching networks. Second, by performing a new coordinate and input transformation, we convert our problem into the cooperative global robust stabilization problem of a more complex augmented system via the distributed internal model principle. Third, we solve the stabilization problem by a distributed state feedback control law. Our result is illustrated by the leader-following consensus problem for a group of Van der Pol oscillators.

A small world of weak ties provides optimal global integration of self-similar modules in functional brain networks.

PubMed

Gallos, Lazaros K; Makse, Hernán A; Sigman, Mariano

2012-02-21

The human brain is organized in functional modules. Such an organization presents a basic conundrum: Modules ought to be sufficiently independent to guarantee functional specialization and sufficiently connected to bind multiple processors for efficient information transfer. It is commonly accepted that small-world architecture of short paths and large local clustering may solve this problem. However, there is intrinsic tension between shortcuts generating small worlds and the persistence of modularity, a global property unrelated to local clustering. Here, we present a possible solution to this puzzle. We first show that a modified percolation theory can define a set of hierarchically organized modules made of strong links in functional brain networks. These modules are "large-world" self-similar structures and, therefore, are far from being small-world. However, incorporating weaker ties to the network converts it into a small world preserving an underlying backbone of well-defined modules. Remarkably, weak ties are precisely organized as predicted by theory maximizing information transfer with minimal wiring cost. This trade-off architecture is reminiscent of the "strength of weak ties" crucial concept of social networks. Such a design suggests a natural solution to the paradox of efficient information flow in the highly modular structure of the brain.

A small world of weak ties provides optimal global integration of self-similar modules in functional brain networks

PubMed Central

Gallos, Lazaros K.; Makse, Hernán A.; Sigman, Mariano

2012-01-01

The human brain is organized in functional modules. Such an organization presents a basic conundrum: Modules ought to be sufficiently independent to guarantee functional specialization and sufficiently connected to bind multiple processors for efficient information transfer. It is commonly accepted that small-world architecture of short paths and large local clustering may solve this problem. However, there is intrinsic tension between shortcuts generating small worlds and the persistence of modularity, a global property unrelated to local clustering. Here, we present a possible solution to this puzzle. We first show that a modified percolation theory can define a set of hierarchically organized modules made of strong links in functional brain networks. These modules are “large-world” self-similar structures and, therefore, are far from being small-world. However, incorporating weaker ties to the network converts it into a small world preserving an underlying backbone of well-defined modules. Remarkably, weak ties are precisely organized as predicted by theory maximizing information transfer with minimal wiring cost. This trade-off architecture is reminiscent of the “strength of weak ties” crucial concept of social networks. Such a design suggests a natural solution to the paradox of efficient information flow in the highly modular structure of the brain. PMID:22308319

Network organization of the human autophagy system.

PubMed

Behrends, Christian; Sowa, Mathew E; Gygi, Steven P; Harper, J Wade

2010-07-01

Autophagy, the process by which proteins and organelles are sequestered in autophagosomal vesicles and delivered to the lysosome/vacuole for degradation, provides a primary route for turnover of stable and defective cellular proteins. Defects in this system are linked with numerous human diseases. Although conserved protein kinase, lipid kinase and ubiquitin-like protein conjugation subnetworks controlling autophagosome formation and cargo recruitment have been defined, our understanding of the global organization of this system is limited. Here we report a proteomic analysis of the autophagy interaction network in human cells under conditions of ongoing (basal) autophagy, revealing a network of 751 interactions among 409 candidate interacting proteins with extensive connectivity among subnetworks. Many new autophagy interaction network components have roles in vesicle trafficking, protein or lipid phosphorylation and protein ubiquitination, and affect autophagosome number or flux when depleted by RNA interference. The six ATG8 orthologues in humans (MAP1LC3/GABARAP proteins) interact with a cohort of 67 proteins, with extensive binding partner overlap between family members, and frequent involvement of a conserved surface on ATG8 proteins known to interact with LC3-interacting regions in partner proteins. These studies provide a global view of the mammalian autophagy interaction landscape and a resource for mechanistic analysis of this critical protein homeostasis pathway.

Chromatin-Specific Regulation of Mammalian rDNA Transcription by Clustered TTF-I Binding Sites

PubMed Central

Diermeier, Sarah D.; Németh, Attila; Rehli, Michael; Grummt, Ingrid; Längst, Gernot

2013-01-01

Enhancers and promoters often contain multiple binding sites for the same transcription factor, suggesting that homotypic clustering of binding sites may serve a role in transcription regulation. Here we show that clustering of binding sites for the transcription termination factor TTF-I downstream of the pre-rRNA coding region specifies transcription termination, increases the efficiency of transcription initiation and affects the three-dimensional structure of rRNA genes. On chromatin templates, but not on free rDNA, clustered binding sites promote cooperative binding of TTF-I, loading TTF-I to the downstream terminators before it binds to the rDNA promoter. Interaction of TTF-I with target sites upstream and downstream of the rDNA transcription unit connects these distal DNA elements by forming a chromatin loop between the rDNA promoter and the terminators. The results imply that clustered binding sites increase the binding affinity of transcription factors in chromatin, thus influencing the timing and strength of DNA-dependent processes. PMID:24068958

Functional hemispheric asymmetries of global/local processing mirrored by the steady-state visual evoked potential.

PubMed

Martens, Ulla; Hübner, Ronald

2013-03-01

While hemispheric differences in global/local processing have been reported by various studies, it is still under dispute at which processing stage they occur. Primarily, it was assumed that these asymmetries originate from an early perceptual stage. Instead, the content-level binding theory (Hübner & Volberg, 2005) suggests that the hemispheres differ at a later stage at which the stimulus information is bound to its respective level. The present study tested this assumption by means of steady-state evoked potentials (SSVEPs). In particular, we presented hierarchical letters flickering at 12Hz while participants categorised the letters at a pre- cued level (global or local). The information at the two levels could be congruent or incongruent with respect to the required response. Since content-binding is only necessary if there is a response conflict, asymmetric hemispheric processing should be observed only for incongruent stimuli. Indeed, our results show that the cue and congruent stimuli elicited equal SSVEP global/local effects in both hemispheres. In contrast, incongruent stimuli elicited lower SSVEP amplitudes for a local than for a global target level at left posterior electrodes, whereas a reversed pattern was seen at right hemispheric electrodes. These findings provide further evidence for a level-specific hemispheric advantage with respect to content-level binding. Moreover, the fact that the SSVEP is sensitive to these processes offers the possibility to separately track global and local processing by presenting both level contents with different frequencies. Copyright © 2012 Elsevier Inc. All rights reserved.

The storage capacity of Potts models for semantic memory retrieval

NASA Astrophysics Data System (ADS)

Kropff, Emilio; Treves, Alessandro

2005-08-01

We introduce and analyse a minimal network model of semantic memory in the human brain. The model is a global associative memory structured as a collection of N local modules, each coding a feature, which can take S possible values, with a global sparseness a (the average fraction of features describing a concept). We show that, under optimal conditions, the number cM of modules connected on average to a module can range widely between very sparse connectivity (high dilution, c_{M}/N\\to 0 ) and full connectivity (c_{M}\\to N ), maintaining a global network storage capacity (the maximum number pc of stored and retrievable concepts) that scales like pc~cMS2/a, with logarithmic corrections consistent with the constraint that each synapse may store up to a fraction of a bit.

Nonequilibrium landscape theory of neural networks.

PubMed

Yan, Han; Zhao, Lei; Hu, Liang; Wang, Xidi; Wang, Erkang; Wang, Jin

2013-11-05

The brain map project aims to map out the neuron connections of the human brain. Even with all of the wirings mapped out, the global and physical understandings of the function and behavior are still challenging. Hopfield quantified the learning and memory process of symmetrically connected neural networks globally through equilibrium energy. The energy basins of attractions represent memories, and the memory retrieval dynamics is determined by the energy gradient. However, the realistic neural networks are asymmetrically connected, and oscillations cannot emerge from symmetric neural networks. Here, we developed a nonequilibrium landscape-flux theory for realistic asymmetrically connected neural networks. We uncovered the underlying potential landscape and the associated Lyapunov function for quantifying the global stability and function. We found the dynamics and oscillations in human brains responsible for cognitive processes and physiological rhythm regulations are determined not only by the landscape gradient but also by the flux. We found that the flux is closely related to the degrees of the asymmetric connections in neural networks and is the origin of the neural oscillations. The neural oscillation landscape shows a closed-ring attractor topology. The landscape gradient attracts the network down to the ring. The flux is responsible for coherent oscillations on the ring. We suggest the flux may provide the driving force for associations among memories. We applied our theory to rapid-eye movement sleep cycle. We identified the key regulation factors for function through global sensitivity analysis of landscape topography against wirings, which are in good agreements with experiments.

Nonequilibrium landscape theory of neural networks

PubMed Central

Yan, Han; Zhao, Lei; Hu, Liang; Wang, Xidi; Wang, Erkang; Wang, Jin

2013-01-01

The brain map project aims to map out the neuron connections of the human brain. Even with all of the wirings mapped out, the global and physical understandings of the function and behavior are still challenging. Hopfield quantified the learning and memory process of symmetrically connected neural networks globally through equilibrium energy. The energy basins of attractions represent memories, and the memory retrieval dynamics is determined by the energy gradient. However, the realistic neural networks are asymmetrically connected, and oscillations cannot emerge from symmetric neural networks. Here, we developed a nonequilibrium landscape–flux theory for realistic asymmetrically connected neural networks. We uncovered the underlying potential landscape and the associated Lyapunov function for quantifying the global stability and function. We found the dynamics and oscillations in human brains responsible for cognitive processes and physiological rhythm regulations are determined not only by the landscape gradient but also by the flux. We found that the flux is closely related to the degrees of the asymmetric connections in neural networks and is the origin of the neural oscillations. The neural oscillation landscape shows a closed-ring attractor topology. The landscape gradient attracts the network down to the ring. The flux is responsible for coherent oscillations on the ring. We suggest the flux may provide the driving force for associations among memories. We applied our theory to rapid-eye movement sleep cycle. We identified the key regulation factors for function through global sensitivity analysis of landscape topography against wirings, which are in good agreements with experiments. PMID:24145451

Fungal-type carbohydrate binding modules from the coccolithophore Emiliania huxleyi show binding affinity to cellulose and chitin

PubMed Central

Rooijakkers, Bart J. M.

2018-01-01

Six fungal-type cellulose binding domains were found in the genome of the coccolithophore Emiliania huxleyi and cloned and expressed in Escherichia coli. Sequence comparison indicate high similarity to fungal cellulose binding domains, raising the question of why these domains exist in coccolithophores. The proteins were tested for binding with cellulose and chitin as ligands, which resulted in the identification of two functional carbohydrate binding modules: EHUX2 and EHUX4. Compared to benchmark fungal cellulose binding domain Cel7A-CBM1 from Trichoderma reesei, these proteins showed slightly lower binding to birch and bacterial cellulose, but were more efficient chitin binders. Finally, a set of cellulose binding domains was created based on the shuffling of one well-functioning and one non-functional domain. These were characterized in order to get more information of the binding domain’s sequence–function relationship, indicating characteristic differences between the molecular basis of cellulose versus chitin recognition. As previous reports have showed the presence of cellulose in coccoliths and here we find functional cellulose binding modules, a possible connection is discussed. PMID:29782536

Fungal-type carbohydrate binding modules from the coccolithophore Emiliania huxleyi show binding affinity to cellulose and chitin.

PubMed

Rooijakkers, Bart J M; Ikonen, Martina S; Linder, Markus B

2018-01-01

Six fungal-type cellulose binding domains were found in the genome of the coccolithophore Emiliania huxleyi and cloned and expressed in Escherichia coli. Sequence comparison indicate high similarity to fungal cellulose binding domains, raising the question of why these domains exist in coccolithophores. The proteins were tested for binding with cellulose and chitin as ligands, which resulted in the identification of two functional carbohydrate binding modules: EHUX2 and EHUX4. Compared to benchmark fungal cellulose binding domain Cel7A-CBM1 from Trichoderma reesei, these proteins showed slightly lower binding to birch and bacterial cellulose, but were more efficient chitin binders. Finally, a set of cellulose binding domains was created based on the shuffling of one well-functioning and one non-functional domain. These were characterized in order to get more information of the binding domain's sequence-function relationship, indicating characteristic differences between the molecular basis of cellulose versus chitin recognition. As previous reports have showed the presence of cellulose in coccoliths and here we find functional cellulose binding modules, a possible connection is discussed.

Copper and the Prion Protein: Methods, Structures, Function, and Disease

NASA Astrophysics Data System (ADS)

Millhauser, Glenn L.

2007-05-01

The transmissible spongiform encephalopathies (TSEs) arise from conversion of the membrane-bound prion protein from PrPC to PrPSc. Examples of the TSEs include mad cow disease, chronic wasting disease in deer and elk, scrapie in goats and sheep, and kuru and Creutzfeldt-Jakob disease in humans. Although the precise function of PrPC in healthy tissues is not known, recent research demonstrates that it binds Cu(II) in an unusual and highly conserved region of the protein termed the octarepeat domain. This review describes recent connections between copper and PrPC, with an emphasis on the electron paramagnetic resonance elucidation of the specific copper-binding sites, insights into PrPC function, and emerging connections between copper and prion disease.

Improvement of Aptamer Affinity by Dimerization

PubMed Central

Hasegawa, Hijiri; Taira, Ken-ichi; Sode, Koji; Ikebukuro, Kazunori

2008-01-01

To increase the affinities of aptamers for their targets, we designed an aptamer dimer for thrombin and VEGF. This design is based on the avidity of the antibody, which enables the aptamer to connect easily since it is a single-strand nucleic acid. In this study, we connected a 15-mer thrombin-binding aptamer with a 29-mer thrombin-binding aptamer. Each aptamer recognizes a different part of the thrombin molecule, and the aptamer dimer has a Kd value which is 1/10 of that of the monomers from which it is composed. Also, the designed aptamer dimer has higher inhibitory activity than the reported (15-mer) thrombin-inhibiting aptamer. Additionally, we connected together two identical aptamers against vascular endothelial growth factor (VEGF165), which is a homodimeric protein. As in the case of the anti-thrombin aptamer, the dimeric anti-VEGF aptamer had a much lower Kd value than that of the monomer. This study demonstrated that the dimerization of aptamers effectively improves the affinities of those aptamers for their targets. PMID:27879754

Multiple conserved cell adhesion protein interactions mediate neural wiring of a sensory circuit in C. elegans.

PubMed

Kim, Byunghyuk; Emmons, Scott W

2017-09-13

Nervous system function relies on precise synaptic connections. A number of widely-conserved cell adhesion proteins are implicated in cell recognition between synaptic partners, but how these proteins act as a group to specify a complex neural network is poorly understood. Taking advantage of known connectivity in C. elegans , we identified and studied cell adhesion genes expressed in three interacting neurons in the mating circuits of the adult male. Two interacting pairs of cell surface proteins independently promote fasciculation between sensory neuron HOA and its postsynaptic target interneuron AVG: BAM-2/neurexin-related in HOA binds to CASY-1/calsyntenin in AVG; SAX-7/L1CAM in sensory neuron PHC binds to RIG-6/contactin in AVG. A third, basal pathway results in considerable HOA-AVG fasciculation and synapse formation in the absence of the other two. The features of this multiplexed mechanism help to explain how complex connectivity is encoded and robustly established during nervous system development.

Analyzing the association between functional connectivity of the brain and intellectual performance

PubMed Central

Pamplona, Gustavo S. P.; Santos Neto, Gérson S.; Rosset, Sara R. E.; Rogers, Baxter P.; Salmon, Carlos E. G.

2015-01-01

Measurements of functional connectivity support the hypothesis that the brain is composed of distinct networks with anatomically separated nodes but common functionality. A few studies have suggested that intellectual performance may be associated with greater functional connectivity in the fronto-parietal network and enhanced global efficiency. In this fMRI study, we performed an exploratory analysis of the relationship between the brain's functional connectivity and intelligence scores derived from the Portuguese language version of the Wechsler Adult Intelligence Scale (WAIS-III) in a sample of 29 people, born and raised in Brazil. We examined functional connectivity between 82 regions, including graph theoretic properties of the overall network. Some previous findings were extended to the Portuguese-speaking population, specifically the presence of small-world organization of the brain and relationships of intelligence with connectivity of frontal, pre-central, parietal, occipital, fusiform and supramarginal gyrus, and caudate nucleus. Verbal comprehension was associated with global network efficiency, a new finding. PMID:25713528

Brain functional network connectivity based on a visual task: visual information processing-related brain regions are significantly activated in the task state.

PubMed

Yang, Yan-Li; Deng, Hong-Xia; Xing, Gui-Yang; Xia, Xiao-Luan; Li, Hai-Fang

2015-02-01

It is not clear whether the method used in functional brain-network related research can be applied to explore the feature binding mechanism of visual perception. In this study, we investigated feature binding of color and shape in visual perception. Functional magnetic resonance imaging data were collected from 38 healthy volunteers at rest and while performing a visual perception task to construct brain networks active during resting and task states. Results showed that brain regions involved in visual information processing were obviously activated during the task. The components were partitioned using a greedy algorithm, indicating the visual network existed during the resting state. Z-values in the vision-related brain regions were calculated, confirming the dynamic balance of the brain network. Connectivity between brain regions was determined, and the result showed that occipital and lingual gyri were stable brain regions in the visual system network, the parietal lobe played a very important role in the binding process of color features and shape features, and the fusiform and inferior temporal gyri were crucial for processing color and shape information. Experimental findings indicate that understanding visual feature binding and cognitive processes will help establish computational models of vision, improve image recognition technology, and provide a new theoretical mechanism for feature binding in visual perception.

Christian Commitment and Personal Well Being: Exploring the Connection between Religious Affect and Global Happiness among Young Churchgoers in Australia

ERIC Educational Resources Information Center

Francis, Leslie J.; Penny, Gemma

2016-01-01

Drawing on data from the 2011 Australian National Church Life Survey, this study was designed to assess the connection between religious affect (as a measure of Christian commitment) and global happiness (as a measure of personal well being) among a sample of 6,194 young churchgoers in Australia between the ages of 8 and 14 years, attending a…

Synchronization Experiments With A Global Coupled Model of Intermediate Complexity

NASA Astrophysics Data System (ADS)

Selten, Frank; Hiemstra, Paul; Shen, Mao-Lin

2013-04-01

In the super modeling approach an ensemble of imperfect models are connected through nudging terms that nudge the solution of each model to the solution of all other models in the ensemble. The goal is to obtain a synchronized state through a proper choice of connection strengths that closely tracks the trajectory of the true system. For the super modeling approach to be successful, the connections should be dense and strong enough for synchronization to occur. In this study we analyze the behavior of an ensemble of connected global atmosphere-ocean models of intermediate complexity. All atmosphere models are connected to the same ocean model through the surface fluxes of heat, water and momentum, the ocean is integrated using weighted averaged surface fluxes. In particular we analyze the degree of synchronization between the atmosphere models and the characteristics of the ensemble mean solution. The results are interpreted using a low order atmosphere-ocean toy model.

Progression of Brain Network Alterations in Cerebral Amyloid Angiopathy.

PubMed

Reijmer, Yael D; Fotiadis, Panagiotis; Riley, Grace A; Xiong, Li; Charidimou, Andreas; Boulouis, Gregoire; Ayres, Alison M; Schwab, Kristin; Rosand, Jonathan; Gurol, M Edip; Viswanathan, Anand; Greenberg, Steven M

2016-10-01

We recently showed that cerebral amyloid angiopathy (CAA) is associated with functionally relevant brain network impairments, in particular affecting posterior white matter connections. Here we examined how these brain network impairments progress over time. Thirty-three patients with probable CAA underwent multimodal brain magnetic resonance imaging at 2 time points (mean follow-up time: 1.3±0.4 years). Brain networks of the hemisphere free of intracerebral hemorrhages were reconstructed using fiber tractography and graph theory. The global efficiency of the network and mean fractional anisotropies of posterior-posterior, frontal-frontal, and posterior-frontal network connections were calculated. Patients with moderate versus severe CAA were defined based on microbleed count, dichotomized at the median (median=35). Global efficiency of the intracerebral hemorrhage-free hemispheric network declined from baseline to follow-up (-0.008±0.003; P=0.029). The decline in global efficiency was most pronounced for patients with severe CAA (group×time interaction P=0.03). The decline in global network efficiency was associated with worse executive functioning (β=0.46; P=0.03). Examination of subgroups of network connections revealed a decline in fractional anisotropies of posterior-posterior connections at both levels of CAA severity (-0.006±0.002; P=0.017; group×time interaction P=0.16). The fractional anisotropies of posterior-frontal and frontal-frontal connections declined in patients with severe but not moderate CAA (group×time interaction P=0.007 and P=0.005). Associations were independent of change in white matter hyperintensity volume. Brain network impairment in patients with CAA worsens measurably over just 1.3-year follow-up and seem to progress from posterior to frontal connections with increasing disease severity. © 2016 American Heart Association, Inc.

Teacher Research: Limits and Possibilities of Global and International Connections.

ERIC Educational Resources Information Center

Diniz-Pereira, Julio Emilio

This paper suggests that teacher research, as an international movement, has the potential to become a counter-hegemonic strategy to construct critical teacher education approaches in a globalized world. It begins by describing globalization and discussing the distinction between hegemonic and counter-hegemonic globalization, or between…

Toward a Global Sociology of Religion

ERIC Educational Resources Information Center

Parvez, Z. Fareen

2017-01-01

This article offers an example of a global approach to teaching the sociology of religion, a course that typically focuses on American religious phenomena. It builds on three interventions in the movement for a global sociology: connecting the local and global, moving beyond methodological nationalism, and developing an ethical orientation toward…

Website Policies / Important Links | DOepatents

Science.gov Websites

Global to push GA events into Global to push GA events into skip to main content PATENTS Toggle Science Resources: SciTech Connect DOE PAGES More DOE Collections » U.S. / Global Science Resources

The Bacterial Response Regulator ArcA Uses a Diverse Binding Site Architecture to Regulate Carbon Oxidation Globally

PubMed Central

Park, Dan M.; Akhtar, Md. Sohail; Ansari, Aseem Z.; Landick, Robert; Kiley, Patricia J.

2013-01-01

Despite the importance of maintaining redox homeostasis for cellular viability, how cells control redox balance globally is poorly understood. Here we provide new mechanistic insight into how the balance between reduced and oxidized electron carriers is regulated at the level of gene expression by mapping the regulon of the response regulator ArcA from Escherichia coli, which responds to the quinone/quinol redox couple via its membrane-bound sensor kinase, ArcB. Our genome-wide analysis reveals that ArcA reprograms metabolism under anaerobic conditions such that carbon oxidation pathways that recycle redox carriers via respiration are transcriptionally repressed by ArcA. We propose that this strategy favors use of catabolic pathways that recycle redox carriers via fermentation akin to lactate production in mammalian cells. Unexpectedly, bioinformatic analysis of the sequences bound by ArcA in ChIP-seq revealed that most ArcA binding sites contain additional direct repeat elements beyond the two required for binding an ArcA dimer. DNase I footprinting assays suggest that non-canonical arrangements of cis-regulatory modules dictate both the length and concentration-sensitive occupancy of DNA sites. We propose that this plasticity in ArcA binding site architecture provides both an efficient means of encoding binding sites for ArcA, σ70-RNAP and perhaps other transcription factors within the same narrow sequence space and an effective mechanism for global control of carbon metabolism to maintain redox homeostasis. PMID:24146625

Genomewide Analysis of Aryl Hydrocarbon Receptor Binding Targets Reveals an Extensive Array of Gene Clusters that Control Morphogenetic and Developmental Programs

PubMed Central

Sartor, Maureen A.; Schnekenburger, Michael; Marlowe, Jennifer L.; Reichard, John F.; Wang, Ying; Fan, Yunxia; Ma, Ci; Karyala, Saikumar; Halbleib, Danielle; Liu, Xiangdong; Medvedovic, Mario; Puga, Alvaro

2009-01-01

Background The vertebrate aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that regulates cellular responses to environmental polycyclic and halogenated compounds. The naive receptor is believed to reside in an inactive cytosolic complex that translocates to the nucleus and induces transcription of xenobiotic detoxification genes after activation by ligand. Objectives We conducted an integrative genomewide analysis of AHR gene targets in mouse hepatoma cells and determined whether AHR regulatory functions may take place in the absence of an exogenous ligand. Methods The network of AHR-binding targets in the mouse genome was mapped through a multipronged approach involving chromatin immunoprecipitation/chip and global gene expression signatures. The findings were integrated into a prior functional knowledge base from Gene Ontology, interaction networks, Kyoto Encyclopedia of Genes and Genomes pathways, sequence motif analysis, and literature molecular concepts. Results We found the naive receptor in unstimulated cells bound to an extensive array of gene clusters with functions in regulation of gene expression, differentiation, and pattern specification, connecting multiple morphogenetic and developmental programs. Activation by the ligand displaced the receptor from some of these targets toward sites in the promoters of xenobiotic metabolism genes. Conclusions The vertebrate AHR appears to possess unsuspected regulatory functions that may be potential targets of environmental injury. PMID:19654925

STOREKEEPER RELATED1/G-Element Binding Protein (STKR1) Interacts with Protein Kinase SnRK1.

PubMed

Nietzsche, Madlen; Guerra, Tiziana; Alseekh, Saleh; Wiermer, Marcel; Sonnewald, Sophia; Fernie, Alisdair R; Börnke, Frederik

2018-02-01

Sucrose nonfermenting related kinase1 (SnRK1) is a conserved energy sensor kinase that regulates cellular adaptation to energy deficit in plants. Activation of SnRK1 leads to the down-regulation of ATP-consuming biosynthetic processes and the stimulation of energy-generating catabolic reactions by transcriptional reprogramming and posttranslational modifications. Although considerable progress has been made during the last years in understanding the SnRK1 signaling pathway, many of its components remain unidentified. Here, we show that the catalytic α-subunits KIN10 and KIN11 of the Arabidopsis ( Arabidopsis thaliana ) SnRK1 complex interact with the STOREKEEPER RELATED1/G-Element Binding Protein (STKR1) inside the plant cell nucleus. Overexpression of STKR1 in transgenic Arabidopsis plants led to reduced growth, a delay in flowering, and strongly attenuated senescence. Metabolite profiling revealed that the transgenic lines exhausted their carbohydrates during the dark period to a greater extent than the wild type and accumulated a range of amino acids. At the global transcriptome level, genes affected by STKR1 overexpression were broadly associated with systemic acquired resistance, and transgenic plants showed enhanced resistance toward a virulent strain of the biotrophic oomycete pathogen Hyaloperonospora arabidopsidis Noco2. We discuss a possible connection of STKR1 function, SnRK1 signaling, and plant immunity. © 2018 American Society of Plant Biologists. All Rights Reserved.

Identification of a two-component fatty acid kinase responsible for host fatty acid incorporation by Staphylococcus aureus

PubMed Central

Parsons, Joshua B.; Broussard, Tyler C.; Bose, Jeffrey L.; Rosch, Jason W.; Jackson, Pamela; Subramanian, Chitra; Rock, Charles O.

2014-01-01

Extracellular fatty acid incorporation into the phospholipids of Staphylococcus aureus occurs via fatty acid phosphorylation. We show that fatty acid kinase (Fak) is composed of two dissociable protein subunits encoded by separate genes. FakA provides the ATP binding domain and interacts with two distinct FakB proteins to produce acyl-phosphate. The FakBs are fatty acid binding proteins that exchange bound fatty acid/acyl-phosphate with fatty acid/acyl-phosphate presented in detergent micelles or liposomes. The ΔfakA and ΔfakB1 ΔfakB2 strains were unable to incorporate extracellular fatty acids into phospholipid. FakB1 selectively bound saturated fatty acids whereas FakB2 preferred unsaturated fatty acids. Affymetrix array showed a global perturbation in the expression of virulence genes in the ΔfakA strain. The severe deficiency in α-hemolysin protein secretion in ΔfakA and ΔfakB1 ΔfakB2 mutants coupled with quantitative mRNA measurements showed that fatty acid kinase activity was required to support virulence factor transcription. These data reveal the function of two conserved gene families, their essential role in the incorporation of host fatty acids by Gram-positive pathogens, and connects fatty acid kinase to the regulation of virulence factor transcription in S. aureus. PMID:25002480

STOREKEEPER RELATED1/G-Element Binding Protein (STKR1) Interacts with Protein Kinase SnRK11[OPEN

PubMed Central

Nietzsche, Madlen; Guerra, Tiziana; Fernie, Alisdair R.

2018-01-01

Sucrose nonfermenting related kinase1 (SnRK1) is a conserved energy sensor kinase that regulates cellular adaptation to energy deficit in plants. Activation of SnRK1 leads to the down-regulation of ATP-consuming biosynthetic processes and the stimulation of energy-generating catabolic reactions by transcriptional reprogramming and posttranslational modifications. Although considerable progress has been made during the last years in understanding the SnRK1 signaling pathway, many of its components remain unidentified. Here, we show that the catalytic α-subunits KIN10 and KIN11 of the Arabidopsis (Arabidopsis thaliana) SnRK1 complex interact with the STOREKEEPER RELATED1/G-Element Binding Protein (STKR1) inside the plant cell nucleus. Overexpression of STKR1 in transgenic Arabidopsis plants led to reduced growth, a delay in flowering, and strongly attenuated senescence. Metabolite profiling revealed that the transgenic lines exhausted their carbohydrates during the dark period to a greater extent than the wild type and accumulated a range of amino acids. At the global transcriptome level, genes affected by STKR1 overexpression were broadly associated with systemic acquired resistance, and transgenic plants showed enhanced resistance toward a virulent strain of the biotrophic oomycete pathogen Hyaloperonospora arabidopsidis Noco2. We discuss a possible connection of STKR1 function, SnRK1 signaling, and plant immunity. PMID:29192025

On the connection between inherent DNA flexure and preferred binding of hydroxymethyluracil-containing DNA by the type II DNA-binding protein TF1.

PubMed

Grove, A; Galeone, A; Mayol, L; Geiduschek, E P

1996-07-12

TF1 is a member of the family of type II DNA-binding proteins, which also includes the bacterial HU proteins and the Escherichia coli integration host factor (IHF). Distinctive to TF1, which is encoded by the Bacillus subtilis bacteriophage SPO1, is its preferential binding to DNA in which thymine is replaced by 5-hydroxymethyluracil (hmU), as it is in the phage genome. TF1 binds to preferred sites within the phage genome and generates pronounced DNA bending. The extent to which DNA flexibility contributes to the sequence-specific binding of TF1, and the connection between hmU preference and DNA flexibility has been examined. Model flexible sites, consisting of consecutive mismatches, increase the affinity of thymine-containing DNA for TF1. In particular, tandem mismatches separated by nine base-pairs generate an increase, by orders of magnitude, in the affinity of TF1 for T-containing DNA with the sequence of a preferred TF1 binding site, and fully match the affinity of TF1 for this cognate site in hmU-containing DNA (Kd approximately 3 nM). Other placements of loops generate suboptimal binding. This is consistent with a significant contribution of site-specific DNA flexibility to complex formation. Analysis of complexes with hmU-DNA of decreasing length shows that a major part of the binding affinity is generated within a central 19 bp segment (delta G0 = 41.7 kJ mol-1) with more-distal DNA contributing modestly to the affinity (delta delta G = -0.42 kJ mol-1 bp-1 on increasing duplex length to 37 bp). However, a previously characterised thermostable and more tightly binding mutant TF1, TF1(E15G/T32I), derives most of its extra affinity from interaction with flanking DNA. We propose that inherent but sequence-dependent deformability of hmU-containing DNA underlies the preferential binding of TF1 and that TF1-induced DNA bendings is a result of distortions at two distinct sites separated by 9 bp of duplex DNA.

Individual differences in the dominance of interhemispheric connections predict cognitive ability beyond sex and brain size.

PubMed

Martínez, Kenia; Janssen, Joost; Pineda-Pardo, José Ángel; Carmona, Susanna; Román, Francisco Javier; Alemán-Gómez, Yasser; Garcia-Garcia, David; Escorial, Sergio; Quiroga, María Ángeles; Santarnecchi, Emiliano; Navas-Sánchez, Francisco Javier; Desco, Manuel; Arango, Celso; Colom, Roberto

2017-07-15

Global structural brain connectivity has been reported to be sex-dependent with women having increased interhemispheric connectivity (InterHc) and men having greater intrahemispheric connectivity (IntraHc). However, (a) smaller brains show greater InterHc, (b) larger brains show greater IntraHc, and (c) women have, on average, smaller brains than men. Therefore, sex differences in brain size may modulate sex differences in global brain connectivity. At the behavioural level, sex-dependent differences in connectivity are thought to contribute to men-women differences in spatial and verbal abilities. But this has never been tested at the individual level. The current study assessed whether individual differences in global structural connectome measures (InterHc, IntraHc and the ratio of InterHc relative to IntraHc) predict spatial and verbal ability while accounting for the effect of sex and brain size. The sample included forty men and forty women, who did neither differ in age nor in verbal and spatial latent components defined by a broad battery of tests and tasks. High-resolution T 1 -weighted and diffusion-weighted images were obtained for computing brain size and reconstructing the structural connectome. Results showed that men had higher IntraHc than women, while women had an increased ratio InterHc/IntraHc. However, these sex differences were modulated by brain size. Increased InterHc relative to IntraHc predicted higher spatial and verbal ability irrespective of sex and brain size. The positive correlations between the ratio InterHc/IntraHc and the spatial and verbal abilities were confirmed in 1000 random samples generated by bootstrapping. Therefore, sex differences in global structural connectome connectivity were modulated by brain size and did not underlie sex differences in verbal and spatial abilities. Rather, the level of dominance of InterHc over IntraHc may be associated with individual differences in verbal and spatial abilities in both men and women. Copyright © 2017 Elsevier Inc. All rights reserved.

Global Governance Mechanisms to Address Antimicrobial Resistance.

PubMed

Padiyara, Ponnu; Inoue, Hajime; Sprenger, Marc

2018-01-01

Since their discovery, antibiotics, and more broadly, antimicrobials, have been a cornerstone of modern medicine. But the overuse and misuse of these drugs have led to rising rates of antimicrobial resistance, which occurs when bacteria adapt in ways that render antibiotics ineffective. A world without effective antibiotics can have drastic impacts on population health, global development, and the global economy. As a global common good, antibiotic effectiveness is vulnerable to the tragedy of the commons, where a shared limited resource is overused by a community when each individual exploits the finite resource for their own benefit. A borderless threat like antimicrobial resistance requires global governance mechanisms to mitigate its emergence and spread, and it is the responsibility of all countries and relevant multilateral organizations. These mechanisms can be in the form of legally binding global governance mechanisms such as treaties and regulatory standards or nonbinding mechanisms such as political declarations, resolutions, or guidelines. In this article, we argue that while both are effective methods, the strong, swift, and coordinated action needed to address rising rates of antimicrobial resistance will be better served through legally binding governance mechanisms.

Responses to climate change in hot desert ecosystems: connecting local to global scales

USDA-ARS?s Scientific Manuscript database

The consequences of connectivity in resources, propagules, and information to the interplay between drivers and responses across scales can result in ecological dynamics that are not easily predicted based on local drivers. Three major classes of connectivity events link local ecological dynamics wi...

Allosteric response and substrate sensitivity in peptide binding of the signal recognition particle.

PubMed

Wang, Connie Y; Miller, Thomas F

2014-10-31

We characterize the conformational dynamics and substrate selectivity of the signal recognition particle (SRP) using a thermodynamic free energy cycle approach and microsecond timescale molecular dynamics simulations. The SRP is a central component of the co-translational protein targeting machinery that binds to the N-terminal signal peptide (SP) of nascent proteins. We determined the shift in relative conformational stability of the SRP upon substrate binding to quantify allosteric coupling between SRP domains. In particular, for dipeptidyl aminopeptidase, an SP that is recognized by the SRP for co-translational targeting, it is found that substrate binding induces substantial changes in the SRP toward configurations associated with targeting of the nascent protein, and it is found that the changes are modestly enhanced by a mutation that increases the hydrophobicity of the SP. However, for alkaline phosphatase, an SP that is recognized for post-translational targeting, substrate binding induces the reverse change in the SRP conformational distribution away from targeting configurations. Microsecond timescale trajectories reveal the intrinsic flexibility of the SRP conformational landscape and provide insight into recent single molecule studies by illustrating that 10-nm lengthscale changes between FRET pairs occur via the rigid-body movement of SRP domains connected by the flexible linker region. In combination, these results provide direct evidence for the hypothesis that substrate-controlled conformational switching in the SRP provides a mechanism for discriminating between different SPs and for connecting substrate binding to downstream steps in the protein targeting pathway. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

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

PubMed

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.

Sex Hormones Modulate the Relationship Between Global Advantage, Lateralization, and Interhemispheric Connectivity in a Navon Paradigm

PubMed Central

Harris, TiAnni

2018-01-01

Abstract Sex, stimulus material, and attention condition have previously been related to global advantage (GA; faster responses to global targets than to local targets) on the one hand and lateralization during global–local processing on the other hand. It is presumed that the lateralization of brain functions is either related to the inhibitory influence of the dominant on the nondominant hemisphere or reduced excitation between hemispheres. However, a direct relationship between the GA and lateralization and interhemispheric connectivity has not been previously established. In this study, 58 participants (29 men, 29 naturally cycling women) completed a Navon paradigm, modulating attention condition (divided vs. focused) and stimulus material (letters vs. shapes) during functional magnetic resonance imaging. The size of the GA effect, lateralization indices, interhemispheric connectivity, and sex hormone levels were assessed. In summary, this study suggests that interhemispheric connectivity during global–local processing is affected by sex and material. Furthermore, the relationship between interhemispheric connectivity, lateralization, and behavior was modulated by sex and sex hormones. Results suggest (1) differential roles of interhemispheric connectivity for lateralization in men and women and (2) differential roles of lateralization for behavior in men and women. Importantly, the classic assumption that a more negative connectivity leads to stronger lateralization, which in turn leads to a stronger GA effect, was observed in men, whereas the opposite pattern was found in women. The relationship between connectivity and lateralization was mediated through testosterone levels, whereas the relationship between lateralization and behavior was mediated through progesterone levels. Results are discussed in light of differential functions of inhibitory and excitatory interhemispheric processes in men and women. PMID:29226703

Information processing architecture of functionally defined clusters in the macaque cortex.

PubMed

Shen, Kelly; Bezgin, Gleb; Hutchison, R Matthew; Gati, Joseph S; Menon, Ravi S; Everling, Stefan; McIntosh, Anthony R

2012-11-28

Computational and empirical neuroimaging studies have suggested that the anatomical connections between brain regions primarily constrain their functional interactions. Given that the large-scale organization of functional networks is determined by the temporal relationships between brain regions, the structural limitations may extend to the global characteristics of functional networks. Here, we explored the extent to which the functional network community structure is determined by the underlying anatomical architecture. We directly compared macaque (Macaca fascicularis) functional connectivity (FC) assessed using spontaneous blood oxygen level-dependent functional magnetic resonance imaging (BOLD-fMRI) to directed anatomical connectivity derived from macaque axonal tract tracing studies. Consistent with previous reports, FC increased with increasing strength of anatomical connection, and FC was also present between regions that had no direct anatomical connection. We observed moderate similarity between the FC of each region and its anatomical connectivity. Notably, anatomical connectivity patterns, as described by structural motifs, were different within and across functional modules: partitioning of the functional network was supported by dense bidirectional anatomical connections within clusters and unidirectional connections between clusters. Together, our data directly demonstrate that the FC patterns observed in resting-state BOLD-fMRI are dictated by the underlying neuroanatomical architecture. Importantly, we show how this architecture contributes to the global organizational principles of both functional specialization and integration.

Detecting Local Ligand-Binding Site Similarity in Non-Homologous Proteins by Surface Patch Comparison

PubMed Central

Sael, Lee; Kihara, Daisuke

2012-01-01

Functional elucidation of proteins is one of the essential tasks in biology. Function of a protein, specifically, small ligand molecules that bind to a protein, can be predicted by finding similar local surface regions in binding sites of known proteins. Here, we developed an alignment free local surface comparison method for predicting a ligand molecule which binds to a query protein. The algorithm, named Patch-Surfer, represents a binding pocket as a combination of segmented surface patches, each of which is characterized by its geometrical shape, the electrostatic potential, the hydrophobicity, and the concaveness. Representing a pocket by a set of patches is effective to absorb difference of global pocket shape while capturing local similarity of pockets. The shape and the physicochemical properties of surface patches are represented using the 3D Zernike descriptor, which is a series expansion of mathematical 3D function. Two pockets are compared using a modified weighted bipartite matching algorithm, which matches similar patches from the two pockets. Patch-Surfer was benchmarked on three datasets, which consist in total of 390 proteins that bind to one of 21 ligands. Patch-Surfer showed superior performance to existing methods including a global pocket comparison method, Pocket-Surfer, which we have previously introduced. Particularly, as intended, the accuracy showed large improvement for flexible ligand molecules, which bind to pockets in different conformations. PMID:22275074

Detecting local ligand-binding site similarity in nonhomologous proteins by surface patch comparison.

PubMed

Sael, Lee; Kihara, Daisuke

2012-04-01

Functional elucidation of proteins is one of the essential tasks in biology. Function of a protein, specifically, small ligand molecules that bind to a protein, can be predicted by finding similar local surface regions in binding sites of known proteins. Here, we developed an alignment free local surface comparison method for predicting a ligand molecule which binds to a query protein. The algorithm, named Patch-Surfer, represents a binding pocket as a combination of segmented surface patches, each of which is characterized by its geometrical shape, the electrostatic potential, the hydrophobicity, and the concaveness. Representing a pocket by a set of patches is effective to absorb difference of global pocket shape while capturing local similarity of pockets. The shape and the physicochemical properties of surface patches are represented using the 3D Zernike descriptor, which is a series expansion of mathematical 3D function. Two pockets are compared using a modified weighted bipartite matching algorithm, which matches similar patches from the two pockets. Patch-Surfer was benchmarked on three datasets, which consist in total of 390 proteins that bind to one of 21 ligands. Patch-Surfer showed superior performance to existing methods including a global pocket comparison method, Pocket-Surfer, which we have previously introduced. Particularly, as intended, the accuracy showed large improvement for flexible ligand molecules, which bind to pockets in different conformations. Copyright © 2011 Wiley Periodicals, Inc.

