Intranasal Oxytocin and Vasopressin Modulate Divergent Brainwide Functional Substrates.

PubMed

Galbusera, Alberto; De Felice, Alessia; Girardi, Stefano; Bassetto, Giacomo; Maschietto, Marta; Nishimori, Katsuhiko; Chini, Bice; Papaleo, Francesco; Vassanelli, Stefano; Gozzi, Alessandro

2017-06-01

The neuropeptides oxytocin (OXT) and vasopressin (AVP) have been identified as modulators of emotional social behaviors and associated with neuropsychiatric disorders characterized by social dysfunction. Experimental and therapeutic use of OXT and AVP via the intranasal route is the subject of extensive clinical research. However, the large-scale functional substrates directly engaged by these peptides and their functional dynamics remain elusive. By using cerebral blood volume (CBV) weighted fMRI in the mouse, we show that intranasal administration of OXT rapidly elicits the transient activation of cortical regions and a sustained activation of hippocampal and forebrain areas characterized by high oxytocin receptor density. By contrast, intranasal administration of AVP produced a robust and sustained deactivation in cortico-parietal, thalamic and mesolimbic regions. Importantly, intravenous administration of OXT and AVP did not recapitulate the patterns of modulation produced by intranasal dosing, supporting a central origin of the observed functional changes. In keeping with this notion, hippocampal local field potential recordings revealed multi-band power increases upon intranasal OXT administration. We also show that the selective OXT-derivative TGOT reproduced the pattern of activation elicited by OXT and that the deletion of OXT receptors does not affect AVP-mediated deactivation. Collectively, our data document divergent modulation of brainwide neural systems by intranasal administration of OXT and AVP, an effect that involves key substrates of social and emotional behavior. The observed divergence calls for a deeper investigation of the systems-level mechanisms by which exogenous OXT and AVP modulate brain function and exert their putative therapeutic effects.

Functional Module Analysis for Gene Coexpression Networks with Network Integration.

PubMed

Zhang, Shuqin; Zhao, Hongyu; Ng, Michael K

2015-01-01

Network has been a general tool for studying the complex interactions between different genes, proteins, and other small molecules. Module as a fundamental property of many biological networks has been widely studied and many computational methods have been proposed to identify the modules in an individual network. However, in many cases, a single network is insufficient for module analysis due to the noise in the data or the tuning of parameters when building the biological network. The availability of a large amount of biological networks makes network integration study possible. By integrating such networks, more informative modules for some specific disease can be derived from the networks constructed from different tissues, and consistent factors for different diseases can be inferred. In this paper, we have developed an effective method for module identification from multiple networks under different conditions. The problem is formulated as an optimization model, which combines the module identification in each individual network and alignment of the modules from different networks together. An approximation algorithm based on eigenvector computation is proposed. Our method outperforms the existing methods, especially when the underlying modules in multiple networks are different in simulation studies. We also applied our method to two groups of gene coexpression networks for humans, which include one for three different cancers, and one for three tissues from the morbidly obese patients. We identified 13 modules with three complete subgraphs, and 11 modules with two complete subgraphs, respectively. The modules were validated through Gene Ontology enrichment and KEGG pathway enrichment analysis. We also showed that the main functions of most modules for the corresponding disease have been addressed by other researchers, which may provide the theoretical basis for further studying the modules experimentally.

Human intellectual disability genes form conserved functional modules in Drosophila.