Bringing the Global Home: Students Research Local Areas through Postcolonial Perspectives

ERIC Educational Resources Information Center

Hammer, Ricarda

2018-01-01

This article describes a class that draws on postcolonial insights to create a global sociological imagination. Postcolonial approaches can make visible how global connections have shaped our local environments even if these relations are not always immediately visible. Specifically, students in this class highlight how global relations, such as…

Local/Global Cognitive Interfaces within Industrial Districts: An Italian Case Study

ERIC Educational Resources Information Center

Grandinetti, Roberto

2011-01-01

Purpose: With the advance of globalization the competitive chances of industrial districts depends increasingly on their ability to connect to the cognitive circuits of the global economy. This challenge demands the presence of local actors capable of acting as cognitive interfaces between the district context and the global environment. The paper…

Globalization and Chinese Education in the Early 20th Century

ERIC Educational Resources Information Center

Bailey, Paul J.

2013-01-01

With China's growing significance in the global economy ever more evident, studies in recent years have highlighted multiple aspects of China's "Globalization" (or global connections) that predate the contemporary period. This article focuses on educational reform in the late Qing and early Republic as a way of illuminating a significant…

Creating a Global Law Graduate: The Need, Benefits and Practical Approaches to Internationalise the Curriculum

ERIC Educational Resources Information Center

O'Sullivan, Carmel; McNamara, Judith

2015-01-01

The increasingly integrated world has facilitated important international and trans-border trends, such as a progressively connected global economy, a significant growth in transnational business transactions and an increase in global regulation of global issues. Such globalisation has had a transformational impact on the legal profession in a…

Catchment-fed cyanobacterial blooms in brownified temperate lakes

NASA Astrophysics Data System (ADS)

Senar, O.; Creed, I. F.

2017-12-01

One of the most significant impacts of global atmospheric change is the alteration of hydrological regimes and the associated disruption of hydrological connectivity within watersheds. We show how changes in the frequency, magnitude, and duration of hydrological connectivity and disconnectivity is compromising the capacity of forest soils to store organic carbon, and increasing its export to both aquatic and atmospheric systems. Increases in dissolved organic matter (DOM) loads from forested landscapes to aquatic systems and the shift of the DOM pool to a more refractory mixture of organic compounds, a process known as brownification, alters the physical and chemical characteristics of lake environments. Furthermore, by characterizing the stages of brownification (from low to high concentrations of refractory DOM), we show a shift in the limiting factors for phytoplankton growth from macronutrients (nitrogen -N- and phosphorus -P) to micronutrients (iron -Fe) and light availability. This shift is driven by the low concentrations of DOM supplying N and P in early stages of brownification, to the strong Fe-binding capacity of refractory DOM in brownified lakes. As lakes undergo brownification, cyanobacteria adapted to scavenge Fe from DOM-Fe complexes have a competitive advantage leading to the formation of cyanobacterial blooms. Our findings provide evidence that brownification is a driving force leading to cyanobacterial blooms in lakes on forested landscapes, with expected cascading consequences to lake food webs.

High-cost, high-capacity backbone for global brain communication.

PubMed

van den Heuvel, Martijn P; Kahn, René S; Goñi, Joaquín; Sporns, Olaf

2012-07-10

Network studies of human brain structural connectivity have identified a specific set of brain regions that are both highly connected and highly central. Recent analyses have shown that these putative hub regions are mutually and densely interconnected, forming a "rich club" within the human brain. Here we show that the set of pathways linking rich club regions forms a central high-cost, high-capacity backbone for global brain communication. Diffusion tensor imaging (DTI) data of two sets of 40 healthy subjects were used to map structural brain networks. The contributions to network cost and communication capacity of global cortico-cortical connections were assessed through measures of their topology and spatial embedding. Rich club connections were found to be more costly than predicted by their density alone and accounted for 40% of the total communication cost. Furthermore, 69% of all minimally short paths between node pairs were found to travel through the rich club and a large proportion of these communication paths consisted of ordered sequences of edges ("path motifs") that first fed into, then traversed, and finally exited the rich club, while passing through nodes of increasing and then decreasing degree. The prevalence of short paths that follow such ordered degree sequences suggests that neural communication might take advantage of strategies for dynamic routing of information between brain regions, with an important role for a highly central rich club. Taken together, our results show that rich club connections make an important contribution to interregional signal traffic, forming a central high-cost, high-capacity backbone for global brain communication.

The impact of global signal regression on resting state correlations: Are anti-correlated networks introduced?

PubMed Central

Murphy, Kevin; Birn, Rasmus M.; Handwerker, Daniel A.; Jones, Tyler B.; Bandettini, Peter A.

2009-01-01

Low-frequency fluctuations in fMRI signal have been used to map several consistent resting state networks in the brain. Using the posterior cingulate cortex as a seed region, functional connectivity analyses have found not only positive correlations in the default mode network but negative correlations in another resting state network related to attentional processes. The interpretation is that the human brain is intrinsically organized into dynamic, anti-correlated functional networks. Global variations of the BOLD signal are often considered nuisance effects and are commonly removed using a general linear model (GLM) technique. This global signal regression method has been shown to introduce negative activation measures in standard fMRI analyses. The topic of this paper is whether such a correction technique could be the cause of anti-correlated resting state networks in functional connectivity analyses. Here we show that, after global signal regression, correlation values to a seed voxel must sum to a negative value. Simulations also show that small phase differences between regions can lead to spurious negative correlation values. A combination breath holding and visual task demonstrates that the relative phase of global and local signals can affect connectivity measures and that, experimentally, global signal regression leads to bell-shaped correlation value distributions, centred on zero. Finally, analyses of negatively correlated networks in resting state data show that global signal regression is most likely the cause of anti-correlations. These results call into question the interpretation of negatively correlated regions in the brain when using global signal regression as an initial processing step. PMID:18976716

The impact of global signal regression on resting state correlations: are anti-correlated networks introduced?

PubMed

Murphy, Kevin; Birn, Rasmus M; Handwerker, Daniel A; Jones, Tyler B; Bandettini, Peter A

2009-02-01

Low-frequency fluctuations in fMRI signal have been used to map several consistent resting state networks in the brain. Using the posterior cingulate cortex as a seed region, functional connectivity analyses have found not only positive correlations in the default mode network but negative correlations in another resting state network related to attentional processes. The interpretation is that the human brain is intrinsically organized into dynamic, anti-correlated functional networks. Global variations of the BOLD signal are often considered nuisance effects and are commonly removed using a general linear model (GLM) technique. This global signal regression method has been shown to introduce negative activation measures in standard fMRI analyses. The topic of this paper is whether such a correction technique could be the cause of anti-correlated resting state networks in functional connectivity analyses. Here we show that, after global signal regression, correlation values to a seed voxel must sum to a negative value. Simulations also show that small phase differences between regions can lead to spurious negative correlation values. A combination breath holding and visual task demonstrates that the relative phase of global and local signals can affect connectivity measures and that, experimentally, global signal regression leads to bell-shaped correlation value distributions, centred on zero. Finally, analyses of negatively correlated networks in resting state data show that global signal regression is most likely the cause of anti-correlations. These results call into question the interpretation of negatively correlated regions in the brain when using global signal regression as an initial processing step.

Persistent Organic Pollutants: A Global Issue, A Global Response

EPA Pesticide Factsheets

The site explains the importance of the Stockholm Convention, a legally binding international agreement finalized in 2001, in which governments agreed to act to reduce or eliminate the production, use, and/or release of certain of these pollutants.

The eHealth agenda for developing countries.

PubMed

Drury, Peter

2005-01-01

Delivering eHealth in developing countries faces different health and socio-economic challenges to the developed one. But, if a global health infrastructure is to evolve, then developing countries need to play their part. So, whilst the context may differ, the localization-globalization of content issues needs to be jointly addressed. In providing robust and affordable connectivity, particularly to rural areas, developing countries can fully exploit the potential of handheld computers and wireless connectivity. Over such an infrastructure new ways of building capacity, both locally and globally, can be supported. Finally, an eHealth infrastructure can support the delivery of healthcare in communities, thereby supporting individuals and community development.

Fluctuations in Mass-Action Equilibrium of Protein Binding Networks

NASA Astrophysics Data System (ADS)

Yan, Koon-Kiu; Walker, Dylan; Maslov, Sergei

2008-12-01

We consider two types of fluctuations in the mass-action equilibrium in protein binding networks. The first type is driven by slow changes in total concentrations of interacting proteins. The second type (spontaneous) is caused by quickly decaying thermodynamic deviations away from equilibrium. We investigate the effects of network connectivity on fluctuations by comparing them to scenarios in which the interacting pair is isolated from the network and analytically derives bounds on fluctuations. Collective effects are shown to sometimes lead to large amplification of spontaneous fluctuations. The strength of both types of fluctuations is positively correlated with the complex connectivity and negatively correlated with complex concentration. Our general findings are illustrated using a curated network of protein interactions and multiprotein complexes in baker’s yeast, with empirical protein concentrations.

Global Conformational Selection and Local Induced Fit for the Recognition between Intrinsic Disordered p53 and CBP

PubMed Central

Yu, Qingfen; Ye, Wei; Wang, Wei; Chen, Hai-Feng

2013-01-01

The transactivation domain (TAD) of tumor suppressor p53 can bind with the nuclear coactivator binding domain (NCBD) of cyclic-AMP response element binding protein (CBP) and activate transcription. NMR experiments demonstrate that both apo-NCBD and TAD are intrinsic disordered and bound NCBD/TAD undergoes a transition to well folded. The recognition mechanism between intrinsic disordered proteins is still hotly debated. Molecular dynamics (MD) simulations in explicit solvent are used to study the recognition mechanism between intrinsic disordered TAD and NCBD. The average RMSD values between bound and corresponding apo states and Kolmogorov-Smirnov P test analysis indicate that TAD and NCBD may follow an induced fit mechanism. Quantitative analysis indicates there is also a global conformational selection. In summary, the recognition of TAD and NCBD might obey a local induced fit and global conformational selection. These conclusions are further supported by high-temperature unbinding kinetics and room temperature landscape analysis. These methods can be used to study the recognition mechanism of other intrinsic disordered proteins. PMID:23555731

Histone and RNA-binding protein interaction creates crosstalk network for regulation of alternative splicing.

PubMed

Kim, Yong-Eun; Park, Chungoo; Kim, Kyoon Eon; Kim, Kee K

2018-04-30

Alternative splicing is an essential process in eukaryotes, as it increases the complexity of gene expression by generating multiple proteins from a single pre-mRNA. However, information on the regulatory mechanisms for alternative splicing is lacking, because splicing occurs over a short period via the transient interactions of proteins within functional complexes of the spliceosome. Here, we investigated in detail the molecular mechanisms connecting alternative splicing with epigenetic mechanisms. We identified interactions between histone proteins and splicing factors such as Rbfox2, Rbfox3, and splicing factor proline and glutamine rich protein (SFPQ) by in vivo crosslinking and immunoprecipitation. Furthermore, we confirmed that splicing factors were bound to specific modified residues of histone proteins. Additionally, changes in histone methylation due to histone methyltransferase inhibitor treatment notably affected alternative splicing in selected genes. Therefore, we suggested that there may be crosstalk mechanisms connecting histone modifications and RNA-binding proteins that increase the local concentration of RNA-binding proteins in alternative exon loci of nucleosomes by binding specific modified histone proteins, leading to alternative splicing. This crosstalk mechanism may play a major role in epigenetic processes such as histone modification and the regulation of alternative splicing. Copyright © 2018 Elsevier Inc. All rights reserved.

Source Space Estimation of Oscillatory Power and Brain Connectivity in Tinnitus

PubMed Central

Zobay, Oliver; Palmer, Alan R.; Hall, Deborah A.; Sereda, Magdalena; Adjamian, Peyman

2015-01-01

Tinnitus is the perception of an internally generated sound that is postulated to emerge as a result of structural and functional changes in the brain. However, the precise pathophysiology of tinnitus remains unknown. Llinas’ thalamocortical dysrhythmia model suggests that neural deafferentation due to hearing loss causes a dysregulation of coherent activity between thalamus and auditory cortex. This leads to a pathological coupling of theta and gamma oscillatory activity in the resting state, localised to the auditory cortex where normally alpha oscillations should occur. Numerous studies also suggest that tinnitus perception relies on the interplay between auditory and non-auditory brain areas. According to the Global Brain Model, a network of global fronto—parietal—cingulate areas is important in the generation and maintenance of the conscious perception of tinnitus. Thus, the distress experienced by many individuals with tinnitus is related to the top—down influence of this global network on auditory areas. In this magnetoencephalographic study, we compare resting-state oscillatory activity of tinnitus participants and normal-hearing controls to examine effects on spectral power as well as functional and effective connectivity. The analysis is based on beamformer source projection and an atlas-based region-of-interest approach. We find increased functional connectivity within the auditory cortices in the alpha band. A significant increase is also found for the effective connectivity from a global brain network to the auditory cortices in the alpha and beta bands. We do not find evidence of effects on spectral power. Overall, our results provide only limited support for the thalamocortical dysrhythmia and Global Brain models of tinnitus. PMID:25799178

Anterior hippocampal dysconnectivity in posttraumatic stress disorder: a dimensional and multimodal approach.

PubMed

Abdallah, C G; Wrocklage, K M; Averill, C L; Akiki, T; Schweinsburg, B; Roy, A; Martini, B; Southwick, S M; Krystal, J H; Scott, J C

2017-02-28

The anterior hippocampus (aHPC) has a central role in the regulation of anxiety-related behavior, stress response, emotional memory and fear. However, little is known about the presence and extent of aHPC abnormalities in posttraumatic stress disorder (PTSD). In this study, we used a multimodal approach, along with graph-based measures of global brain connectivity (GBC) termed functional GBC with global signal regression (f-GBCr) and diffusion GBC (d-GBC), in combat-exposed US Veterans with and without PTSD. Seed-based aHPC anatomical connectivity analyses were also performed. A whole-brain voxel-wise data-driven investigation revealed a significant association between elevated PTSD symptoms and reduced medial temporal f-GBCr, particularly in the aHPC. Similarly, aHPC d-GBC negatively correlated with PTSD severity. Both functional and anatomical aHPC dysconnectivity measures remained significant after controlling for hippocampal volume, age, gender, intelligence, education, combat severity, depression, anxiety, medication status, traumatic brain injury and alcohol/substance comorbidities. Depression-like PTSD dimensions were associated with reduced connectivity in the ventromedial and dorsolateral prefrontal cortex. In contrast, hyperarousal symptoms were positively correlated with ventromedial and dorsolateral prefrontal connectivity. We believe the findings provide first evidence of functional and anatomical dysconnectivity in the aHPC of veterans with high PTSD symptomatology. The data support the putative utility of aHPC connectivity as a measure of overall PTSD severity. Moreover, prefrontal global connectivity may be of clinical value as a brain biomarker to potentially distinguish between PTSD subgroups.

Communication efficiency and congestion of signal traffic in large-scale brain networks.

PubMed

Mišić, Bratislav; Sporns, Olaf; McIntosh, Anthony R

2014-01-01

The complex connectivity of the cerebral cortex suggests that inter-regional communication is a primary function. Using computational modeling, we show that anatomical connectivity may be a major determinant for global information flow in brain networks. A macaque brain network was implemented as a communication network in which signal units flowed between grey matter nodes along white matter paths. Compared to degree-matched surrogate networks, information flow on the macaque brain network was characterized by higher loss rates, faster transit times and lower throughput, suggesting that neural connectivity may be optimized for speed rather than fidelity. Much of global communication was mediated by a "rich club" of hub regions: a sub-graph comprised of high-degree nodes that are more densely interconnected with each other than predicted by chance. First, macaque communication patterns most closely resembled those observed for a synthetic rich club network, but were less similar to those seen in a synthetic small world network, suggesting that the former is a more fundamental feature of brain network topology. Second, rich club regions attracted the most signal traffic and likewise, connections between rich club regions carried more traffic than connections between non-rich club regions. Third, a number of rich club regions were significantly under-congested, suggesting that macaque connectivity actively shapes information flow, funneling traffic towards some nodes and away from others. Together, our results indicate a critical role of the rich club of hub nodes in dynamic aspects of global brain communication.

Communication Efficiency and Congestion of Signal Traffic in Large-Scale Brain Networks

PubMed Central

Mišić, Bratislav; Sporns, Olaf; McIntosh, Anthony R.

2014-01-01

The complex connectivity of the cerebral cortex suggests that inter-regional communication is a primary function. Using computational modeling, we show that anatomical connectivity may be a major determinant for global information flow in brain networks. A macaque brain network was implemented as a communication network in which signal units flowed between grey matter nodes along white matter paths. Compared to degree-matched surrogate networks, information flow on the macaque brain network was characterized by higher loss rates, faster transit times and lower throughput, suggesting that neural connectivity may be optimized for speed rather than fidelity. Much of global communication was mediated by a “rich club” of hub regions: a sub-graph comprised of high-degree nodes that are more densely interconnected with each other than predicted by chance. First, macaque communication patterns most closely resembled those observed for a synthetic rich club network, but were less similar to those seen in a synthetic small world network, suggesting that the former is a more fundamental feature of brain network topology. Second, rich club regions attracted the most signal traffic and likewise, connections between rich club regions carried more traffic than connections between non-rich club regions. Third, a number of rich club regions were significantly under-congested, suggesting that macaque connectivity actively shapes information flow, funneling traffic towards some nodes and away from others. Together, our results indicate a critical role of the rich club of hub nodes in dynamic aspects of global brain communication. PMID:24415931

Global Synchronization of Multiple Recurrent Neural Networks With Time Delays via Impulsive Interactions.

PubMed

Yang, Shaofu; Guo, Zhenyuan; Wang, Jun

2017-07-01

In this paper, new results on the global synchronization of multiple recurrent neural networks (NNs) with time delays via impulsive interactions are presented. Impulsive interaction means that a number of NNs communicate with each other at impulse instants only, while they are independent at the remaining time. The communication topology among NNs is not required to be always connected and can switch ON and OFF at different impulse instants. By using the concept of sequential connectivity and the properties of stochastic matrices, a set of sufficient conditions depending on time delays is derived to ascertain global synchronization of multiple continuous-time recurrent NNs. In addition, a counterpart on the global synchronization of multiple discrete-time NNs is also discussed. Finally, two examples are presented to illustrate the results.

Resonant spatiotemporal learning in large random recurrent networks.

PubMed

Daucé, Emmanuel; Quoy, Mathias; Doyon, Bernard

2002-09-01

Taking a global analogy with the structure of perceptual biological systems, we present a system composed of two layers of real-valued sigmoidal neurons. The primary layer receives stimulating spatiotemporal signals, and the secondary layer is a fully connected random recurrent network. This secondary layer spontaneously displays complex chaotic dynamics. All connections have a constant time delay. We use for our experiments a Hebbian (covariance) learning rule. This rule slowly modifies the weights under the influence of a periodic stimulus. The effect of learning is twofold: (i) it simplifies the secondary-layer dynamics, which eventually stabilizes to a periodic orbit; and (ii) it connects the secondary layer to the primary layer, and realizes a feedback from the secondary to the primary layer. This feedback signal is added to the incoming signal, and matches it (i.e., the secondary layer performs a one-step prediction of the forthcoming stimulus). After learning, a resonant behavior can be observed: the system resonates with familiar stimuli, which activates a feedback signal. In particular, this resonance allows the recognition and retrieval of partial signals, and dynamic maintenance of the memory of past stimuli. This resonance is highly sensitive to the temporal relationships and to the periodicity of the presented stimuli. When we present stimuli which do not match in time or space, the feedback remains silent. The number of different stimuli for which resonant behavior can be learned is analyzed. As with Hopfield networks, the capacity is proportional to the size of the second, recurrent layer. Moreover, the high capacity displayed allows the implementation of our model on real-time systems interacting with their environment. Such an implementation is reported in the case of a simple behavior-based recognition task on a mobile robot. Finally, we present some functional analogies with biological systems in terms of autonomy and dynamic binding, and present some hypotheses on the computational role of feedback connections.

Towards a "Global Educational Justice" Research Paradigm: Cognitive Justice, Decolonizing Methodologies and Critical Pedagogy

ERIC Educational Resources Information Center

Chan-Tiberghien, Jennifer

2004-01-01

This article challenges three predominant narratives on educational globalization--"educational restructuring," "educational institutionalism," and "educational multilateralism"--and shows how they have largely failed to propose alternatives to the neoliberal order. I connect two disparate literatures--on educational globalization and…

The Global Thinking Project.

ERIC Educational Resources Information Center

Hassard, Jack; Weisburg, Julie

1992-01-01

Describes the Global Thinking Project, a collaborative effort between Georgia State University and the Russian Academy of Pedagogical Sciences to develop strategies, methods, and teaching materials to help students think globally. Students are connected through the AppleLink network. Student and teacher attitudes toward the project are reported.…

Preparing Global Citizens

ERIC Educational Resources Information Center

Roberts, Dennis C.; Welch, Lucas; Al-Khanji, Khalid

2013-01-01

Global citizens are those who are aware of, demonstrate respect for, and are comfortable engaging across cultural boundaries. This article explores why preparing global citizens is important and how positive psychology can inform our understanding of those who engage comfortably in today's complicated world. Soliya's Connect program is described…

Building Global Learning Communities

ERIC Educational Resources Information Center

Cochrane, Thomas; Buchem, Ilona; Camacho, Mar; Cronin, Catherine; Gordon, Averill; Keegan, Helen

2013-01-01

Within the background where education is increasingly driven by the economies of scale and research funding, we propose an alternative online open and connected framework (OOC) for building global learning communities using mobile social media. We critique a three year action research case study involving building collaborative global learning…

Commentary: Addressing Double Binds in Educating for an Ecologically Sustainable Future.

ERIC Educational Resources Information Center

Bowers, Chet A.

2001-01-01

Contrary to computer advocates' globalism = empowerment rhetoric, the dominant globalization pattern involves relentless commodification of knowledge, skills, and interdependent relationships. Few consider the ecological implications of commodifying (digitizing) leisure, education, health care, or communications. Posing community regeneration…

Chiral direction and interconnection of helical three-connected networks in metal-organic frameworks.

PubMed

Prior, T J; Rosseinsky, M J

2003-03-10

The control of the interpenetration and chirality of a family of metal-organic frameworks is discussed. These systems contain two- (A) and four-fold (B) interpenetration of helical three-connected networks generated by binding the 1,3,5-benzenetricarboxylate (btc) ligand to a metal center. These frameworks have the general formula Ni(3)(btc)(2)X(m)Y(n).solvent (where X = pyridine or 4-picoline, Y = ethylene glycol, 1,2-propanediol, 1,4-butanediol, meso-2,3-butanediol, 1,2,6-hexanetriol, glycerol). The structural and chemical effects of modifying the alcohol and aromatic amine ligands bound to the metal center include controlling the thermal stability and the degree of interpenetration. Covalent linking of the four interpenetrating networks in the A family and the switching of diol binding from mono- to bidentate are demonstrated. Recognition of chiral diols by the hand of the network helices is investigated by binding an alcohol ligand with two chiral centers of opposite sense to the same helix. This reveals the subtle nature of the helix-ligand interaction.

Carbachol dimers as homobivalent modulators of muscarinic receptors.

PubMed

Matucci, Rosanna; Nesi, Marta; Martino, Maria Vittoria; Bellucci, Cristina; Manetti, Dina; Ciuti, Elisa; Mazzolari, Angelica; Dei, Silvia; Guandalini, Luca; Teodori, Elisabetta; Vistoli, Giulio; Romanelli, Maria Novella

2016-05-15

A series of homodimers of the well-known cholinergic agonist carbachol have been synthesized, showing the two agonist units symmetrically connected through a methylene chain of variable length. The new compounds have been tested on the five cloned muscarinic receptors (hM1-5) expressed in CHO cells by means of equilibrium binding studies, showing an increase in affinity by rising the number of methylene units up to 7 and 9. Functional experiments on guinea-pig ileum and assessment of ERK1/2 phosphorylation on hM1, hM2 and hM3 on CHO cells have shown that the new compounds are endowed with muscarinic antagonistic properties. Kinetic binding studies have revealed that some of the tested compounds are able to slow the rate of dissociation of NMS, suggesting a bitopic behavior. Docking simulations, performed on the hM1 and hM2 receptors, give a sound rationalization of the experimental data revealing how these compounds are able to interact with both orthosteric and allosteric binding sites depending on the length of their connecting chain. Copyright © 2016 Elsevier Inc. All rights reserved.

Syntaxin1a variants lacking an N-peptide or bearing the LE mutation bind to Munc18a in a closed conformation

DOE PAGES

Colbert, Karen N.; Hattendorf, Douglas A.; Weiss, Thomas M.; ...

2013-07-15

In neurons, soluble N-ethylmaleimide–sensitive factor attachment receptor (SNARE) proteins drive the fusion of synaptic vesicles to the plasma membrane through the formation of a four-helix SNARE complex. Members of the Sec1/Munc18 protein family regulate membrane fusion through interactions with the syntaxin family of SNARE proteins. The neuronal protein Munc18a interacts with a closed conformation of the SNARE protein syntaxin1a (Syx1a) and with an assembled SNARE complex containing Syx1a in an open conformation. The N-peptide of Syx1a (amino acids 1–24) has been implicated in the transition of Munc18a-bound Syx1a to Munc18a-bound SNARE complex, but the underlying mechanism is not understood. Inmore » addition, we report the X-ray crystal structures of Munc18a bound to Syx1a with and without its native N-peptide (Syx1aΔN), along with small-angle X-ray scattering (SAXS) data for Munc18a bound to Syx1a, Syx1aΔN, and Syx1a L165A/E166A (LE), a mutation thought to render Syx1a in a constitutively open conformation. We show that all three complexes adopt the same global structure, in which Munc18a binds a closed conformation of Syx1a. We also identify a possible structural connection between the Syx1a N-peptide and SNARE domain that might be important for the transition of closed-to-open Syx1a in SNARE complex assembly. Although the role of the N-peptide in Munc18a-mediated SNARE complex assembly remains unclear, our results demonstrate that the N-peptide and LE mutation have no effect on the global conformation of the Munc18a–Syx1a complex.« less

Global Invasion History of the Tropical Fire Ant, Solenopsis geminata: A Stowaway on the First Global Trade Routes

USDA-ARS?s Scientific Manuscript database

Biological invasions are largely thought to be contemporary, having recently increased sharply in the wake of globalization. However, human commerce had already become global in scope by the mid-16th century, when the Spanish connected the New World with Europe and Asia via their Manila galleon and ...

Social Software: A Powerful Paradigm for Building Technology for Global Learning

ERIC Educational Resources Information Center

Wooding, Amy; Wooding, Kjell

2018-01-01

It is not difficult to imagine a world where internet-connected mobile devices are accessible to everyone. Can these technologies be used to help solve the challenges of global education? This was the challenge posed by the Global Learning XPRIZE--a $15 million grand challenge competition aimed at addressing this global teaching shortfall. In…

A regulatory network-based approach dissects late maturation processes related to the acquisition of desiccation tolerance and longevity of Medicago truncatula seeds.

PubMed

Verdier, Jerome; Lalanne, David; Pelletier, Sandra; Torres-Jerez, Ivone; Righetti, Karima; Bandyopadhyay, Kaustav; Leprince, Olivier; Chatelain, Emilie; Vu, Benoit Ly; Gouzy, Jerome; Gamas, Pascal; Udvardi, Michael K; Buitink, Julia

2013-10-01

In seeds, desiccation tolerance (DT) and the ability to survive the dry state for prolonged periods of time (longevity) are two essential traits for seed quality that are consecutively acquired during maturation. Using transcriptomic and metabolomic profiling together with a conditional-dependent network of global transcription interactions, we dissected the maturation events from the end of seed filling to final maturation drying during the last 3 weeks of seed development in Medicago truncatula. The network revealed distinct coexpression modules related to the acquisition of DT, longevity, and pod abscission. The acquisition of DT and dormancy module was associated with abiotic stress response genes, including late embryogenesis abundant (LEA) genes. The longevity module was enriched in genes involved in RNA processing and translation. Concomitantly, LEA polypeptides accumulated, displaying an 18-d delayed accumulation compared with transcripts. During maturation, gulose and stachyose levels increased and correlated with longevity. A seed-specific network identified known and putative transcriptional regulators of DT, including ABSCISIC ACID-INSENSITIVE3 (MtABI3), MtABI4, MtABI5, and APETALA2/ ETHYLENE RESPONSE ELEMENT BINDING PROTEIN (AtAP2/EREBP) transcription factor as major hubs. These transcriptional activators were highly connected to LEA genes. Longevity genes were highly connected to two MtAP2/EREBP and two basic leucine zipper transcription factors. A heat shock factor was found at the transition of DT and longevity modules, connecting to both gene sets. Gain- and loss-of-function approaches of MtABI3 confirmed 80% of its predicted targets, thereby experimentally validating the network. This study captures the coordinated regulation of seed maturation and identifies distinct regulatory networks underlying the preparation for the dry and quiescent states.

A Regulatory Network-Based Approach Dissects Late Maturation Processes Related to the Acquisition of Desiccation Tolerance and Longevity of Medicago truncatula Seeds1[C][W][OPEN

PubMed Central

Verdier, Jerome; Lalanne, David; Pelletier, Sandra; Torres-Jerez, Ivone; Righetti, Karima; Bandyopadhyay, Kaustav; Leprince, Olivier; Chatelain, Emilie; Vu, Benoit Ly; Gouzy, Jerome; Gamas, Pascal; Udvardi, Michael K.; Buitink, Julia

2013-01-01

In seeds, desiccation tolerance (DT) and the ability to survive the dry state for prolonged periods of time (longevity) are two essential traits for seed quality that are consecutively acquired during maturation. Using transcriptomic and metabolomic profiling together with a conditional-dependent network of global transcription interactions, we dissected the maturation events from the end of seed filling to final maturation drying during the last 3 weeks of seed development in Medicago truncatula. The network revealed distinct coexpression modules related to the acquisition of DT, longevity, and pod abscission. The acquisition of DT and dormancy module was associated with abiotic stress response genes, including late embryogenesis abundant (LEA) genes. The longevity module was enriched in genes involved in RNA processing and translation. Concomitantly, LEA polypeptides accumulated, displaying an 18-d delayed accumulation compared with transcripts. During maturation, gulose and stachyose levels increased and correlated with longevity. A seed-specific network identified known and putative transcriptional regulators of DT, including ABSCISIC ACID-INSENSITIVE3 (MtABI3), MtABI4, MtABI5, and APETALA2/ ETHYLENE RESPONSE ELEMENT BINDING PROTEIN (AtAP2/EREBP) transcription factor as major hubs. These transcriptional activators were highly connected to LEA genes. Longevity genes were highly connected to two MtAP2/EREBP and two basic leucine zipper transcription factors. A heat shock factor was found at the transition of DT and longevity modules, connecting to both gene sets. Gain- and loss-of-function approaches of MtABI3 confirmed 80% of its predicted targets, thereby experimentally validating the network. This study captures the coordinated regulation of seed maturation and identifies distinct regulatory networks underlying the preparation for the dry and quiescent states. PMID:23929721

Explaining the heterogeneity of functional connectivity findings in multiple sclerosis: An empirically informed modeling study.

PubMed

Tewarie, Prejaas; Steenwijk, Martijn D; Brookes, Matthew J; Uitdehaag, Bernard M J; Geurts, Jeroen J G; Stam, Cornelis J; Schoonheim, Menno M

2018-06-01

To understand the heterogeneity of functional connectivity results reported in the literature, we analyzed the separate effects of grey and white matter damage on functional connectivity and networks in multiple sclerosis. For this, we employed a biophysical thalamo-cortical model consisting of interconnected cortical and thalamic neuronal populations, informed and amended by empirical diffusion MRI tractography data, to simulate functional data that mimic neurophysiological signals. Grey matter degeneration was simulated by decreasing within population connections and white matter degeneration by lowering between population connections, based on lesion predilection sites in multiple sclerosis. For all simulations, functional connectivity and functional network organization are quantified by phase synchronization and network integration, respectively. Modeling results showed that both cortical and thalamic grey matter damage induced a global increase in functional connectivity, whereas white matter damage induced an initially increased connectivity followed by a global decrease. Both white and especially grey matter damage, however, induced a decrease in network integration. These empirically informed simulations show that specific topology and timing of structural damage are nontrivial aspects in explaining functional abnormalities in MS. Insufficient attention to these aspects likely explains contradictory findings in multiple sclerosis functional imaging studies so far. © 2018 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.

Molecular Dynamics Pinpoint the Global Fluorine Effect in Balanoid Binding to PKCε and PKA.

PubMed

Hardianto, Ari; Liu, Fei; Ranganathan, Shoba

2018-02-26

(-)-Balanol is an adenosine triphosphate mimic that inhibits protein kinase C (PKC) isozymes and cAMP-dependent protein kinase (PKA) with limited selectivity. While PKA is known as a tumor promoter, PKC isozymes can be tumor promoters or suppressors. In particular, PKCε is frequently involved in tumorigenesis and a potential target for anticancer drugs. We recently reported that stereospecific fluorination of balanol yielded a balanoid with enhanced selectivity for PKCε over other PKC isozymes and PKA, although the global fluorine effect behind the selectivity enhancement is not fully understood. Interestingly, in contrast to PKA, PKCε is more sensitive to this fluorine effect. Here we investigate the global fluorine effect on the different binding responses of PKCε and PKA to balanoids using molecular dynamics (MD) simulations. For the first time to the best of our knowledge, we found that a structurally equivalent residue in each kinase, Thr184 in PKA and Ala549 in PKCε, is essential for the different binding responses. Furthermore, the study revealed that the invariant Lys, Lys73 in PKA and Lys437 in PKCε, already known to have a crucial role in the catalytic activity of kinases, serves as the main anchor for balanol binding. Overall, while Thr184 in PKA attenuates the effect of fluorination, Ala549 permits remote response of PKCε to fluorine substitution, with implications for rational design of future balanol-based PKCε inhibitors.

75 FR 24754 - Notice of Information Collection

Federal Register 2010, 2011, 2012, 2013, 2014

2010-05-05

... to Sky, by measuring awareness and understanding of global climate change in visitors to NPS and... awareness and understanding of global climate change; meaning of and connection to park resources; and perception of trust in sources of information regarding global climate change. Data will be collected in a...

Digital Storytelling for Transformative Global Citizenship Education

ERIC Educational Resources Information Center

Truong-White, Hoa; McLean, Lorna

2015-01-01

This article explores how digital storytelling offers the potential to support transformative global citizenship education (TGCE) through a case study of the Bridges to Understanding program that connected middle and high school students globally using digital storytelling. Drawing on a TGCE framework, this research project probed the curriculum…

Competitive Binding of Natural Amphiphiles with Graphene Derivatives

NASA Astrophysics Data System (ADS)

Radic, Slaven; Geitner, Nicholas K.; Podila, Ramakrishna; Käkinen, Aleksandr; Chen, Pengyu; Ke, Pu Chun; Ding, Feng

2013-07-01

Understanding the transformation of graphene derivatives by natural amphiphiles is essential for elucidating the biological and environmental implications of this emerging class of engineered nanomaterials. Using rapid discrete-molecular-dynamics simulations, we examined the binding of graphene and graphene oxide with peptides, fatty acids, and cellulose, and complemented our simulations by experimental studies of Raman spectroscopy, FTIR, and UV-Vis spectrophotometry. Specifically, we established a connection between the differential binding and the conformational flexibility, molecular geometry, and hydrocarbon content of the amphiphiles. Importantly, our dynamics simulations revealed a Vroman-like competitive binding of the amphiphiles for the graphene oxide substrate. This study provides a mechanistic basis for addressing the transformation, evolution, transport, biocompatibility, and toxicity of graphene derivatives in living systems and the natural environment.

Competitive Binding of Natural Amphiphiles with Graphene Derivatives

PubMed Central

Radic, Slaven; Geitner, Nicholas K.; Podila, Ramakrishna; Käkinen, Aleksandr; Chen, Pengyu; Ke, Pu Chun; Ding, Feng

2013-01-01

Understanding the transformation of graphene derivatives by natural amphiphiles is essential for elucidating the biological and environmental implications of this emerging class of engineered nanomaterials. Using rapid discrete-molecular-dynamics simulations, we examined the binding of graphene and graphene oxide with peptides, fatty acids, and cellulose, and complemented our simulations by experimental studies of Raman spectroscopy, FTIR, and UV-Vis spectrophotometry. Specifically, we established a connection between the differential binding and the conformational flexibility, molecular geometry, and hydrocarbon content of the amphiphiles. Importantly, our dynamics simulations revealed a Vroman-like competitive binding of the amphiphiles for the graphene oxide substrate. This study provides a mechanistic basis for addressing the transformation, evolution, transport, biocompatibility, and toxicity of graphene derivatives in living systems and the natural environment. PMID:23881402

Phase synchronization of bursting neurons in clustered small-world networks

NASA Astrophysics Data System (ADS)

Batista, C. A. S.; Lameu, E. L.; Batista, A. M.; Lopes, S. R.; Pereira, T.; Zamora-López, G.; Kurths, J.; Viana, R. L.

2012-07-01

We investigate the collective dynamics of bursting neurons on clustered networks. The clustered network model is composed of subnetworks, each of them presenting the so-called small-world property. This model can also be regarded as a network of networks. In each subnetwork a neuron is connected to other ones with regular as well as random connections, the latter with a given intracluster probability. Moreover, in a given subnetwork each neuron has an intercluster probability to be connected to the other subnetworks. The local neuron dynamics has two time scales (fast and slow) and is modeled by a two-dimensional map. In such small-world network the neuron parameters are chosen to be slightly different such that, if the coupling strength is large enough, there may be synchronization of the bursting (slow) activity. We give bounds for the critical coupling strength to obtain global burst synchronization in terms of the network structure, that is, the probabilities of intracluster and intercluster connections. We find that, as the heterogeneity in the network is reduced, the network global synchronizability is improved. We show that the transitions to global synchrony may be abrupt or smooth depending on the intercluster probability.

The Anatomical Distance of Functional Connections Predicts Brain Network Topology in Health and Schizophrenia

PubMed Central

Vértes, Petra E.; Stidd, Reva; Lalonde, François; Clasen, Liv; Rapoport, Judith; Giedd, Jay; Bullmore, Edward T.; Gogtay, Nitin

2013-01-01

The human brain is a topologically complex network embedded in anatomical space. Here, we systematically explored relationships between functional connectivity, complex network topology, and anatomical (Euclidean) distance between connected brain regions, in the resting-state functional magnetic resonance imaging brain networks of 20 healthy volunteers and 19 patients with childhood-onset schizophrenia (COS). Normal between-subject differences in average distance of connected edges in brain graphs were strongly associated with variation in topological properties of functional networks. In addition, a club or subset of connector hubs was identified, in lateral temporal, parietal, dorsal prefrontal, and medial prefrontal/cingulate cortical regions. In COS, there was reduced strength of functional connectivity over short distances especially, and therefore, global mean connection distance of thresholded graphs was significantly greater than normal. As predicted from relationships between spatial and topological properties of normal networks, this disorder-related proportional increase in connection distance was associated with reduced clustering and modularity and increased global efficiency of COS networks. Between-group differences in connection distance were localized specifically to connector hubs of multimodal association cortex. In relation to the neurodevelopmental pathogenesis of schizophrenia, we argue that the data are consistent with the interpretation that spatial and topological disturbances of functional network organization could arise from excessive “pruning” of short-distance functional connections in schizophrenia. PMID:22275481

Network architecture of the cerebral nuclei (basal ganglia) association and commissural connectome.

PubMed

Swanson, Larry W; Sporns, Olaf; Hahn, Joel D

2016-10-04

The cerebral nuclei form the ventral division of the cerebral hemisphere and are thought to play an important role in neural systems controlling somatic movement and motivation. Network analysis was used to define global architectural features of intrinsic cerebral nuclei circuitry in one hemisphere (association connections) and between hemispheres (commissural connections). The analysis was based on more than 4,000 reports of histologically defined axonal connections involving all 45 gray matter regions of the rat cerebral nuclei and revealed the existence of four asymmetrically interconnected modules. The modules form four topographically distinct longitudinal columns that only partly correspond to previous interpretations of cerebral nuclei structure-function organization. The network of connections within and between modules in one hemisphere or the other is quite dense (about 40% of all possible connections), whereas the network of connections between hemispheres is weak and sparse (only about 5% of all possible connections). Particularly highly interconnected regions (rich club and hubs within it) form a topologically continuous band extending through two of the modules. Connection path lengths among numerous pairs of regions, and among some of the network's modules, are relatively long, thus accounting for low global efficiency in network communication. These results provide a starting point for reexamining the connectional organization of the cerebral hemispheres as a whole (right and left cerebral cortex and cerebral nuclei together) and their relation to the rest of the nervous system.

DNA sequence determinants controlling affinity, stability and shape of DNA complexes bound by the nucleoid protein Fis

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

Hancock, Stephen P.; Stella, Stefano; Cascio, Duilio

The abundant Fis nucleoid protein selectively binds poorly related DNA sequences with high affinities to regulate diverse DNA reactions. Fis binds DNA primarily through DNA backbone contacts and selects target sites by reading conformational properties of DNA sequences, most prominently intrinsic minor groove widths. High-affinity binding requires Fis-stabilized DNA conformational changes that vary depending on DNA sequence. In order to better understand the molecular basis for high affinity site recognition, we analyzed the effects of DNA sequence within and flanking the core Fis binding site on binding affinity and DNA structure. X-ray crystal structures of Fis-DNA complexes containing variable sequencesmore » in the noncontacted center of the binding site or variations within the major groove interfaces show that the DNA can adapt to the Fis dimer surface asymmetrically. We show that the presence and position of pyrimidine-purine base steps within the major groove interfaces affect both local DNA bending and minor groove compression to modulate affinities and lifetimes of Fis-DNA complexes. Sequences flanking the core binding site also modulate complex affinities, lifetimes, and the degree of local and global Fis-induced DNA bending. In particular, a G immediately upstream of the 15 bp core sequence inhibits binding and bending, and A-tracts within the flanking base pairs increase both complex lifetimes and global DNA curvatures. Taken together, our observations support a revised DNA motif specifying high-affinity Fis binding and highlight the range of conformations that Fis-bound DNA can adopt. Lastly, the affinities and DNA conformations of individual Fis-DNA complexes are likely to be tailored to their context-specific biological functions.« less

DNA sequence determinants controlling affinity, stability and shape of DNA complexes bound by the nucleoid protein Fis

DOE PAGES

Hancock, Stephen P.; Stella, Stefano; Cascio, Duilio; ...

2016-03-09

The abundant Fis nucleoid protein selectively binds poorly related DNA sequences with high affinities to regulate diverse DNA reactions. Fis binds DNA primarily through DNA backbone contacts and selects target sites by reading conformational properties of DNA sequences, most prominently intrinsic minor groove widths. High-affinity binding requires Fis-stabilized DNA conformational changes that vary depending on DNA sequence. In order to better understand the molecular basis for high affinity site recognition, we analyzed the effects of DNA sequence within and flanking the core Fis binding site on binding affinity and DNA structure. X-ray crystal structures of Fis-DNA complexes containing variable sequencesmore » in the noncontacted center of the binding site or variations within the major groove interfaces show that the DNA can adapt to the Fis dimer surface asymmetrically. We show that the presence and position of pyrimidine-purine base steps within the major groove interfaces affect both local DNA bending and minor groove compression to modulate affinities and lifetimes of Fis-DNA complexes. Sequences flanking the core binding site also modulate complex affinities, lifetimes, and the degree of local and global Fis-induced DNA bending. In particular, a G immediately upstream of the 15 bp core sequence inhibits binding and bending, and A-tracts within the flanking base pairs increase both complex lifetimes and global DNA curvatures. Taken together, our observations support a revised DNA motif specifying high-affinity Fis binding and highlight the range of conformations that Fis-bound DNA can adopt. Lastly, the affinities and DNA conformations of individual Fis-DNA complexes are likely to be tailored to their context-specific biological functions.« less

Modes of caldesmon binding to actin: sites of caldesmon contact and modulation of interactions by phosphorylation.

PubMed

Foster, D Brian; Huang, Renjian; Hatch, Victoria; Craig, Roger; Graceffa, Philip; Lehman, William; Wang, C-L Albert

2004-12-17

Smooth muscle caldesmon binds actin and inhibits actomyosin ATPase activity. Phosphorylation of caldesmon by extracellular signal-regulated kinase (ERK) reverses this inhibitory effect and weakens actin binding. To better understand this function, we have examined the phosphorylation-dependent contact sites of caldesmon on actin by low dose electron microscopy and three-dimensional reconstruction of actin filaments decorated with a C-terminal fragment, hH32K, of human caldesmon containing the principal actin-binding domains. Helical reconstruction of negatively stained filaments demonstrated that hH32K is located on the inner portion of actin subdomain 1, traversing its upper surface toward the C-terminal segment of actin, and forms a bridge to the neighboring actin monomer of the adjacent long pitch helical strand by connecting to its subdomain 3. Such lateral binding was supported by cross-linking experiments using a mutant isoform, which was capable of cross-linking actin subunits. Upon ERK phosphorylation, however, the mutant no longer cross-linked actin to polymers. Three-dimensional reconstruction of ERK-phosphorylated hH32K indeed indicated loss of the interstrand connectivity. These results, together with fluorescence quenching data, are consistent with a phosphorylation-dependent conformational change that moves the C-terminal end segment of caldesmon near the phosphorylation site but not the upstream region around Cys(595), away from F-actin, thus neutralizing its inhibitory effect on actomyosin interactions. The binding pattern of hH32K suggests a mechanism by which unphosphorylated, but not ERK-phosphorylated, caldesmon could stabilize actin filaments and resist F-actin severing or depolymerization in both smooth muscle and nonmuscle cells.

Association of Hippocampal Substructure Resting-State Functional Connectivity with Memory Performance in Older Adults.

PubMed

Smagula, Stephen F; Karim, Helmet T; Rangarajan, Anusha; Santos, Fernando Pasquini; Wood, Sossena C; Santini, Tales; Jakicic, John M; Reynolds, Charles F; Cameron, Judy L; Vallejo, Abbe N; Butters, Meryl A; Rosano, Caterina; Ibrahim, Tamer S; Erickson, Kirk I; Aizenstein, Howard J

2018-06-01

Hippocampal hyperactivation marks preclinical dementia pathophysiology, potentially due to differences in the connectivity of specific medial temporal lobe structures. Our aims were to characterize the resting-state functional connectivity of medial temporal lobe sub-structures in older adults, and evaluate whether specific substructural (rather than global) functional connectivity relates to memory function. In 15 adults (mean age: 69 years), we evaluated the resting state functional connectivity of medial temporal lobe substructures: dentate/Cornu Ammonis (CA) 4, CA1, CA2/3, subiculum, the molecular layer, entorhinal cortex, and parahippocampus. We used 7-Tesla susceptibility weighted imaging and magnetization-prepared rapid gradient echo sequences to segment substructures of the hippocampus, which were used as structural seeds for examining functional connectivity in a resting BOLD sequence. We then assessed correlations between functional connectivity with memory performance (short and long delay free recall on the California Verbal Learning Test [CVLT]). All the seed regions had significant connectivity within the temporal lobe (including the fusiform, temporal, and lingual gyri). The left CA1 was the only seed with significant functional connectivity to the amygdala. The left entorhinal cortex was the only seed to have significant functional connectivity with frontal cortex (anterior cingulate and superior frontal gyrus). Only higher left dentate-left lingual connectivity was associated with poorer CVLT performance (Spearman r = -0.81, p = 0.0003, Benjamini-Hochberg false discovery rate: 0.01) after multiple comparison correction. Rather than global hyper-connectivity of the medial temporal lobe, left dentate-lingual connectivity may provide a specific assay of medial temporal lobe hyper-connectivity relevant to memory in aging. Copyright © 2018 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.

Evaluating population connectivity for species of conservation concern in the American Great Plains

Treesearch

Samuel A. Cushman; Erin L. Landguth; Curtis H. Flather

2013-01-01

Habitat loss and fragmentation are widely recognized as among the most important threats to global biodiversity. New analytical approaches are providing an improved ability to predict the effects of landscape change on population connectivity at vast spatial extents. This paper presents an analysis of population connectivity for three species of conservation concern [...

Making Connections for Themselves and Their Students: Examining Teachers' Organization of World History

ERIC Educational Resources Information Center

Harris, Lauren McArthur

2014-01-01

The ability to make connections is an important aspect of teaching history and a vital skill in our increasingly globalized world. This study examines how preservice and practicing teachers organize and connect world historical events and concepts for themselves and for instructional purposes. Findings are based on interviews with 2 card-sorting…

Predicting global population connectivity and targeting conservation action for snow leopard across its range

Treesearch

Philip Riordan; Samuel A. Cushman; David Mallon; Kun Shi; Joelene Hughes

2016-01-01

Movements of individuals within and among populations help to maintain genetic variability and population viability. Therefore, understanding landscape connectivity is vital for effective species conservation. The snow leopard is endemic to mountainous areas of central Asia and occurs within 12 countries. We assess potential connectivity across the species’...

Why Ecologists Should Care about Financial Markets.

PubMed

Galaz, Victor; Gars, Johan; Moberg, Fredrik; Nykvist, Björn; Repinski, Cecilia

2015-10-01

Financial actors such as international banks and investors play an important role in the global economy. This role is shifting due to financial innovations, increased sustainability ambitions from large financial actors, and changes in international commodity markets. These changes are creating new global connections that potentially make financial markets, actors, and instruments important aspects of global environmental change. Despite this, the way financial markets and actors affect ecosystem change in different parts of the world has seldom been elaborated in the literature. We summarize these financial trends, explore how they connect to ecosystems and ecological change in both direct and indirect ways, and elaborate on crucial research gaps. Copyright © 2015 Elsevier Ltd. All rights reserved.

Global Interdependence--Knocking the World We Know Off Its Axis.

ERIC Educational Resources Information Center

Hamilton, John Maxwell; Roberts, Lesley

1989-01-01

Discusses the need for teaching about global interdependence. Points out that nearly every dimension of life in the United States shows proliferating connections to other nations. Describes techniques for finding global links and appreciating their importance. Notes that information emanating from the school will increase general knowledge…

Towards Critical Global Education Worker Subjectivity: An Exploration of Narratives of American Women Engaged in Education-Related International Volunteerism

ERIC Educational Resources Information Center

Mule, Lucy

2017-01-01

International volunteerism is increasingly associated with shaping global subjectivities of participants. Significant numbers of Global North volunteers--whether working through established volunteer organizations, corporations, nonprofits, academia, or personal networks and connections--engage in education related activities while in the Global…

Fostering Global Citizenship--Tree Planting as a Connective Practice

ERIC Educational Resources Information Center

Haigh, Martin

2016-01-01

Education for Global Citizenship is about living as though the future mattered. This evaluates learner reactions to a tree-planting exercise that invites reflection upon hopes for the world, personal responsibilities and acting locally while thinking globally. Participant hopes concerned: environmental sustainability, peace on earth, then the…

78 FR 31576 - Enforcement Proceeding; Certain Two-Way Global Satellite Communication Devices, System and...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-05-24

...-Way Global Satellite Communication Devices, System and Components Thereof; Notice of Institution of...-confidential documents filed in connection with this investigation are or will be available for inspection... importation of certain two-way global satellite communication devices, system and components thereof by reason...

Learner Analysis Framework for Globalized E-Learning: A Case Study

ERIC Educational Resources Information Center

Saxena, Mamta

2011-01-01

The shift to technology-mediated modes of instructional delivery and increased global connectivity has led to the rise in globalized e-learning programs. Educational institutions face multiple challenges as they seek to design effective, engaging, and culturally competent instruction for an increasingly diverse learner population. The purpose of…

Cytokinesis: breaking the ties that bind.

PubMed

McCollum, Dannel

2005-12-20

It has been unclear how cells complete cell division and resolve membrane connections to bring about cell separation. Recent work has shown that targeted secretion to the midbody is required to complete cell division.

Decomposition of metabolic network into functional modules based on the global connectivity structure of reaction graph.

PubMed

Ma, Hong-Wu; Zhao, Xue-Ming; Yuan, Ying-Jin; Zeng, An-Ping

2004-08-12

Metabolic networks are organized in a modular, hierarchical manner. Methods for a rational decomposition of the metabolic network into relatively independent functional subsets are essential to better understand the modularity and organization principle of a large-scale, genome-wide network. Network decomposition is also necessary for functional analysis of metabolism by pathway analysis methods that are often hampered by the problem of combinatorial explosion due to the complexity of metabolic network. Decomposition methods proposed in literature are mainly based on the connection degree of metabolites. To obtain a more reasonable decomposition, the global connectivity structure of metabolic networks should be taken into account. In this work, we use a reaction graph representation of a metabolic network for the identification of its global connectivity structure and for decomposition. A bow-tie connectivity structure similar to that previously discovered for metabolite graph is found also to exist in the reaction graph. Based on this bow-tie structure, a new decomposition method is proposed, which uses a distance definition derived from the path length between two reactions. An hierarchical classification tree is first constructed from the distance matrix among the reactions in the giant strong component of the bow-tie structure. These reactions are then grouped into different subsets based on the hierarchical tree. Reactions in the IN and OUT subsets of the bow-tie structure are subsequently placed in the corresponding subsets according to a 'majority rule'. Compared with the decomposition methods proposed in literature, ours is based on combined properties of the global network structure and local reaction connectivity rather than, primarily, on the connection degree of metabolites. The method is applied to decompose the metabolic network of Escherichia coli. Eleven subsets are obtained. More detailed investigations of the subsets show that reactions in the same subset are really functionally related. The rational decomposition of metabolic networks, and subsequent studies of the subsets, make it more amenable to understand the inherent organization and functionality of metabolic networks at the modular level. http://genome.gbf.de/bioinformatics/

Optimizing Instruction Scheduling and Register Allocation for Register-File-Connected Clustered VLIW Architectures

PubMed Central

Tang, Haijing; Wang, Siye; Zhang, Yanjun

2013-01-01

Clustering has become a common trend in very long instruction words (VLIW) architecture to solve the problem of area, energy consumption, and design complexity. Register-file-connected clustered (RFCC) VLIW architecture uses the mechanism of global register file to accomplish the inter-cluster data communications, thus eliminating the performance and energy consumption penalty caused by explicit inter-cluster data move operations in traditional bus-connected clustered (BCC) VLIW architecture. However, the limit number of access ports to the global register file has become an issue which must be well addressed; otherwise the performance and energy consumption would be harmed. In this paper, we presented compiler optimization techniques for an RFCC VLIW architecture called Lily, which is designed for encryption systems. These techniques aim at optimizing performance and energy consumption for Lily architecture, through appropriate manipulation of the code generation process to maintain a better management of the accesses to the global register file. All the techniques have been implemented and evaluated. The result shows that our techniques can significantly reduce the penalty of performance and energy consumption due to access port limitation of global register file. PMID:23970841

The Global Regulatory Architecture of Transcription during the Caulobacter Cell Cycle

PubMed Central

Zhou, Bo; Schrader, Jared M.; Kalogeraki, Virginia S.; Abeliuk, Eduardo; Dinh, Cong B.; Pham, James Q.; Cui, Zhongying Z.; Dill, David L.; McAdams, Harley H.; Shapiro, Lucy

2015-01-01

Each Caulobacter cell cycle involves differentiation and an asymmetric cell division driven by a cyclical regulatory circuit comprised of four transcription factors (TFs) and a DNA methyltransferase. Using a modified global 5′ RACE protocol, we globally mapped transcription start sites (TSSs) at base-pair resolution, measured their transcription levels at multiple times in the cell cycle, and identified their transcription factor binding sites. Out of 2726 TSSs, 586 were shown to be cell cycle-regulated and we identified 529 binding sites for the cell cycle master regulators. Twenty-three percent of the cell cycle-regulated promoters were found to be under the combinatorial control of two or more of the global regulators. Previously unknown features of the core cell cycle circuit were identified, including 107 antisense TSSs which exhibit cell cycle-control, and 241 genes with multiple TSSs whose transcription levels often exhibited different cell cycle timing. Cumulatively, this study uncovered novel new layers of transcriptional regulation mediating the bacterial cell cycle. PMID:25569173

The global regulatory architecture of transcription during the Caulobacter cell cycle.

PubMed

Zhou, Bo; Schrader, Jared M; Kalogeraki, Virginia S; Abeliuk, Eduardo; Dinh, Cong B; Pham, James Q; Cui, Zhongying Z; Dill, David L; McAdams, Harley H; Shapiro, Lucy

2015-01-01

Each Caulobacter cell cycle involves differentiation and an asymmetric cell division driven by a cyclical regulatory circuit comprised of four transcription factors (TFs) and a DNA methyltransferase. Using a modified global 5' RACE protocol, we globally mapped transcription start sites (TSSs) at base-pair resolution, measured their transcription levels at multiple times in the cell cycle, and identified their transcription factor binding sites. Out of 2726 TSSs, 586 were shown to be cell cycle-regulated and we identified 529 binding sites for the cell cycle master regulators. Twenty-three percent of the cell cycle-regulated promoters were found to be under the combinatorial control of two or more of the global regulators. Previously unknown features of the core cell cycle circuit were identified, including 107 antisense TSSs which exhibit cell cycle-control, and 241 genes with multiple TSSs whose transcription levels often exhibited different cell cycle timing. Cumulatively, this study uncovered novel new layers of transcriptional regulation mediating the bacterial cell cycle.

Enhancement of Spike Synchrony in Hindmarsh-Rose Neural Networks by Randomly Rewiring Connections

NASA Astrophysics Data System (ADS)

Yang, Renhuan; Song, Aiguo; Yuan, Wujie

Spike synchrony of the neural system is thought to have very dichotomous roles. On the one hand, it is ubiquitously present in the healthy brain and is thought to underlie feature binding during information processing. On the other hand, large scale synchronization is an underlying mechanism of epileptic seizures. In this paper, we investigate the spike synchrony of Hindmarsh-Rose (HR) neural networks. Our focus is the influence of the network connections on the spike synchrony of the neural networks. The simulations show that desynchronization in the nearest-neighbor coupled network evolves into accurate synchronization with connection-rewiring probability p increasing. We uncover a phenomenon of enhancement of spike synchrony by randomly rewiring connections. With connection strength c and average connection number m increasing spike synchrony is enhanced but it is not the whole story. Furthermore, the possible mechanism behind such synchronization is also addressed.

Global terrestrial water storage connectivity revealed using complex climate network analyses

NASA Astrophysics Data System (ADS)

Sun, A. Y.; Chen, J.; Donges, J.

2015-07-01

Terrestrial water storage (TWS) exerts a key control in global water, energy, and biogeochemical cycles. Although certain causal relationship exists between precipitation and TWS, the latter quantity also reflects impacts of anthropogenic activities. Thus, quantification of the spatial patterns of TWS will not only help to understand feedbacks between climate dynamics and the hydrologic cycle, but also provide new insights and model calibration constraints for improving the current land surface models. This work is the first attempt to quantify the spatial connectivity of TWS using the complex network theory, which has received broad attention in the climate modeling community in recent years. Complex networks of TWS anomalies are built using two global TWS data sets, a remote sensing product that is obtained from the Gravity Recovery and Climate Experiment (GRACE) satellite mission, and a model-generated data set from the global land data assimilation system's NOAH model (GLDAS-NOAH). Both data sets have 1° × 1° grid resolutions and cover most global land areas except for permafrost regions. TWS networks are built by first quantifying pairwise correlation among all valid TWS anomaly time series, and then applying a cutoff threshold derived from the edge-density function to retain only the most important features in the network. Basinwise network connectivity maps are used to illuminate connectivity of individual river basins with other regions. The constructed network degree centrality maps show the TWS anomaly hotspots around the globe and the patterns are consistent with recent GRACE studies. Parallel analyses of networks constructed using the two data sets reveal that the GLDAS-NOAH model captures many of the spatial patterns shown by GRACE, although significant discrepancies exist in some regions. Thus, our results provide further measures for constraining the current land surface models, especially in data sparse regions.

Abnormal functional global and local brain connectivity in female patients with anorexia nervosa

PubMed Central

Geisler, Daniel; Borchardt, Viola; Lord, Anton R.; Boehm, Ilka; Ritschel, Franziska; Zwipp, Johannes; Clas, Sabine; King, Joseph A.; Wolff-Stephan, Silvia; Roessner, Veit; Walter, Martin; Ehrlich, Stefan

2016-01-01

Background Previous resting-state functional connectivity studies in patients with anorexia nervosa used independent component analysis or seed-based connectivity analysis to probe specific brain networks. Instead, modelling the entire brain as a complex network allows determination of graph-theoretical metrics, which describe global and local properties of how brain networks are organized and how they interact. Methods To determine differences in network properties between female patients with acute anorexia nervosa and pairwise matched healthy controls, we used resting-state fMRI and computed well-established global and local graph metrics across a range of network densities. Results Our analyses included 35 patients and 35 controls. We found that the global functional network structure in patients with anorexia nervosa is characterized by increases in both characteristic path length (longer average routes between nodes) and assortativity (more nodes with a similar connectedness link together). Accordingly, we found locally decreased connectivity strength and increased path length in the posterior insula and thalamus. Limitations The present results may be limited to the methods applied during preprocessing and network construction. Conclusion We demonstrated anorexia nervosa–related changes in the network configuration for, to our knowledge, the first time using resting-state fMRI and graph-theoretical measures. Our findings revealed an altered global brain network architecture accompanied by local degradations indicating wide-scale disturbance in information flow across brain networks in patients with acute anorexia nervosa. Reduced local network efficiency in the thalamus and posterior insula may reflect a mechanism that helps explain the impaired integration of visuospatial and homeostatic signals in patients with this disorder, which is thought to be linked to abnormal representations of body size and hunger. PMID:26252451

Abnormal functional global and local brain connectivity in female patients with anorexia nervosa.

PubMed

Geisler, Daniel; Borchardt, Viola; Lord, Anton R; Boehm, Ilka; Ritschel, Franziska; Zwipp, Johannes; Clas, Sabine; King, Joseph A; Wolff-Stephan, Silvia; Roessner, Veit; Walter, Martin; Ehrlich, Stefan

2016-01-01

Previous resting-state functional connectivity studies in patients with anorexia nervosa used independent component analysis or seed-based connectivity analysis to probe specific brain networks. Instead, modelling the entire brain as a complex network allows determination of graph-theoretical metrics, which describe global and local properties of how brain networks are organized and how they interact. To determine differences in network properties between female patients with acute anorexia nervosa and pairwise matched healthy controls, we used resting-state fMRI and computed well-established global and local graph metrics across a range of network densities. Our analyses included 35 patients and 35 controls. We found that the global functional network structure in patients with anorexia nervosa is characterized by increases in both characteristic path length (longer average routes between nodes) and assortativity (more nodes with a similar connectedness link together). Accordingly, we found locally decreased connectivity strength and increased path length in the posterior insula and thalamus. The present results may be limited to the methods applied during preprocessing and network construction. We demonstrated anorexia nervosa-related changes in the network configuration for, to our knowledge, the first time using resting-state fMRI and graph-theoretical measures. Our findings revealed an altered global brain network architecture accompanied by local degradations indicating wide-scale disturbance in information flow across brain networks in patients with acute anorexia nervosa. Reduced local network efficiency in the thalamus and posterior insula may reflect a mechanism that helps explain the impaired integration of visuospatial and homeostatic signals in patients with this disorder, which is thought to be linked to abnormal representations of body size and hunger.

Integration of a complex regulatory cascade involving the SirA/BarA and Csr global regulatory systems that controls expression of the Salmonella SPI-1 and SPI-2 virulence regulons through HilD.

PubMed

Martínez, Luary C; Yakhnin, Helen; Camacho, Martha I; Georgellis, Dimitris; Babitzke, Paul; Puente, José L; Bustamante, Víctor H

2011-06-01

Salmonella pathogenicity islands 1 and 2 (SPI-1 and SPI-2) play key roles in the pathogenesis of Salmonella enterica. Previously, we showed that when Salmonella grows in Luria-Bertani medium, HilD, encoded in SPI-1, first induces the expression of hilA, located in SPI-1, and subsequently of the ssrAB operon, located in SPI-2. These genes code for HilA and the SsrA/B two-component system, the positive regulators of the SPI-1 and SPI-2 regulons respectively. In this study, we demonstrate that CsrA, a global regulatory RNA binding protein, post-transcriptionally regulates hilD expression by directly binding near the Shine-Dalgarno and translation initiation codon sequences of the hilD mRNA, preventing its translation and leading to its accelerated turnover. Negative regulation is counteracted by the global SirA/BarA two-component system, which directly activates the expression of CsrB and CsrC, two non-coding regulatory RNAs that sequester CsrA, thereby preventing it from binding to its target mRNAs. Our results illustrate the integration of global and specific regulators into a multifactorial regulatory cascade controlling the expression of virulence genes acquired by horizontal transfer events. © 2011 Blackwell Publishing Ltd.

NMR unfolding studies on a liver bile acid binding protein reveal a global two-state unfolding and localized singular behaviors.

PubMed

D'Onofrio, Mariapina; Ragona, Laura; Fessas, Dimitrios; Signorelli, Marco; Ugolini, Raffaella; Pedò, Massimo; Assfalg, Michael; Molinari, Henriette

2009-01-01

The folding properties of a bile acid binding protein, belonging to a subfamily of the fatty acid binding proteins, have been here investigated both by hydrogen exchange measurements, using the SOFAST NMR approach, and urea denaturation experiments. The urea unfolding profiles of individual residues, acting as single probes, were simultaneously analyzed through a global fit, according to a two-state unfolding model. The resulting conformational stability DeltaG(U)(H(2)O)=7.2+/-0.25kcal mol(-1) is in good agreement with hydrogen exchange stability DeltaG(op). While the majority of protein residues satisfy this model, few amino-acids display a singular behavior, not directly amenable to the presence of a folding intermediate, as reported for other fatty acid binding proteins. These residues are part of a protein patch characterized by enhanced plasticity. To explain this singular behavior a tentative model has been proposed which takes into account the interplay between the dynamic features and the formation of transient aggregates. A functional role for this plasticity, related to translocation across the nuclear membrane, is discussed.

Isolation from genomic DNA of sequences binding specific regulatory proteins by the acceleration of protein electrophoretic mobility upon DNA binding.

PubMed

Subrahmanyam, S; Cronan, J E

1999-01-21

We report an efficient and flexible in vitro method for the isolation of genomic DNA sequences that are the binding targets of a given DNA binding protein. This method takes advantage of the fact that binding of a protein to a DNA molecule generally increases the rate of migration of the protein in nondenaturing gel electrophoresis. By the use of a radioactively labeled DNA-binding protein and nonradioactive DNA coupled with PCR amplification from gel slices, we show that specific binding sites can be isolated from Escherichia coli genomic DNA. We have applied this method to isolate a binding site for FadR, a global regulator of fatty acid metabolism in E. coli. We have also isolated a second binding site for BirA, the biotin operon repressor/biotin ligase, from the E. coli genome that has a very low binding efficiency compared with the bio operator region.

Role of platinum DNA damage-induced transcriptional inhibition in chemotherapy-induced neuronal atrophy and peripheral neurotoxicity.

PubMed

Yan, Fang; Liu, Johnson J; Ip, Virginia; Jamieson, Stephen M F; McKeage, Mark J

2015-12-01

Platinum-based anticancer drugs cause peripheral neurotoxicity by damaging sensory neurons within the dorsal root ganglia (DRG), but the mechanisms are incompletely understood. The roles of platinum DNA binding, transcription inhibition and altered cell size were investigated in primary cultures of rat DRG cells. Click chemistry quantitative fluorescence imaging of RNA-incorporated 5-ethynyluridine showed high, but wide ranging, global levels of transcription in individual neurons that correlated with their cell body size. Treatment with platinum drugs reduced neuronal transcription and cell body size to an extent that corresponded to the amount of preceding platinum DNA binding, but without any loss of neuronal cells. The effects of platinum drugs on neuronal transcription and cell body size were inhibited by blocking platinum DNA binding with sodium thiosulfate, and mimicked by treatment with a model transcriptional inhibitor, actinomycin D. In vivo oxaliplatin treatment depleted the total RNA content of DRG tissue concurrently with altering DRG neuronal size. These findings point to a mechanism of chemotherapy-induced peripheral neurotoxicity, whereby platinum DNA damage induces global transcriptional arrest leading in turn to neuronal atrophy. DRG neurons may be particularly vulnerable to this mechanism of toxicity because of their requirements for high basal levels of global transcriptional activity. Findings point to a new stepwise mechanism of chemotherapy-induced peripheral neurotoxicity, whereby platinum DNA damage induces global transcriptional arrest leading in turn to neuronal atrophy. Dorsal root ganglion neurons may be particularly vulnerable to this neurotoxicity because of their high global transcriptional outputs, demonstrated in this study by click chemistry quantitative fluorescence imaging. © 2015 International Society for Neurochemistry.

Post-transcriptional regulation in corticogenesis: how RNA-binding proteins help build the brain

PubMed Central

Pilaz, Louis-Jan; Silver, Debra L.

2015-01-01

The cerebral cortex, the brain structure responsible for our higher cognitive functions, is built during embryonic development in a process called corticogenesis. During corticogenesis, neural stem cells generate distinct populations of progenitors and excitatory neurons. These new neurons migrate radially in the cortex, eventually forming neuronal layers and establishing synaptic connections with other neurons both within and outside the cortex. Perturbations to corticogenesis can result in severe neurodevelopmental disorders, thus emphasizing the need to better understand molecular regulation of brain development. Recent studies in both model organisms and humans have collectively highlighted roles for post-transcriptional regulation in virtually all steps of corticogenesis. Genomic approaches have revealed global RNA changes associated with spatial and temporal regulation of cortical development. Additionally, genetic studies have uncovered RNA-binding proteins (RBPs) critical for cell proliferation, differentiation, and migration within the developing neocortex. Many of these same RBPs play causal roles in neurodevelopmental pathologies. In the developing neocortex, RBPs influence diverse steps of mRNA metabolism, including splicing, stability, translation, and localization. With the advent of new technologies, researchers have begun to uncover key transcripts regulated by these RBPs. Given the complexity of the developing mammalian cortex, a major challenge for the future will be to understand how dynamic RNA regulation occurs within heterogeneous cell populations, across space and time. In sum, post-transcriptional regulation has emerged as a critical mechanism for driving corticogenesis and exciting direction of future research. PMID:26088328

Fluorescent Protein-Based Ca2+ Sensor Reveals Global, Divalent Cation-Dependent Conformational Changes in Cardiac Troponin C.

PubMed

Badr, Myriam A; Pinto, Jose R; Davidson, Michael W; Chase, P Bryant

2016-01-01

Cardiac troponin C (cTnC) is a key effector in cardiac muscle excitation-contraction coupling as the Ca2+ sensing subunit responsible for controlling contraction. In this study, we generated several FRET sensors for divalent cations based on cTnC flanked by a donor fluorescent protein (CFP) and an acceptor fluorescent protein (YFP). The sensors report Ca2+ and Mg2+ binding, and relay global structural information about the structural relationship between cTnC's N- and C-domains. The sensors were first characterized using end point titrations to decipher the response to Ca2+ binding in the presence or absence of Mg2+. The sensor that exhibited the largest responses in end point titrations, CTV-TnC, (Cerulean, TnC, and Venus) was characterized more extensively. Most of the divalent cation-dependent FRET signal originates from the high affinity C-terminal EF hands. CTV-TnC reconstitutes into skinned fiber preparations indicating proper assembly of troponin complex, with only ~0.2 pCa unit rightward shift of Ca2+-sensitive force development compared to WT-cTnC. Affinity of CTV-TnC for divalent cations is in agreement with known values for WT-cTnC. Analytical ultracentrifugation indicates that CTV-TnC undergoes compaction as divalent cations bind. C-terminal sites induce ion-specific (Ca2+ versus Mg2+) conformational changes in cTnC. Our data also provide support for the presence of additional, non-EF-hand sites on cTnC for Mg2+ binding. In conclusion, we successfully generated a novel FRET-Ca2+ sensor based on full length cTnC with a variety of cellular applications. Our sensor reveals global structural information about cTnC upon divalent cation binding.

Integrated Analysis and Visualization of Group Differences in Structural and Functional Brain Connectivity: Applications in Typical Ageing and Schizophrenia.

PubMed

Langen, Carolyn D; White, Tonya; Ikram, M Arfan; Vernooij, Meike W; Niessen, Wiro J

2015-01-01

Structural and functional brain connectivity are increasingly used to identify and analyze group differences in studies of brain disease. This study presents methods to analyze uni- and bi-modal brain connectivity and evaluate their ability to identify differences. Novel visualizations of significantly different connections comparing multiple metrics are presented. On the global level, "bi-modal comparison plots" show the distribution of uni- and bi-modal group differences and the relationship between structure and function. Differences between brain lobes are visualized using "worm plots". Group differences in connections are examined with an existing visualization, the "connectogram". These visualizations were evaluated in two proof-of-concept studies: (1) middle-aged versus elderly subjects; and (2) patients with schizophrenia versus controls. Each included two measures derived from diffusion weighted images and two from functional magnetic resonance images. The structural measures were minimum cost path between two anatomical regions according to the "Statistical Analysis of Minimum cost path based Structural Connectivity" method and the average fractional anisotropy along the fiber. The functional measures were Pearson's correlation and partial correlation of mean regional time series. The relationship between structure and function was similar in both studies. Uni-modal group differences varied greatly between connectivity types. Group differences were identified in both studies globally, within brain lobes and between regions. In the aging study, minimum cost path was highly effective in identifying group differences on all levels; fractional anisotropy and mean correlation showed smaller differences on the brain lobe and regional levels. In the schizophrenia study, minimum cost path and fractional anisotropy showed differences on the global level and within brain lobes; mean correlation showed small differences on the lobe level. Only fractional anisotropy and mean correlation showed regional differences. The presented visualizations were helpful in comparing and evaluating connectivity measures on multiple levels in both studies.

Ligand Binding Site Detection by Local Structure Alignment and Its Performance Complementarity

PubMed Central

Lee, Hui Sun; Im, Wonpil

2013-01-01

Accurate determination of potential ligand binding sites (BS) is a key step for protein function characterization and structure-based drug design. Despite promising results of template-based BS prediction methods using global structure alignment (GSA), there is a room to improve the performance by properly incorporating local structure alignment (LSA) because BS are local structures and often similar for proteins with dissimilar global folds. We present a template-based ligand BS prediction method using G-LoSA, our LSA tool. A large benchmark set validation shows that G-LoSA predicts drug-like ligands’ positions in single-chain protein targets more precisely than TM-align, a GSA-based method, while the overall success rate of TM-align is better. G-LoSA is particularly efficient for accurate detection of local structures conserved across proteins with diverse global topologies. Recognizing the performance complementarity of G-LoSA to TM-align and a non-template geometry-based method, fpocket, a robust consensus scoring method, CMCS-BSP (Complementary Methods and Consensus Scoring for ligand Binding Site Prediction), is developed and shows improvement on prediction accuracy. The G-LoSA source code is freely available at http://im.bioinformatics.ku.edu/GLoSA. PMID:23957286

Connectivity patterns in cognitive control networks predict naturalistic multitasking ability.

PubMed

Wen, Tanya; Liu, De-Cyuan; Hsieh, Shulan

2018-06-01

Multitasking is a fundamental aspect of everyday life activities. To achieve a complex, multi-component goal, the tasks must be subdivided into sub-tasks and component steps, a critical function of prefrontal networks. The prefrontal cortex is considered to be organized in a cascade of executive processes from the sensorimotor to anterior prefrontal cortex, which includes execution of specific goal-directed action, to encoding and maintaining task rules, and finally monitoring distal goals. In the current study, we used a virtual multitasking paradigm to tap into real-world performance and relate it to each individual's resting-state functional connectivity in fMRI. While did not find any correlation between global connectivity of any of the major networks with multitasking ability, global connectivity of the lateral prefrontal cortex (LPFC) was predictive of multitasking ability. Further analysis showed that multivariate connectivity patterns within the sensorimotor network (SMN), and between-network connectivity of the frontoparietal network (FPN) and dorsal attention network (DAN), predicted individual multitasking ability and could be generalized to novel individuals. Together, these results support previous research that prefrontal networks underlie multitasking abilities and show that connectivity patterns in the cascade of prefrontal networks may explain individual differences in performance. Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

Abnormal rich club organization and impaired correlation between structural and functional connectivity in migraine sufferers.

PubMed

Li, Kang; Liu, Lijun; Yin, Qin; Dun, Wanghuan; Xu, Xiaolin; Liu, Jixin; Zhang, Ming

2017-04-01

Because of the unique position of the topologically central role of densely interconnected brain hubs, our study aimed to investigate whether these regions and their related connections would be particularly vulnerable to migraine. In our study, we explored the rich club structure and its role in global functional dynamics in 30 patients with migraine without aura and 30 healthy controls. DTI and resting fMRI were used to construct structural connectivity (SC) and functional connectivity (FC) networks. An independent replication data set of 26 patients and 26 controls was included to replicate and validate significant findings. As compared with the controls, the structural networks of patients exhibited altered rich club organization with higher level of feeder connection density, abnormal small-world organization with increased global efficiency and decreased strength of SC-FC coupling. As these abnormal topological properties and headache attack duration exhibited a significant association with increased density of feeder connections, our results indicated that migraine may be characterized by a selective alteration of the structural connectivity of the rich club regions, tending to have higher 'bridgeness' with non-rich club regions, which may increase the integration among pain-related brain circuits with more excitability but less inhibition for the modulation of migraine.

Sex differences in the relationship between white matter connectivity and creativity.

PubMed

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.

Structure of the ACF7 EF-Hand-GAR Module and Delineation of Microtubule Binding Determinants.

PubMed

Lane, Thomas R; Fuchs, Elaine; Slep, Kevin C

2017-07-05

Spectraplakins are large molecules that cross-link F-actin and microtubules (MTs). Mutations in spectraplakins yield defective cell polarization, aberrant focal adhesion dynamics, and dystonia. We present the 2.8 Å crystal structure of the hACF7 EF1-EF2-GAR MT-binding module and delineate the GAR residues critical for MT binding. The EF1-EF2 and GAR domains are autonomous domains connected by a flexible linker. The EF1-EF2 domain is an EFβ-scaffold with two bound Ca 2+ ions that straddle an N-terminal α helix. The GAR domain has a unique α/β sandwich fold that coordinates Zn 2+ . While the EF1-EF2 domain is not sufficient for MT binding, the GAR domain is and likely enhances EF1-EF2-MT engagement. Residues in a conserved basic patch, distal to the GAR domain's Zn 2+ -binding site, mediate MT binding. Copyright © 2017 Elsevier Ltd. All rights reserved.

Interaction between two adapter proteins, PAG and EBP50: a possible link between membrane rafts and actin cytoskeleton.

PubMed

Brdicková, N; Brdicka, T; Andera, L; Spicka, J; Angelisová, P; Milgram, S L; Horejsí, V

2001-10-26

Phosphoprotein associated with GEMs (PAG), also known as Csk-binding protein (Cbp), is a broadly expressed palmitoylated transmembrane adapter protein found in membrane rafts, also called GEMs (glycosphingolipid-enriched membrane microdomains). PAG is known to bind and activate the essential regulator of Src-family kinases, cytoplasmic protein tyrosine kinase Csk. In the present study we used the yeast 2-hybrid system to search for additional proteins which might bind to PAG. We have identified the abundant cytoplasmic adapter protein EBP50 (ezrin/radixin/moesin (ERM)-binding phosphoprotein of 50 kDa), also known as NHERF (Na(+)/H(+) exchanger regulatory factor), as a specific PAG-binding partner. The interaction involves the C-terminal sequence (TRL) of PAG and N-terminal PDZ domain(s) of EBP50. As EBP50 is known to interact via its C-terminal domain with the ERM-family proteins, which in turn bind to actin cytoskeleton, the PAG-EBP50 interaction may be important for connecting membrane rafts to the actin cytoskeleton.

Connecting phenological predictions with population growth rates for mountain pine beetle, an outbreak insect

Treesearch

James A. Powell; Barbara J. Bentz

2009-01-01

It is expected that a significant impact of global warming will be disruption of phenology as environmental cues become disassociated from their selective impacts. However there are few, if any, models directly connecting phenology with population growth rates. In this paper we discuss connecting a distributional model describing mountain pine beetle phenology with a...

Providing nearest neighbor point-to-point communications among compute nodes of an operational group in a global combining network of a parallel computer

DOEpatents

Archer, Charles J.; Faraj, Ahmad A.; Inglett, Todd A.; Ratterman, Joseph D.

2012-10-23

Methods, apparatus, and products are disclosed for providing nearest neighbor point-to-point communications among compute nodes of an operational group in a global combining network of a parallel computer, each compute node connected to each adjacent compute node in the global combining network through a link, that include: identifying each link in the global combining network for each compute node of the operational group; designating one of a plurality of point-to-point class routing identifiers for each link such that no compute node in the operational group is connected to two adjacent compute nodes in the operational group with links designated for the same class routing identifiers; and configuring each compute node of the operational group for point-to-point communications with each adjacent compute node in the global combining network through the link between that compute node and that adjacent compute node using that link's designated class routing identifier.

Combining NMR spectral and structural data to form models of polychlorinated dibenzodioxins, dibenzofurans, and biphenyls binding to the AhR

NASA Astrophysics Data System (ADS)

Beger, Richard D.; Buzatu, Dan A.; Wilkes, Jon G.

2002-10-01

A three-dimensional quantitative spectrometric data-activity relationship (3D-QSDAR) modeling technique which uses NMR spectral and structural information that is combined in a 3D-connectivity matrix has been developed. A 3D-connectivity matrix was built by displaying all possible assigned carbon NMR chemical shifts, carbon-to-carbon connections, and distances between the carbons. Two-dimensional 13C-13C COSY and 2D slices from the distance dimension of the 3D-connectivity matrix were used to produce a relationship among the 2D spectral patterns for polychlorinated dibenzofurans, dibenzodioxins, and biphenyls (PCDFs, PCDDs, and PCBs respectively) binding to the aryl hydrocarbon receptor (AhR). We refer to this technique as comparative structural connectivity spectral analysis (CoSCoSA) modeling. All CoSCoSA models were developed using forward multiple linear regression analysis of the predicted 13C NMR structure-connectivity spectral bins. A CoSCoSA model for 26 PCDFs had an explained variance (r2) of 0.93 and an average leave-four-out cross-validated variance (q4 2) of 0.89. A CoSCoSA model for 14 PCDDs produced an r2 of 0.90 and an average leave-two-out cross-validated variance (q2 2) of 0.79. One CoSCoSA model for 12 PCBs gave an r2 of 0.91 and an average q2 2 of 0.80. Another CoSCoSA model for all 52 compounds had an r2 of 0.85 and an average q4 2 of 0.52. Major benefits of CoSCoSA modeling include ease of development since the technique does not use molecular docking routines.

A Flexible Binding Site Architecture Provides New Insights into CcpA Global Regulation in Gram-Positive Bacteria.