PubMed

Oortveld, Merel A W; Keerthikumar, Shivakumar; Oti, Martin; Nijhof, Bonnie; Fernandes, Ana Clara; Kochinke, Korinna; Castells-Nobau, Anna; van Engelen, Eva; Ellenkamp, Thijs; Eshuis, Lilian; Galy, Anne; van Bokhoven, Hans; Habermann, Bianca; Brunner, Han G; Zweier, Christiane; Verstreken, Patrik; Huynen, Martijn A; Schenck, Annette

2013-10-01

Intellectual Disability (ID) disorders, defined by an IQ below 70, are genetically and phenotypically highly heterogeneous. Identification of common molecular pathways underlying these disorders is crucial for understanding the molecular basis of cognition and for the development of therapeutic intervention strategies. To systematically establish their functional connectivity, we used transgenic RNAi to target 270 ID gene orthologs in the Drosophila eye. Assessment of neuronal function in behavioral and electrophysiological assays and multiparametric morphological analysis identified phenotypes associated with knockdown of 180 ID gene orthologs. Most of these genotype-phenotype associations were novel. For example, we uncovered 16 genes that are required for basal neurotransmission and have not previously been implicated in this process in any system or organism. ID gene orthologs with morphological eye phenotypes, in contrast to genes without phenotypes, are relatively highly expressed in the human nervous system and are enriched for neuronal functions, suggesting that eye phenotyping can distinguish different classes of ID genes. Indeed, grouping genes by Drosophila phenotype uncovered 26 connected functional modules. Novel links between ID genes successfully predicted that MYCN, PIGV and UPF3B regulate synapse development. Drosophila phenotype groups show, in addition to ID, significant phenotypic similarity also in humans, indicating that functional modules are conserved. The combined data indicate that ID disorders, despite their extreme genetic diversity, are caused by disruption of a limited number of highly connected functional modules.

Enhancing biological relevance of a weighted gene co-expression network for functional module identification.

PubMed

Prom-On, Santitham; Chanthaphan, Atthawut; Chan, Jonathan Hoyin; Meechai, Asawin

2011-02-01

Relationships among gene expression levels may be associated with the mechanisms of the disease. While identifying a direct association such as a difference in expression levels between case and control groups links genes to disease mechanisms, uncovering an indirect association in the form of a network structure may help reveal the underlying functional module associated with the disease under scrutiny. This paper presents a method to improve the biological relevance in functional module identification from the gene expression microarray data by enhancing the structure of a weighted gene co-expression network using minimum spanning tree. The enhanced network, which is called a backbone network, contains only the essential structural information to represent the gene co-expression network. The entire backbone network is decoupled into a number of coherent sub-networks, and then the functional modules are reconstructed from these sub-networks to ensure minimum redundancy. The method was tested with a simulated gene expression dataset and case-control expression datasets of autism spectrum disorder and colorectal cancer studies. The results indicate that the proposed method can accurately identify clusters in the simulated dataset, and the functional modules of the backbone network are more biologically relevant than those obtained from the original approach.

Coexpression network analysis identifies transcriptional modules associated with genomic alterations in neuroblastoma.

PubMed

Yang, Liulin; Li, Yun; Wei, Zhi; Chang, Xiao

2018-06-01

Neuroblastoma is a highly complex and heterogeneous cancer in children. Acquired genomic alterations including MYCN amplification, 1p deletion and 11q deletion are important risk factors and biomarkers in neuroblastoma. Here, we performed a co-expression-based gene network analysis to study the intrinsic association between specific genomic changes and transcriptome organization. We identified multiple gene coexpression modules which are recurrent in two independent datasets and associated with functional pathways including nervous system development, cell cycle, immune system process and extracellular matrix/space. Our results also indicated that modules involved in nervous system development and cell cycle are highly associated with MYCN amplification and 1p deletion, while modules responding to immune system process are associated with MYCN amplification only. In summary, this integrated analysis provides novel insights into molecular heterogeneity and pathogenesis of neuroblastoma. This article is part of a Special Issue entitled: Accelerating Precision Medicine through Genetic and Genomic Big Data Analysis edited by Yudong Cai & Tao Huang. Copyright © 2017. Published by Elsevier B.V.

Systems genetics identifies Hp1bp3 as a novel modulator of cognitive aging.