PubMed

Yang, Yunpeng; Zhang, Lu; Huang, He; Yang, Chen; Yang, Sheng; Gu, Yang; Jiang, Weihong

2017-01-24

Catabolite control protein A (CcpA) is the master regulator in Gram-positive bacteria that mediates carbon catabolite repression (CCR) and carbon catabolite activation (CCA), two fundamental regulatory mechanisms that enable competitive advantages in carbon catabolism. It is generally regarded that CcpA exerts its regulatory role by binding to a typical 14- to 16-nucleotide (nt) consensus site that is called a catabolite response element (cre) within the target regions. However, here we report a previously unknown noncanonical flexible architecture of the CcpA-binding site in solventogenic clostridia, providing new mechanistic insights into catabolite regulation. This novel CcpA-binding site, named cre var , has a unique architecture that consists of two inverted repeats and an intervening spacer, all of which are variable in nucleotide composition and length, except for a 6-bp core palindromic sequence (TGTAAA/TTTACA). It was found that the length of the intervening spacer of cre var can affect CcpA binding affinity, and moreover, the core palindromic sequence of cre var is the key structure for regulation. Such a variable architecture of cre var shows potential importance for CcpA's diverse and fine regulation. A total of 103 potential cre var sites were discovered in solventogenic Clostridium acetobutylicum, of which 42 sites were picked out for electrophoretic mobility shift assays (EMSAs), and 30 sites were confirmed to be bound by CcpA. These 30 cre var sites are associated with 27 genes involved in many important pathways. Also of significance, the cre var sites are found to be widespread and function in a great number of taxonomically different Gram-positive bacteria, including pathogens, suggesting their global role in Gram-positive bacteria. In Gram-positive bacteria, the global regulator CcpA controls a large number of important physiological and metabolic processes. Although a typical consensus CcpA-binding site, cre, has been identified, it remains poorly explored for the diversity of CcpA-mediated catabolite regulation. Here, we discovered a novel flexible CcpA-binding site architecture (cre var ) that is highly variable in both length and base composition but follows certain principles, providing new insights into how CcpA can differentially recognize a variety of target genes to form a complicated regulatory network. A comprehensive search further revealed the wide distribution of cre var sites in Gram-positive bacteria, indicating it may have a universal function. This finding is the first to characterize such a highly flexible transcription factor-binding site architecture, which would be valuable for deeper understanding of CcpA-mediated global catabolite regulation in bacteria. Copyright © 2017 Yang et al.

Cortical Circuit for Binding Object Identity and Location During Multiple-Object Tracking

PubMed Central

Nummenmaa, Lauri; Oksama, Lauri; Glerean, Erico; Hyönä, Jukka

2017-01-01

Abstract Sustained multifocal attention for moving targets requires binding object identities with their locations. The brain mechanisms of identity-location binding during attentive tracking have remained unresolved. In 2 functional magnetic resonance imaging experiments, we measured participants’ hemodynamic activity during attentive tracking of multiple objects with equivalent (multiple-object tracking) versus distinct (multiple identity tracking, MIT) identities. Task load was manipulated parametrically. Both tasks activated large frontoparietal circuits. MIT led to significantly increased activity in frontoparietal and temporal systems subserving object recognition and working memory. These effects were replicated when eye movements were prohibited. MIT was associated with significantly increased functional connectivity between lateral temporal and frontal and parietal regions. We propose that coordinated activity of this network subserves identity-location binding during attentive tracking. PMID:27913430

Global Connections to Global Partnerships: Navigating the Changing Landscape of Internationalism and Cross-Border Higher Education

ERIC Educational Resources Information Center

Olcott, Don, Jr.

2009-01-01

The purpose of this article is to provide continuing higher education leaders with a comprehensive overview of the major considerations for doing business in the global market. Included is an analysis of the driving forces in global higher education and current trends in cross-border programs and a brief review of activities that may be part of a…

Think Globally, Act Locally: Teaching Climate Change through Digital Inquiry

ERIC Educational Resources Information Center

Castek, Jill; Dwyer, Bernadette

2018-01-01

In the 21st century, our students increasingly communicate, connect, collaborate, and interact with diverse cultures and traditions around the world, so they need to develop global literacy. This department column highlights research and research-to-practice at the international level to bring global best teaching practices to the forefront.…

Who Is the Lifelong Learner? Globalization, Lifelong Learning and Hermeneutics

ERIC Educational Resources Information Center

Uggla, Bengt Kristensson

2008-01-01

The aim of this essay is to elaborate on the inner connection between three such diverse entities as lifelong learning, globalization and hermeneutics. After placing lifelong learning in a societal context framed by globalization, my intention is to reflect on the prerequisites for introducing a hermeneutical contribution to the understanding of…

"Nobody Spoke Like I Did": Picture Books, Critical Literacy, and Global Contexts

ERIC Educational Resources Information Center

Callow, Jon

2017-01-01

In the 21st century, our students increasingly communicate, connect, collaborate, and interact with diverse cultures and traditions around the world, so they need to develop global literacy. This department column highlights research and research-to-practice at the international level to bring global best teaching practices to the forefront.…

Creating Global-Ready Places: The Campus-Community Connection

ERIC Educational Resources Information Center

Chapman, M. Perry

2009-01-01

Globalization is reshaping the relationship between U.S. universities and their host cities. U.S. universities must adjust to momentous changes in the worldwide higher education system, and U.S. cities must retool to maintain their place in the innovation economy. Institutional and civic resources are being pooled to form global-ready urban…

Reading Globally, K-8: Connecting Students to the World through Literature

ERIC Educational Resources Information Center

Lehman, Barbara A.; Freeman, Evelyn B.; Scharer, Patricia L.

2010-01-01

With an increasingly diverse nation and an ever-smaller world, global awareness is a necessity for today's students. This unique and indispensable handbook shows how teachers can use global literature to help students expand their worldview while developing increased respect for cultural diversity. The authors explain how to infuse global…

The Global Education Reform Movement and Its Effect on the Local African American Community

ERIC Educational Resources Information Center

Rushek, Kelli A.

2017-01-01

This conceptual research paper explores educational reformation through the theoretical work of Appadurai (1996) and Castells (2000) in the flows and connectivity of global networks. It discusses the global, national, and local effects of the neoliberal ideological reformations in education and their effects on the African American student…

Global Market Access in the Internet Era: South Africa's Wood Furniture Industry.

ERIC Educational Resources Information Center

Moodley, Sagren

2002-01-01

Explores the link between Internet connectivity and access to global markets, and uses the South African wood furniture producers as they are integrated into global value chains and exposed to the demands of more sophisticated markets. Articulates policy recommendations to promote greater diffusion of e-commerce technologies in the wood furniture…

Panwapa: Global Kids, Global Connections

ERIC Educational Resources Information Center

Berson, Ilene R.; Berson, Michael J.

2009-01-01

Panwapa, created by the Sesame Street Workshop of PBS, is an example of an initiative on the Internet designed to enhance students' learning by exposing them to global communities. Panwapa means "Here on Earth" in Tshiluba, a Bantu language spoken in the Democratic Republic of Congo. At the Panwapa website, www.panwapa.org, children aged…

Geomagnetic South Atlantic Anomaly and global sea level rise: A direct connection?

NASA Astrophysics Data System (ADS)

de Santis, A.; Qamili, E.; Spada, G.; Gasperini, P.

2012-01-01

We highlight the existence of an intriguing and to date unreported relationship between the surface area of the South Atlantic Anomaly (SAA) of the geomagnetic field and the current trend in global sea level rise. These two geophysical variables have been growing coherently during the last three centuries, thus strongly suggesting a causal relationship supported by some statistical tests. The monotonic increase of the SAA surface area since 1600 may have been associated with an increased inflow of radiation energy through the inner Van Allen belt with a consequent warming of the Earth's atmosphere and finally global sea level rise. An alternative suggestive and original explanation is also offered, in which pressure changes at the core-mantle boundary cause surface deformations and relative sea level variations. Although we cannot establish a clear connection between SAA dynamics and global warming, the strong correlation between the former and global sea level supports the idea that global warming may be at least partly controlled by deep Earth processes triggering geomagnetic phenomena, such as the South Atlantic Anomaly, on a century time scale.

The CORALS Connection

ERIC Educational Resources Information Center

Plankis, Brian; Klein, Carolyn

2010-01-01

The Ocean, Reefs, Aquariums, Literacy, and Stewardship (CORALS) research program helps students connect global environmental issues to local concerns and personal choices. During the 18-week program, students strengthen their understanding of coral reef decline through a classroom aquarium activity, communicate with science experts, and create…

Increased corticolimbic connectivity in cocaine dependence versus pathological gambling is associated with drug severity and emotion-related impulsivity.

PubMed

Contreras-Rodríguez, Oren; Albein-Urios, Natalia; Vilar-López, Raquel; Perales, Jose C; Martínez-Gonzalez, Jose M; Fernández-Serrano, Maria J; Lozano-Rojas, Oscar; Clark, Luke; Verdejo-García, Antonio

2016-05-01

Neural biomarkers for the active detrimental effects of cocaine dependence (CD) are lacking. Direct comparisons of brain connectivity in cocaine-targeted networks between CD and behavioural addictions (i.e. pathological gambling, PG) may be informative. This study therefore contrasted the resting-state functional connectivity networks of 20 individuals with CD, 19 individuals with PG and 21 healthy individuals (controls). Study groups were assessed to rule out psychiatric co-morbidities (except alcohol abuse and nicotine dependence) and current substance use or gambling (except PG). We first examined global connectivity differences in the corticolimbic reward network and then utilized seed-based analyses to characterize the connectivity of regions displaying between-group differences. We examined the relationships between seed-based connectivity and trait impulsivity and cocaine severity. CD compared with PG displayed increased global functional connectivity in a large-scale ventral corticostriatal network involving the orbitofrontal cortex, caudate, thalamus and amygdala. Seed-based analyses showed that CD compared with PG exhibited enhanced connectivity between the orbitofrontal and subgenual cingulate cortices and between caudate and lateral prefrontal cortex, which are involved in representing the value of decision-making feedback. CD and PG compared with controls showed overlapping connectivity changes between the orbitofrontal and dorsomedial prefrontal cortices and between amygdala and insula, which are involved in stimulus-outcome learning. Orbitofrontal-subgenual cingulate cortical connectivity correlated with impulsivity and caudate/amygdala connectivity correlated with cocaine severity. We conclude that CD is linked to enhanced connectivity in a large-scale ventral corticostriatal-amygdala network that is relevant to decision making and likely to reflect an active cocaine detrimental effect. © 2015 Society for the Study of Addiction.

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

PubMed

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.

Dynamic functional connectivity reveals altered variability in functional connectivity among patients with major depressive disorder.

PubMed

Demirtaş, Murat; Tornador, Cristian; Falcón, Carles; López-Solà, Marina; Hernández-Ribas, Rosa; Pujol, Jesús; Menchón, José M; Ritter, Petra; Cardoner, Narcis; Soriano-Mas, Carles; Deco, Gustavo

2016-08-01

Resting-state fMRI (RS-fMRI) has become a useful tool to investigate the connectivity structure of mental health disorders. In the case of major depressive disorder (MDD), recent studies regarding the RS-fMRI have found abnormal connectivity in several regions of the brain, particularly in the default mode network (DMN). Thus, the relevance of the DMN to self-referential thoughts and ruminations has made the use of the resting-state approach particularly important for MDD. The majority of such research has relied on the grand averaged functional connectivity measures based on the temporal correlations between the BOLD time series of various brain regions. We, in our study, investigated the variations in the functional connectivity over time at global and local level using RS-fMRI BOLD time series of 27 MDD patients and 27 healthy control subjects. We found that global synchronization and temporal stability were significantly increased in the MDD patients. Furthermore, the participants with MDD showed significantly increased overall average (static) functional connectivity (sFC) but decreased variability of functional connectivity (vFC) within specific networks. Static FC increased to predominance among the regions pertaining to the default mode network (DMN), while the decreased variability of FC was observed in the connections between the DMN and the frontoparietal network. Hum Brain Mapp 37:2918-2930, 2016. © 2016 Wiley Periodicals, Inc. © 2016 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.

Altered resting-state functional connectivity in women with chronic fatigue syndrome.

PubMed

Kim, Byung-Hoon; Namkoong, Kee; Kim, Jae-Jin; Lee, Seojung; Yoon, Kang Joon; Choi, Moonjong; Jung, Young-Chul

2015-12-30

The biological underpinnings of the psychological factors characterizing chronic fatigue syndrome (CFS) have not been extensively studied. Our aim was to evaluate alterations of resting-state functional connectivity in CFS patients. Participants comprised 18 women with CFS and 18 age-matched female healthy controls who were recruited from the local community. Structural and functional magnetic resonance images were acquired during a 6-min passive-viewing block scan. Posterior cingulate cortex seeded resting-state functional connectivity was evaluated, and correlation analyses of connectivity strength were performed. Graph theory analysis of 90 nodes of the brain was conducted to compare the global and local efficiency of connectivity networks in CFS patients with that in healthy controls. The posterior cingulate cortex in CFS patients showed increased resting-state functional connectivity with the dorsal and rostral anterior cingulate cortex. Connectivity strength of the posterior cingulate cortex to the dorsal anterior cingulate cortex significantly correlated with the Chalder Fatigue Scale score, while the Beck Depression Inventory (BDI) score was controlled. Connectivity strength to the rostral anterior cingulate cortex significantly correlated with the Chalder Fatigue Scale score. Global efficiency of the posterior cingulate cortex was significantly lower in CFS patients, while local efficiency showed no difference from findings in healthy controls. The findings suggest that CFS patients show inefficient increments in resting-state functional connectivity that are linked to the psychological factors observed in the syndrome. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Network architecture of the cerebral nuclei (basal ganglia) association and commissural connectome

PubMed Central

Swanson, Larry W.; Sporns, Olaf; Hahn, Joel D.

2016-01-01

The cerebral nuclei form the ventral division of the cerebral hemisphere and are thought to play an important role in neural systems controlling somatic movement and motivation. Network analysis was used to define global architectural features of intrinsic cerebral nuclei circuitry in one hemisphere (association connections) and between hemispheres (commissural connections). The analysis was based on more than 4,000 reports of histologically defined axonal connections involving all 45 gray matter regions of the rat cerebral nuclei and revealed the existence of four asymmetrically interconnected modules. The modules form four topographically distinct longitudinal columns that only partly correspond to previous interpretations of cerebral nuclei structure–function organization. The network of connections within and between modules in one hemisphere or the other is quite dense (about 40% of all possible connections), whereas the network of connections between hemispheres is weak and sparse (only about 5% of all possible connections). Particularly highly interconnected regions (rich club and hubs within it) form a topologically continuous band extending through two of the modules. Connection path lengths among numerous pairs of regions, and among some of the network’s modules, are relatively long, thus accounting for low global efficiency in network communication. These results provide a starting point for reexamining the connectional organization of the cerebral hemispheres as a whole (right and left cerebral cortex and cerebral nuclei together) and their relation to the rest of the nervous system. PMID:27647882

Positron Emission Tomography of Brain β-Amyloid and Tau Levels in Adults With Down Syndrome

PubMed Central

Nelson, Linda D.; Siddarth, Prabha; Kepe, Vladimir; Scheibel, Kevin E.; Huang, S. C.; Barrio, Jorge R.; Small, Gary W.

2012-01-01

Objectives To determine the neuropathological load in the living brain of nondemented adults with Down syndrome using positron emission tomography with 2-(1-{6-[(2-fluorine 18–labeled fluoroethyl)methylamino]-2-napthyl}ethylidene) malononitrile ([18F]FDDNP) and to assess the influence of age and cognitive and behavioral functioning. For reference, [18F]FDDNP binding values and patterns were compared with those from patients with Alzheimer disease and cognitively intact control participants. Design Cross-sectional clinical study. Participants Volunteer sample of 19 persons with Down syndrome without dementia (mean age, 36.7 years), 10 patients with Alzheimer disease (mean age, 66.5 years), and 10 controls (mean age, 43.8 years). Main Outcome Measures Binding of [18F]FDDNP in brain regions of interest, including the parietal, medial temporal, lateral temporal, and frontal lobes and posterior cingulate gyrus, and the average of all regions (global binding). Results The [18F]FDDNP binding values were higher in all brain regions in the Down syndrome group than in controls. Compared with the Alzheimer disease group, the Down syndrome group had higher [18F]FDDNP binding values in the parietal and frontal regions, whereas binding levels in other regions were comparable. Within the Down syndrome group, age correlated with [18F]FDDNP binding values in all regions except the posterior cingulate, and several measures of behavioral dysfunction showed positive correlations with global, frontal, parietal, and posterior cingulate [18F]FDDNP binding. Conclusions Consistent with neuropathological findings from postmortem studies, [18F]FDDNP positron emission tomography shows high binding levels in Down syndrome comparable to Alzheimer disease and greater levels than in members of a control group. The positive associations between [18F]FDDNP binding levels and age as well as behavioral dysfunction in Down syndrome are consistent with the age-related progression of Alzheimer-type neuropathological findings in this population. PMID:21670401

Rich club network analysis shows distinct patterns of disruption in frontotemporal dementia and Alzheimer’s disease

PubMed Central

Daianu, Madelaine; Jahanshad, Neda; Villalon-Reina, Julio E.; Mendez, Mario F.; Bartzokis, George; Jimenez, Elvira E.; Joshi, Aditi; Barsuglia, Joseph; Thompson, Paul M.

2015-01-01

Diffusion imaging and brain connectivity analyses can reveal the underlying organizational patterns of the human brain, described as complex networks of densely interlinked regions. Here, we analyzed 1.5-Tesla whole-brain diffusion-weighted images from 64 participants – 15 patients with behavioral variant frontotemporal (bvFTD) dementia, 19 with early-onset Alzheimer’s disease (EOAD), and 30 healthy elderly controls. Based on whole-brain tractography, we reconstructed structural brain connectivity networks to map connections between cortical regions. We examined how bvFTD and EOAD disrupt the weighted ‘rich club’ – a network property where high-degree network nodes are more interconnected than expected by chance. bvFTD disrupts both the nodal and global organization of the network in both low- and high-degree regions of the brain. EOAD targets the global connectivity of the brain, mainly affecting the fiber density of high-degree (highly connected) regions that form the rich club network. These rich club analyses suggest distinct patterns of disruptions among different forms of dementia. PMID:26161050

Discussion about the Pros and Cons and Recommendations for Multimedia Teaching in Local Vocational Schools

NASA Astrophysics Data System (ADS)

Dai, Wenhui; Fan, Ling

Globalization is an inevitable developing trend of multimedia network teaching. In our contemporary society, the world has connected by internet; it is incredible that people can not use the boundless information through campus network, multimedia classroom or single multimedia computer with out connecting the WAN. The new internet based teaching method breaking the constrains of the limited resources, distance and size of the LAN, bringing multimedia network teaching method to the world. "Open University", "Virtual Schools", "Global Classroom" and a number of new teaching systems merged rapidly.

High trait aggression in men is associated with low 5-HT levels, as indexed by 5-HT4 receptor binding

PubMed Central

Mc Mahon, Brenda; MacDonald Fisher, Patrick; Jensen, Peter Steen; Svarer, Claus; Moos Knudsen, Gitte

2016-01-01

Impulsive aggression has commonly been associated with a dysfunction of the serotonin (5-HT) system: many, but not all, studies point to an inverse relationship between 5-HT and aggression. As cerebral 5-HT4 receptor (5-HT4R) binding has recently been recognized as a proxy for stable brain levels of 5-HT, we here test the hypothesis in healthy men and women that brain 5-HT levels, as indexed by cerebral 5-HT4R, are inversely correlated with trait aggression and impulsivity. Sixty-one individuals (47 men) underwent positron emission tomography scanning with the radioligand [11C]SB207145 for quantification of brain 5-HT4R binding. The Buss–Perry Aggression Questionnaire (BPAQ) and the Barratt Impulsiveness Scale were used for assessment of trait aggression and trait impulsivity. Among male subjects, there was a positive correlation between global 5-HT4R and BPAQ total score (P = 0.037) as well as BPAQ physical aggression (P = 0.025). No main effect of global 5-HT4R on trait aggression or impulsivity was found in the mixed gender sample, but there was evidence for sex interaction effects in the relationship between global 5-HT4R and BPAQ physical aggression. In conclusion we found that low cerebral 5-HT levels, as indexed by 5-HT4R binding were associated with high trait aggression in males, but not in females. PMID:26772668

Study Finds a Connection between Glaucoma and Sleep Apnea

MedlinePlus

... Plastic Surgery Center Laser Surgery Education Center Redmond Ethics Center Global Ophthalmology Guide Academy Publications EyeNet Ophthalmology ... Plastic Surgery Center Laser Surgery Education Center Redmond Ethics Center Global Ophthalmology Guide Find an Ophthalmologist Advanced ...

Selective enrichment of metal-binding proteins based on magnetic core/shell microspheres functionalized with metal cations.

PubMed

Fang, Caiyun; Zhang, Lei; Zhang, Xiaoqin; Lu, Haojie

2015-06-21

Metal binding proteins play many important roles in a broad range of biological processes. Characterization of metal binding proteins is important for understanding their structure and biological functions, thus leading to a clear understanding of metal associated diseases. The present study is the first to investigate the effectiveness of magnetic microspheres functionalized with metal cations (Ca(2+), Cu(2+), Zn(2+) and Fe(3+)) as the absorbent matrix in IMAC technology to enrich metal containing/binding proteins. The putative metal binding proteins in rat liver were then globally characterized by using this strategy which is very easy to handle and can capture a number of metal binding proteins effectively. In total, 185 putative metal binding proteins were identified from rat liver including some known less abundant and membrane-bound metal binding proteins such as Plcg1, Acsl5, etc. The identified proteins are involved in many important processes including binding, catalytic activity, translation elongation factor activity, electron carrier activity, and so on.

Quantitative relation between intermolecular and intramolecular binding of pro-rich peptides to SH3 domains.

PubMed

Zhou, Huan-Xiang

2006-11-01

Flexible linkers are often found to tether binding sequence motifs or connect protein domains. Here we analyze three usages of flexible linkers: 1), intramolecular binding of proline-rich peptides (PRPs) to SH3 domains for kinase regulation; 2), intramolecular binding of PRP for increasing the folding stability of SH3 domains; and 3), covalent linking of PRPs and other ligands for high-affinity bivalent binding. The basis of these analyses is a quantitative relation between intermolecular and intramolecular binding constants. This relation has the form K(i) = K(e0)p for intramolecular binding and K(e) = K(e01)K(e02)p for bivalent binding. The effective concentration p depends on the length of the linker and the distance between the linker attachment points in the bound state. Several applications illustrate the usefulness of the quantitative relation. These include intramolecular binding to the Itk SH3 domain by an internal PRP and to a circular permutant of the alpha-spectrin SH3 domain by a designed PRP, and bivalent binding to the two SH3 domains of Grb2 by two linked PRPs. These and other examples suggest that flexible linkers and sequence motifs tethered to them, like folded protein domains, are also subject to tight control during evolution.

Using "CONNected objECT (CONNECT)" Algorithm to Explore Intense Global Water Vapor Transport to Investigate Impacts of Climate Variability and Change

NASA Astrophysics Data System (ADS)

Kawzenuk, B.; Sellars, S. L.; Nguyen, P.; Ralph, F. M.; Sorooshian, S.

2017-12-01

The CONNected objECT (CONNECT) algorithm is applied to Integrated Water Vapor Transport (IVT) data from the NASA's Modern-Era Retrospective Analysis for Research and Applications - Version 2 reanalysis product for the period 1980 to 2016 to study water vapor transport globally. The algorithm generates life-cycle records as statistical objects for the time and space location of the evolving strong vapor transport events. Global statistics are presented and used to investigate how climate variability impacts the events' location and frequency. Results show distinct water vapor object frequency and seasonal peaks during NH and SH Winter. Moreover, a positive linear trend in the annual number of objects is reported, increasing by 3.58 objects year-over-year (with 95% confidence, +/- 1.39). In addition, we show five distinct regions where these events typically exist (southeastern United States, eastern China, South Pacific south of 25°S, eastern South America and off the southern tip of South Africa), and where they rarely exist (eastern South Pacific Ocean and central southern Atlantic Ocean between 5°N-25°S). In addition, the event frequency and geographical location are also shown to be related to the Arctic Oscillation, Pacific North American Pattern, and the Quasi-Biennial Oscillation.

Multilevel Deficiency of White Matter Connectivity Networks in Alzheimer's Disease: A Diffusion MRI Study with DTI and HARDI Models.

PubMed

Wang, Tao; Shi, Feng; Jin, Yan; Yap, Pew-Thian; Wee, Chong-Yaw; Zhang, Jianye; Yang, Cece; Li, Xia; Xiao, Shifu; Shen, Dinggang

2016-01-01

Alzheimer's disease (AD) is the most common form of dementia in elderly people. It is an irreversible and progressive brain disease. In this paper, we utilized diffusion-weighted imaging (DWI) to detect abnormal topological organization of white matter (WM) structural networks. We compared the differences between WM connectivity characteristics at global, regional, and local levels in 26 patients with probable AD and 16 normal control (NC) elderly subjects, using connectivity networks constructed with the diffusion tensor imaging (DTI) model and the high angular resolution diffusion imaging (HARDI) model, respectively. At the global level, we found that the WM structural networks of both AD and NC groups had a small-world topology; however, the AD group showed a significant decrease in both global and local efficiency, but an increase in clustering coefficient and the average shortest path length. We further found that the AD patients had significantly decreased nodal efficiency at the regional level, as well as weaker connections in multiple local cortical and subcortical regions, such as precuneus, temporal lobe, hippocampus, and thalamus. The HARDI model was found to be more advantageous than the DTI model, as it was more sensitive to the deficiencies in AD at all of the three levels.

The quaternary architecture of RARβ–RXRα heterodimer facilitates domain–domain signal transmission

DOE PAGES

Chandra, Vikas; Wu, Dalei; Li, Sheng; ...

2017-10-11

Assessing the physical connections and allosteric communications in multi-domain nuclear receptor (NR) polypeptides has remained challenging, with few crystal structures available to show their overall structural organizations. Here we report the quaternary architecture of multi-domain retinoic acid receptor beta-retinoic X receptor alpha (RAR beta-RXR alpha) heterodimer bound to DNA, ligands and coactivator peptides, examined through crystallographic, hydrogen-deuterium exchange mass spectrometry, mutagenesis and functional studies. The RAR beta ligand-binding domain (LBD) and DNA-binding domain (DBD) are physically connected to foster allosteric signal transmission between them. Direct comparisons among all the multi-domain NRs studied crystallographically to date show significant variations within theirmore » quaternary architectures, rather than a common architecture adhering to strict rules. RXR remains flexible and adaptive by maintaining loosely organized domains, while its hetero-dimerization partners use a surface patch on their LBDs to form domain-domain interactions with DBDs.« less

The quaternary architecture of RARβ–RXRα heterodimer facilitates domain–domain signal transmission

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

Chandra, Vikas; Wu, Dalei; Li, Sheng

Assessing the physical connections and allosteric communications in multi-domain nuclear receptor (NR) polypeptides has remained challenging, with few crystal structures available to show their overall structural organizations. Here we report the quaternary architecture of multi-domain retinoic acid receptor beta-retinoic X receptor alpha (RAR beta-RXR alpha) heterodimer bound to DNA, ligands and coactivator peptides, examined through crystallographic, hydrogen-deuterium exchange mass spectrometry, mutagenesis and functional studies. The RAR beta ligand-binding domain (LBD) and DNA-binding domain (DBD) are physically connected to foster allosteric signal transmission between them. Direct comparisons among all the multi-domain NRs studied crystallographically to date show significant variations within theirmore » quaternary architectures, rather than a common architecture adhering to strict rules. RXR remains flexible and adaptive by maintaining loosely organized domains, while its hetero-dimerization partners use a surface patch on their LBDs to form domain-domain interactions with DBDs.« less

Making Connections: Where STEM Learning and Earth Science Data Services Meet

NASA Technical Reports Server (NTRS)

Bugbee, Kaylin; Ramachandran, Rahul; Maskey, Manil; Gatlin, Patrick; Weigel, Amanda

2016-01-01

STEM (Science, Technology, Engineering, Mathematics) learning is most effective when students are encouraged to see the connections between science, technology and real world problems. Helping to make these connections has become an increasingly important aspect of Earth Science data research. The Global Hydrology Resource Center (GHRC), one of NASA's 12 EOSDIS (Earth Observing System Data Information System) data centers, has developed a new type of documentation called the micro article to facilitate making connections between data and Earth science research problems.

ASIST 2002: Information, Connections and Community. Proceedings of the ASIST Annual Meeting (65th, Philadelphia, Pennsylvania, November 18-21, 2002).

ERIC Educational Resources Information Center

Toms, Elaine G., Ed.

The theme of the 2002 ASIST (American Society for Information Science and Technology) annual conference was "Knowledge, Connections and Community," which covers the role of information in a complex global society and the way in which information connects and impacts our environment. The program included 43 SIG (Special Interest Group) programs, 49…

Actin-Binding Protein Requirement for Cortical Stability and Efficient Locomotion

NASA Astrophysics Data System (ADS)

Cunningham, C. Casey; Gorlin, Jed B.; Kwiatkowski, David J.; Hartwig, John H.; Janmey, Paul A.; Randolph Byers, H.; Stossel, Thomas P.

1992-01-01

Three unrelated tumor cell lines derived from human malignant melanomas lack actin-binding protein (ABP), which cross-links actin filaments in vitro and connects these filaments to plasma membrane glycoproteins. The ABP-deficient cells have impaired locomotion and display circumferential blebbing of the plasma membrane. Expression of ABP in one of the lines after transfection restored translocational motility and reduced membrane blebbing. These findings establish that ABP functions to stabilize cortical actin in vivo and is required for efficient cell locomotion.

Patterns and plasticity in RNA-protein interactions enable recruitment of multiple proteins through a single site

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

Valley, Cary T.; Porter, Douglas F.; Qiu, Chen

2012-06-28

mRNA control hinges on the specificity and affinity of proteins for their RNA binding sites. Regulatory proteins must bind their own sites and reject even closely related noncognate sites. In the PUF [Pumilio and fem-3 binding factor (FBF)] family of RNA binding proteins, individual proteins discriminate differences in the length and sequence of binding sites, allowing each PUF to bind a distinct battery of mRNAs. Here, we show that despite these differences, the pattern of RNA interactions is conserved among PUF proteins: the two ends of the PUF protein make critical contacts with the two ends of the RNA sites.more » Despite this conserved 'two-handed' pattern of recognition, the RNA sequence is flexible. Among the binding sites of yeast Puf4p, RNA sequence dictates the pattern in which RNA bases are flipped away from the binding surface of the protein. Small differences in RNA sequence allow new modes of control, recruiting Puf5p in addition to Puf4p to a single site. This embedded information adds a new layer of biological meaning to the connections between RNA targets and PUF proteins.« less

Crystal structure of the Escherichia coli regulator of sigma70, Rsd, in complex with sigma70 domain 4.

PubMed

Patikoglou, Georgia A; Westblade, Lars F; Campbell, Elizabeth A; Lamour, Valérie; Lane, William J; Darst, Seth A

2007-09-21

The Escherichia coli Rsd protein binds tightly and specifically to the RNA polymerase (RNAP) sigma(70) factor. Rsd plays a role in alternative sigma factor-dependent transcription by biasing the competition between sigma(70) and alternative sigma factors for the available core RNAP. Here, we determined the 2.6 A-resolution X-ray crystal structure of Rsd bound to sigma(70) domain 4 (sigma(70)(4)), the primary determinant for Rsd binding within sigma(70). The structure reveals that Rsd binding interferes with the two primary functions of sigma(70)(4), core RNAP binding and promoter -35 element binding. Interestingly, the most highly conserved Rsd residues form a network of interactions through the middle of the Rsd structure that connect the sigma(70)(4)-binding surface with three cavities exposed on distant surfaces of Rsd, suggesting functional coupling between sigma(70)(4) binding and other binding surfaces of Rsd, either for other proteins or for as yet unknown small molecule effectors. These results provide a structural basis for understanding the role of Rsd, as well as its ortholog, AlgQ, a positive regulator of Pseudomonas aeruginosa virulence, in transcription regulation.

Crystal structure of the Escherichia coli regulator of σ70, Rsd, in complex with σ70 domain 4

PubMed Central

Patikoglou, Georgia A.; Westblade, Lars F.; Campbell, Elizabeth A.; Lamour, Valérie; Lane, William J.; Darst, Seth A.

2007-01-01

Summary The Escherichia coli Rsd protein binds tightly and specifically to the RNA polymerase (RNAP) σ70 factor. Rsd plays a role in alternative σ factor-dependent transcription by biasing the competition between σ70 and alternative σ factors for the available core RNAP. Here, we determined the 2.6 Å-resolution X-ray crystal structure of Rsd bound to σ70 domain 4 (σ704), the primary determinant for Rsd binding within σ70. The structure reveals that Rsd binding interferes with the two primary functions of σ704, core RNAP binding and promoter –35 element binding. Interestingly, the most highly conserved Rsd residues form a network of interactions through the middle of the Rsd structure that connect the σ704-binding surface with three cavities exposed on distant surfaces of Rsd, suggesting functional coupling between σ704 binding and other binding surfaces of Rsd, either for other proteins or for as yet unknown small molecule effectors. These results provide a structural basis for understanding the role of Rsd, as well as its ortholog, AlgQ, a positive regulator of Pseudomonas aeruginosa virulence, in transcription regulation. PMID:17681541

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

Patikoglou,G.; Westblade, L.; Campbell, E.

The Escherichia coli Rsd protein binds tightly and specifically to the RNA polymerase (RNAP) {sigma}{sup 70} factor. Rsd plays a role in alternative {sigma} factor-dependent transcription by biasing the competition between {sigma}{sup 70} and alternative {sigma} factors for the available core RNAP. Here, we determined the 2.6 {angstrom}-resolution X-ray crystal structure of Rsd bound to {sigma}{sup 70} domain 4 ({sigma}{sup 70}{sub 4}), the primary determinant for Rsd binding within {sigma}{sup 70}. The structure reveals that Rsd binding interferes with the two primary functions of {sigma}{sup 70}{sub 4}, core RNAP binding and promoter -35 element binding. Interestingly, the most highly conservedmore » Rsd residues form a network of interactions through the middle of the Rsd structure that connect the {sigma}{sup 70}{sub 4}-binding surface with three cavities exposed on distant surfaces of Rsd, suggesting functional coupling between {sigma}{sup 70}{sub 4} binding and other binding surfaces of Rsd, either for other proteins or for as yet unknown small molecule effectors. These results provide a structural basis for understanding the role of Rsd, as well as its ortholog, AlgQ, a positive regulator of Pseudomonas aeruginosa virulence, in transcription regulation.« less

Strategic Challenges during Changing Times: A Prioritized Research Program, 1994

DTIC Science & Technology

1994-04-01

and planning. 14, SUBJECT T[RMS 15 NUMBER OF PAGES strategic assessments; domestic and global issues and 5 trends; peace operations; political...1994 or which, for a variety of reasons, will riot be published. 3 SECTION I TRANSREGIONAL SECURITY CONCERNS Regional Challenges, Global Issues . When...but global issues . Global security issues derive from three forms of connectivity. The first is economic. Today, there is truly a world economy. Markets

Ablation as targeted perturbation to rewire communication network of persistent atrial fibrillation

PubMed Central

Tao, Susumu; Way, Samuel F.; Garland, Joshua; Chrispin, Jonathan; Ciuffo, Luisa A.; Balouch, Muhammad A.; Nazarian, Saman; Spragg, David D.; Marine, Joseph E.; Berger, Ronald D.; Calkins, Hugh

2017-01-01

Persistent atrial fibrillation (AF) can be viewed as disintegrated patterns of information transmission by action potential across the communication network consisting of nodes linked by functional connectivity. To test the hypothesis that ablation of persistent AF is associated with improvement in both local and global connectivity within the communication networks, we analyzed multi-electrode basket catheter electrograms of 22 consecutive patients (63.5 ± 9.7 years, 78% male) during persistent AF before and after the focal impulse and rotor modulation-guided ablation. Eight patients (36%) developed recurrence within 6 months after ablation. We defined communication networks of AF by nodes (cardiac tissue adjacent to each electrode) and edges (mutual information between pairs of nodes). To evaluate patient-specific parameters of communication, thresholds of mutual information were applied to preserve 10% to 30% of the strongest edges. There was no significant difference in network parameters between both atria at baseline. Ablation effectively rewired the communication network of persistent AF to improve the overall connectivity. In addition, successful ablation improved local connectivity by increasing the average clustering coefficient, and also improved global connectivity by decreasing the characteristic path length. As a result, successful ablation improved the efficiency and robustness of the communication network by increasing the small-world index. These changes were not observed in patients with AF recurrence. Furthermore, a significant increase in the small-world index after ablation was associated with synchronization of the rhythm by acute AF termination. In conclusion, successful ablation rewires communication networks during persistent AF, making it more robust, efficient, and easier to synchronize. Quantitative analysis of communication networks provides not only a mechanistic insight that AF may be sustained by spatially localized sources and global connectivity, but also patient-specific metrics that could serve as a valid endpoint for therapeutic interventions. PMID:28678805

Global brain connectivity alterations in patients with schizophrenia and bipolar spectrum disorders.

PubMed

Skåtun, Kristina C; Kaufmann, Tobias; Tønnesen, Siren; Biele, Guido; Melle, Ingrid; Agartz, Ingrid; Alnæs, Dag; Andreassen, Ole A; Westlye, Lars T

2016-08-01

The human brain is organized into functionally distinct modules of which interactions constitute the human functional connectome. Accumulating evidence has implicated perturbations in the patterns of brain connectivity across a range of neurologic and neuropsychiatric disorders, but little is known about diagnostic specificity. Schizophrenia and bipolar disorders are severe mental disorders with partly overlapping symptomatology. Neuroimaging has demonstrated brain network disintegration in the pathophysiologies; however, to which degree the 2 diagnoses present with overlapping abnormalities remains unclear. We collected resting-state fMRI data from patients with schizophrenia or bipolar disorder and from healthy controls. Aiming to characterize connectivity differences across 2 severe mental disorders, we derived global functional connectivity using eigenvector centrality mapping, which allows for regional inference of centrality or importance in the brain network. Seventy-one patients with schizophrenia, 43 with bipolar disorder and 196 healthy controls participated in our study. We found significant effects of diagnosis in 12 clusters, where pairwise comparisons showed decreased global connectivity in high-centrality clusters: sensory regions in patients with schizophrenia and subcortical regions in both patient groups. Increased connectivity occurred in frontal and parietal clusters in patients with schizophrenia, with intermediate effects in those with bipolar disorder. Patient groups differed in most cortical clusters, with the strongest effects in sensory regions. Methodological concerns of in-scanner motion and the use of full correlation measures may make analyses more vulnerable to noise. Our results show decreased eigenvector centrality of limbic structures in both patient groups and in sensory regions in patients with schizophrenia as well as increased centrality in frontal and parietal regions in both groups, with stronger effects in patients with schizophrenia.

U.S. Global Change Research Program

MedlinePlus

... Announcing... Read more The Deepening Story of How Climate Change Threatens Human Health Read more Celebrating the 25th Anniversary of the U.S. Global Change Research... Read more Nomination Period Open for ... more Connecting America’s Communities with Actionable Climate ...

WorldWideScience.org: the global science gateway.

PubMed

Fitzpatrick, Roberta Bronson

2009-10-01

WorldWideScience.org is a Web-based global gateway connecting users to both national and international scientific databases and portals. This column will provide background information on the resource as well as introduce basic searching practices for users.

A ChIP-seq-defined genome-wide map of MEF2C binding reveals inflammatory pathways associated with its role in bone density determination.

PubMed

Johnson, Matthew E; Deliard, Sandra; Zhu, Fengchang; Xia, Qianghua; Wells, Andrew D; Hankenson, Kurt D; Grant, Struan F A

2014-04-01

Genome-wide association studies (GWAS) have demonstrated that genetic variation at the MADS box transcription enhancer factor 2, polypeptide C (MEF2C) locus is robustly associated with bone mineral density, primarily at the femoral neck. MEF2C is a transcription factor known to operate via the Wnt signaling pathway. Our hypothesis was that MEF2C regulates the expression of a set of molecular pathways critical to skeletal function. Drawing on our laboratory and bioinformatic experience with ChIP-seq, we analyzed ChIP-seq data for MEF2C available via the ENCODE project to gain insight in to its global genomic binding pattern. We aligned the ChIP-seq data generated for GM12878 (an established lymphoblastoid cell line) and, using the analysis package HOMER, a total of 17,611 binding sites corresponding to 8,118 known genes were observed. We then performed a pathway analysis of the gene list using Ingenuity. At 5 kb, the gene list yielded 'EIF2 Signaling' as the most significant annotation, with a P value of 5.01 × 10(-26). Moving further out, this category remained the top pathway at 50 and 100 kb, then dropped to just second place at 500 kb and beyond by 'Molecular Mechanisms of Cancer'. In addition, at 50 kb and beyond 'RANK Signaling in Osteoclasts' was a consistent feature and resonates with the main general finding from GWAS of bone density. We also observed that MEF2C binding sites were significantly enriched primarily near inflammation associated genes identified from GWAS; indeed, a similar enrichment for inflammation genes has been reported previously using a similar approach for the vitamin D receptor, an established key regulator of bone turnover. Our analyses point to known connective tissue and skeletal processes but also provide novel insights in to networks involved in skeletal regulation. The fact that a specific GWAS category is enriched points to a possible role of inflammation through which it impacts bone mineral density.

The global repressor FliZ antagonizes gene expression by σS-containing RNA polymerase due to overlapping DNA binding specificity.

PubMed

Pesavento, Christina; Hengge, Regine

2012-06-01

FliZ, a global regulatory protein under the control of the flagellar master regulator FlhDC, was shown to antagonize σ(S)-dependent gene expression in Escherichia coli. Thereby it plays a pivotal role in the decision between alternative life-styles, i.e. FlhDC-controlled flagellum-based motility or σ(S)-dependent curli fimbriae-mediated adhesion and biofilm formation. Here, we show that FliZ is an abundant DNA-binding protein that inhibits gene expression mediated by σ(S) by recognizing operator sequences that resemble the -10 region of σ(S)-dependent promoters. FliZ does so with a structural element that is similar to region 3.0 of σ(S). Within this element, R108 in FliZ corresponds to K173 in σ(S), which contacts a conserved cytosine at the -13 promoter position that is specific for σ(S)-dependent promoters. R108 as well as C(-13) are also crucial for DNA binding by FliZ. However, while a number of FliZ binding sites correspond to known σ(S)-dependent promoters, promoter activity is not a prerequisite for FliZ binding and repressor function. Thus, we demonstrate that FliZ also feedback-controls flagellar gene expression by binding to a site in the flhDC control region that shows similarity only to a -10 element of a σ(S)-dependent promoter, but does not function as a promoter.

International Perspectives in LIS Education: Global Education, Research, and Collaboration at the SJSU School of Information

ERIC Educational Resources Information Center

Hirsh, Sandra; Simmons, Michelle Holschuh; Christensen, Paul; Sellar, Melanie; Stenström, Cheryl; Hagar, Christine; Bernier, Anthony; Faires, Debbie; Fisher, Jane; Alman, Susan

2015-01-01

The IFLA Trend Report identified five trends that will impact the information environment (IFLA, 2015), such as access to information with new technologies, online education for global learning, hyper-connected communities, and the global information environment. The faculty at San José State University (SJSU) School of Information (iSchool) is…

Connecting the Dots: How U.S. Global Health Programs Can Improve International Health Regulation Compliance

DTIC Science & Technology

2014-12-01

50 E. ACTIVITIES , FUNDING, AND ANALYSIS .............................................51 1. Global Emerging Infectious Disease System...Organizational Chart ..............................................................................71 Figure 9. CDC: Global Health Activities Map...of the WHO was roughly $2.2 billion the same year.12 New threats like antibacterial -resistant infections have resulted in at least 23,000 deaths with

Thinking Globally, Interviewing Locally: Using an Intensive Interview Project to Teach Globalization and Social Change

ERIC Educational Resources Information Center

Anderson, Norma J.

2017-01-01

In this article, I connect globalization and qualitative methodological practice, describing a semester-long intensive interview project about the anti-apartheid movement. I provide a detailed overview of the project as well as considerations for those who might want to adapt it for their own courses. Using students' reflections on the projects…

People, Pope and Planet: A Hermeneutic and Spectacle Analysis of "Laudato Si'" for Global Citizenship Educators

ERIC Educational Resources Information Center

Gaudelli, William

2017-01-01

Global citizenship education presents a number of challenges for educators, including the wide variety of texts available to be studied. I explore "Laudato Si'," Pope Francis' 2015 statement on global warming and human development. "Laudato Si'" includes contents that are broad, connective, and significant/relevant, making it a…

Internationalizing the Curriculum: Improving Learning through International Education-- Preparing Students for Success in a Global Society

ERIC Educational Resources Information Center

Guerin, Stephen H.

2009-01-01

In the expanded and updated version of "The World is Flat: A Brief History of the Twenty-First Century" (Friedman, 2006), Thomas Friedman cogently describes the promise and peril of an economic and geopolitical future shaped by the forces of globalization wrought by technologically driven global connectivity, international commerce, and…

Doing More with Less: Civic Practices for Longer-Term Impact in Global Service-Learning

ERIC Educational Resources Information Center

Alonso García, Nuria; Longo, Nicholas V.

2017-01-01

This essay explores the potential value of short-term study abroad experiences within the unique framework of a new global service-learning program at Providence College which connects international with local engagement as a way to "do more with less." The authors first introduce a typology for global service-learning, illustrating how…

The Development of the International Baccalaureate in Spanish Speaking Countries: A Global Comparative Approach

ERIC Educational Resources Information Center

Resnik, Julia

2016-01-01

This paper compares the development of International Baccalaureate (IB) schools in four different settings: Argentine, Chile, Spain and Ecuador. The global comparative approach used in this study, based on actor-network theory (ANT), allows us to analyse the connections and interactions between global actors and the plurality of national,…

Estimated benefits of connected vehicle applications : dynamic mobility applications, AERIS, V2I safety, and road weather management applications.

DOT National Transportation Integrated Search

2015-08-01

Connected vehicles have the potential to transform travel as we know it by combining leading edge technologies advanced wireless communications, on-board computer processing, advanced vehicle-sensors, Global Positioning System (GPS) navigation, sm...

‘Research clinics’: online journal clubs between south and north for student mentoring

PubMed Central

Atkins, Salla; Varshney, Dinansha; Meragia, Elnta; Zwarenstein, Merrick; Diwan, Vishal

2016-01-01

Background Capacity development in health research is high on the agenda of many low- and middle-income countries. Objective The ARCADE projects, funded by the EU, have been working in Africa and Asia since 2011 in order to build postgraduate students’ health research capacity. In this short communication, we describe one initiative in these projects, that of research clinics – online journal clubs connecting southern and northern students and experts. Design We describe the implementation of these research clinics together with student and participant experiences. Results From 2012 to 2015, a total of seven journal clubs were presented by students and junior researchers on topics related to global health. Sessions were connected through web conferencing, connecting experts and students from different countries. Conclusions The research clinics succeeded in engaging young researchers across the globe and connecting them with global experts. The contacts and suggestions made were appreciated by students. This format has potential to contribute toward research capacity building in low- and middle-income countries. PMID:27725079

Making connections: Where STEM learning and Earth science data services meet

NASA Astrophysics Data System (ADS)

Bugbee, K.; Ramachandran, R.; Maskey, M.; Gatlin, P. N.; Weigel, A. M.

2016-12-01

STEM learning is most effective when students are encouraged to see the connections between science, technology and real world problems. Helping to make these connections has become an increasingly important aspect of Earth science data research. The Global Hydrology Resource Center (GHRC), one of NASA's 12 EOSDIS data centers, has developed a new type of documentation called the micro article to facilitate making connections between data and Earth science research problems. Micro articles are short academic texts that enable a reader to quickly understand a scientific phenomena, a case study, or an instrument used to collect data. While originally designed to increase data discovery and usability, micro articles also serve as a reliable starting point for project-based learning, an educational approach in STEM education, for high school and higher education environments. This presentation will highlight micro articles at the Global Hydrology Resource Center data center and will demonstrate the potential applications of micro articles in project-based learning.

Hemispheric asymmetry of electroencephalography-based functional brain networks.

PubMed

Jalili, Mahdi

2014-11-12

Electroencephalography (EEG)-based functional brain networks have been investigated frequently in health and disease. It has been shown that a number of graph theory metrics are disrupted in brain disorders. EEG-based brain networks are often studied in the whole-brain framework, where all the nodes are grouped into a single network. In this study, we studied the brain networks in two hemispheres and assessed whether there are any hemispheric-specific patterns in the properties of the networks. To this end, resting state closed-eyes EEGs from 44 healthy individuals were processed and the network structures were extracted separately for each hemisphere. We examined neurophysiologically meaningful graph theory metrics: global and local efficiency measures. The global efficiency did not show any hemispheric asymmetry, whereas the local connectivity showed rightward asymmetry for a range of intermediate density values for the constructed networks. Furthermore, the age of the participants showed significant direct correlations with the global efficiency of the left hemisphere, but only in the right hemisphere, with local connectivity. These results suggest that only local connectivity of EEG-based functional networks is associated with brain hemispheres.

Conformation-controlled binding kinetics of antibodies

NASA Astrophysics Data System (ADS)

Galanti, Marta; Fanelli, Duccio; Piazza, Francesco

2016-01-01

Antibodies are large, extremely flexible molecules, whose internal dynamics is certainly key to their astounding ability to bind antigens of all sizes, from small hormones to giant viruses. In this paper, we build a shape-based coarse-grained model of IgG molecules and show that it can be used to generate 3D conformations in agreement with single-molecule Cryo-Electron Tomography data. Furthermore, we elaborate a theoretical model that can be solved exactly to compute the binding rate constant of a small antigen to an IgG in a prescribed 3D conformation. Our model shows that the antigen binding process is tightly related to the internal dynamics of the IgG. Our findings pave the way for further investigation of the subtle connection between the dynamics and the function of large, flexible multi-valent molecular machines.

Aptamer-Conjugated Calcium Phosphate Nanoparticles for Reducing Diabetes Risk via Retinol Binding Protein 4 Inhibition.

PubMed

Torabi, Raheleh; Ghourchian, Hedayatollah; Amanlou, Massoud; Pasalar, Parvin

2017-06-01

Inhibition of the binding of retinol to its carrier, retinol binding protein 4, is a new strategy for treating type 2 diabetes; for this purpose, we have provided an aptamer-functionalized multishell calcium phosphate nanoparticle. First, calcium phosphate nanoparticles were synthesized and conjugated to the aptamer. The cytotoxicity of nanoparticles releases the process of aptamer from nanoparticles and their inhibition function of binding retinol to retinol binding protein 4. After synthesizing and characterizing the multishell calcium phosphate nanoparticles and observing the noncytotoxicity of conjugate, the optimum time (48 hours) and the pH (7.4) for releasing the aptamer from the nanoparticles was determined. The half-maximum inhibitory concentration (IC 50 ) value for inhibition of retinol binding to retinol binding protein 4 was 210 femtomolar (fmol). The results revealed that the aptamer could prevent connection between retinol and retinol binding protein 4 at a very low IC 50 value (210 fmol) compared to other reported inhibitors. It seems that this aptamer could be used as an efficient candidate not only for decreasing the insulin resistance in type 2 diabetes, but also for inhibiting the other retinol binding protein 4-related diseases. Copyright © 2017 Diabetes Canada. Published by Elsevier Inc. All rights reserved.

Early life stress predicts thalamic hyperconnectivity: A transdiagnostic study of global connectivity.

PubMed

Philip, Noah S; Tyrka, Audrey R; Albright, Sarah E; Sweet, Lawrence H; Almeida, Jorge; Price, Lawrence H; Carpenter, Linda L

2016-08-01

Early life stress (ELS) is an established risk factor for psychiatric illness and is associated with altered functional connectivity within- and between intrinsic neural networks. The widespread nature of these disruptions suggests that broad imaging measures of neural connectivity, such as global based connectivity (GBC), may be particularly appropriate for studies of this population. GBC is designed to identify brain regions having maximal functional connectedness with the rest of the brain, and alterations in GBC may reflect a restriction or broadening of network synchronization. We evaluated whether ELS severity predicted GBC in a sample (N = 46) with a spectrum of ELS exposure. Participants included healthy controls without ELS, those with at least moderate ELS but without psychiatric disorders, and a group of patients with ELS- related psychiatric disorders. The spatial distribution of GBC peaked in regions of the salience and default mode networks, and ELS severity predicted increased GBC of the left thalamus (corrected p < 0.005, r = 0.498). Thalamic connectivity was subsequently evaluated and revealed reduced connectivity with the salience network, particularly the dorsal anterior cingulate cortex (corrected p < 0.005), only in the patient group. These findings support a model of disrupted thalamic connectivity in ELS and trauma-related negative affect states, and underscore the importance of a transdiagnostic, dimensional neuroimaging approach to understanding the sequelae of trauma exposure. Published by Elsevier Ltd.

America's container ports : freight hubs that connect our nation to global markets

DOT National Transportation Integrated Search

2009-06-01

The U.S. marine transportation system continues to handle large volumes of domestic and international : freight in support of the nations economic activities. The demand for freight transportation : responds to trends in global economic activity a...

Splitting the chromosome: cutting the ties that bind sister chromatids.

PubMed

Nasmyth, K; Peters, J M; Uhlmann, F

2000-05-26

In eukaryotic cells, sister DNA molecules remain physically connected from their production at S phase until their separation during anaphase. This cohesion is essential for the separation of sister chromatids to opposite poles of the cell at mitosis. It also permits chromosome segregation to take place long after duplication has been completed. Recent work has identified a multisubunit complex called cohesin that is essential for connecting sisters. Proteolytic cleavage of one of cohesin's subunits may trigger sister separation at the onset of anaphase.

Providing full point-to-point communications among compute nodes of an operational group in a global combining network of a parallel computer

DOEpatents

Archer, Charles J; Faraj, Ahmad A; Inglett, Todd A; Ratterman, Joseph D

2013-04-16

Methods, apparatus, and products are disclosed for providing full point-to-point communications among compute nodes of an operational group in a global combining network of a parallel computer, each compute node connected to each adjacent compute node in the global combining network through a link, that include: receiving a network packet in a compute node, the network packet specifying a destination compute node; selecting, in dependence upon the destination compute node, at least one of the links for the compute node along which to forward the network packet toward the destination compute node; and forwarding the network packet along the selected link to the adjacent compute node connected to the compute node through the selected link.

Reinforcement of the Brain's Rich-Club Architecture Following Early Neurodevelopmental Disruption Caused by Very Preterm Birth

PubMed Central

Karolis, Vyacheslav R.; Froudist-Walsh, Sean; Brittain, Philip J.; Kroll, Jasmin; Ball, Gareth; Edwards, A. David; Dell'Acqua, Flavio; Williams, Steven C.; Murray, Robin M.; Nosarti, Chiara

2016-01-01

The second half of pregnancy is a crucial period for the development of structural brain connectivity, and an abrupt interruption of the typical processes of development during this phase caused by the very preterm birth (<33 weeks of gestation) is likely to result in long-lasting consequences. We used structural and diffusion imaging data to reconstruct the brain structural connectome in very preterm-born adults. We assessed its rich-club organization and modularity as 2 characteristics reflecting the capacity to support global and local information exchange, respectively. Our results suggest that the establishment of global connectivity patterns is prioritized over peripheral connectivity following early neurodevelopmental disruption. The very preterm brain exhibited a stronger rich-club architecture than the control brain, despite possessing a relative paucity of white matter resources. Using a simulated lesion approach, we also investigated whether putative structural reorganization takes place in the very preterm brain in order to compensate for its anatomical constraints. We found that connections between the basal ganglia and (pre-) motor regions, as well as connections between subcortical regions, assumed an altered role in the structural connectivity of the very preterm brain, and that such alterations had functional implications for information flow, rule learning, and verbal IQ. PMID:26742566

Fasting and feeding variations of insulin requirements and insulin binding to erythrocytes at different times of the day in insulin dependent diabetics--assessed under the condition of glucose-controlled insulin infusion.

PubMed

Hung, C T; Beyer, J; Schulz, G

1986-07-01

Nine insulin-dependent diabetic patients were examined for insulin requirement, counterregulatory hormones, and receptor binding during their connection to glucose-controlled insulin infusion system. They were of 103% ideal body weight. A diet of 45% carbohydrate, 20% protein and 35% fat was divided into three meals and three snacks averaging the daily calorie intake of 1859 kcal. Following an equilibrating phase of 14 hours after the connection to the glucose-controlled insulin infusion system the blood samples were taken at 0800, 1200 and 1800. The insulin infusion rate increased at 0300 in the early morning from 0.128 mU/kg/min to 0.221 mU/kg/min (P less than 0.02). The postprandial insulin infusion rate jumped from 0.7 U/h (0700-0800) to 7.5 U/h (0800-0900). The calorie related and carbohydrate related insulin demands after breakfast were also highest and declined after lunch respectively (1.16 uU/kg/min kj vs. 0.61 uU/kg/min kj, P less than 0.05 and 236 mU/g CHO vs. 129 mU/g CHO and 143 mU/g CHO). Of the counterregulatory hormones the cortisol showed a significant diurnal rhythm to insulin demands. The insulin tracer binding was higher at 0800 before breakfast than that at 1200 before lunch (P less than 0.05). The increased binding could be better attributed to receptor concentration change than to affinity change. The cause of insulin relative insensitivity in the morning could be due to altered liver response to the cortisol peak in type 1 diabetics. The preserved variation of insulin binding in our patients might be referred to feeding.

Modification of Titanium Substrates with Chimeric Peptides Comprising Antimicrobial and Titanium-Binding Motifs Connected by Linkers To Inhibit Biofilm Formation.

PubMed

Liu, Zihao; Ma, Shiqing; Duan, Shun; Xuliang, Deng; Sun, Yingchun; Zhang, Xi; Xu, Xinhua; Guan, Binbin; Wang, Chao; Hu, Meilin; Qi, Xingying; Zhang, Xu; Gao, Ping

2016-03-02

Bacterial adhesion and biofilm formation are the primary causes of implant-associated infection, which is difficult to eliminate and may induce failure in dental implants. Chimeric peptides with both binding and antimicrobial motifs may provide a promising alternative to inhibit biofilm formation on titanium surfaces. In this study, chimeric peptides were designed by connecting an antimicrobial motif (JH8194: KRLFRRWQWRMKKY) with a binding motif (minTBP-1: RKLPDA) directly or via flexible/rigid linkers to modify Ti surfaces. We evaluated the binding behavior of peptides using quartz crystal microbalance (QCM) and atomic force microscopy (AFM) techniques and investigated the effect of the modification of titanium surfaces with these peptides on the bioactivity of Streptococcus gordonii (S. gordonii) and Streptococcus sanguis (S. sanguis). Compared with the flexible linker (GGGGS), the rigid linker (PAPAP) significantly increased the adsorption of the chimeric peptide on titanium surfaces (p < 0.05). Concentration-dependent adsorption is consistent with a single Langmuir model, whereas time-dependent adsorption is in line with a two-domain Langmuir model. Additionally, the chimeric peptide with the rigid linker exhibited more effective antimicrobial ability than the peptide with the flexible linker. This finding was ascribed to the ability of the rigid linker to separate functional domains and reduce their interference to the maximum extent. Consequently, the performance of chimeric peptides with specific titanium-binding motifs and antimicrobial motifs against bacteria can be optimized by the proper selection of linkers. This rational design of chimeric peptides provides a promising alternative to inhibit the formation of biofilms on titanium surfaces with the potential to prevent peri-implantitis and peri-implant mucositis.

Global and system-specific resting-state fMRI fluctuations are uncorrelated: principal component analysis reveals anti-correlated networks.

PubMed

Carbonell, Felix; Bellec, Pierre; Shmuel, Amir

2011-01-01

The influence of the global average signal (GAS) on functional-magnetic resonance imaging (fMRI)-based resting-state functional connectivity is a matter of ongoing debate. The global average fluctuations increase the correlation between functional systems beyond the correlation that reflects their specific functional connectivity. Hence, removal of the GAS is a common practice for facilitating the observation of network-specific functional connectivity. This strategy relies on the implicit assumption of a linear-additive model according to which global fluctuations, irrespective of their origin, and network-specific fluctuations are super-positioned. However, removal of the GAS introduces spurious negative correlations between functional systems, bringing into question the validity of previous findings of negative correlations between fluctuations in the default-mode and the task-positive networks. Here we present an alternative method for estimating global fluctuations, immune to the complications associated with the GAS. Principal components analysis was applied to resting-state fMRI time-series. A global-signal effect estimator was defined as the principal component (PC) that correlated best with the GAS. The mean correlation coefficient between our proposed PC-based global effect estimator and the GAS was 0.97±0.05, demonstrating that our estimator successfully approximated the GAS. In 66 out of 68 runs, the PC that showed the highest correlation with the GAS was the first PC. Since PCs are orthogonal, our method provides an estimator of the global fluctuations, which is uncorrelated to the remaining, network-specific fluctuations. Moreover, unlike the regression of the GAS, the regression of the PC-based global effect estimator does not introduce spurious anti-correlations beyond the decrease in seed-based correlation values allowed by the assumed additive model. After regressing this PC-based estimator out of the original time-series, we observed robust anti-correlations between resting-state fluctuations in the default-mode and the task-positive networks. We conclude that resting-state global fluctuations and network-specific fluctuations are uncorrelated, supporting a Resting-State Linear-Additive Model. In addition, we conclude that the network-specific resting-state fluctuations of the default-mode and task-positive networks show artifact-free anti-correlations.

Why double-stranded RNA resists condensation

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

Tolokh, Igor S.; Pabit, Suzette; Katz, Andrea M.

2014-09-15

The addition of small amounts of multivalent cations to solutions containing double-stranded DNA leads to attraction between the negatively charged helices and eventually to condensation. Surprisingly, this effect is suppressed in double-stranded RNA, which carries the same charge as the DNA, but assumes a different double helical form. However, additional characterization of short (25 base-pairs) nucleic acid (NA) duplex structures by circular dichroism shows that measured differences in condensation are not solely determined by duplex helical geometry. Here we combine experiment, theory, and atomistic simulations to propose a mechanism that connects the observed variations in condensation of short NA duplexesmore » with the spatial variation of cobalt hexammine (CoHex) binding at the NA duplex surface. The atomistic picture that emerged showed that CoHex distributions around the NA reveals two major NA-CoHex binding modes -- internal and external -- distinguished by the proximity of bound CoHex to the helical axis. Decreasing trends in experimentally observed condensation propensity of the four studied NA duplexes (from B-like form of homopolymeric DNA, to mixed sequence DNA, to DNA:RNA hybrid, to A-like RNA) are explained by the progressive decrease of a single quantity: the fraction of CoHex ions in the external binding mode. Thus, while NA condensation depends on a complex interplay between various structural and sequence features, our coupled experimental and theoretical results suggest a new model in which a single parameter connects the NA condensation propensity with geometry and sequence dependence of CoHex binding.« less

What Factors Influence the Direction of Global Brain Circulation: The Case of Chinese Canada Research Chairholders

ERIC Educational Resources Information Center

Zha, Qiang

2016-01-01

As part of globalisation, academics have become more mobile and are tempted to move to institutions that have the most favourable research funding and work environment. The university is now viewed as a global magnet for academic talent and a key institution that enhances competitiveness by connecting cities and nations to global flows of…

ME31B globally represses maternal mRNAs by two distinct mechanisms during the Drosophila maternal-to-zygotic transition.

PubMed

Wang, Miranda; Ly, Michael; Lugowski, Andrew; Laver, John D; Lipshitz, Howard D; Smibert, Craig A; Rissland, Olivia S

2017-09-06

In animal embryos, control of development is passed from exclusively maternal gene products to those encoded by the embryonic genome in a process referred to as the maternal-to-zygotic transition (MZT). We show that the RNA-binding protein, ME31B, binds to and represses the expression of thousands of maternal mRNAs during the Drosophila MZT. However, ME31B carries out repression in different ways during different phases of the MZT. Early, it represses translation while, later, its binding leads to mRNA destruction, most likely as a consequence of translational repression in the context of robust mRNA decay. In a process dependent on the PNG kinase, levels of ME31B and its partners, Cup and Trailer Hitch (TRAL), decrease by over 10-fold during the MZT, leading to a change in the composition of mRNA-protein complexes. We propose that ME31B is a global repressor whose regulatory impact changes based on its biological context.

A computational study of whole-brain connectivity in resting state and task fMRI

PubMed Central

Goparaju, Balaji; Rana, Kunjan D.; Calabro, Finnegan J.; Vaina, Lucia Maria

2014-01-01

Background We compared the functional brain connectivity produced during resting-state in which subjects were not actively engaged in a task with that produced while they actively performed a visual motion task (task-state). Material/Methods In this paper we employed graph-theoretical measures and network statistics in novel ways to compare, in the same group of human subjects, functional brain connectivity during resting-state fMRI with brain connectivity during performance of a high level visual task. We performed a whole-brain connectivity analysis to compare network statistics in resting and task states among anatomically defined Brodmann areas to investigate how brain networks spanning the cortex changed when subjects were engaged in task performance. Results In the resting state, we found strong connectivity among the posterior cingulate cortex (PCC), precuneus, medial prefrontal cortex (MPFC), lateral parietal cortex, and hippocampal formation, consistent with previous reports of the default mode network (DMN). The connections among these areas were strengthened while subjects actively performed an event-related visual motion task, indicating a continued and strong engagement of the DMN during task processing. Regional measures such as degree (number of connections) and betweenness centrality (number of shortest paths), showed that task performance induces stronger inter-regional connections, leading to a denser processing network, but that this does not imply a more efficient system as shown by the integration measures such as path length and global efficiency, and from global measures such as small-worldness. Conclusions In spite of the maintenance of connectivity and the “hub-like” behavior of areas, our results suggest that the network paths may be rerouted when performing the task condition. PMID:24947491

Integration of Network Topological and Connectivity Properties for Neuroimaging Classification

PubMed Central

Jie, Biao; Gao, Wei; Wang, Qian; Wee, Chong-Yaw

2014-01-01

Rapid advances in neuroimaging techniques have provided an efficient and noninvasive way for exploring the structural and functional connectivity of the human brain. Quantitative measurement of abnormality of brain connectivity in patients with neurodegenerative diseases, such as mild cognitive impairment (MCI) and Alzheimer’s disease (AD), have also been widely reported, especially at a group level. Recently, machine learning techniques have been applied to the study of AD and MCI, i.e., to identify the individuals with AD/MCI from the healthy controls (HCs). However, most existing methods focus on using only a single property of a connectivity network, although multiple network properties, such as local connectivity and global topological properties, can potentially be used. In this paper, by employing multikernel based approach, we propose a novel connectivity based framework to integrate multiple properties of connectivity network for improving the classification performance. Specifically, two different types of kernels (i.e., vector-based kernel and graph kernel) are used to quantify two different yet complementary properties of the network, i.e., local connectivity and global topological properties. Then, multikernel learning (MKL) technique is adopted to fuse these heterogeneous kernels for neuroimaging classification. We test the performance of our proposed method on two different data sets. First, we test it on the functional connectivity networks of 12 MCI and 25 HC subjects. The results show that our method achieves significant performance improvement over those using only one type of network property. Specifically, our method achieves a classification accuracy of 91.9%, which is 10.8% better than those by single network-property-based methods. Then, we test our method for gender classification on a large set of functional connectivity networks with 133 infants scanned at birth, 1 year, and 2 years, also demonstrating very promising results. PMID:24108708

High trait aggression in men is associated with low 5-HT levels, as indexed by 5-HT4 receptor binding.

PubMed

da Cunha-Bang, Sofi; Mc Mahon, Brenda; Fisher, Patrick MacDonald; Jensen, Peter Steen; Svarer, Claus; Knudsen, Gitte Moos

2016-04-01

Impulsive aggression has commonly been associated with a dysfunction of the serotonin (5-HT) system: many, but not all, studies point to an inverse relationship between 5-HT and aggression. As cerebral 5-HT4 receptor (5-HT4R) binding has recently been recognized as a proxy for stable brain levels of 5-HT, we here test the hypothesis in healthy men and women that brain 5-HT levels, as indexed by cerebral 5-HT4R, are inversely correlated with trait aggression and impulsivity. Sixty-one individuals (47 men) underwent positron emission tomography scanning with the radioligand [(11)C]SB207145 for quantification of brain 5-HT4R binding. The Buss-Perry Aggression Questionnaire (BPAQ) and the Barratt Impulsiveness Scale were used for assessment of trait aggression and trait impulsivity. Among male subjects, there was a positive correlation between global 5-HT4R and BPAQ total score (P = 0.037) as well as BPAQ physical aggression (P = 0.025). No main effect of global 5-HT4R on trait aggression or impulsivity was found in the mixed gender sample, but there was evidence for sex interaction effects in the relationship between global 5-HT4R and BPAQ physical aggression. In conclusion we found that low cerebral 5-HT levels, as indexed by 5-HT4R binding were associated with high trait aggression in males, but not in females. © The Author (2016). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

Quantifying the topography of the intrinsic energy landscape of flexible biomolecular recognition

PubMed Central

Chu, Xiakun; Gan, Linfeng; Wang, Erkang; Wang, Jin

2013-01-01

Biomolecular functions are determined by their interactions with other molecules. Biomolecular recognition is often flexible and associated with large conformational changes involving both binding and folding. However, the global and physical understanding for the process is still challenging. Here, we quantified the intrinsic energy landscapes of flexible biomolecular recognition in terms of binding–folding dynamics for 15 homodimers by exploring the underlying density of states, using a structure-based model both with and without considering energetic roughness. By quantifying three individual effective intrinsic energy landscapes (one for interfacial binding, two for monomeric folding), the association mechanisms for flexible recognition of 15 homodimers can be classified into two-state cooperative “coupled binding–folding” and three-state noncooperative “folding prior to binding” scenarios. We found that the association mechanism of flexible biomolecular recognition relies on the interplay between the underlying effective intrinsic binding and folding energy landscapes. By quantifying the whole global intrinsic binding–folding energy landscapes, we found strong correlations between the landscape topography measure Λ (dimensionless ratio of energy gap versus roughness modulated by the configurational entropy) and the ratio of the thermodynamic stable temperature versus trapping temperature, as well as between Λ and binding kinetics. Therefore, the global energy landscape topography determines the binding–folding thermodynamics and kinetics, crucial for the feasibility and efficiency of realizing biomolecular function. We also found “U-shape” temperature-dependent kinetic behavior and a dynamical cross-over temperature for dividing exponential and nonexponential kinetics for two-state homodimers. Our study provides a unique way to bridge the gap between theory and experiments. PMID:23754431

West Indians and Afro-Americans: A Partnership

ERIC Educational Resources Information Center

Best, Tony

1975-01-01

In addition to the difficulties connected with their status as immigrants, West Indians must contend with the problems arising because of their blackness. The ties that bind Afro-Americans and West Indians together are said to consist in survival processes. (Author/AM)

ITS National Intelligent Transportation Systems Program Plan: Five Year Horizon Plan

DOT National Transportation Integrated Search

2000-08-01

Transportation is vital to the social and economic health of the nation. Surface transportation systems - the net-works of highways, local streets, bus routes, and rail lines - are the ties that bind communities and facilitate commerce, connecting re...

Elementary Particles and Forces.

ERIC Educational Resources Information Center

Quigg, Chris

1985-01-01

Discusses subatomic particles (quarks, leptons, and others) revealed by higher accelerator energies. A connection between forces at this subatomic level has been established, and prospects are good for a description of forces that encompass binding atomic nuclei. Colors, fundamental interactions, screening, camouflage, electroweak symmetry, and…

The structure of binding curves and practical identifiability of equilibrium ligand-binding parameters

PubMed Central

Middendorf, Thomas R.

2017-01-01

A critical but often overlooked question in the study of ligands binding to proteins is whether the parameters obtained from analyzing binding data are practically identifiable (PI), i.e., whether the estimates obtained from fitting models to noisy data are accurate and unique. Here we report a general approach to assess and understand binding parameter identifiability, which provides a toolkit to assist experimentalists in the design of binding studies and in the analysis of binding data. The partial fraction (PF) expansion technique is used to decompose binding curves for proteins with n ligand-binding sites exactly and uniquely into n components, each of which has the form of a one-site binding curve. The association constants of the PF component curves, being the roots of an n-th order polynomial, may be real or complex. We demonstrate a fundamental connection between binding parameter identifiability and the nature of these one-site association constants: all binding parameters are identifiable if the constants are all real and distinct; otherwise, at least some of the parameters are not identifiable. The theory is used to construct identifiability maps from which the practical identifiability of binding parameters for any two-, three-, or four-site binding curve can be assessed. Instructions for extending the method to generate identifiability maps for proteins with more than four binding sites are also given. Further analysis of the identifiability maps leads to the simple rule that the maximum number of structurally identifiable binding parameters (shown in the previous paper to be equal to n) will also be PI only if the binding curve line shape contains n resolved components. PMID:27993951

The RNA-binding complex ESCRT-II in Xenopus laevis eggs recognizes purine-rich sequences through its subunit Vps25.

PubMed

Emerman, Amy B; Blower, Michael

2018-06-14

RNA-binding proteins (RBPs) are critical regulators of gene expression. Recent studies have uncovered hundreds of mRNA-binding proteins that do not contain annotated RNA-binding domains and have well-established roles in other cellular processes. Investigation of these nonconventional RBPs is critical for revealing novel RNA-binding domains and may disclose connections between RNA regulation and other aspects of cell biology. Endosomal sorting complex required for transport II (ESCRT-II) is a nonconventional RNA-binding complex that has a canonical role in multivesicular body formation. ESCRT-II previously has been identified as an RNA-binding complex in Drosophila oocytes, but whether its RNA-binding properties extend beyond Drosophila is unknown. In this study, we found that the RNA-binding properties of ESCRT-II are conserved in Xenopus eggs, where ESCRT-II interacted with hundreds of mRNAs. Using a UV-crosslinking approach, we demonstrated that ESCRT-II binds directly to RNA through its subunit Vps25. UV-crosslinking and immunoprecipitation (CLIP)-Seq revealed that Vps25 specifically recognizes a polypurine (i.e. GA-rich) motif in RNA. Using purified components, we could reconstitute the selective Vps25-mediated binding of the polypurine motif in vitro. Our results provide insight into the mechanism by which ESCRT-II selectively binds to mRNAs and also suggest an unexpected link between endosome biology and RNA regulation. Published under license by The American Society for Biochemistry and Molecular Biology, Inc.

INTERdependence Curriculum Aid.

ERIC Educational Resources Information Center

World Affairs Council of Philadelphia, PA.

Stressing global interdependence, this guide suggests resources, materials, and activities related to major world problems. Global interdependence is interpreted as connections between and among nations in areas of war and peace, human rights, environmental use, economics, and international law. The major objective is to help students understand…

Enzymatic properties of a GH19 chitinase isolated from rice lacking a major loop structure involved in chitin binding.

PubMed

Tanaka, Jun; Fukamizo, Tamo; Ohnuma, Takayuki

2017-05-01

The catalytic domains of family GH19 chitinases have been found to consist of a conserved, α-helical core-region and different numbers (1-6) of loop structures, located at both ends of the substrate-binding groove and which extend over the glycon- and aglycon-binding sites. We expressed, purified and enzymatically characterized a GH19 chitinase from rice, Oryza sativa L. cv. Nipponbare (OsChia2a), lacking a major loop structure (loop III) connected to the functionally important β-stranded region. The new enzyme thus contained the five remaining loop structures (loops I, II, IV, V and C-term). The OsChia2a recombinant protein catalyzed hydrolysis of chitin oligosaccharides, (GlcNAc)n (n = 3-6), with inversion of anomeric configuration, indicating that OsChia2a correctly folded without loop III. From thermal unfolding experiments and calorimetric titrations using the inactive OsChia2a mutant (OsChia2a-E68Q), in which the catalytic residue Glu68 was mutated to glutamine, we found that the binding affinities towards (GlcNAc)n (n = 2-6) were almost proportional to the degree of polymerization of (GlcNAc)n, but were much lower than those obtained for a moss GH19 chitinase having only loop III [Ohnuma T, Sørlie M, Fukuda T, Kawamoto N, Taira T, Fukamizo T. 2011. Chitin oligosaccharide binding to a family GH19 chitinase from the moss, Bryum coronatum. FEBS J. 278:3991-4001]. Nevertheless, OsChia2a exhibited significant antifungal activity. It appears that loop III connected to the β-stranded region is important for (GlcNAc)n binding, but is not essential for antifungal activity. © The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Using Auditory Steady State Responses to Outline the Functional Connectivity in the Tinnitus Brain

PubMed Central

Schlee, Winfried; Weisz, Nathan; Bertrand, Olivier; Hartmann, Thomas; Elbert, Thomas

2008-01-01

Background Tinnitus is an auditory phantom perception that is most likely generated in the central nervous system. Most of the tinnitus research has concentrated on the auditory system. However, it was suggested recently that also non-auditory structures are involved in a global network that encodes subjective tinnitus. We tested this assumption using auditory steady state responses to entrain the tinnitus network and investigated long-range functional connectivity across various non-auditory brain regions. Methods and Findings Using whole-head magnetoencephalography we investigated cortical connectivity by means of phase synchronization in tinnitus subjects and healthy controls. We found evidence for a deviating pattern of long-range functional connectivity in tinnitus that was strongly correlated with individual ratings of the tinnitus percept. Phase couplings between the anterior cingulum and the right frontal lobe and phase couplings between the anterior cingulum and the right parietal lobe showed significant condition x group interactions and were correlated with the individual tinnitus distress ratings only in the tinnitus condition and not in the control conditions. Conclusions To the best of our knowledge this is the first study that demonstrates existence of a global tinnitus network of long-range cortical connections outside the central auditory system. This result extends the current knowledge of how tinnitus is generated in the brain. We propose that this global extend of the tinnitus network is crucial for the continuos perception of the tinnitus tone and a therapeutical intervention that is able to change this network should result in relief of tinnitus. PMID:19005566

Generalized Squashing Factors for Covariant Description of Magnetic Connectivity in the Solar Corona

NASA Technical Reports Server (NTRS)

Titov, V. S.

2007-01-01

The study of magnetic connectivity in the solar corona reveals a need to generalize the field line mapping technique to arbitrary geometry of the boundaries and systems of coordinates. Indeed, the global description of the connectivity in the corona requires the use of the photospheric and solar wind boundaries. Both are closed surfaces and therefore do not admit a global regular system of coordinates. At least two overlapping regular systems of coordinates for each of the boundaries are necessary in this case to avoid spherical-pole-like singularities in the coordinates of the footpoints. This implies that the basic characteristic of magnetic connectivity-the squashing degree or factor Q of elemental flux tubes, according to Titov and coworkers-must be rewritten in covariant form. Such a covariant expression of Q is derived in this work. The derived expression is very flexible and highly efficient for describing the global magnetic connectivity in the solar corona. In addition, a general expression for a new characteristic Q1, which defines a squashing of the flux tubes in the directions perpendicular to the field lines, is determined. This new quantity makes it possible to filter out the quasi-separatrix layers whose large values of Q are caused by a projection effect at the field lines nearly touching the photosphere. Thus, the value Q1 provides a much more precise description of the volumetric properties of the magnetic field structure. The difference between Q and Q1 is illustrated by comparing their distributions for two configurations, one of which is the Titov-Demoulin model of a twisted magnetic field.

Dexmedetomidine Disrupts the Local and Global Efficiencies of Large-scale Brain Networks.

PubMed

Hashmi, Javeria A; Loggia, Marco L; Khan, Sheraz; Gao, Lei; Kim, Jieun; Napadow, Vitaly; Brown, Emery N; Akeju, Oluwaseun

2017-03-01

A clear understanding of the neural basis of consciousness is fundamental to research in clinical and basic neuroscience disciplines and anesthesia. Recently, decreased efficiency of information integration was suggested as a core network feature of propofol-induced unconsciousness. However, it is unclear whether this finding can be generalized to dexmedetomidine, which has a different molecular target. Dexmedetomidine was administered as a 1-μg/kg bolus over 10 min, followed by a 0.7-μg · kg · h infusion to healthy human volunteers (age range, 18 to 36 yr; n = 15). Resting-state functional magnetic resonance imaging data were acquired during baseline, dexmedetomidine-induced altered arousal, and recovery states. Zero-lag correlations between resting-state functional magnetic resonance imaging signals extracted from 131 brain parcellations were used to construct weighted brain networks. Network efficiency, degree distribution, and node strength were computed using graph analysis. Parcellated brain regions were also mapped to known resting-state networks to study functional connectivity changes. Dexmedetomidine significantly reduced the local and global efficiencies of graph theory-derived networks. Dexmedetomidine also reduced the average brain connectivity strength without impairing the degree distribution. Functional connectivity within and between all resting-state networks was modulated by dexmedetomidine. Dexmedetomidine is associated with a significant drop in the capacity for efficient information transmission at both the local and global levels. These changes result from reductions in the strength of connectivity and also manifest as reduced within and between resting-state network connectivity. These findings strengthen the hypothesis that conscious processing relies on an efficient system of information transfer in the brain.

Cascading events in linked ecological and socioeconomic systems

USGS Publications Warehouse

Peters, Debra P.C.; Sala, O.E.; Allen, Craig D.; Covich, A.; Brunson, M.

2007-01-01

Cascading events that start at small spatial scales and propagate non-linearly through time to influence larger areas often have major impacts on ecosystem goods and services. Events such as wildfires and hurricanes are increasing in frequency and magnitude as systems become more connected through globalization processes. We need to improve our understanding of these events in order to predict their occurrence, minimize potential impacts, and allow for strategic recovery. Here, we synthesize information about cascading events in systems located throughout the Americas. We discuss a variety of examples of cascading events that share a common feature: they are often driven by linked ecological and human processes across scales. In this era of globalization, we recommend studies that explicitly examine connections across scales and examine the role of connectivity among non-contiguous as well as contiguous areas.

Enhanced economic connectivity to foster heat stress-related losses.

PubMed

Wenz, Leonie; Levermann, Anders

2016-06-01

Assessing global impacts of unexpected meteorological events in an increasingly connected world economy is important for estimating the costs of climate change. We show that since the beginning of the 21st century, the structural evolution of the global supply network has been such as to foster an increase of climate-related production losses. We compute first- and higher-order losses from heat stress-induced reductions in productivity under changing economic and climatic conditions between 1991 and 2011. Since 2001, the economic connectivity has augmented in such a way as to facilitate the cascading of production loss. The influence of this structural change has dominated over the effect of the comparably weak climate warming during this decade. Thus, particularly under future warming, the intensification of international trade has the potential to amplify climate losses if no adaptation measures are taken.

Breakdown of the brain’s functional network modularity with awareness

PubMed Central

Godwin, Douglass; Barry, Robert L.; Marois, René

2015-01-01

Neurobiological theories of awareness propose divergent accounts of the spatial extent of brain changes that support conscious perception. Whereas focal theories posit mostly local regional changes, global theories propose that awareness emerges from the propagation of neural signals across a broad extent of sensory and association cortex. Here we tested the scalar extent of brain changes associated with awareness using graph theoretical analysis applied to functional connectivity data acquired at ultra-high field while subjects performed a simple masked target detection task. We found that awareness of a visual target is associated with a degradation of the modularity of the brain’s functional networks brought about by an increase in intermodular functional connectivity. These results provide compelling evidence that awareness is associated with truly global changes in the brain’s functional connectivity. PMID:25759440

Enhanced economic connectivity to foster heat stress–related losses

PubMed Central

Wenz, Leonie; Levermann, Anders

2016-01-01

Assessing global impacts of unexpected meteorological events in an increasingly connected world economy is important for estimating the costs of climate change. We show that since the beginning of the 21st century, the structural evolution of the global supply network has been such as to foster an increase of climate-related production losses. We compute first- and higher-order losses from heat stress–induced reductions in productivity under changing economic and climatic conditions between 1991 and 2011. Since 2001, the economic connectivity has augmented in such a way as to facilitate the cascading of production loss. The influence of this structural change has dominated over the effect of the comparably weak climate warming during this decade. Thus, particularly under future warming, the intensification of international trade has the potential to amplify climate losses if no adaptation measures are taken. PMID:27386555

Sovereign public debt crisis in Europe. A network analysis

NASA Astrophysics Data System (ADS)

Matesanz, David; Ortega, Guillermo J.

2015-10-01

In this paper we analyse the evolving network structure of the quarterly public debt-to-GDP ratio from 2000 to 2014. By applying tools and concepts coming from complex systems we study the effects of the global financial crisis over public debt network connections and communities. Two main results arise from this analysis: firstly, countries public debts tend to synchronize their evolution, increasing global connectivity in the network and dramatically decreasing the number of communities. Secondly, a disruption in previous structure is observed at the time of the shock, emerging a more centralized and less diversify network topological organization which might be more prone to suffer contagion effects. This last fact is evidenced by an increasing tendency in countries of similar level of public debt to be connected between them, which we have quantified by the network assortativity.