PubMed

Neuner, Sarah M; Garfinkel, Benjamin P; Wilmott, Lynda A; Ignatowska-Jankowska, Bogna M; Citri, Ami; Orly, Joseph; Lu, Lu; Overall, Rupert W; Mulligan, Megan K; Kempermann, Gerd; Williams, Robert W; O'Connell, Kristen M S; Kaczorowski, Catherine C

2016-10-01

An individual's genetic makeup plays an important role in determining susceptibility to cognitive aging. Identifying the specific genes that contribute to cognitive aging may aid in early diagnosis of at-risk patients, as well as identify novel therapeutics targets to treat or prevent development of symptoms. Challenges to identifying these specific genes in human studies include complex genetics, difficulty in controlling environmental factors, and limited access to human brain tissue. Here, we identify Hp1bp3 as a novel modulator of cognitive aging using a genetically diverse population of mice and confirm that HP1BP3 protein levels are significantly reduced in the hippocampi of cognitively impaired elderly humans relative to cognitively intact controls. Deletion of functional Hp1bp3 in mice recapitulates memory deficits characteristic of aged impaired mice and humans, further supporting the idea that Hp1bp3 and associated molecular networks are modulators of cognitive aging. Overall, our results suggest Hp1bp3 may serve as a potential target against cognitive aging and demonstrate the utility of genetically diverse animal models for the study of complex human disease. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Human Intellectual Disability Genes Form Conserved Functional Modules in Drosophila

PubMed Central

Oortveld, Merel A. W.; Keerthikumar, Shivakumar; Oti, Martin; Nijhof, Bonnie; Fernandes, Ana Clara; Kochinke, Korinna; Castells-Nobau, Anna; van Engelen, Eva; Ellenkamp, Thijs; Eshuis, Lilian; Galy, Anne; van Bokhoven, Hans; Habermann, Bianca; Brunner, Han G.; Zweier, Christiane; Verstreken, Patrik; Huynen, Martijn A.; Schenck, Annette

2013-01-01

Intellectual Disability (ID) disorders, defined by an IQ below 70, are genetically and phenotypically highly heterogeneous. Identification of common molecular pathways underlying these disorders is crucial for understanding the molecular basis of cognition and for the development of therapeutic intervention strategies. To systematically establish their functional connectivity, we used transgenic RNAi to target 270 ID gene orthologs in the Drosophila eye. Assessment of neuronal function in behavioral and electrophysiological assays and multiparametric morphological analysis identified phenotypes associated with knockdown of 180 ID gene orthologs. Most of these genotype-phenotype associations were novel. For example, we uncovered 16 genes that are required for basal neurotransmission and have not previously been implicated in this process in any system or organism. ID gene orthologs with morphological eye phenotypes, in contrast to genes without phenotypes, are relatively highly expressed in the human nervous system and are enriched for neuronal functions, suggesting that eye phenotyping can distinguish different classes of ID genes. Indeed, grouping genes by Drosophila phenotype uncovered 26 connected functional modules. Novel links between ID genes successfully predicted that MYCN, PIGV and UPF3B regulate synapse development. Drosophila phenotype groups show, in addition to ID, significant phenotypic similarity also in humans, indicating that functional modules are conserved. The combined data indicate that ID disorders, despite their extreme genetic diversity, are caused by disruption of a limited number of highly connected functional modules. PMID:24204314

An NPARC Turbulence Module with Wall Functions

NASA Technical Reports Server (NTRS)

Zhu, J.; Shih, T.-H.

1997-01-01

The turbulence module recently developed for the NPARC code has been extended to include wall functions. The Van Driest transformation is used so that the wall functions can be applied to both incompressible and compressible flows. The module is equipped with three two-equation K-epsilon turbulence models: Chien, Shih-Lumley and CMOTR models. Details of the wall functions as well as their numerical implementation are reported. It is shown that the inappropriate artificial viscosity in the near-wall region has a big influence on the solution of the wall function approach. A simple way to eliminate this influence is proposed, which gives satisfactory results during the code validation. The module can be easily linked to the NPARC code for practical applications.

A Walsh Function Module Users' Manual

NASA Technical Reports Server (NTRS)

Gnoffo, Peter A.