Ribosome protection by antibiotic resistance ATP-binding cassette protein.

PubMed

Su, Weixin; Kumar, Veerendra; Ding, Yichen; Ero, Rya; Serra, Aida; Lee, Benjamin Sian Teck; Wong, Andrew See Weng; Shi, Jian; Sze, Siu Kwan; Yang, Liang; Gao, Yong-Gui

2018-05-15

The ribosome is one of the richest targets for antibiotics. Unfortunately, antibiotic resistance is an urgent issue in clinical practice. Several ATP-binding cassette family proteins confer resistance to ribosome-targeting antibiotics through a yet unknown mechanism. Among them, MsrE has been implicated in macrolide resistance. Here, we report the cryo-EM structure of ATP form MsrE bound to the ribosome. Unlike previously characterized ribosomal protection proteins, MsrE is shown to bind to ribosomal exit site. Our structure reveals that the domain linker forms a unique needle-like arrangement with two crossed helices connected by an extended loop projecting into the peptidyl-transferase center and the nascent peptide exit tunnel, where numerous antibiotics bind. In combination with biochemical assays, our structure provides insight into how MsrE binding leads to conformational changes, which results in the release of the drug. This mechanism appears to be universal for the ABC-F type ribosome protection proteins. Copyright © 2018 the Author(s). Published by PNAS.

Instantaneous global spatial interaction? Exploring the Gaussian inequality, distance and Internet pings in a global network

NASA Astrophysics Data System (ADS)

Baker, R. G. V.

2005-12-01

The Internet has been publicly portrayed as a new technological horizon yielding instantaneous interaction to a point where geography no longer matters. This research aims to dispel this impression by applying a dynamic form of trip modelling to investigate pings in a global computer network compiled by the Stanford Linear Accelerator Centre (SLAC) from 1998 to 2004. Internet flows have been predicted to have the same mathematical operators as trips to a supermarket, since they are both periodic and constrained by a distance metric. Both actual and virtual trips are part of a spectrum of origin-destination pairs in the time-space convergence of trip time-lines. Internet interaction is very near to the convergence of these time-lines (at a very small time scale in milliseconds, but with interactions over thousands of kilometres). There is a lag effect and this is formalised by the derivation of Gaussian and gravity inequalities between the time taken (Δ t) and the partitioning of distance (Δ x). This inequality seems to be robust for a regression of Δ t to Δ x in the SLAC data set for each year (1998 to 2004). There is a constant ‘forbidden zone’ in the interaction, underpinned by the fact that pings do not travel faster than the speed of light. Superimposed upon this zone is the network capacity where a linear regression of Δ t to Δ x is a proxy summarising global Internet connectivity for that year. The results suggest that there has been a substantial improvement in connectivity over the period with R 2 increasing steadily from 0.39 to 0.65 from less Gaussian spreading of the ping latencies. Further, the regression line shifts towards the inequality boundary from 1998 to 2004, where the increased slope shows a greater proportional rise in local connectivity over global connectivity. A conclusion is that national geography still does matter in spatial interaction modelling of the Internet.

Change of Brain Functional Connectivity in Patients With Spinal Cord Injury: Graph Theory Based Approach.

PubMed

Min, Yu-Sun; Chang, Yongmin; Park, Jang Woo; Lee, Jong-Min; Cha, Jungho; Yang, Jin-Ju; Kim, Chul-Hyun; Hwang, Jong-Moon; Yoo, Ji-Na; Jung, Tae-Du

2015-06-01

To investigate the global functional reorganization of the brain following spinal cord injury with graph theory based approach by creating whole brain functional connectivity networks from resting state-functional magnetic resonance imaging (rs-fMRI), characterizing the reorganization of these networks using graph theoretical metrics and to compare these metrics between patients with spinal cord injury (SCI) and age-matched controls. Twenty patients with incomplete cervical SCI (14 males, 6 females; age, 55±14.1 years) and 20 healthy subjects (10 males, 10 females; age, 52.9±13.6 years) participated in this study. To analyze the characteristics of the whole brain network constructed with functional connectivity using rs-fMRI, graph theoretical measures were calculated including clustering coefficient, characteristic path length, global efficiency and small-worldness. Clustering coefficient, global efficiency and small-worldness did not show any difference between controls and SCIs in all density ranges. The normalized characteristic path length to random network was higher in SCI patients than in controls and reached statistical significance at 12%-13% of density (p<0.05, uncorrected). The graph theoretical approach in brain functional connectivity might be helpful to reveal the information processing after SCI. These findings imply that patients with SCI can build on preserved competent brain control. Further analyses, such as topological rearrangement and hub region identification, will be needed for better understanding of neuroplasticity in patients with SCI.

Effect of Resting-State fNIRS Scanning Duration on Functional Brain Connectivity and Graph Theory Metrics of Brain Network.

PubMed

Geng, Shujie; Liu, Xiangyu; Biswal, Bharat B; Niu, Haijing

2017-01-01

As an emerging brain imaging technique, functional near infrared spectroscopy (fNIRS) has attracted widespread attention for advancing resting-state functional connectivity (FC) and graph theoretical analyses of brain networks. However, it remains largely unknown how the duration of the fNIRS signal scanning is related to stable and reproducible functional brain network features. To answer this question, we collected resting-state fNIRS signals (10-min duration, two runs) from 18 participants and then truncated the hemodynamic time series into 30-s time bins that ranged from 1 to 10 min. Measures of nodal efficiency, nodal betweenness, network local efficiency, global efficiency, and clustering coefficient were computed for each subject at each fNIRS signal acquisition duration. Analyses of the stability and between-run reproducibility were performed to identify optimal time length for each measure. We found that the FC, nodal efficiency and nodal betweenness stabilized and were reproducible after 1 min of fNIRS signal acquisition, whereas network clustering coefficient, local and global efficiencies stabilized after 1 min and were reproducible after 5 min of fNIRS signal acquisition for only local and global efficiencies. These quantitative results provide direct evidence regarding the choice of the resting-state fNIRS scanning duration for functional brain connectivity and topological metric stability of brain network connectivity.

Network organization is globally atypical in autism: A graph theory study of intrinsic functional connectivity.

PubMed

Keown, Christopher L; Datko, Michael C; Chen, Colleen P; Maximo, José Omar; Jahedi, Afrooz; Müller, Ralph-Axel

2017-01-01

Despite abundant evidence of brain network anomalies in autism spectrum disorder (ASD), findings have varied from broad functional underconnectivity to broad overconnectivity. Rather than pursuing overly simplifying general hypotheses ('under' vs. 'over'), we tested the hypothesis of atypical network distribution in ASD (i.e., participation of unusual loci in distributed functional networks). We used a selective high-quality data subset from the ABIDE datashare (including 111 ASD and 174 typically developing [TD] participants) and several graph theory metrics. Resting state functional MRI data were preprocessed and analyzed for detection of low-frequency intrinsic signal correlations. Groups were tightly matched for available demographics and head motion. As hypothesized, the Rand Index (reflecting how similar network organization was to a normative set of networks) was significantly lower in ASD than TD participants. This was accounted for by globally reduced cohesion and density, but increased dispersion of networks. While differences in hub architecture did not survive correction, rich club connectivity (among the hubs) was increased in the ASD group. Our findings support the model of reduced network integration (connectivity with networks) and differentiation (or segregation; based on connectivity outside network boundaries) in ASD. While the findings applied at the global level, they were not equally robust across all networks and in one case (greater cohesion within ventral attention network in ASD) even reversed.

Globalizing the English Curriculum through Caribbean Literature.

ERIC Educational Resources Information Center

Spoelman, Linda; Thomas, Katherine

Although Caribbean (English) writers hold differing views on the effectiveness of making connections in an area of so much diversity, Caribbean literature can be connected to the English curriculum to promote diversity and understanding. V. S. Naipaul, Nobel Prize winning author from the region, presents a pessimistic view of Caribbean society in…

15 CFR Appendix IV to Subpart P of... - Ecological Reserves Boundary

Code of Federal Regulations, 2014 CFR

2014-01-01

... succession the points at the following coordinates: Western Sambo [Based on differential Global Positioning... Tortugas South. (3) The boundary of Tortugas North is formed by connecting in succession the points at the... South is formed by connecting in succession the points at the following coordinates: Tortugas South...

15 CFR Appendix IV to Subpart P of... - Ecological Reserves Boundary

Code of Federal Regulations, 2011 CFR

2011-01-01

... succession the points at the following coordinates: Western Sambo [Based on differential Global Positioning... Tortugas South. (3) The boundary of Tortugas North is formed by connecting in succession the points at the... South is formed by connecting in succession the points at the following coordinates: Tortugas South...

15 CFR Appendix IV to Subpart P of... - Ecological Reserves Boundary

Code of Federal Regulations, 2012 CFR

2012-01-01

... succession the points at the following coordinates: Western Sambo [Based on differential Global Positioning... Tortugas South. (3) The boundary of Tortugas North is formed by connecting in succession the points at the... South is formed by connecting in succession the points at the following coordinates: Tortugas South...

15 CFR Appendix IV to Subpart P of... - Ecological Reserves Boundary

Code of Federal Regulations, 2013 CFR

2013-01-01

... succession the points at the following coordinates: Western Sambo [Based on differential Global Positioning... Tortugas South. (3) The boundary of Tortugas North is formed by connecting in succession the points at the... South is formed by connecting in succession the points at the following coordinates: Tortugas South...

Ecopedagogy in the Age of Globalization: Educators' Perspectives of Environmental Education Programs in the Americas Which Incorporate Social Justice Models

ERIC Educational Resources Information Center

Misiaszek, Gregery William

2011-01-01

Ecopedagogy is defined in this research as transformative environmental education which critically and dialectically deconstructs how social conflicts and environmental (socio-environmental) devastation are connected. Understanding these connections is necessary because environmental destructive actions are inherently political--benefiting some…

Fragile X mental retardation protein: A paradigm for translational control by RNA-binding proteins.

PubMed

Chen, Eileen; Joseph, Simpson

2015-07-01

Translational control is a common mechanism used to regulate gene expression and occur in bacteria to mammals. Typically in translational control, an RNA-binding protein binds to a unique sequence in the mRNA to regulate protein synthesis by the ribosomes. Alternatively, a protein may bind to or modify a translation factor to globally regulate protein synthesis by the cell. Here, we review translational control by the fragile X mental retardation protein (FMRP), the absence of which causes the neurological disease, fragile X syndrome (FXS). Copyright © 2015 Elsevier B.V. and Société française de biochimie et biologie Moléculaire (SFBBM). All rights reserved.

Identical linkage and cooperativity of oxygen and carbon monoxide binding to Octopus dofleini hemocyanin

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

Connelly, P.R.; Gill, S.J.; Miller, K.I.

1989-02-21

Employment of high-precision thin-layer methods has enabled detailed functional characterization of oxygen and carbon monoxide binding for (1) the fully assembled form with 70 binding sites and (2) the isolated chains with 7 binding sites of octopus dofleini hemocyanin. The striking difference in the cooperativities of the two ligands for the assembled decamer is revealed through an examination of the binding capacities and the partition coefficient, determined as functions of the activities of both ligands. A global analysis of the data sets supported by a two-state allosteric model assuming an allosteric unit of 7. Higher level allosteric interactions were notmore » indicated. This contrasts to results obtained for arthropod hemocyanins. Oxygen and carbon monoxide experiments performed on the isolated subunit chain confirmed the presence of functional heterogeneity reported previously. The analysis shows two types of binding sites in the ratio of 4:3.« less

Effects of Information Capitalism and Globalization on Teaching and Learning

ERIC Educational Resources Information Center

Adeoye, Blessing F., Ed.; Tomei, Lawrence, Ed.

2014-01-01

As computers and Internet connections become widely available in schools and classrooms, it is critical to examine cross-cultural issues in the utilization of information and communication technologies. "Effects of Information Capitalism and Globalization on Teaching and Learning" examines issues concerning emerging multimedia…

Ultrascale collaborative visualization using a display-rich global cyberinfrastructure.

PubMed

Jeong, Byungil; Leigh, Jason; Johnson, Andrew; Renambot, Luc; Brown, Maxine; Jagodic, Ratko; Nam, Sungwon; Hur, Hyejung

2010-01-01

The scalable adaptive graphics environment (SAGE) is high-performance graphics middleware for ultrascale collaborative visualization using a display-rich global cyberinfrastructure. Dozens of sites worldwide use this cyberinfrastructure middleware, which connects high-performance-computing resources over high-speed networks to distributed ultraresolution displays.

The Change of South Korean Adult Education in Globalization.

ERIC Educational Resources Information Center

Park, Sung-Jung

2002-01-01

Describes the development of adult education in South Korea from postwar modernization to the current globalized environment. Notes that adult higher education is increasingly formalized and institutionalized, with expanded credentialism, inequality, and government intervention and a weakening connection between adult education and social…

Mapping Global Research on International Higher Education

ERIC Educational Resources Information Center

Kuzhabekova, Aliya; Hendel, Darwin D.; Chapman, David W.

2015-01-01

The purpose of the study is to map global research in international higher education. Specifically, the study uses bibliometric and social network analysis methods to identify key individuals, institutions, countries, and disciplines contributing to research in international higher education and to investigate patterns of connectivity among…

Genesis, Pathways, and Terminations of Intense Global Water Vapor Transport in Association with Large-Scale Climate Patterns

NASA Astrophysics Data System (ADS)

Sellars, S. L.; Kawzenuk, B.; Nguyen, P.; Ralph, F. M.; Sorooshian, S.

2017-12-01

The CONNected objECT (CONNECT) algorithm is applied to global Integrated Water Vapor Transport data from the NASA's Modern-Era Retrospective Analysis for Research and Applications - Version 2 reanalysis product for the period of 1980 to 2016. The algorithm generates life-cycle records in time and space evolving strong vapor transport events. We show five regions, located in the midlatitudes, where events typically exist (off the coast of the southeast United States, eastern China, eastern South America, off the southern tip of South Africa, and in the southeastern Pacific Ocean). Global statistics show distinct genesis and termination regions and global seasonal peak frequency during Northern Hemisphere late fall/winter and Southern Hemisphere winter. In addition, the event frequency and geographical location are shown to be modulated by the Arctic Oscillation, Pacific North American Pattern, and the quasi-biennial oscillation. Moreover, a positive linear trend in the annual number of objects is reported, increasing by 3.58 objects year-over-year.

Connecting Restricted, High-Availability, or Low-Latency Resources to a Seamless Global Pool for CMS

NASA Astrophysics Data System (ADS)

Balcas, J.; Bockelman, B.; Hufnagel, D.; Hurtado Anampa, K.; Jayatilaka, B.; Khan, F.; Larson, K.; Letts, J.; Mascheroni, M.; Mohapatra, A.; Marra Da Silva, J.; Mason, D.; Perez-Calero Yzquierdo, A.; Piperov, S.; Tiradani, A.; Verguilov, V.; CMS Collaboration

2017-10-01

The connection of diverse and sometimes non-Grid enabled resource types to the CMS Global Pool, which is based on HTCondor and glideinWMS, has been a major goal of CMS. These resources range in type from a high-availability, low latency facility at CERN for urgent calibration studies, called the CAF, to a local user facility at the Fermilab LPC, allocation-based computing resources at NERSC and SDSC, opportunistic resources provided through the Open Science Grid, commercial clouds, and others, as well as access to opportunistic cycles on the CMS High Level Trigger farm. In addition, we have provided the capability to give priority to local users of beyond WLCG pledged resources at CMS sites. Many of the solutions employed to bring these diverse resource types into the Global Pool have common elements, while some are very specific to a particular project. This paper details some of the strategies and solutions used to access these resources through the Global Pool in a seamless manner.

Relative Differences in Resting-State Brain Connectivity Associated with Long Term Intensive Lifestyle Intervention

PubMed Central

Casanova, Ramon; Hayasaka, Satoru; Saldana, Santiago; Bryan, Nick R.; Demos, Kathryn E.; Desiderio, Lisa; Erickson, Kirk I.; Espeland, Mark A.; Nasrallah, Ilya M.; Wadden, Thomas; Laurienti, Paul J.

2016-01-01

A number of studies have reported that type 2 diabetes mellitus (T2DM) is associated with alterations in resting-state activity and connectivity in the brain. There is also evidence that interventions involving physical activity and weight loss may affect brain functional connectivity. In this study, we examined the effects of nearly 10 years of an intensive lifestyle intervention (ILI), designed to induce and sustain weight loss through lower caloric intake and increased physical activity, on resting-state networks in adults with T2DM. We performed a cross-sectional comparison of global and local characteristics from functional brain networks between individuals who had been randomly assigned to ILI or a control condition of health education and support. Upon examining brain networks from 312 participants (average age: 68.8 for ILI and 67.9 for controls), we found that ILI participants (N=160) had attenuated local efficiency at the network-level compared with controls (N=152). Although there was no group difference in the network-level global efficiency, we found that, among ILI participants, nodal global efficiency was elevated in left fusiform gyrus, right middle frontal gyrus, and pars opercularis of right inferior frontal gyrus. These effects were age-dependent, with more pronounced effects for older participants. Overall these results indicate that the individuals assigned to the ILI had brain networks with less regional and more global connectivity, particularly involving frontal lobes. Such patterns would support greater distributed information processing. Future studies are needed to determine if these differences are associated with age-related compensatory function in the ILI group or worse pathology in the control group. PMID:27685338

Functional Hemispheric Asymmetries of Global/Local Processing Mirrored by the Steady-State Visual Evoked Potential

ERIC Educational Resources Information Center

Martens, Ulla; Hubner, Ronald

2013-01-01

While hemispheric differences in global/local processing have been reported by various studies, it is still under dispute at which processing stage they occur. Primarily, it was assumed that these asymmetries originate from an early perceptual stage. Instead, the content-level binding theory (Hubner & Volberg, 2005) suggests that the hemispheres…

Mapping of epitopes for monoclonal antibodies against human platelet thrombospondin with electron microscopy and high sensitivity amino acid sequencing

PubMed Central

1985-01-01

A panel of monoclonal antibodies (Mab's) has been raised against human platelet thrombospondin (TSP). One Mab, designated A2.5, inhibits the hemagglutinating activity of TSP and immunoprecipitates the NH2 terminal 25 kD heparin binding domain of TSP (Dixit, V.M., D. M. Haverstick, K. M. O'Rourke, S. W. Hennessy, G. A. Grant, S. A. Santoro, and W. A. Frazier, 1985, Biochemistry, in press). Another Mab, C6.7, blocks the thrombin-stimulated aggregation of live platelets and immunoprecipitates an 18-kD fragment distinct from the heparin binding domain (Dixit, V. M., D. M. Haverstick, K. M. O'Rourke, S. W. Hennessy, G. A. Grant, S. A. Santoro, and W. A. Frazier, 1985, Proc. Natl. Acad. Sci. 82: 3472-3476). To determine the relative locations of the epitopes for these Mabs in the three-dimensional structure of TSP, we have examined TSP-Mab complexes by electron microscopy of rotary- shadowed proteins. The TSP molecule is composed of three 180-kD subunits, each of which consists of a small globular domain (approximately 8 nm diam) and a larger globular domain (approximately 16 nm diam) connected by a thin, flexible strand. The subunit interaction site is on the thin connecting strands, nearer the small globular domains. Mab A2.5 binds to the cluster of three small domains, indicating that this region contains the heparin binding domain and thus represents the NH2 termini of the TSP peptide chains. Mab C6.7 binds to the large globular domains on the side opposite the point at which the connecting strand enters the domain, essentially the maximum possible distance from the A2.5 epitope. Using high sensitivity automated NH2 terminal sequencing of TSP chymotryptic peptides we have ordered these fragments within the TSP peptide chain and have confirmed that the epitope for C6.7 in fact lies near the extreme COOH terminus of the peptide chain. In combination with other data, we have been able to construct a map of the linear order of the identified domains of TSP that indicates that to a large extent, the domains are arranged co- linearly with the peptide chain. PMID:2413043

A dynamically coupled allosteric network underlies binding cooperativity in Src kinase

PubMed Central

Foda, Zachariah H.; Shan, Yibing; Kim, Eric T.; Shaw, David E.; Seeliger, Markus A.

2015-01-01

Protein tyrosine kinases are attractive drug targets because many human diseases are associated with the deregulation of kinase activity. However, how the catalytic kinase domain integrates different signals and switches from an active to an inactive conformation remains incompletely understood. Here we identify an allosteric network of dynamically coupled amino acids in Src kinase that connects regulatory sites to the ATP- and substrate-binding sites. Surprisingly, reactants (ATP and peptide substrates) bind with negative cooperativity to Src kinase while products (ADP and phosphopeptide) bind with positive cooperativity. We confirm the molecular details of the signal relay through the allosteric network by biochemical studies. Experiments on two additional protein tyrosine kinases indicate that the allosteric network may be largely conserved among these enzymes. Our work provides new insights into the regulation of protein tyrosine kinases and establishes a potential conduit by which resistance mutations to ATP-competitive kinase inhibitors can affect their activity. PMID:25600932

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

PubMed Central

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

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 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 connectivity network. PMID:29507827

The role of criteria in design and management of space systems

NASA Technical Reports Server (NTRS)

Blair, J. C.; Ryan, R. S.

1992-01-01

Explicit requirements and standards arising in connection with space systems management serve as a framework for technical management and furnish legally binding control of development, verification, and operations. As a project develops, additional requirements are derived which are unique to the system in question; these are designated 'derived requirements'. The reliability and cost-effectiveness of a space system are best ensured where a balance has arisen between formal (legally binding) and informal. Attention is presently given to the development of criteria consistent with total quality management.

Structure of a short-chain dehydrogenase/reductase from Bacillus anthracis

PubMed Central

Hou, Jing; Wojciechowska, Kamila; Zheng, Heping; Chruszcz, Maksymilian; Cooper, David R.; Cymborowski, Marcin; Skarina, Tatiana; Gordon, Elena; Luo, Haibin; Savchenko, Alexei; Minor, Wladek

2012-01-01

The crystal structure of a short-chain dehydrogenase/reductase from Bacillus anthracis strain ‘Ames Ancestor’ complexed with NADP has been determined and refined to 1.87 Å resolution. The structure of the enzyme consists of a Rossmann fold composed of seven parallel β-strands sandwiched by three α-­helices on each side. An NADP molecule from an endogenous source is bound in the conserved binding pocket in the syn conformation. The loop region responsible for binding another substrate forms two perpendicular short helices connected by a sharp turn. PMID:22684058

Interactions of Human Nucleotide Excision Repair Protein XPA with DNA and RPA70 Delta c327: Chemical Shift Mapping and N-15 NMR Relaxation Studies

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

Buchko, Garry W.; Daughdrill, Gary W.; De Lorimier, Robert

1999-12-28

Human XPA is an essential component in the multienzyme nucleotide excision repair (NER) pathway. The solution structure of the minimal DNA binding domain of XPA (XPA-MBD: M98-F219) was recently determined [Buchko et al. (1998) Nucleic Acids Res. 26, 2779-2788, Ikegami et al (1998) Nat. Struct. Biol. 5, 701-706] and shown to consist of a compact zinc-binding core and a loop-rich C-terminal subdomain connected by a linker sequence.

NSAIDs as potential treatment option for preventing amyloid β toxicity in Alzheimer's disease: an investigation by docking, molecular dynamics, and DFT studies.

PubMed

Azam, Faizul; Alabdullah, Nada Hussin; Ehmedat, Hadeel Mohammed; Abulifa, Abdullah Ramadan; Taban, Ismail; Upadhyayula, Sreedevi

2018-06-01

Aggregation of amyloid beta (Aβ) protein considered as one of contributors in development of Alzheimer's disease (AD). Several investigations have identified the importance of non-steroidal anti-inflammatory drugs (NSAIDs) as Aβ aggregation inhibitors. Here, we have examined the binding interactions of 24 NSAIDs belonging to eight different classes, with Aβ fibrils by exploiting docking and molecular dynamics studies. Minimum energy conformation of the docked NSAIDs were further optimized by density functional theory (DFT) employing Becke's three-parameter hybrid model, Lee-Yang-Parr (B3LYP) correlation functional method. DFT-based global reactivity descriptors, such as electron affinity, hardness, softness, chemical potential, electronegativity, and electrophilicity index were calculated to inspect the expediency of these descriptors for understanding the reactive nature and sites of the molecules. Few selected NSAID-Aβ fibrils complexes were subjected to molecular dynamics simulation to illustrate the stability of these complexes and the most prominent interactions during the simulated trajectory. All of the NSAIDs exhibited potential activity against Aβ fibrils in terms of predicted binding affinity. Sulindac was found to be the most active compound underscoring the contribution of indene methylene substitution, whereas acetaminophen was observed as least active NSAID. General structural requirements for interaction of NSAIDs with Aβ fibril include: aryl/heteroaryl aromatic moiety connected through a linker of 1-2 atoms to a distal aromatic group. Considering these structural requirements and electronic features, new potent agents can be designed and developed as potential Aβ fibril inhibitors for the treatment of AD.

Time-Resolved Stark Spectroscopy in CdSe Nanoplatelets: Exciton Binding Energy, Polarizability, and Field-Dependent Radiative Rates.

PubMed

Scott, Riccardo; Achtstein, Alexander W; Prudnikau, Anatol V; Antanovich, Artsiom; Siebbeles, Laurens D A; Artemyev, Mikhail; Woggon, Ulrike

2016-10-12

We present a study of the application potential of CdSe nanoplatelets (NPLs), a model system for colloidal 2D materials, as field-controlled emitters. We demonstrate that their emission can be changed by 28% upon application of electrical fields up to 175 kV/cm, a very high modulation depth for field-controlled nanoemitters. From our experimental results we estimate the exciton binding energy in 5.5 monolayer CdSe nanoplatelets to be E B = 170 meV; hence CdSe NPLs exhibit highly robust excitons which are stable even at room temperature. This opens up the possibility to tune the emission and recombination dynamics efficiently by external fields. Our analysis further allows a quantitative discrimination of spectral changes of the emission energy and changes in PL intensity related to broadening of the emission line width as well as changes in the intrinsic radiative rates which are directly connected to the measured changes in the PL decay dynamics. With the developed field-dependent population model treating all occurring field-dependent effects in a global analysis, we are able to quantify, e.g., the ground state exciton transition dipole moment (3.0 × 10 -29 Cm) and its polarizability, which determine the radiative rate, as well as the (static) exciton polarizability (8.6 × 10 -8 eV cm 2 /kV 2 ), all in good agreement with theory. Our results show that an efficient field control over the exciton recombination dynamics, emission line width, and emission energy in these nanoparticles is feasible and opens up application potential as field-controlled emitters.

Van’t Hoff global analyses of variable temperature isothermal titration calorimetry data

PubMed Central

Freiburger, Lee A.; Auclair, Karine; Mittermaier, Anthony K.

2016-01-01

Isothermal titration calorimetry (ITC) can provide detailed information on the thermodynamics of biomolecular interactions in the form of equilibrium constants, KA, and enthalpy changes, ΔHA. A powerful application of this technique involves analyzing the temperature dependences of ITC-derived KA and ΔHA values to gain insight into thermodynamic linkage between binding and additional equilibria, such as protein folding. We recently developed a general method for global analysis of variable temperature ITC data that significantly improves the accuracy of extracted thermodynamic parameters and requires no prior knowledge of the coupled equilibria. Here we report detailed validation of this method using Monte Carlo simulations and an application to study coupled folding and binding in an aminoglycoside acetyltransferase enzyme. PMID:28018008

Theoretical Study of Fe(CO)n-

NASA Technical Reports Server (NTRS)

Ricca, Alessandra; Baushlicher, Charles W., Jr.

1995-01-01

The structures and CO binding energies are computed for Fe(CO)n- using a hybrid density functional theory (DFT) approach. The structures and ground states can be explained in terms of maximizing the Fe to CO 2pi* donation and minimizing Fe-CO 5 sigma repulsion. The trends in the CO binding energies for Fe(CO)n- and the differences between the trends for Fe(CO)n- and Fe(CO)n are also explained. For Fe(CO)n-, the second, third, and fourth CO bonding energies are in good agreement with experiment, while the first is too small. The first CO binding is also too small using the coupled cluster singles and doubles approach including a perturbation estimate of the connected triple excitations.

Ankyrin binding activity shared by the neurofascin/L1/NrCAM family of nervous system cell adhesion molecules.

PubMed

Davis, J Q; Bennett, V

1994-11-04

Neurofascin, L1, NrCAM, NgCAM, and neuroglian are membrane-spanning cell adhesion molecules with conserved cytoplasmic domains that are believed to play important roles in development of the nervous system. This report presents biochemical evidence that the cytoplasmic domains of these molecules associate directly with ankyrins, a family of spectrin-binding proteins located on the cytoplasmic surface of specialized plasma membrane domains. Rat neurofascin and NrCAM together comprise over 0.5% of the membrane protein in adult brain tissue. Linkage of these ankyrin-binding cell adhesion molecules to spectrin-based structures may provide a major class of membrane-cytoskeletal connections in adult brain as well as earlier stages of development.

Protein-ligand interactions investigated by thermal shift assays (TSA) and dual polarization interferometry (DPI).

PubMed

Grøftehauge, Morten K; Hajizadeh, Nelly R; Swann, Marcus J; Pohl, Ehmke

2015-01-01

Over the last decades, a wide range of biophysical techniques investigating protein-ligand interactions have become indispensable tools to complement high-resolution crystal structure determinations. Current approaches in solution range from high-throughput-capable methods such as thermal shift assays (TSA) to highly accurate techniques including microscale thermophoresis (MST) and isothermal titration calorimetry (ITC) that can provide a full thermodynamic description of binding events. Surface-based methods such as surface plasmon resonance (SPR) and dual polarization interferometry (DPI) allow real-time measurements and can provide kinetic parameters as well as binding constants. DPI provides additional spatial information about the binding event. Here, an account is presented of new developments and recent applications of TSA and DPI connected to crystallography.

Protein–ligand interactions investigated by thermal shift assays (TSA) and dual polarization interferometry (DPI)

PubMed Central

Grøftehauge, Morten K.; Hajizadeh, Nelly R.; Swann, Marcus J.; Pohl, Ehmke

2015-01-01

Over the last decades, a wide range of biophysical techniques investigating protein–ligand interactions have become indispensable tools to complement high-resolution crystal structure determinations. Current approaches in solution range from high-throughput-capable methods such as thermal shift assays (TSA) to highly accurate techniques including microscale thermophoresis (MST) and isothermal titration calorimetry (ITC) that can provide a full thermodynamic description of binding events. Surface-based methods such as surface plasmon resonance (SPR) and dual polarization interferometry (DPI) allow real-time measurements and can provide kinetic parameters as well as binding constants. DPI provides additional spatial information about the binding event. Here, an account is presented of new developments and recent applications of TSA and DPI connected to crystallography. PMID:25615858

Globalization to amplify economic climate losses

NASA Astrophysics Data System (ADS)

Otto, C.; Wenz, L.; Levermann, A.

2015-12-01

Economic welfare under enhanced anthropogenic carbon emissions and associated future warming poses a major challenge for a society with an evolving globally connected economy. Unabated climate change will impact economic output for example through heat-stress-related reductions in productivity. Since meteorologically-induced production reductions can propagate along supply chains, structural changes in the economic network may influence climate-related losses. The role of the economic network evolution for climate impacts has been neither quantified nor qualitatively understood. Here we show that since the beginning of the 21st century the structural change of the global supply network has been such that an increase of spillover losses due to unanticipated climatic events has to be expected. We quantify primary, secondary and higher-order losses from reduced labor productivity under past and present economic and climatic conditions and find that indirect losses are significant and increase with rising temperatures. The connectivity of the economic network has increased in such a way as to foster the propagation of production loss. This supply chain connectivity robustly exhibits the characteristic distribution of self-organized criticality which has been shifted towards higher values since 2001. Losses due to this structural evolution dominated over the effect of comparably weak climatic changes during this decade. Our finding suggests that the current form of globalization may amplify losses due to climatic extremes and thus necessitate structural adaptation that requires more foresight than presently prevalent.

USSOCOM’s Role in Addressing Human Trafficking

DTIC Science & Technology

2010-12-02

global issue runs parallel and at times intersects with the increasing prevalence of VEOs as a transnational threat. Already tasked to synchronize...There are 104 countries without laws, policies, or regulations to prevent victims’ deportation.8 These numbers indicate both the size of global HT...whole of government response through USSOCOM integration. HT exhibits the global connectivity of other transnational crimes, but is also

Low profile, high load vertical rolling positioning stage

DOEpatents

Shu, Deming; Barraza, Juan

1996-01-01

A stage or support platform assembly for use in a synchrotron accurately positions equipment to be used in the beam line of the synchrotron. The support platform assembly includes an outer housing in which is disposed a lifting mechanism having a lifting platform or stage at its upper extremity on which the equipment is mounted. A worm gear assembly is located in the housing and is adapted to raise and lower a lifting shaft that is fixed to the lifting platform by an anti-binding connection. The lifting platform is moved vertically as the lifting shaft is moved vertically. The anti-binding connection prevents the shaft from rotating with respect to the platform, but does permit slight canting of the shaft with respect to the lifting platform so as to eliminate binding and wear due to possible tolerance mismatches. In order to ensure that the lifting mechanism does not move in a horizontal direction as it is moved vertically, at least three linear roller bearing assemblies are arranged around the outer-periphery of the lifting mechanism. One of the linear roller bearing assemblies can be adjusted so that the roller bearings apply a loading force against the lifting mechanism. Alternatively, a cam mechanism can be used to provide such a loading force.

Characterization of the interactions of type XII collagen with two small proteoglycans from fetal bovine tendon, decorin and fibromodulin.

PubMed

Font, B; Eichenberger, D; Rosenberg, L M; van der Rest, M

1996-11-01

In addition to the major collagens, such as type I or type II, connective tissues contain a number of less abundant collagens and proteoglycans, whose association contributes to the different properties of the tissues. Type XII and type XIV collagens have been described in soft connective tissues, and type XIV collagen has been shown to interact specifically with decorin through its glycosaminoglycan chain (Font et al., J. Biol. Chem. 268, 25015-25018, 1993). Interactions between these collagens and the small proteoglycans have been characterized further by studying the binding of type XII collagen to decorin by solid phase assays. Our results show a saturable binding of the proteoglycan through its glycosaminoglycan chain to type XII collagen, which does not seem to involve the large non-collagenous NC3 domain of the molecule. This interaction is strongly inhibited by heparin. Furthermore, we report that another small proteoglycan, fibromodulin, isolated from tendon under non-denaturing conditions, is able to bind to type XII collagen. This interaction has been characterized and, unlike that observed with decorin, type XII collagen-fibromodulin interaction seems to take place with the core protein of the proteoglycan. In addition, we report that type XII-type I collagen interactions are not necessarily mediated by decorin as previously suggested.

Transsynaptic Coordination of Synaptic Growth, Function, and Stability by the L1-Type CAM Neuroglian

PubMed Central

Moreno, Eliza; Stephan, Raiko; Boerner, Jana; Godenschwege, Tanja A.; Pielage, Jan

2013-01-01

The precise control of synaptic connectivity is essential for the development and function of neuronal circuits. While there have been significant advances in our understanding how cell adhesion molecules mediate axon guidance and synapse formation, the mechanisms controlling synapse maintenance or plasticity in vivo remain largely uncharacterized. In an unbiased RNAi screen we identified the Drosophila L1-type CAM Neuroglian (Nrg) as a central coordinator of synapse growth, function, and stability. We demonstrate that the extracellular Ig-domains and the intracellular Ankyrin-interaction motif are essential for synapse development and stability. Nrg binds to Ankyrin2 in vivo and mutations reducing the binding affinities to Ankyrin2 cause an increase in Nrg mobility in motoneurons. We then demonstrate that the Nrg–Ank2 interaction controls the balance of synapse growth and stability at the neuromuscular junction. In contrast, at a central synapse, transsynaptic interactions of pre- and postsynaptic Nrg require a dynamic, temporal and spatial, regulation of the intracellular Ankyrin-binding motif to coordinate pre- and postsynaptic development. Our study at two complementary model synapses identifies the regulation of the interaction between the L1-type CAM and Ankyrin as an important novel module enabling local control of synaptic connectivity and function while maintaining general neuronal circuit architecture. PMID:23610557

Transsynaptic coordination of synaptic growth, function, and stability by the L1-type CAM Neuroglian.

PubMed

Enneking, Eva-Maria; Kudumala, Sirisha R; Moreno, Eliza; Stephan, Raiko; Boerner, Jana; Godenschwege, Tanja A; Pielage, Jan

2013-01-01

The precise control of synaptic connectivity is essential for the development and function of neuronal circuits. While there have been significant advances in our understanding how cell adhesion molecules mediate axon guidance and synapse formation, the mechanisms controlling synapse maintenance or plasticity in vivo remain largely uncharacterized. In an unbiased RNAi screen we identified the Drosophila L1-type CAM Neuroglian (Nrg) as a central coordinator of synapse growth, function, and stability. We demonstrate that the extracellular Ig-domains and the intracellular Ankyrin-interaction motif are essential for synapse development and stability. Nrg binds to Ankyrin2 in vivo and mutations reducing the binding affinities to Ankyrin2 cause an increase in Nrg mobility in motoneurons. We then demonstrate that the Nrg-Ank2 interaction controls the balance of synapse growth and stability at the neuromuscular junction. In contrast, at a central synapse, transsynaptic interactions of pre- and postsynaptic Nrg require a dynamic, temporal and spatial, regulation of the intracellular Ankyrin-binding motif to coordinate pre- and postsynaptic development. Our study at two complementary model synapses identifies the regulation of the interaction between the L1-type CAM and Ankyrin as an important novel module enabling local control of synaptic connectivity and function while maintaining general neuronal circuit architecture.

Plugfest 2009: Global Interoperability in Telerobotics and Telemedicine

PubMed Central

King, H. Hawkeye; Hannaford, Blake; Kwok, Ka-Wai; Yang, Guang-Zhong; Griffiths, Paul; Okamura, Allison; Farkhatdinov, Ildar; Ryu, Jee-Hwan; Sankaranarayanan, Ganesh; Arikatla, Venkata; Tadano, Kotaro; Kawashima, Kenji; Peer, Angelika; Schauß, Thomas; Buss, Martin; Miller, Levi; Glozman, Daniel; Rosen, Jacob; Low, Thomas

2014-01-01

Despite the great diversity of teleoperator designs and applications, their underlying control systems have many similarities. These similarities can be exploited to enable inter-operability between heterogeneous systems. We have developed a network data specification, the Interoperable Telerobotics Protocol, that can be used for Internet based control of a wide range of teleoperators. In this work we test interoperable telerobotics on the global Internet, focusing on the telesurgery application domain. Fourteen globally dispersed telerobotic master and slave systems were connected in thirty trials in one twenty four hour period. Users performed common manipulation tasks to demonstrate effective master-slave operation. With twenty eight (93%) successful, unique connections the results show a high potential for standardizing telerobotic operation. Furthermore, new paradigms for telesurgical operation and training are presented, including a networked surgery trainer and upper-limb exoskeleton control of micro-manipulators. PMID:24748993

Providing full point-to-point communications among compute nodes of an operational group in a global combining network of a parallel computer

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

Archer, Charles J.; Faraj, Daniel A.; Inglett, Todd A.

Methods, apparatus, and products are disclosed for providing full point-to-point communications among compute nodes of an operational group in a global combining network of a parallel computer, each compute node connected to each adjacent compute node in the global combining network through a link, that include: receiving a network packet in a compute node, the network packet specifying a destination compute node; selecting, in dependence upon the destination compute node, at least one of the links for the compute node along which to forward the network packet toward the destination compute node; and forwarding the network packet along the selectedmore » link to the adjacent compute node connected to the compute node through the selected link.« less

Left frontal cortex connectivity underlies cognitive reserve in prodromal Alzheimer disease

PubMed Central

Franzmeier, Nicolai; Duering, Marco; Weiner, Michael; Dichgans, Martin

2017-01-01

Objective: To test whether higher global functional connectivity of the left frontal cortex (LFC) in Alzheimer disease (AD) is associated with more years of education (a proxy of cognitive reserve [CR]) and mitigates the association between AD-related fluorodeoxyglucose (FDG)-PET hypometabolism and episodic memory. Methods: Forty-four amyloid-PET–positive patients with amnestic mild cognitive impairment (MCI-Aβ+) and 24 amyloid-PET–negative healthy controls (HC) were included. Voxel-based linear regression analyses were used to test the association between years of education and FDG-PET in MCI-Aβ+, controlled for episodic memory performance. Global LFC (gLFC) connectivity was computed through seed-based resting-state fMRI correlations between the LFC (seed) and each voxel in the gray matter. In linear regression analyses, education as a predictor of gLFC connectivity and the interaction of gLFC connectivity × FDG-PET hypometabolism on episodic memory were tested. Results: FDG-PET metabolism in the precuneus was reduced in MCI-Aβ+ compared to HC (p = 0.028), with stronger reductions observed in MCI-Aβ+ with more years of education (p = 0.006). In MCI-Aβ+, higher gLFC connectivity was associated with more years of education (p = 0.021). At higher levels of gLFC connectivity, the association between precuneus FDG-PET hypometabolism and lower memory performance was attenuated (p = 0.027). Conclusions: Higher gLFC connectivity is a functional substrate of CR that helps to maintain episodic memory relatively well in the face of emerging FDG-PET hypometabolism in early-stage AD. PMID:28188306

Left frontal cortex connectivity underlies cognitive reserve in prodromal Alzheimer disease.

PubMed

Franzmeier, Nicolai; Duering, Marco; Weiner, Michael; Dichgans, Martin; Ewers, Michael

2017-03-14

To test whether higher global functional connectivity of the left frontal cortex (LFC) in Alzheimer disease (AD) is associated with more years of education (a proxy of cognitive reserve [CR]) and mitigates the association between AD-related fluorodeoxyglucose (FDG)-PET hypometabolism and episodic memory. Forty-four amyloid-PET-positive patients with amnestic mild cognitive impairment (MCI-Aβ+) and 24 amyloid-PET-negative healthy controls (HC) were included. Voxel-based linear regression analyses were used to test the association between years of education and FDG-PET in MCI-Aβ+, controlled for episodic memory performance. Global LFC (gLFC) connectivity was computed through seed-based resting-state fMRI correlations between the LFC (seed) and each voxel in the gray matter. In linear regression analyses, education as a predictor of gLFC connectivity and the interaction of gLFC connectivity × FDG-PET hypometabolism on episodic memory were tested. FDG-PET metabolism in the precuneus was reduced in MCI-Aβ+ compared to HC ( p = 0.028), with stronger reductions observed in MCI-Aβ+ with more years of education ( p = 0.006). In MCI-Aβ+, higher gLFC connectivity was associated with more years of education ( p = 0.021). At higher levels of gLFC connectivity, the association between precuneus FDG-PET hypometabolism and lower memory performance was attenuated ( p = 0.027). Higher gLFC connectivity is a functional substrate of CR that helps to maintain episodic memory relatively well in the face of emerging FDG-PET hypometabolism in early-stage AD. © 2017 American Academy of Neurology.

Cohesive and coherent connected speech deficits in mild stroke.

PubMed

Barker, Megan S; Young, Breanne; Robinson, Gail A

2017-05-01

Spoken language production theories and lesion studies highlight several important prelinguistic conceptual preparation processes involved in the production of cohesive and coherent connected speech. Cohesion and coherence broadly connect sentences with preceding ideas and the overall topic. Broader cognitive mechanisms may mediate these processes. This study aims to investigate (1) whether stroke patients without aphasia exhibit impairments in cohesion and coherence in connected speech, and (2) the role of attention and executive functions in the production of connected speech. Eighteen stroke patients (8 right hemisphere stroke [RHS]; 6 left [LHS]) and 21 healthy controls completed two self-generated narrative tasks to elicit connected speech. A multi-level analysis of within and between-sentence processing ability was conducted. Cohesion and coherence impairments were found in the stroke group, particularly RHS patients, relative to controls. In the whole stroke group, better performance on the Hayling Test of executive function, which taps verbal initiation/suppression, was related to fewer propositional repetitions and global coherence errors. Better performance on attention tasks was related to fewer propositional repetitions, and decreased global coherence errors. In the RHS group, aspects of cohesive and coherent speech were associated with better performance on attention tasks. Better Hayling Test scores were related to more cohesive and coherent speech in RHS patients, and more coherent speech in LHS patients. Thus, we documented connected speech deficits in a heterogeneous stroke group without prominent aphasia. Our results suggest that broader cognitive processes may play a role in producing connected speech at the early conceptual preparation stage. Copyright © 2017 Elsevier Inc. All rights reserved.

Rich club analysis in the Alzheimer's disease connectome reveals a relatively undisturbed structural core network

PubMed Central

Daianu, Madelaine; Jahanshad, Neda; Nir, Talia M.; Jack, Clifford R.; Weiner, Michael W.; Bernstein, Matthew; Thompson, Paul M.

2015-01-01

Diffusion imaging can assess the white matter connections within the brain, revealing how neural pathways break down in Alzheimer's disease (AD). We analyzed 3-Tesla whole-brain diffusion-weighted images from 202 participants scanned by the Alzheimer's Disease Neuroimaging Initiative – 50 healthy controls, 110 with mild cognitive impairment (MCI) and 42 AD patients. From whole-brain tractography, we reconstructed structural brain connectivity networks to map connections between cortical regions. We tested whether AD disrupts the ‘rich-club’ – a network property where high-degree network nodes are more interconnected than expected by chance. We calculated the rich-club properties at a range of degree thresholds, as well as other network topology measures including global degree, clustering coefficient, path length and efficiency. Network disruptions predominated in the low-degree regions of the connectome in patients, relative to controls. The other metrics also showed alterations, suggesting a distinctive pattern of disruption in AD, less pronounced in MCI, targeting global brain connectivity, and focusing on more remotely connected nodes rather than the central core of the network. AD involves severely reduced structural connectivity; our step-wise rich club coefficients analyze points to disruptions predominantly in the peripheral network components; other modalities of data are needed to know if this indicates impaired communication among non rich-club regions. The highly connected core was relatively preserved, offering new evidence on the neural basis of progressive risk for cognitive decline. PMID:26037224

Graph Metrics of Structural Brain Networks in Individuals with Schizophrenia and Healthy Controls: Group Differences, Relationships with Intelligence, and Genetics.

PubMed

Yeo, Ronald A; Ryman, Sephira G; van den Heuvel, Martijn P; de Reus, Marcel A; Jung, Rex E; Pommy, Jessica; Mayer, Andrew R; Ehrlich, Stefan; Schulz, S Charles; Morrow, Eric M; Manoach, Dara; Ho, Beng-Choon; Sponheim, Scott R; Calhoun, Vince D

2016-02-01

One of the most prominent features of schizophrenia is relatively lower general cognitive ability (GCA). An emerging approach to understanding the roots of variation in GCA relies on network properties of the brain. In this multi-center study, we determined global characteristics of brain networks using graph theory and related these to GCA in healthy controls and individuals with schizophrenia. Participants (N=116 controls, 80 patients with schizophrenia) were recruited from four sites. GCA was represented by the first principal component of a large battery of neurocognitive tests. Graph metrics were derived from diffusion-weighted imaging. The global metrics of longer characteristic path length and reduced overall connectivity predicted lower GCA across groups, and group differences were noted for both variables. Measures of clustering, efficiency, and modularity did not differ across groups or predict GCA. Follow-up analyses investigated three topological types of connectivity--connections among high degree "rich club" nodes, "feeder" connections to these rich club nodes, and "local" connections not involving the rich club. Rich club and local connectivity predicted performance across groups. In a subsample (N=101 controls, 56 patients), a genetic measure reflecting mutation load, based on rare copy number deletions, was associated with longer characteristic path length. Results highlight the importance of characteristic path lengths and rich club connectivity for GCA and provide no evidence for group differences in the relationships between graph metrics and GCA.

Brain resting-state networks in adolescents with high-functioning autism: Analysis of spatial connectivity and temporal neurodynamics.

PubMed

Bernas, Antoine; Barendse, Evelien M; Aldenkamp, Albert P; Backes, Walter H; Hofman, Paul A M; Hendriks, Marc P H; Kessels, Roy P C; Willems, Frans M J; de With, Peter H N; Zinger, Svitlana; Jansen, Jacobus F A

2018-02-01

Autism spectrum disorder (ASD) is mainly characterized by functional and communication impairments as well as restrictive and repetitive behavior. The leading hypothesis for the neural basis of autism postulates globally abnormal brain connectivity, which can be assessed using functional magnetic resonance imaging (fMRI). Even in the absence of a task, the brain exhibits a high degree of functional connectivity, known as intrinsic, or resting-state, connectivity. Global default connectivity in individuals with autism versus controls is not well characterized, especially for a high-functioning young population. The aim of this study is to test whether high-functioning adolescents with ASD (HFA) have an abnormal resting-state functional connectivity. We performed spatial and temporal analyses on resting-state networks (RSNs) in 13 HFA adolescents and 13 IQ- and age-matched controls. For the spatial analysis, we used probabilistic independent component analysis (ICA) and a permutation statistical method to reveal the RSN differences between the groups. For the temporal analysis, we applied Granger causality to find differences in temporal neurodynamics. Controls and HFA display very similar patterns and strengths of resting-state connectivity. We do not find any significant differences between HFA adolescents and controls in the spatial resting-state connectivity. However, in the temporal dynamics of this connectivity, we did find differences in the causal effect properties of RSNs originating in temporal and prefrontal cortices. The results show a difference between HFA and controls in the temporal neurodynamics from the ventral attention network to the salience-executive network: a pathway involving cognitive, executive, and emotion-related cortices. We hypothesized that this weaker dynamic pathway is due to a subtle trigger challenging the cognitive state prior to the resting state.

Discriminating the Difference between Remote and Close Association with Relation to White-Matter Structural Connectivity

PubMed Central

Wu, Chinglin; Zhong, Suyu; Chen, Hsuehchih

2016-01-01

Remote association is a core ability that influences creative output. In contrast to close association, remote association is commonly agreed to be connected with more original and unique concepts. However, although existing studies have discovered that creativity is closely related to the white-matter structure of the brain, there are no studies that examine the relevance between the connectivity efficiencies and creativity of the brain regions from the perspective of networks. Consequently, this study constructed a brain white matter network structure that consisted of cerebral tissues and nerve fibers and used graph theory to analyze the connection efficiencies among the network nodes, further illuminating the differences between remote and close association in relation to the connectivity of the brain network. Researchers analyzed correlations between the scores of 35 healthy adults with regard to remote and close associations and the connectivity efficiencies of the white-matter network of the brain. Controlling for gender, age, and verbal intelligence, the remote association positively correlated with the global efficiency and negatively correlated with the levels of small-world. A close association negatively correlated with the global efficiency. Notably, the node efficiency in the middle temporal gyrus (MTG) positively correlated with remote association and negatively correlated with close association. To summarize, remote and close associations work differently as patterns in the brain network. Remote association requires efficient and convenient mutual connections between different brain regions, while close association emphasizes the limited connections that exist in a local region. These results are consistent with previous results, which indicate that creativity is based on the efficient integration and connection between different regions of the brain and that temporal lobes are the key regions for discriminating remote and close associations. PMID:27760177

WHO's role in the global health system: what can be learned from global R&D debates?

PubMed

Moon, Suerie

2014-02-01

Recent global debates on the research and development (R&D) of health technologies, such as drugs, diagnostics and vaccines, can be seen as a microcosm of discussions on the role of the World Health Organization (WHO) in the global health system more broadly. The global R&D system has come under heightened scrutiny with the publication of a 2012 report by the WHO Consultative Expert Working Group on Research and Development (CEWG), which made a number of recommendations to more equitably meet global health needs. The CEWG report followed a decade-long process of debate at the WHO on the weaknesses of the global R&D system, which include problems of affordability, limited research where market returns are small or uncertain (such as the 'neglected diseases' that predominantly affect the world's poorest), inefficient overlap of research efforts, and overuse of medicines such as antibiotics. The CEWG report called on WHO Member States to develop a global framework to improve monitoring, coordination and financing of R&D efforts through the establishment of a Global Health R&D Observatory and the negotiation of a binding treaty on R&D. While the treaty option has been put on the back-burner for several years, Member States nevertheless agreed at the 2013 World Health Assembly (WHA) on concrete steps towards a global framework. Progress at the 2013 WHA reaffirmed the central role of WHO as a convener, and the WHA's decision to create the Observatory within the WHO Secretariat underscored the organization's role as a source of strategic knowledge in the global health system. However, despite WHO's constitutional mandate as the 'directing and coordinating authority on international health work', in reality it faces major challenges in coordinating autonomous R&D actors such as states, firms and foundations in the global system. Strengthening its ability to do so requires, at a minimum, reforming its financing arrangements to provide it with a greater degree of independence from its largest donors. In addition, WHO may seem to be the natural arena for negotiating a binding R&D treaty, but negotiating new global agreements in other arenas such as the WTO, WIPO, or plurilateral fora offer the possibility of more enforceable and stronger public health norms. Nevertheless, no single arena in the existing system of global governance is perfectly suitable for the negotiation of progressive, inclusive, binding, enforceable, global health rules. While tradeoffs are inherent in the choice of any particular arena, leadership from either the multilateral institutions or influential governments can make a key difference in how beneficial any R&D treaty may be for health. In the coming years, global R&D debates will remain a critical issue to watch. The evolution of the global R&D system will be a harbinger not only of WHO's place in a rapidly-changing global health system, but also of our collective capacity to strengthen institutions of global governance for health. Copyright © 2013 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.

(Dis-) Locating the Transformative Dimension of Global Citizenship Education

ERIC Educational Resources Information Center

Bamber, Philip; Lewin, David; White, Morgan

2018-01-01

Despite a groundswell of evidence for transformative education, manifestos for 'transformative pedagogy for global citizenship' remain under-theorized and pay limited attention to implications for practice. This paper connects theory and practice through analyzing a curriculum development project that sought to produce a framework for 'engaged…

International Dimension in Engineering Education

ERIC Educational Resources Information Center

Borri, C.; Guberti, E.; Melsa, J.

2007-01-01

Engineers of the 21st century will spend appreciable portions of their careers in environments rich with global connections. Therefore, engineering colleges and universities must develop strategies that provide the global perspectives and international experiences that will help their graduates excel in this new world order. The current paper…

Radiation safety standards and their application: international policies and current issues.

PubMed

González, Abel J

2004-09-01

This paper briefly describes the current policies of the United Nations Scientific Committee on the Effects of Atomic Radiation and the International Commission on Radiological Protection and how these policies are converted into international radiation safety standards by the International Atomic Energy Agency, which is the only global organization-within the United Nations family of international agencies-with a statutory mandate not only to establish such standards but also to provide for their application. It also summarizes the current status of the established corpus of such international standards, and of it foreseeable evolution, as well as of legally binding undertakings by countries around the world that are linked to these standards. Moreover, this paper also reviews some major current global issues related to the application of international standards, including the following: strengthening of national infrastructures for radiation safety, including technical cooperation programs for assisting developing countries; occupational radiation safety challenges, including the protection of pregnant workers and their unborn children, dealing with working environments with high natural radiation levels, and occupational attributability of health effects (probability of occupational causation); restricting discharges of radioactive substances into the environment: reviewing current international policies vis-a-vis the growing concern on the radiation protection of the "environment;" radiological protection of patients undergoing radiodiagnostic and radiotherapeutic procedures: the current International Action Plan; safety and security of radiation sources: post-11 September developments; preparedness and response to radiation emergencies: enhancing the international network; safe transport of radioactive materials: new apprehensions; safety of radioactive waste management: concerns and connections with radiation protection; and radioactive residues remaining after the termination of activities: radiation protection response to the forthcoming wave of decommissioning of installations with radioactive materials. The ultimate aim of this paper is to encourage information exchange, cooperation, and collaboration within the radiation protection professional community. In particular, the paper tries to facilitate consolidation of the growing international regime on radiation safety, including the expansion of legally binding undertakings by countries, the strengthening of the current corpus of international radiation safety standards, and the development of international provisions for ensuring the proper worldwide application of these standards, such as a system of international appraisals by peer review.

New Global Art Connection: Paying Tribute to the Wave-Makers (1910-2010)

ERIC Educational Resources Information Center

Kan, Koon Hwee

2013-01-01

This paper highlights "Wave-Makers (1910--2010)", a collaborative timeline redesign project, which involves interactive and advanced web-based technology to connect and complement arts curricula at two higher education institutions, one located in China and another in the United States. Through in-depth research, video-conferencing,…

Mathematical Connections and Their Relationship to Mathematics Knowledge for Teaching Geometry

ERIC Educational Resources Information Center

Eli, Jennifer A.; Mohr-Schroeder, Margaret J.; Lee, Carl W.

2013-01-01

Effective competition in a rapidly growing global economy places demands on a society to produce individuals capable of higher-order critical thinking, creative problem solving, connection making, and innovation. We must look to our teacher education programs to help prospective middle grades teachers build the mathematical habits of mind that…

Simulation of Fault Tolerance in a Hypercube Arrangement of Discrete Processors.

DTIC Science & Technology

1987-12-01

Geometric Properties .................... 22 Binary Properties ....................... 26 Intel Hypercube Hardware Arrangement ... 28 IV. Cube-Connected... Properties of the CCC..............35 CCC Redundancy............................... 38 iii 6L V. Re-Configurable Cube-Connected Cycles ....... 40 Global...o........ 74 iv List of Figures Page Figure 1: Hypercubes of Different Dimensions ......... 21 Figure 2: Hypercube Properties

Environmental Education and Service Learning in the Tropics: Making Global Connections

ERIC Educational Resources Information Center

Haines, Sarah

2010-01-01

Research has suggested that a service-learning component can add a powerful dimension to learning course content in a variety of science disciplines, in addition to assisting students in seeing connections between their studies and the world outside the classroom. This article describes a tropical ecology course designed for science preservice…

Ecopedagogy as an Element of Citizenship Education: The Dialectic of Global/Local Spheres of Citizenship and Critical Environmental Pedagogies

ERIC Educational Resources Information Center

Misiaszek, Greg William

2016-01-01

Emerging from popular education movements in Latin America, "ecopedagogy" is a critical environmental pedagogy which focuses on understanding the connections between social conflict and environmentally harmful acts carried out by humans. These connections are often politically hidden in education. Ecopedagogy, while being pluralistic, is…

Multimodal analysis of cortical chemoarchitecture and macroscale fMRI resting‐state functional connectivity

PubMed Central

Scholtens, Lianne H.; Turk, Elise; Mantini, Dante; Vanduffel, Wim; Feldman Barrett, Lisa

2016-01-01

Abstract The cerebral cortex is well known to display a large variation in excitatory and inhibitory chemoarchitecture, but the effect of this variation on global scale functional neural communication and synchronization patterns remains less well understood. Here, we provide evidence of the chemoarchitecture of cortical regions to be associated with large‐scale region‐to‐region resting‐state functional connectivity. We assessed the excitatory versus inhibitory chemoarchitecture of cortical areas as an ExIn ratio between receptor density mappings of excitatory (AMPA, M1) and inhibitory (GABAA, M2) receptors, computed on the basis of data collated from pioneering studies of autoradiography mappings as present in literature of the human (2 datasets) and macaque (1 dataset) cortex. Cortical variation in ExIn ratio significantly correlated with total level of functional connectivity as derived from resting‐state functional connectivity recordings of cortical areas across all three datasets (human I: P = 0.0004; human II: P = 0.0008; macaque: P = 0.0007), suggesting cortical areas with an overall more excitatory character to show higher levels of intrinsic functional connectivity during resting‐state. Our findings are indicative of the microscale chemoarchitecture of cortical regions to be related to resting‐state fMRI connectivity patterns at the global system's level of connectome organization. Hum Brain Mapp 37:3103–3113, 2016. © 2016 Wiley Periodicals, Inc. PMID:27207489

Developmental Reorganization of the Core and Extended Face Networks Revealed by Global Functional Connectivity.

PubMed

Wang, Xu; Zhu, Qi; Song, Yiying; Liu, Jia

2017-08-28

Prior studies on development of functional specialization in human brain mainly focus on age-related increases in regional activation and connectivity among regions. However, a few recent studies on the face network demonstrate age-related decrease in face-specialized activation in the extended face network (EFN), in addition to increase in activation in the core face network (CFN). Here we used a voxel-based global brain connectivity approach to investigate whether development of the face network exhibited both increase and decrease in network connectivity. We found the voxel-wise resting-state functional connectivity (FC) within the CFN increased with age in bilateral posterior superior temporal sulcus, suggesting the integration of the CFN during development. Interestingly, the FC of the voxels in the EFN to the right fusiform face area and occipital face area decreased with age, suggesting that the CFN segregated from the EFN during development. Moreover, the age-related connectivity in the CFN was related to behavioral performance in face processing. Overall, our study demonstrated developmental reorganization of the face network achieved by both integration within the CFN and segregation of the CFN from the EFN, which may account for the simultaneous increases and decreases in neural activation during the development of the face network. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Crystal Structure of the Pseudomonas aeruginosa Virulence Factor Regulator

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

Cordes, Timothy J.; Worzalla, Gregory A.; Ginster, Aaron M.

2012-09-07

Virulence factor regulator (Vfr) enhances Pseudomonas aeruginosa pathogenicity through its role as a global transcriptional regulator. The crystal structure of Vfr shows that it is a winged-helix DNA-binding protein like its homologue cyclic AMP receptor protein (CRP). In addition to an expected primary cyclic AMP-binding site, a second ligand-binding site is nestled between the N-terminal domain and the C-terminal helix-turn-helix domain. Unlike CRP, Vfr is a symmetric dimer in the absence of DNA. Removal of seven disordered N-terminal residues of Vfr prvents the growth of P. aeruginosa.

The timescales of global surface-ocean connectivity.

PubMed

Jönsson, Bror F; Watson, James R

2016-04-19

Planktonic communities are shaped through a balance of local evolutionary adaptation and ecological succession driven in large part by migration. The timescales over which these processes operate are still largely unresolved. Here we use Lagrangian particle tracking and network theory to quantify the timescale over which surface currents connect different regions of the global ocean. We find that the fastest path between two patches--each randomly located anywhere in the surface ocean--is, on average, less than a decade. These results suggest that marine planktonic communities may keep pace with climate change--increasing temperatures, ocean acidification and changes in stratification over decadal timescales--through the advection of resilient types.

Heat balance statistics derived from four-dimensional assimilations with a global circulation model

NASA Technical Reports Server (NTRS)

Schubert, S. D.; Herman, G. F.

1981-01-01

The reported investigation was conducted to develop a reliable procedure for obtaining the diabatic and vertical terms required for atmospheric heat balance studies. The method developed employs a four-dimensional assimilation mode in connection with the general circulation model of NASA's Goddard Laboratory for Atmospheric Sciences. The initial analysis was conducted with data obtained in connection with the 1976 Data Systems Test. On the basis of the results of the investigation, it appears possible to use the model's observationally constrained diagnostics to provide estimates of the global distribution of virtually all of the quantities which are needed to compute the atmosphere's heat and energy balance.

The timescales of global surface-ocean connectivity

PubMed Central

Jönsson, Bror F.; Watson, James R.

2016-01-01

Planktonic communities are shaped through a balance of local evolutionary adaptation and ecological succession driven in large part by migration. The timescales over which these processes operate are still largely unresolved. Here we use Lagrangian particle tracking and network theory to quantify the timescale over which surface currents connect different regions of the global ocean. We find that the fastest path between two patches—each randomly located anywhere in the surface ocean—is, on average, less than a decade. These results suggest that marine planktonic communities may keep pace with climate change—increasing temperatures, ocean acidification and changes in stratification over decadal timescales—through the advection of resilient types. PMID:27093522

A weighted communicability measure applied to complex brain networks

PubMed Central

Crofts, Jonathan J.; Higham, Desmond J.

2009-01-01

Recent advances in experimental neuroscience allow non-invasive studies of the white matter tracts in the human central nervous system, thus making available cutting-edge brain anatomical data describing these global connectivity patterns. Through magnetic resonance imaging, this non-invasive technique is able to infer a snapshot of the cortical network within the living human brain. Here, we report on the initial success of a new weighted network communicability measure in distinguishing local and global differences between diseased patients and controls. This approach builds on recent advances in network science, where an underlying connectivity structure is used as a means to measure the ease with which information can flow between nodes. One advantage of our method is that it deals directly with the real-valued connectivity data, thereby avoiding the need to discretize the corresponding adjacency matrix, i.e. to round weights up to 1 or down to 0, depending upon some threshold value. Experimental results indicate that the new approach is able to extract biologically relevant features that are not immediately apparent from the raw connectivity data. PMID:19141429

Beware of ligand efficiency (LE): understanding LE data in modeling structure-activity and structure-economy relationships.

PubMed

Polanski, Jaroslaw; Tkocz, Aleksandra; Kucia, Urszula

2017-09-11

On the one hand, ligand efficiency (LE) and the binding efficiency index (BEI), which are binding properties (B) averaged versus the heavy atom count (HAC: LE) or molecular weight (MW: BEI), have recently been declared a novel universal tool for drug design. On the other hand, questions have been raised about the mathematical validity of the LE approach. In fact, neither the critics nor the advocates are precise enough to provide a generally understandable and accepted chemistry of the LE metrics. In particular, this refers to the puzzle of the LE trends for small and large molecules. In this paper, we explain the chemistry and mathematics of the LE type of data. Because LE is a weight metrics related to binding per gram, its hyperbolic decrease with an increasing number of heavy atoms can be easily understood by its 1/MW dependency. Accordingly, we analyzed how this influences the LE trends for ligand-target binding, economic big data or molecular descriptor data. In particular, we compared the trends for the thermodynamic ∆G data of a series of ligands that interact with 14 different target classes, which were extracted from the BindingDB database with the market prices of a commercial compound library of ca. 2.5 mln synthetic building blocks. An interpretation of LE and BEI that clearly explains the observed trends for these parameters are presented here for the first time. Accordingly, we show that the main misunderstanding of the chemical meaning of the BEI and LE parameters is their interpretation as molecular descriptors that are connected with a single molecule, while binding is a statistical effect in which a population of ligands limits the formation of ligand-receptor complexes. Therefore, LE (BEI) should not be interpreted as a molecular (physicochemical) descriptor that is connected with a single molecule but as a property (binding per gram). Accordingly, the puzzle of the surprising behavior of LE is explained by the 1/MW dependency. This effect clearly explains the hyperbolic LE trend not as a real increase in binding potency but as a physical limitation due to the different population of ligands with different MWs in a 1 g sample available for the formation of ligand-receptor complexes. Graphical abstract .

A FYVE zinc finger domain protein specifically links mRNA transport to endosome trafficking.

PubMed

Pohlmann, Thomas; Baumann, Sebastian; Haag, Carl; Albrecht, Mario; Feldbrügge, Michael

2015-05-18

An emerging theme in cellular logistics is the close connection between mRNA and membrane trafficking. A prominent example is the microtubule-dependent transport of mRNAs and associated ribosomes on endosomes. This coordinated process is crucial for correct septin filamentation and efficient growth of polarised cells, such as fungal hyphae. Despite detailed knowledge on the key RNA-binding protein and the molecular motors involved, it is unclear how mRNAs are connected to membranes during transport. Here, we identify a novel factor containing a FYVE zinc finger domain for interaction with endosomal lipids and a new PAM2-like domain required for interaction with the MLLE domain of the key RNA-binding protein. Consistently, loss of this FYVE domain protein leads to specific defects in mRNA, ribosome, and septin transport without affecting general functions of endosomes or their movement. Hence, this is the first endosomal component specific for mRNP trafficking uncovering a new mechanism to couple mRNPs to endosomes.

Joining the dots - protein-RNA interactions mediating local mRNA translation in neurons.

PubMed

Gallagher, Christopher; Ramos, Andres

2018-06-01

Establishing and maintaining the complex network of connections required for neuronal communication requires the transport and in situ translation of large groups of mRNAs to create local proteomes. In this Review, we discuss the regulation of local mRNA translation in neurons and the RNA-binding proteins that recognise RNA zipcode elements and connect the mRNAs to the cellular transport networks, as well as regulate their translation control. However, mRNA recognition by the regulatory proteins is mediated by the combinatorial action of multiple RNA-binding domains. This increases the specificity and affinity of the interaction, while allowing the protein to recognise a diverse set of targets and mediate a range of mechanisms for translational regulation. The structural and molecular understanding of the interactions can be used together with novel microscopy and transcriptome-wide data to build a mechanistic framework for the regulation of local mRNA translation. © 2018 Federation of European Biochemical Societies.

Splitting the chromosome: cutting the ties that bind sister chromatids.

PubMed

Nasmyth, K; Peters, J M; Uhlmann, F

2001-01-01

In eukaryotic cells, replicated DNA molecules remain physically connected from their synthesis in S phase until they are separated during anaphase. This phenomenon, called sister chromatid cohesion, is essential for the temporal separation of DNA replication and mitosis and for the equal separation of the duplicated genome. Recent work has identified a number of chromosomal proteins required for cohesion. In this review we discuss how these proteins may connect sister chromatids and how they are removed from chromosomes to allow sister chromatid separation at the onset of anaphase.

Increasing Susceptibility of the Global Network of Food Trade to Climate Disturbances

NASA Astrophysics Data System (ADS)

Puma, M. J.; Bose, S.; Chon, S.; Cook, B.

2013-12-01

Globalization of agriculture through trade liberalization has led to a dramatic transformation of the global network of food trade. The many benefits of this globalization include greater and more efficient global agricultural production, reduced variability of regional and global food supplies, and savings in global water resources. However, a potential hidden cost is an increasingly fragile network that is more susceptible to shocks or disruptions. Recent studies suggest that complex systems, like the global food trade network, may have architectural features typically associated with the existence of tipping points and susceptibility to collapse. Here we present evidence that this global agricultural network is increasingly connected, homogeneous, and in a state where network nodes (here countries) can flip between alternate states. We use production and trade data from 1986 to 2009 to identify shifts in national self sufficiency and to quantify changes in connectivity and homogeneity of the wheat, maize and rice trade. We then simulate the possible impacts of climate and crop-disease disruptions, which could potentially trigger a global food crisis through an export-restriction-induced domino effect. Changes in self-sufficiency ratio (SSR) over time for various country groups. The SSR is computed based on production and trade of cereals and starchy roots. (Top row) Time series of SSR for the Group of Eight + Five (G8+5) countries. The '+ Five' refers to the five leading emerging economies in the world. (Bottom row) Boxplots of average SSR over two periods (1986-1990 and 2005-2009) for countries designated as 'Annex I' and 'Least Developed Countries' (LDC) by the United Nations.

Longitudinal assessment of local and global functional connectivity following sports-related concussion.

PubMed

Meier, Timothy B; Bellgowan, Patrick S F; Mayer, Andrew R

2017-02-01

Growing evidence suggests that sports-related concussions (SRC) may lead to acute changes in intrinsic functional connectivity, although most studies to date have been cross-sectional in nature with relatively modest sample sizes. We longitudinally assessed changes in local and global resting state functional connectivity using metrics that do not require a priori seed or network selection (regional homogeneity; ReHo and global brain connectivity; GBC, respectively). A large sample of collegiate athletes (N = 43) was assessed approximately one day (1.74 days post-injury, N = 34), one week (8.44 days, N = 34), and one month post-concussion (32.47 days, N = 30). Healthy contact sport-athletes served as controls (N = 51). Concussed athletes showed improvement in mood symptoms at each time point (p's < 0.05), but had significantly higher mood scores than healthy athletes at every time point (p's < 0.05). In contrast, self-reported symptoms and cognitive deficits improved over time following concussion (p's < 0.001), returning to healthy levels by one week post-concussion. ReHo in sensorimotor, visual, and temporal cortices increased over time post-concussion, and was greatest at one month post-injury. Conversely, ReHo in the frontal cortex decreased over time following SRC, with the greatest decrease evident at one month post-concussion. Differences in ReHo relative to healthy athletes were primarily observed at one month post-concussion rather than the more acute time points. Contrary to our hypothesis, no significant cross-sectional or longitudinal differences in GBC were observed. These results are suggestive of a delayed onset of local connectivity changes following SRC.

Impacts of spatial resolution and representation of flow connectivity on large-scale simulation of floods

NASA Astrophysics Data System (ADS)

Mateo, Cherry May R.; Yamazaki, Dai; Kim, Hyungjun; Champathong, Adisorn; Vaze, Jai; Oki, Taikan

2017-10-01

Global-scale river models (GRMs) are core tools for providing consistent estimates of global flood hazard, especially in data-scarce regions. Due to former limitations in computational power and input datasets, most GRMs have been developed to use simplified representations of flow physics and run at coarse spatial resolutions. With increasing computational power and improved datasets, the application of GRMs to finer resolutions is becoming a reality. To support development in this direction, the suitability of GRMs for application to finer resolutions needs to be assessed. This study investigates the impacts of spatial resolution and flow connectivity representation on the predictive capability of a GRM, CaMa-Flood, in simulating the 2011 extreme flood in Thailand. Analyses show that when single downstream connectivity (SDC) is assumed, simulation results deteriorate with finer spatial resolution; Nash-Sutcliffe efficiency coefficients decreased by more than 50 % between simulation results at 10 km resolution and 1 km resolution. When multiple downstream connectivity (MDC) is represented, simulation results slightly improve with finer spatial resolution. The SDC simulations result in excessive backflows on very flat floodplains due to the restrictive flow directions at finer resolutions. MDC channels attenuated these effects by maintaining flow connectivity and flow capacity between floodplains in varying spatial resolutions. While a regional-scale flood was chosen as a test case, these findings should be universal and may have significant impacts on large- to global-scale simulations, especially in regions where mega deltas exist.These results demonstrate that a GRM can be used for higher resolution simulations of large-scale floods, provided that MDC in rivers and floodplains is adequately represented in the model structure.

Differential binding of calmodulin-related proteins to their targets revealed through high-density Arabidopsis protein microarrays

PubMed Central

Popescu, Sorina C.; Popescu, George V.; Bachan, Shawn; Zhang, Zimei; Seay, Montrell; Gerstein, Mark; Snyder, Michael; Dinesh-Kumar, S. P.

2007-01-01

Calmodulins (CaMs) are the most ubiquitous calcium sensors in eukaryotes. A number of CaM-binding proteins have been identified through classical methods, and many proteins have been predicted to bind CaMs based on their structural homology with known targets. However, multicellular organisms typically contain many CaM-like (CML) proteins, and a global identification of their targets and specificity of interaction is lacking. In an effort to develop a platform for large-scale analysis of proteins in plants we have developed a protein microarray and used it to study the global analysis of CaM/CML interactions. An Arabidopsis thaliana expression collection containing 1,133 ORFs was generated and used to produce proteins with an optimized medium-throughput plant-based expression system. Protein microarrays were prepared and screened with several CaMs/CMLs. A large number of previously known and novel CaM/CML targets were identified, including transcription factors, receptor and intracellular protein kinases, F-box proteins, RNA-binding proteins, and proteins of unknown function. Multiple CaM/CML proteins bound many binding partners, but the majority of targets were specific to one or a few CaMs/CMLs indicating that different CaM family members function through different targets. Based on our analyses, the emergent CaM/CML interactome is more extensive than previously predicted. Our results suggest that calcium functions through distinct CaM/CML proteins to regulate a wide range of targets and cellular activities. PMID:17360592

A multistep damage recognition mechanism for global genomic nucleotide excision repair

PubMed Central

Sugasawa, Kaoru; Okamoto, Tomoko; Shimizu, Yuichiro; Masutani, Chikahide; Iwai, Shigenori; Hanaoka, Fumio

2001-01-01

A mammalian nucleotide excision repair (NER) factor, the XPC–HR23B complex, can specifically bind to certain DNA lesions and initiate the cell-free repair reaction. Here we describe a detailed analysis of its binding specificity using various DNA substrates, each containing a single defined lesion. A highly sensitive gel mobility shift assay revealed that XPC–HR23B specifically binds a small bubble structure with or without damaged bases, whereas dual incision takes place only when damage is present in the bubble. This is evidence that damage recognition for NER is accomplished through at least two steps; XPC–HR23B first binds to a site that has a DNA helix distortion, and then the presence of injured bases is verified prior to dual incision. Cyclobutane pyrimidine dimers (CPDs) were hardly recognized by XPC–HR23B, suggesting that additional factors may be required for CPD recognition. Although the presence of mismatched bases opposite a CPD potentiated XPC–HR23B binding, probably due to enhancement of the helix distortion, cell-free excision of such compound lesions was much more efficient than expected from the observed affinity for XPC–HR23B. This also suggests that additional factors and steps are required for the recognition of some types of lesions. A multistep mechanism of this sort may provide a molecular basis for ensuring the high level of damage discrimination that is required for global genomic NER. PMID:11238373

A multistep damage recognition mechanism for global genomic nucleotide excision repair.

PubMed

Sugasawa, K; Okamoto, T; Shimizu, Y; Masutani, C; Iwai, S; Hanaoka, F

2001-03-01

A mammalian nucleotide excision repair (NER) factor, the XPC-HR23B complex, can specifically bind to certain DNA lesions and initiate the cell-free repair reaction. Here we describe a detailed analysis of its binding specificity using various DNA substrates, each containing a single defined lesion. A highly sensitive gel mobility shift assay revealed that XPC-HR23B specifically binds a small bubble structure with or without damaged bases, whereas dual incision takes place only when damage is present in the bubble. This is evidence that damage recognition for NER is accomplished through at least two steps; XPC-HR23B first binds to a site that has a DNA helix distortion, and then the presence of injured bases is verified prior to dual incision. Cyclobutane pyrimidine dimers (CPDs) were hardly recognized by XPC-HR23B, suggesting that additional factors may be required for CPD recognition. Although the presence of mismatched bases opposite a CPD potentiated XPC-HR23B binding, probably due to enhancement of the helix distortion, cell-free excision of such compound lesions was much more efficient than expected from the observed affinity for XPC-HR23B. This also suggests that additional factors and steps are required for the recognition of some types of lesions. A multistep mechanism of this sort may provide a molecular basis for ensuring the high level of damage discrimination that is required for global genomic NER.

CELF1 preferentially binds to exon-intron boundary and regulates alternative splicing in HeLa cells.

PubMed

Xia, Heng; Chen, Dong; Wu, Qijia; Wu, Gang; Zhou, Yanhong; Zhang, Yi; Zhang, Libin

2017-09-01

The current RIP-seq approach has been developed for the identification of genome-wide interaction between RNA binding protein (RBP) and the bound RNA transcripts, but still rarely for identifying its binding sites. In this study, we performed RIP-seq experiments in HeLa cells using a monoclonal antibody against CELF1. Mapping of the RIP-seq reads showed a biased distribution at the 3'UTR and intronic regions. A total of 15,285 and 1384 CELF1-specific sense and antisense peaks were identified using the ABLIRC software tool. Our bioinformatics analyses revealed that 5' and 3' splice site motifs and GU-rich motifs were highly enriched in the CELF1-bound peaks. Furthermore, transcriptome analyses revealed that alternative splicing was globally regulated by CELF1 in HeLa cells. For example, the inclusion of exon 16 of LMO7 gene, a marker gene of breast cancer, is positively regulated by CELF1. Taken together, we have shown that RIP-seq data can be used to decipher RBP binding sites and reveal an unexpected landscape of the genome-wide CELF1-RNA interactions in HeLa cells. In addition, we found that CELF1 globally regulates the alternative splicing by binding the exon-intron boundary in HeLa cells, which will deepen our understanding of the regulatory roles of CELF1 in the pre-mRNA splicing process. Copyright © 2017 Elsevier B.V. All rights reserved.

A Global Learning Wiki Project for Pre-Service Teachers

ERIC Educational Resources Information Center

Kuo, Chia-Ling

2015-01-01

In this study the author investigated 228 pre-service teachers' experiences with a global learning wiki project in an undergraduate educational technology course. The project connected pre-service teachers with students in 11 different countries on wiki sites, participants and their overseas partners posting questions about topics of interest to…

Global energy regulation in the solar wind-magnetosphere-ionosphere system

NASA Technical Reports Server (NTRS)

Sato, T.

1985-01-01

Some basic concepts which are essential in the understanding of global energy regulation in the solar wind-magnetosphere-ionosphere system are introduced. The importance of line-tying concept is particularly emphasized in connection with the solar wind energy, energy release in the magnetosphere and energy dissipation in the ionosphere.

Communications Security: A Timeless Requirement While Conducting Warfare

DTIC Science & Technology

2012-04-10

services remotely to connect to the Global Information Grid ( GIG ). The GIG is the essential gateway to the Internet that DISA uses to allow service...nations that 16 thrive off free market and global economies . These hostile actors, such as Al Qaida or Hezbollah, do not posses the

International Collaboration in Secondary Level Education

ERIC Educational Resources Information Center

Loveland, Tom; Miyakawa, Hidetoshi; Hirayama, Yoshitaka

2004-01-01

Global education is the means to teach the world's citizens about the globalization trends. High school students are preparing themselves for college and future careers. Students in discrete subject courses are not given the bigger picture about the internationalization of the world. Students miss the connections of how all of these areas are…

Politics and School Desegregation before and after "Parents Involved"

ERIC Educational Resources Information Center

Brown, Frank; Hunter, Richard C.

2009-01-01

The authors attempt to tell the story of "Brown" and "Parents Involved" on educational inequality and connect these topics to economic competition globally. "Brown" came about in the 1950s in a much different environment: America was less diverse racially and ethnically, and economic competition on a global scale was…

Striving for International Understanding through Literature

ERIC Educational Resources Information Center

Yokota, Junko; Teale, William H.

2017-01-01

In the 21st century, our students increasingly communicate, connect, collaborate, and interact with diverse cultures and traditions around the world, so they need to develop global literacy. This department column highlights research and research-to-practice at the international level to bring global best teaching practices to the forefront.…

Inspired Teachers, Inspired Ideas

ERIC Educational Resources Information Center

Prescott, Jennifer

2012-01-01

Last November, more than 700 school leaders, educators, and reporters gathered in Washington, D.C., to celebrate the promise of innovative teaching and project learning to change global future. The event was the Microsoft Partners in Learning Global Forum, and its purpose was for educators worldwide to connect, learn, and collaborate on some of…

The Techy Teacher/Join the TED-Ed Club

ERIC Educational Resources Information Center

Tucker, Catlin

2016-01-01

Classrooms exist in an insular environment, and the work done there often feels disconnected from students' lives, interests, and hobbies. However, students today must cultivate the ability to navigate an increasingly connected global society. Global-ready graduates must be able to tackle real-world challenges, publish their work online, and…

Women's Marginalization, Economic Flows, and Environmental Flows: A Classroom Approach.

ERIC Educational Resources Information Center

O'Lear, Shannon

1999-01-01

Discusses environmental security, focusing on the meaning of "security." Defines the global economy as a process in which the security of groups is sought, maintained, or threatened. Illustrates connections among environmental security, the global economy, and abuse of women and children in less economically developed places,…

Women and Literacy. Women and World Development Series.

ERIC Educational Resources Information Center

Ballara, Marcela

This book examines the connection between poverty and illiteracy among women in a global context and presents guidelines for developing literacy activities for women. The following topics are covered: defining literacy (negative effects of illiteracy and literacy programs for women); global context (literacy gap, gender disparities, urban/rural…

21st-Century Citizen Science

ERIC Educational Resources Information Center

Nugent, Jill; Smith, Walter; Cook, Linda; Bell, Meredith

2015-01-01

With rapidly evolving technology, the world is more connected than ever, and citizens around the globe can contribute to science like never before (Dickinson and Bonney 2012). Reflecting the growing capacity of citizen science, this article presents a science education continuum that moves from global awareness to global contribution. At each…

Earth Matters: Studies for Our Global Future. 2nd Edition.

ERIC Educational Resources Information Center

Wasserman, Pamela, Ed.

This teacher's guide helps students explore the connection between human population growth and the well-being of the planet. Twelve readings and 34 activities introduce high school students to global society and environmental issues such as climate change, biodiversity loss, gender equality, economics, poverty, energy, wildlife endangerment, waste…

On influences of global and local cues on the rate of synchronization of oscillator networks

PubMed Central

Wang, Yongqiang; Doyle, Francis J.