2014-01-01

The solution of partial differential equations (PDEs) with Walsh functions offers new opportunities to simulate many challenging problems in mathematical physics. The approach was developed to better simulate hypersonic flows with shocks on unstructured grids. It is unique in that integrals and derivatives are computed using simple matrix multiplication of series representations of functions without the need for divided differences. The product of any two Walsh functions is another Walsh function - a feature that radically changes an algorithm for solving PDEs. A FORTRAN module for supporting Walsh function simulations is documented. A FORTRAN code is also documented with options for solving time-dependent problems: an advection equation, a Burgers equation, and a Riemann problem. The sample problems demonstrate the usage of the Walsh function module including such features as operator overloading, Fast Walsh Transforms in multi-dimensions, and a Fast Walsh reciprocal.

Characterization of drug-induced transcriptional modules: towards drug repositioning and functional understanding

PubMed Central

Iskar, Murat; Zeller, Georg; Blattmann, Peter; Campillos, Monica; Kuhn, Michael; Kaminska, Katarzyna H; Runz, Heiko; Gavin, Anne-Claude; Pepperkok, Rainer; van Noort, Vera; Bork, Peer

2013-01-01

In pharmacology, it is crucial to understand the complex biological responses that drugs elicit in the human organism and how well they can be inferred from model organisms. We therefore identified a large set of drug-induced transcriptional modules from genome-wide microarray data of drug-treated human cell lines and rat liver, and first characterized their conservation. Over 70% of these modules were common for multiple cell lines and 15% were conserved between the human in vitro and the rat in vivo system. We then illustrate the utility of conserved and cell-type-specific drug-induced modules by predicting and experimentally validating (i) gene functions, e.g., 10 novel regulators of cellular cholesterol homeostasis and (ii) new mechanisms of action for existing drugs, thereby providing a starting point for drug repositioning, e.g., novel cell cycle inhibitors and new modulators of α-adrenergic receptor, peroxisome proliferator-activated receptor and estrogen receptor. Taken together, the identified modules reveal the conservation of transcriptional responses towards drugs across cell types and organisms, and improve our understanding of both the molecular basis of drug action and human biology. PMID:23632384

Multi-functional Electric Module for a Vehicle

NASA Technical Reports Server (NTRS)

Waligora, Thomas M. (Inventor); Fraser-Chanpong, Nathan (Inventor); Figuered, Joshua M. (Inventor); Reed, Ryan (Inventor); Akinyode, Akinjide Akinniyi (Inventor); Spain, Ivan (Inventor); Dawson, Andrew D. (Inventor); Herrera, Eduardo (Inventor); Markee, Mason M. (Inventor); Bluethmann, William J. (Inventor)

2015-01-01

A multi-functional electric module (eModule) is provided for a vehicle having a chassis, a master controller, and a drive wheel having a propulsion-braking module. The eModule includes a steering control assembly, mounting bracket, propulsion control assembly, brake controller, housing, and control arm. The steering control assembly includes a steering motor controlled by steering controllers in response to control signals from the master controller. A mounting feature of the bracket connects to the chassis. The propulsion control assembly and brake controller are in communication with the propulsion-braking module. The control arm connects to the lower portion and contains elements of a suspension system, with the control arm being connectable to the drive wheel via a wheel input/output block. The controllers are responsive to the master controller to control a respective steering, propulsion, and braking function. The steering motor may have a dual-wound stator with windings controlled via the respective steering controllers.

Function Specifications for the A-7E Function Driver Module.

DTIC Science & Technology

1981-11-27

Computer interface specifications (HEN181). The services and values provided by the Shared Services module are accurately described in the Shared Services Module...None$) FD.7.l.3.1 FD.7.1.7.1 5517a FD.App3 -5 Appendix 3 Event List (Alphabetical) Events Signalled by other Shared Services submodules @F( ABSCI+ip az...the Shared Services and Device Interface modules. Al; Answer this question for each table that appears in the function driver specification being

Extending double modulation: combinatorial rules for identifying the modulations necessary for determining elasticities in metabolic pathways.