2011-01-01

Synchronization of connected oscillator networks under global and local cues is ubiquitous in both science and engineering. Over the last few decades, enormous attention has been paid to study synchronization conditions of connected oscillators in chemistry, physics, mechanics, and particularly in biology. However, the influences of global and local cues on the rate of synchronization have not been fully studied. It is widespread that synchronization is achieved in the simultaneous presence of both global and local cues, such as intercellular coupling signals and external entrainment signals in terms of biological oscillators, and inter-neighbor coupling signals between follower nodes and central guiding signals in terms of groups of mobile autonomous agents. We prove in this paper that strength of the global cue is the only determinant of the rate of synchronization. More specifically, we prove that a stronger global cue means a faster rate of synchronization whereas a stronger local cue does not necessarily make the synchronization rate faster. Our results not only apply to the noise free case, but also apply to the case that the oscillator natural frequencies are subject to white noise. The analysis does not require the interplay to be symmetric or balanced. Simulation results are given to illustrate the proposed results. PMID:21607201

Global health justice and governance.

PubMed

Ruger, Jennifer Prah

2012-01-01

While there is a growing body of work on moral issues and global governance in the fields of global justice and international relations, little work has connected principles of global health justice with those of global health governance for a theory of global health. Such a theory would enable analysis and evaluation of the current global health system and would ethically and empirically ground proposals for reforming it to more closely align with moral values. Global health governance has been framed as an issue of national security, human security, human rights, and global public goods. The global health governance literature is essentially untethered to a theorized framework to illuminate or evaluate governance. This article ties global health justice and ethics to principles for governing the global health realm, developing a theoretical framework for global and domestic institutions and actors.

The ties that bind what is known to the recognition of what is new.

PubMed

Nelson, D L; Zhang, N; McKinney, V M

2001-09-01

Recognition success varies with how information is encoded (e.g., level of processing) and with what is already known as a result of past learning (e.g., word frequency). This article presents the results of experiments showing that preexisting connections involving the associates of studied words facilitate their recognition regardless of whether the words are intentionally encoded or are incidentally encoded under semantic or nonsemantic conditions. Words are more likely to be recognized when they have either more resonant connections coming back to them from their associates or more connections among their associates. Such results occur even though attention is never drawn to these associates. Regression analyses showed that these connections affect recognition independently of frequency, so the present results add to the literature showing that prior lexical knowledge contributes to episodic recognition. In addition, equations that use free-association data to derive composite strength indices of resonance and connectivity were evaluated. Implications for theories of recognition are discussed.

Linking international research to global health equity: the limited contribution of bioethics.

PubMed

Pratt, Bridget; Loff, Bebe

2013-05-01

Health research has been identified as a vehicle for advancing global justice in health. However, in bioethics, issues of global justice are mainly discussed within an ongoing debate on the conditions under which international clinical research is permissible. As a result, current ethical guidance predominantly links one type of international research (biomedical) to advancing one aspect of health equity (access to new treatments). International guidelines largely fail to connect international research to promoting broader aspects of health equity - namely, healthier social environments and stronger health systems. Bioethical frameworks such as the human development approach do consider how international clinical research is connected to the social determinants of health but, again, do so to address the question of when international clinical research is permissible. It is suggested that the narrow focus of this debate is shaped by high-income countries' economic strategies. The article further argues that the debate's focus obscures a stronger imperative to consider how other types of international research might advance justice in global health. Bioethics should consider the need for non-clinical health research and its contribution to advancing global justice. © 2011 Blackwell Publishing Ltd.

Joined at the hip: kinetochores, microtubules, and spindle assembly checkpoint signaling.

PubMed

Sacristan, Carlos; Kops, Geert J P L

2015-01-01

Error-free chromosome segregation relies on stable connections between kinetochores and spindle microtubules. The spindle assembly checkpoint (SAC) monitors such connections and relays their absence to the cell cycle machinery to delay cell division. The molecular network at kinetochores that is responsible for microtubule binding is integrated with the core components of the SAC signaling system. Molecular-mechanistic understanding of how the SAC is coupled to the kinetochore-microtubule interface has advanced significantly in recent years. The latest insights not only provide a striking view of the dynamics and regulation of SAC signaling events at the outer kinetochore but also create a framework for understanding how that signaling may be terminated when kinetochores and microtubules connect. Copyright © 2014 Elsevier Ltd. All rights reserved.

Global and System-Specific Resting-State fMRI Fluctuations Are Uncorrelated: Principal Component Analysis Reveals Anti-Correlated Networks

PubMed Central

Carbonell, Felix; Bellec, Pierre

2011-01-01

Abstract The influence of the global average signal (GAS) on functional-magnetic resonance imaging (fMRI)–based resting-state functional connectivity is a matter of ongoing debate. The global average fluctuations increase the correlation between functional systems beyond the correlation that reflects their specific functional connectivity. Hence, removal of the GAS is a common practice for facilitating the observation of network-specific functional connectivity. This strategy relies on the implicit assumption of a linear-additive model according to which global fluctuations, irrespective of their origin, and network-specific fluctuations are super-positioned. However, removal of the GAS introduces spurious negative correlations between functional systems, bringing into question the validity of previous findings of negative correlations between fluctuations in the default-mode and the task-positive networks. Here we present an alternative method for estimating global fluctuations, immune to the complications associated with the GAS. Principal components analysis was applied to resting-state fMRI time-series. A global-signal effect estimator was defined as the principal component (PC) that correlated best with the GAS. The mean correlation coefficient between our proposed PC-based global effect estimator and the GAS was 0.97±0.05, demonstrating that our estimator successfully approximated the GAS. In 66 out of 68 runs, the PC that showed the highest correlation with the GAS was the first PC. Since PCs are orthogonal, our method provides an estimator of the global fluctuations, which is uncorrelated to the remaining, network-specific fluctuations. Moreover, unlike the regression of the GAS, the regression of the PC-based global effect estimator does not introduce spurious anti-correlations beyond the decrease in seed-based correlation values allowed by the assumed additive model. After regressing this PC-based estimator out of the original time-series, we observed robust anti-correlations between resting-state fluctuations in the default-mode and the task-positive networks. We conclude that resting-state global fluctuations and network-specific fluctuations are uncorrelated, supporting a Resting-State Linear-Additive Model. In addition, we conclude that the network-specific resting-state fluctuations of the default-mode and task-positive networks show artifact-free anti-correlations. PMID:22444074

These School Ties Bind Continents.

ERIC Educational Resources Information Center

Tocco, Stephen P.

1996-01-01

Recruitment of foreign students would be economically advantageous to New England. Currently, the typical foreign student in Boston makes international 15 trips to the area in a lifetime. Alumni connections are especially important, both for institutions and for the region's economy. Increasingly, other states and regions are discovering the…

Destruction of white matter integrity in patients with mild cognitive impairment and Alzheimer disease.

PubMed

Sun, Xiaoyan; Salat, David; Upchurch, Kristen; Deason, Rebecca; Kowall, Neil; Budson, Andrew

2014-10-01

Accumulating evidence shows that gradual loss of white matter integrity plays an important role in the development of Alzheimer disease (AD). The aim of this research was to study the microstructural integrity of white matter in AD in vivo. Global fractional anisotropy, global axial diffusivity (AxD), and global radial diffusivity (RD) were analyzed in subjects with normal controls (NC), mild cognitive impairment (MCI), and AD using Alzheimer's Disease Neuroimaging Initiative data (total N = 210). We further compared specific white matter tracts among the 3 groups. Compared with the NC group, the MCI group had significantly increased global AxD and global RD. Compared with the NC and MCI groups, the AD group had significantly decreased global fractional anisotropy, increased global AxD, and increased global RD. With regard to specific white matter tracts, in the MCI group, we found increased AxD and increased RD in the external capsule, part of the lateral cholinergic pathway, in addition to the tracts connecting the limbic regions, predominantly in the left hemisphere. In the AD group, white matter abnormalities were widespread, including in the external capsule (cholinergic pathway) and limbic region tracts as well as tracts connecting anterior to posterior regions bilaterally. The radiographic manifestation of damaged white matter microstructural integrity in the cholinergic pathway in MCI patients may provide a rational basis for the use of cholinesterase inhibitor drugs in the MCI stage of AD.

Closing the "Know-Do" Gap: eHealth Strategies for the Global South.

PubMed

2008-01-01

For years, the Internet has been the new black, the "in" thing, the must have. And the virtual fever is spreading. According to the World Bank, global Internet use more than quadrupled between 2000 and 2005, from 15 users per 1000 population to 67.[1] Yet, many Global South countries are stalled on the Information Superhighway: the same World Bank report found that only 15 per 1000 population in sub-Saharan Africa are connected to the Internet, and only 21 per1000 in South Asia. To say nothing of glaring access inequalities within countries, lack of foreign investment in the communications sector of developing nations, and deficient connectivity in key areas of national infrastructure - schools, government centers, and health facilities. Yet the same World Bank report noted that eHealth initiatives ranked last in a list of technology strategies among countries surveyed.[1].

Influenza Pandemics in Singapore, a Tropical, Globally Connected City

PubMed Central

Chen, Mark I.; Chan, Siew Pang; Wong, Chia Siong; Cutter, Jeffery; Goh, Kee Tai; Tambyah, Paul Anath

2007-01-01

Tropical cities such as Singapore do not have well-defined influenza seasons but have not been spared from influenza pandemics. The 1918 epidemic in Singapore, which was then already a major global trading hub, occurred in 2 waves, June–July, and October–November, and resulted in >2,870 deaths. The excess mortality rate was higher than that for industrialized nations in the Northern Hemisphere but lower than that for less industrialized countries in Asia and Africa. The 1957 epidemic occurred in May and resulted in widespread illness. The 1968 epidemic occurred in August and lasted a few weeks, again with widespread illness. Tropical cities may be affected early in a pandemic and have higher mortality rates. With the increase in travel and trade, a future pandemic may reach a globally connected city early and spread worldwide. Preparedness and surveillance plans must be developed to include the megacities of the tropical world. PMID:18214178

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

Chen, Dong; Heidelberger, Philip; Sugawara, Yutaka

An apparatus and method for extending the scalability and improving the partitionability of networks that contain all-to-all links for transporting packet traffic from a source endpoint to a destination endpoint with low per-endpoint (per-server) cost and a small number of hops. An all-to-all wiring in the baseline topology is decomposed into smaller all-to-all components in which each smaller all-to-all connection is replaced with star topology by using global switches. Stacking multiple copies of the star topology baseline network creates a multi-planed switching topology for transporting packet traffic. Point-to-point unified stacking method using global switch wiring methods connects multiple planes ofmore » a baseline topology by using the global switches to create a large network size with a low number of hops, i.e., low network latency. Grouped unified stacking method increases the scalability (network size) of a stacked topology.« less

Cation binding to 15-TBA quadruplex DNA is a multiple-pathway cation-dependent process.

PubMed

Reshetnikov, Roman V; Sponer, Jiri; Rassokhina, Olga I; Kopylov, Alexei M; Tsvetkov, Philipp O; Makarov, Alexander A; Golovin, Andrey V

2011-12-01

A combination of explicit solvent molecular dynamics simulation (30 simulations reaching 4 µs in total), hybrid quantum mechanics/molecular mechanics approach and isothermal titration calorimetry was used to investigate the atomistic picture of ion binding to 15-mer thrombin-binding quadruplex DNA (G-DNA) aptamer. Binding of ions to G-DNA is complex multiple pathway process, which is strongly affected by the type of the cation. The individual ion-binding events are substantially modulated by the connecting loops of the aptamer, which play several roles. They stabilize the molecule during time periods when the bound ions are not present, they modulate the route of the ion into the stem and they also stabilize the internal ions by closing the gates through which the ions enter the quadruplex. Using our extensive simulations, we for the first time observed full spontaneous exchange of internal cation between quadruplex molecule and bulk solvent at atomistic resolution. The simulation suggests that expulsion of the internally bound ion is correlated with initial binding of the incoming ion. The incoming ion then readily replaces the bound ion while minimizing any destabilization of the solute molecule during the exchange. © The Author(s) 2011. Published by Oxford University Press.

Binding patterns of vanadium ions with different valence states to human serum transferrin studied by HPLC/high-resolution ICP-MS.

PubMed

Nagaoka, Megumi Hamano; Yamazaki, Takeshi; Maitani, Tamio

2002-09-06

Vanadium (V) is an essential metal for mammals and has different valence states. In blood, V is bound to serum transferrin (Tf), a glycoprotein which has two metal-binding sites, and carbonate is generally required for the binding. In this study, the binding patterns of V(III), V(IV), and V(V) to human serum Tf (hTf) were analyzed using an HPLC system equipped with an anion-exchange column and directly connected to a high-resolution inductively coupled plasma-mass spectrometer for metal detection (51V). In affinity to hTf, the three ions were ranked V(III)>V(IV)>V(V) in the presence of bicarbonate and V(III) reverse congruent V(IV)>V(V) in the absence. Intermediates in the "open forms" binding to the respective sites were detected at the initial stage. V(IV) and V(V) were bound to the N-lobe site in the "closed form" and "open form," respectively. In the absence of bicarbonate, V ions with respective valence states were bound to hTf in the "open form." In terms of binding to hTf, tri-valent V was most favorable in the presence of bicarbonate.

Cation binding to 15-TBA quadruplex DNA is a multiple-pathway cation-dependent process

PubMed Central

Reshetnikov, Roman V.; Sponer, Jiri; Rassokhina, Olga I.; Kopylov, Alexei M.; Tsvetkov, Philipp O.; Makarov, Alexander A.; Golovin, Andrey V.

2011-01-01

A combination of explicit solvent molecular dynamics simulation (30 simulations reaching 4 µs in total), hybrid quantum mechanics/molecular mechanics approach and isothermal titration calorimetry was used to investigate the atomistic picture of ion binding to 15-mer thrombin-binding quadruplex DNA (G-DNA) aptamer. Binding of ions to G-DNA is complex multiple pathway process, which is strongly affected by the type of the cation. The individual ion-binding events are substantially modulated by the connecting loops of the aptamer, which play several roles. They stabilize the molecule during time periods when the bound ions are not present, they modulate the route of the ion into the stem and they also stabilize the internal ions by closing the gates through which the ions enter the quadruplex. Using our extensive simulations, we for the first time observed full spontaneous exchange of internal cation between quadruplex molecule and bulk solvent at atomistic resolution. The simulation suggests that expulsion of the internally bound ion is correlated with initial binding of the incoming ion. The incoming ion then readily replaces the bound ion while minimizing any destabilization of the solute molecule during the exchange. PMID:21893589

Identification of a New Interaction Mode between the Src Homology 2 Domain of C-terminal Src Kinase (Csk) and Csk-binding Protein/Phosphoprotein Associated with Glycosphingolipid Microdomains♦

PubMed Central

Tanaka, Hiroaki; Akagi, Ken-ichi; Oneyama, Chitose; Tanaka, Masakazu; Sasaki, Yuichi; Kanou, Takashi; Lee, Young-Ho; Yokogawa, Daisuke; Dobenecker, Marc-Werner; Nakagawa, Atsushi; Okada, Masato; Ikegami, Takahisa

2013-01-01

Proteins with Src homology 2 (SH2) domains play major roles in tyrosine kinase signaling. Structures of many SH2 domains have been studied, and the regions involved in their interactions with ligands have been elucidated. However, these analyses have been performed using short peptides consisting of phosphotyrosine followed by a few amino acids, which are described as the canonical recognition sites. Here, we report the solution structure of the SH2 domain of C-terminal Src kinase (Csk) in complex with a longer phosphopeptide from the Csk-binding protein (Cbp). This structure, together with biochemical experiments, revealed the existence of a novel binding region in addition to the canonical phosphotyrosine 314-binding site of Cbp. Mutational analysis of this second region in cells showed that both canonical and novel binding sites are required for tumor suppression through the Cbp-Csk interaction. Furthermore, the data indicate an allosteric connection between Cbp binding and Csk activation that arises from residues in the βB/βC loop of the SH2 domain. PMID:23548896

Drawing Connections Between Local and Global Observations: An Essential Element of Geoscience Education

NASA Astrophysics Data System (ADS)

Manduca, C. A.; Mogk, D. W.

2002-12-01

One of the hallmarks of geoscience research is the process of moving between observations and interpretations on local and global scales to develop an integrated understanding of Earth processes. Understanding this interplay is an important aspect of student geoscience learning which leads to an understanding of the fundamental principles of science and geoscience and of the connections between local natural phenomena or human activity and global processes. Several techniques that engage students in inquiry and discovery (as recommended in the National Science Education Standards, NRC 1996, Shaping the Future of Undergraduate Earth Science Education, AGU, 1997) hold promise for helping students make these connections. These include the development of global data sets from local observations (e.g. GLOBE); studying small scale or local phenomenon in the context of global models (e.g. carbon storage in local vegetation and its role in the carbon cycle); or an analysis of local environmental issues in a global context (e.g. a comparison of local flooding to flooding in other countries and analysis in the context of weather, geology and development patterns). Research on learning suggests that data-rich activities linking the local and global have excellent potential for enhancing student learning because 1) students have already developed observations and interpretations of their local environment which can serve as a starting point for constructing new knowledge and 2) this context may motivate learning and develop understanding that can be transferred to other situations. (How People Learn, NRC, 2001). Faculty and teachers at two recent workshops confirm that projects that involve local or global data can engage students in learning by providing real world context, creating student ownership of the learning process, and developing scientific skills applicable to the complex problems that characterize modern science and society. Workshop participants called for increased dissemination of examples of effective practice, evaluation of the impact of data-rich activities on learning, and further development of data access infrastructure and services. (for additional workshop results and discussion see http://serc.carleton.edu/research_education/usingdata)

Architecture of the human regulatory network derived from ENCODE data.

PubMed

Gerstein, Mark B; Kundaje, Anshul; Hariharan, Manoj; Landt, Stephen G; Yan, Koon-Kiu; Cheng, Chao; Mu, Xinmeng Jasmine; Khurana, Ekta; Rozowsky, Joel; Alexander, Roger; Min, Renqiang; Alves, Pedro; Abyzov, Alexej; Addleman, Nick; Bhardwaj, Nitin; Boyle, Alan P; Cayting, Philip; Charos, Alexandra; Chen, David Z; Cheng, Yong; Clarke, Declan; Eastman, Catharine; Euskirchen, Ghia; Frietze, Seth; Fu, Yao; Gertz, Jason; Grubert, Fabian; Harmanci, Arif; Jain, Preti; Kasowski, Maya; Lacroute, Phil; Leng, Jing Jane; Lian, Jin; Monahan, Hannah; O'Geen, Henriette; Ouyang, Zhengqing; Partridge, E Christopher; Patacsil, Dorrelyn; Pauli, Florencia; Raha, Debasish; Ramirez, Lucia; Reddy, Timothy E; Reed, Brian; Shi, Minyi; Slifer, Teri; Wang, Jing; Wu, Linfeng; Yang, Xinqiong; Yip, Kevin Y; Zilberman-Schapira, Gili; Batzoglou, Serafim; Sidow, Arend; Farnham, Peggy J; Myers, Richard M; Weissman, Sherman M; Snyder, Michael

2012-09-06

Transcription factors bind in a combinatorial fashion to specify the on-and-off states of genes; the ensemble of these binding events forms a regulatory network, constituting the wiring diagram for a cell. To examine the principles of the human transcriptional regulatory network, we determined the genomic binding information of 119 transcription-related factors in over 450 distinct experiments. We found the combinatorial, co-association of transcription factors to be highly context specific: distinct combinations of factors bind at specific genomic locations. In particular, there are significant differences in the binding proximal and distal to genes. We organized all the transcription factor binding into a hierarchy and integrated it with other genomic information (for example, microRNA regulation), forming a dense meta-network. Factors at different levels have different properties; for instance, top-level transcription factors more strongly influence expression and middle-level ones co-regulate targets to mitigate information-flow bottlenecks. Moreover, these co-regulations give rise to many enriched network motifs (for example, noise-buffering feed-forward loops). Finally, more connected network components are under stronger selection and exhibit a greater degree of allele-specific activity (that is, differential binding to the two parental alleles). The regulatory information obtained in this study will be crucial for interpreting personal genome sequences and understanding basic principles of human biology and disease.

Solution Binding and Structural Analyses Reveal Potential Multidrug Resistance Functions for SAV2435 and CTR107 and Other GyrI-like Proteins.

PubMed

Moreno, Andrew; Froehlig, John R; Bachas, Sharrol; Gunio, Drew; Alexander, Teressa; Vanya, Aaron; Wade, Herschel

2016-08-30

Multidrug resistance (MDR) refers to the acquired ability of cells to tolerate a broad range of toxic compounds. One mechanism cells employ is to increase the level of expression of efflux pumps for the expulsion of xenobiotics. A key feature uniting efflux-related mechanisms is multidrug (MD) recognition, either by efflux pumps themselves or by their transcriptional regulators. However, models describing MD binding by MDR effectors are incomplete, underscoring the importance of studies focused on the recognition elements and key motifs that dictate polyspecific binding. One such motif is the GyrI-like domain, which is found in several MDR proteins and is postulated to have been adapted for small-molecule binding and signaling. Here we report the solution binding properties and crystal structures of two proteins containing GyrI-like domains, SAV2435 and CTR107, bound to various ligands. Furthermore, we provide a comparison with deposited crystal structures of GyrI-like proteins, revealing key features of GyrI-like domains that not only support polyspecific binding but also are conserved among GyrI-like domains. Together, our studies suggest that GyrI-like domains perform evolutionarily conserved functions connected to multidrug binding and highlight the utility of these types of studies for elucidating mechanisms of MDR.

Broadly neutralizing epitopes in the Plasmodium vivax vaccine candidate Duffy Binding Protein

DOE PAGES

Chen, Edwin; Salinas, Nichole D.; Huang, Yining; ...

2016-05-18

Plasmodium vivax Duffy Binding Protein (PvDBP) is the most promising vaccine candidate for P. vivax malaria. The polymorphic nature of PvDBP induces strain-specific immune responses, however, and the epitopes of broadly neutralizing antibodies are unknown. These features hamper the rational design of potent DBP-based vaccines and necessitate the identification of globally conserved epitopes. Using X-ray crystallography, small-angle X-ray scattering, hydrogen-deuterium exchange mass spectrometry, and mutational mapping, we have defined epitopes for three inhibitory mAbs (mAbs 2D10, 2H2, and 2C6) and one noninhibitory mAb (3D10) that engage DBP. These studies expand the currently known inhibitory epitope repertoire by establishing protective motifsmore » in subdomain three outside the receptor-binding and dimerization residues of DBP, and introduce globally conserved protective targets. All of the epitopes are highly conserved among DBP alleles. In conclusion, the identification of broadly conserved epitopes of inhibitory antibodies provides critical motifs that should be retained in the next generation of potent vaccines for P. vivax malaria.« less

Broadly neutralizing epitopes in the Plasmodium vivax vaccine candidate Duffy Binding Protein

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

Chen, Edwin; Salinas, Nichole D.; Huang, Yining

Plasmodium vivax Duffy Binding Protein (PvDBP) is the most promising vaccine candidate for P. vivax malaria. The polymorphic nature of PvDBP induces strain-specific immune responses, however, and the epitopes of broadly neutralizing antibodies are unknown. These features hamper the rational design of potent DBP-based vaccines and necessitate the identification of globally conserved epitopes. Using X-ray crystallography, small-angle X-ray scattering, hydrogen-deuterium exchange mass spectrometry, and mutational mapping, we have defined epitopes for three inhibitory mAbs (mAbs 2D10, 2H2, and 2C6) and one noninhibitory mAb (3D10) that engage DBP. These studies expand the currently known inhibitory epitope repertoire by establishing protective motifsmore » in subdomain three outside the receptor-binding and dimerization residues of DBP, and introduce globally conserved protective targets. All of the epitopes are highly conserved among DBP alleles. In conclusion, the identification of broadly conserved epitopes of inhibitory antibodies provides critical motifs that should be retained in the next generation of potent vaccines for P. vivax malaria.« less

Helix formation in arrestin accompanies recognition of photoactivated rhodopsin.

PubMed

Feuerstein, Sophie E; Pulvermüller, Alexander; Hartmann, Rudolf; Granzin, Joachim; Stoldt, Matthias; Henklein, Peter; Ernst, Oliver P; Heck, Martin; Willbold, Dieter; Koenig, Bernd W

2009-11-17

Binding of arrestin to photoactivated phosphorylated rhodopsin terminates the amplification of visual signals in photoreceptor cells. Currently, there is no crystal structure of a rhodopsin-arrestin complex available, although structures of unbound rhodopsin and arrestin have been determined. High-affinity receptor binding is dependent on distinct arrestin sites responsible for recognition of rhodopsin activation and phosphorylation. The loop connecting beta-strands V and VI in rod arrestin has been implicated in the recognition of active rhodopsin. We report the structure of receptor-bound arrestin peptide Arr(67-77) mimicking this loop based on solution NMR data. The peptide binds photoactivated rhodopsin in the unphosphorylated and phosphorylated form with similar affinities and stabilizes the metarhodopsin II photointermediate. A largely alpha-helical conformation of the receptor-bound peptide is observed.

Wildlife corridors based on the spatial modeling of the human pressure: A Portuguese case study

Treesearch

Lara Nunes; Ana Luisa Gomes; Alexandra Fonseca

2015-01-01

In times of economical crisis, rewilding can be a less costly conservation management approach, able to generate economic value from wild lands and to rural communities. Simultaneously, improvement of connectivity between protected areas was identified as a global priority for conservation. Allying the rewilding concept and connectivity concern, a model for...

Making the World Real: Using a Civic Engagement Course to Bring Home Our Global Connections

ERIC Educational Resources Information Center

McCartney, Alison Rios Millett

2006-01-01

Civic engagement is an area ripe for increased pedagogical attention in the discipline of Political Science. However, almost all efforts are limited to courses on local, state, and national government. We teach about the often intricate connections between domestic and international politics, but opportunities for students to research and practice…

Global Literacy in Local Learning Contexts: Connecting Home and School. Routledge Research in International and Comparative Education

ERIC Educational Resources Information Center

Mount-Cors, Mary Faith

2016-01-01

Based on qualitative research focused on literacy and health from three schools in coastal Kenya, this book examines country, school, and family contexts to develop a dual-generation maternal-child model for literacy learning and to connect local-specific phenomena with national and international policy arenas. In contrast to international…

Connecting Instructional and Cognitive Aspects of an LE: A Study of the Global Seminar Project

ERIC Educational Resources Information Center

Savelyeva, Tamara

2012-01-01

My research problem is based on the lack of unifying conceptual cohesion between the discourses concerning cognitive and instructional aspects of learning environments (LE). I contrast that lack with practical developments of LE studies connected at the level of practical implementation and evaluation. Next, I briefly review the LE boundaries,…

Edmodo as a Tool for the Global Connection between Japanese and American College Students in Language Learning

ERIC Educational Resources Information Center

Okumura, Shinji

2017-01-01

This study investigated how English learners at a university in Japan perceive connections with students in the US through an educational social network platform, called Edmodo. The instructor of English at the Japanese university cooperated with a Japanese language instructor at an American university and they incorporated Edmodo into their…

Balancing Act: Bridging the Traditional and Technological Aspects of Culture through Art Education

ERIC Educational Resources Information Center

Lawton, Pamela Harris

2007-01-01

This paper addresses the benefits of connecting and balancing education in the visual arts and in technology through discussion of actual examples. This balanced connection accomplishes three goals: to further advance and enhance quality of life, to cultivate humane and ethical behaviors, and to initiate global dialogue on issues that matter among…

Top-Down Network Effective Connectivity in Abstinent Substance Dependent Individuals

PubMed Central

Regner, Michael F.; Saenz, Naomi; Maharajh, Keeran; Yamamoto, Dorothy J.; Mohl, Brianne; Wylie, Korey; Tregellas, Jason; Tanabe, Jody

2016-01-01

Objective We hypothesized that compared to healthy controls, long-term abstinent substance dependent individuals (SDI) will differ in their effective connectivity between large-scale brain networks and demonstrate increased directional information from executive control to interoception-, reward-, and habit-related networks. In addition, using graph theory to compare network efficiencies we predicted decreased small-worldness in SDI compared to controls. Methods 50 SDI and 50 controls of similar sex and age completed psychological surveys and resting state fMRI. fMRI results were analyzed using group independent component analysis; 14 networks-of-interest (NOI) were selected using template matching to a canonical set of resting state networks. The number, direction, and strength of connections between NOI were analyzed with Granger Causality. Within-group thresholds were p<0.005 using a bootstrap permutation. Between group thresholds were p<0.05, FDR-corrected for multiple comparisons. NOI were correlated with behavioral measures, and group-level graph theory measures were compared. Results Compared to controls, SDI showed significantly greater Granger causal connectivity from right executive control network (RECN) to dorsal default mode network (dDMN) and from dDMN to basal ganglia network (BGN). RECN was negatively correlated with impulsivity, behavioral approach, and negative affect; dDMN was positively correlated with impulsivity. Among the 14 NOI, SDI showed greater bidirectional connectivity; controls showed more unidirectional connectivity. SDI demonstrated greater global efficiency and lower local efficiency. Conclusions Increased effective connectivity in long-term abstinent drug users may reflect improved cognitive control over habit and reward processes. Higher global and lower local efficiency across all networks in SDI compared to controls may reflect connectivity changes associated with drug dependence or remission and requires future, longitudinal studies to confirm. PMID:27776135

Diffusing colloidal probes of protein-carbohydrate interactions.

PubMed

Eichmann, Shannon L; Meric, Gulsum; Swavola, Julia C; Bevan, Michael A

2013-02-19

We present diffusing colloidal probe measurements of weak, multivalent, specific protein-polysaccharide interactions mediated by a competing monosaccharide. Specifically, we used integrated evanescent wave and video microscopy methods to monitor the three-dimensional Brownian excursions of conconavilin A (ConA) decorated colloids interacting with dextran-functionalized surfaces in the presence of glucose. Particle trajectories were interpreted as binding lifetime histograms, binding isotherms, and potentials of mean force. Binding lifetimes and isotherms showed clear trends of decreasing ConA-dextran-specific binding with increasing glucose concentration, consistent with expectations. Net potentials were accurately captured by superposition of a short-range, glucose-independent ConA-dextran repulsion and a longer-range, glucose-dependent dextran bridging attraction modeled as a harmonic potential. For glucose concentrations greater than 100 mM, the net ConA-dextran potential was found to have only a nonspecific repulsion, similar to that of bovine serum albumin (BSA) decorated colloids over dextran determined in control experiments. Our results demonstrate the first use of optical microscopy methods to quantify the connections between potentials of mean force and the binding behavior of ConA-decorated colloids on dextran-functionalized surfaces.

Elucidating the druggable interface of protein-protein interactions using fragment docking and coevolutionary analysis.

PubMed

Bai, Fang; Morcos, Faruck; Cheng, Ryan R; Jiang, Hualiang; Onuchic, José N

2016-12-13

Protein-protein interactions play a central role in cellular function. Improving the understanding of complex formation has many practical applications, including the rational design of new therapeutic agents and the mechanisms governing signal transduction networks. The generally large, flat, and relatively featureless binding sites of protein complexes pose many challenges for drug design. Fragment docking and direct coupling analysis are used in an integrated computational method to estimate druggable protein-protein interfaces. (i) This method explores the binding of fragment-sized molecular probes on the protein surface using a molecular docking-based screen. (ii) The energetically favorable binding sites of the probes, called hot spots, are spatially clustered to map out candidate binding sites on the protein surface. (iii) A coevolution-based interface interaction score is used to discriminate between different candidate binding sites, yielding potential interfacial targets for therapeutic drug design. This approach is validated for important, well-studied disease-related proteins with known pharmaceutical targets, and also identifies targets that have yet to be studied. Moreover, therapeutic agents are proposed by chemically connecting the fragments that are strongly bound to the hot spots.

Coherent Conformational Degrees of Freedom as a Structural Basis for Allosteric Communication

PubMed Central

Mitternacht, Simon; Berezovsky, Igor N.

2011-01-01

Conformational changes in allosteric regulation can to a large extent be described as motion along one or a few coherent degrees of freedom. The states involved are inherent to the protein, in the sense that they are visited by the protein also in the absence of effector ligands. Previously, we developed the measure binding leverage to find sites where ligand binding can shift the conformational equilibrium of a protein. Binding leverage is calculated for a set of motion vectors representing independent conformational degrees of freedom. In this paper, to analyze allosteric communication between binding sites, we introduce the concept of leverage coupling, based on the assumption that only pairs of sites that couple to the same conformational degrees of freedom can be allosterically connected. We demonstrate how leverage coupling can be used to analyze allosteric communication in a range of enzymes (regulated by both ligand binding and post-translational modifications) and huge molecular machines such as chaperones. Leverage coupling can be calculated for any protein structure to analyze both biological and latent catalytic and regulatory sites. PMID:22174669

Structural and functional characterization of the CAP domain of pathogen-related yeast 1 (Pry1) protein

NASA Astrophysics Data System (ADS)

Darwiche, Rabih; Kelleher, Alan; Hudspeth, Elissa M.; Schneiter, Roger; Asojo, Oluwatoyin A.

2016-06-01

The production, crystal structure, and functional characterization of the C-terminal cysteine-rich secretory protein/antigen 5/pathogenesis related-1 (CAP) domain of pathogen-related yeast protein-1 (Pry1) from Saccharomyces cerevisiae is presented. The CAP domain of Pry1 (Pry1CAP) is functional in vivo as its expression restores cholesterol export to yeast mutants lacking endogenous Pry1 and Pry2. Recombinant Pry1CAP forms dimers in solution, is sufficient for in vitro cholesterol binding, and has comparable binding properties as full-length Pry1. Two crystal structures of Pry1CAP are reported, one with Mg2+ coordinated to the conserved CAP tetrad (His208, Glu215, Glu233 and His250) in spacegroup I41 and the other without divalent cations in spacegroup P6122. The latter structure contains four 1,4-dioxane molecules from the crystallization solution, one of which sits in the cholesterol binding site. Both structures reveal that the divalent cation and cholesterol binding sites are connected upon dimerization, providing a structural basis for the observed Mg2+-dependent sterol binding by Pry1.

Mid-Task Break Improves Global Integration of Functional Connectivity in Lower Alpha Band

PubMed Central

Li, Junhua; Lim, Julian; Chen, Yu; Wong, Kianfoong; Thakor, Nitish; Bezerianos, Anastasios; Sun, Yu

2016-01-01

Numerous efforts have been devoted to revealing neurophysiological mechanisms of mental fatigue, aiming to find an effective way to reduce the undesirable fatigue-related outcomes. Until recently, mental fatigue is thought to be related to functional dysconnectivity among brain regions. However, the topological representation of brain functional connectivity altered by mental fatigue is only beginning to be revealed. In the current study, we applied a graph theoretical approach to analyse such topological alterations in the lower alpha band (8~10 Hz) of EEG data from 20 subjects undergoing a two-session experiment, in which one session includes four successive blocks with visual oddball tasks (session 1) whereas a mid-task break was introduced in the middle of four task blocks in the other session (session 2). Phase lag index (PLI) was then employed to measure functional connectivity strengths for all pairs of EEG channels. Behavior and connectivity maps were compared between the first and last task blocks in both sessions. Inverse efficiency scores (IES = reaction time/response accuracy) were significantly increased in the last task block, showing a clear effect of time-on-task in participants. Furthermore, a significant block-by-session interaction was revealed in the IES, suggesting the effectiveness of the mid-task break on maintaining task performance. More importantly, a significant session-independent deficit of global integration and an increase of local segregation were found in the last task block across both sessions, providing further support for the presence of a reshaped topology in functional brain connectivity networks under fatigue state. Moreover, a significant block-by-session interaction was revealed in the characteristic path length, small-worldness, and global efficiency, attributing to the significantly disrupted network topology in session 1 in comparison of the maintained network structure in session 2. Specifically, we found increased nodal betweenness centrality in several channels resided in frontal regions in session 1, resembling the observations of more segregated global architecture under fatigue state. Taken together, our findings provide insights into the substrates of brain functional dysconnectivity patterns for mental fatigue and reiterate the effectiveness of the mid-task break on maintaining brain network efficiency. PMID:27378894

The RNA-binding region of human TRBP interacts with microRNA precursors through two independent domains

PubMed Central

Benoit, Matthieu P. M. H.; Imbert, Lionel; Palencia, Andrés; Pérard, Julien; Ebel, Christine; Boisbouvier, Jérôme; Plevin, Michael J.

2013-01-01

MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression through RNA interference. Human miRNAs are generated through a series of enzymatic processing steps. The precursor miRNA (pre-miRNA) is recognized and cleaved by a complex containing Dicer and several non-catalytic accessory proteins. HIV TAR element binding protein (TRBP) is a constituent of the Dicer complex, which augments complex stability and potentially functions in substrate recognition and product transfer to the RNA-induced silencing complex. Here we have analysed the interaction between the RNA-binding region of TRBP and an oncogenic human miRNA, miR-155, at different stages in the biogenesis pathway. We show that the region of TRBP that binds immature miRNAs comprises two independent double-stranded RNA-binding domains connected by a 60-residue flexible linker. No evidence of contact between the two double-stranded RNA-binding domains was observed either in the apo- or RNA-bound state. We establish that the RNA-binding region of TRBP interacts with both pre-miR-155 and the miR-155/miR-155* duplex through the same binding surfaces and with similar affinities, and that two protein molecules can simultaneously interact with each immature miRNA. These data suggest that TRBP could play a role before and after processing of pre-miRNAs by Dicer. PMID:23435228

Consciousness as a global property of brain dynamic activity

NASA Astrophysics Data System (ADS)

Mateos, D. M.; Wennberg, R.; Guevara, R.; Perez Velazquez, J. L.

2017-12-01

We seek general principles of the structure of the cellular collective activity associated with conscious awareness. Can we obtain evidence for features of the optimal brain organization that allows for adequate processing of stimuli and that may guide the emergence of cognition and consciousness? Analyzing brain recordings in conscious and unconscious states, we followed initially the classic approach in physics when it comes to understanding collective behaviours of systems composed of a myriad of units: the assessment of the number of possible configurations (microstates) that the system can adopt, for which we use a global entropic measure associated with the number of connected brain regions. Having found maximal entropy in conscious states, we then inspected the microscopic nature of the configurations of connections using an adequate complexity measure and found higher complexity in states characterized not only by conscious awareness but also by subconscious cognitive processing, such as sleep stages. Our observations indicate that conscious awareness is associated with maximal global (macroscopic) entropy and with the short time scale (microscopic) complexity of the configurations of connected brain networks in pathological unconscious states (seizures and coma), but the microscopic view captures the high complexity in physiological unconscious states (sleep) where there is information processing. As such, our results support the global nature of conscious awareness, as advocated by several theories of cognition. We thus hope that our studies represent preliminary steps to reveal aspects of the structure of cognition that leads to conscious awareness.

Nutrition and Consumer Education as a Constituent Part of Global Education in the Light of the New Education Framework in State Schools in Southern Germany: The Case of Baden-Württemberg

ERIC Educational Resources Information Center

Angele, Claudia

2017-01-01

Nutrition and consumer education may be regarded as a constituent part of global education. It is, however, necessary to explore the connections between the specific subject didactics of nutrition and consumer education, and global education more closely within current academic discourse if we are to understand it better. Currently, there is…

A recessive mutation in the DSP gene linked to cardiomyopathy, skin fragility and hair defects impairs the binding of desmoplakin to epidermal keratins and the muscle-specific intermediate filament desmin.

PubMed

Favre, B; Begré, N; Borradori, L

2018-06-07

Desmoplakin (DSP) is a cytolinker of the plakin family. It mediates the connection of intermediate filaments (IFs) to desmosomes, intercellular adhesion junctions. The carboxyl (C)-terminal tail of DSP binds to IFs, while its amino-terminal part interacts with the armadillo proteins plakophilins and plakoglobin that in turn associate with the desmosomal cadherin desmogleins and desmocollins 1 . This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Virtual water trade of agri-food products: Evidence from italian-chinese relations.

PubMed

Lamastra, Lucrezia; Miglietta, Pier Paolo; Toma, Pierluigi; De Leo, Federica; Massari, Stefania

2017-12-01

At global scale, the majority of world water withdrawal is for the agricultural sector, with differences among countries depending on the relevance of agri-food sector in the economy. Virtual water and water footprint could be useful to express the impact on the water resources of each production process and good with the objective to lead to a sustainable use of water at a global level. International trade could be connected to the virtual water flows, in fact through commodities importation, water poor countries can save their own water resources. The present paper focuses on the bilateral virtual water flows connected to the top ten agri-food products traded between Italy and China. Comparing the virtual water flow related to the top 10 agri-food products, the virtual water flow from Italy to China is bigger than the water flow in the opposite direction. Moreover, the composition of virtual water flows is different; Italy imports significant amounts of grey water from China, depending on the different environmental strategies adopted by the two selected countries. This difference could be also related to the fact that traded commodities are very different; the 91% of virtual water imported by Italy is connected to crops products, while the 95% of virtual water imported by China is related to the animal products. Considering national water saving and global water saving, appears that Italy imports virtual water from China while China exerts pressure on its water resources to supply the exports to Italy. This result at global scale implies a global water loss of 129.29millionm3 because, in general, the agri-food products are traded from the area with lower water productivity to the area with the higher water productivity. Copyright © 2017 Elsevier B.V. All rights reserved.

Growing Global Citizens: Young Children's Lived Experiences with the Development of Their Own Social World

ERIC Educational Resources Information Center

Twigg, Danielle; Pendergast, Donna; Twigg, Justin

2015-01-01

As the result of an increasingly technologically "connected" world, citizens are finding it difficult to effectively exercise civic responsibilities in relation to global issues such as climate change, poverty, and warfare (Tully, 2009). New understandings of the concept of "citizenship" are being extended beyond traditional…

78 FR 75607 - Self-Regulatory Organizations; BATS Exchange, Inc.; Notice of Filing of a Proposed Rule Change in...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-12-12

... the Proposed Business Combination Involving BATS Global Markets, Inc. and Direct Edge Holdings LLC...'') in connection with the proposed business combination (the ``Combination''), as described in more detail below, involving its parent company, BATS Global Markets, Inc. and Direct Edge Holdings LLC (``DE...