PubMed

Giersch, C; Cornish-Bowden, A

1996-10-07

The double modulation method for determining the elasticities of pathway enzymes, originally devised by Kacser & Burns (Biochem. Soc. Trans. 7, 1149-1160, 1979), is extended to pathways of complex topological structure, including branching and feedback loops. An explicit system of linear equations for the unknown elasticities is derived. The constraints imposed on this linear system imply that modulations of more than one enzyme are not necessarily independent. Simple combinatorial rules are described for identifying without using any algebra the set of independent modulations that allow the determination of the elasticities of any enzyme. By repeated application, the minimum numbers of modulations required to determine the elasticities of all enzymes of a given pathway can be determined. The procedure is illustrated with numerous examples.

Morphological integration of anatomical, developmental, and functional postcranial modules in the crab-eating macaque (Macaca fascicularis).

PubMed

Conaway, Mark A; Schroeder, Lauren; von Cramon-Taubadel, Noreen

2018-03-22

Integration and modularity reflect the coordinated action of past evolutionary processes and, in turn, constrain or facilitate phenotypic evolvability. Here, we analyze magnitudes of integration in the macaque postcranium to test whether 20 a priori defined modules are (1) more tightly integrated than random sets of postcranial traits, and (2) are differentiated based on mode of definition, with developmental modules expected to be more integrated than functional or anatomical modules. The 3D morphometric data collected for eight limb and girdle bones for 60 macaques were collated into anatomical, developmental, and functional modules. A resampling technique was used to create random samples of integration values for each module for statistical comparison. Our results found that not all a priori defined modules were more strongly integrated than random samples of postcranial traits and that specific types of modules did not present consistent patterns of integration. Rather, girdle and joint modules were consistently less integrated than limb modules, and forelimb elements were less integrated than hindlimbs. The results suggest that morphometrically complex modules tend to be less integrated than simple limb bones, irrespective of the number of available traits. However, differences in integration of the fore- and hindlimb more likely reflects the multitude of locomotory, feeding, and social functions involved. It remains to be tested whether patterns of integration identified here are primate universals, and to what extent they vary depending on phylogenetic or functional factors. © 2018 Wiley Periodicals, Inc.

Lactoferrin modulation of BCG-infected dendritic cell functions

PubMed Central

Hwang, Shen-An

2009-01-01

Lactoferrin, an 80-kDa iron-binding protein with immune modulating properties, is a unique adjuvant component able to enhance efficacy of the existing Mycobacterium bovis Bacillus Calmette Guerin (BCG) vaccine to protect against murine model of tuberculosis. Although identified as having effects on macrophage presentation events, lactoferrin's capability to modulate dendritic cells (DCs) function when loaded with BCG antigens has not been previously recognized. In this study, the potential of lactoferrin to modulate surface expression of MHC II, CD80, CD86 and CD40 from bone marrow-derived dendritic cells (BMDCs) was examined. Generally, lactoferrin decreased pro-inflammatory cytokines [tumor necrosis factor (TNF)-α, IL-6 and IL-12p40] and chemokines [macrophage inflammatory protein (MIP)-1α and MIP-2] and increased regulatory cytokine, transforming growth factor-β1 and a T-cell chemotatic factor, monocyte chemotactic protein-1, from uninfected or BCG-infected BMDCs. Culturing BCG-infected BMDCs with lactoferrin also enhanced their ability to respond to IFN-γ activation through up-regulation of maturation markers: MHC I, MHC II and the ratio of CD86:CD80 surface expression. Furthermore, lactoferrin-exposed BCG-infected DCs increased stimulation of BCG-specific CD3+CD4+ splenocytes, as defined by increasing IFN-γ production. Finally, BCG-/lactoferrin-vaccinated mice possessed an increased pool of BCG antigen-specific IFN-γ producing CD3+CD4+CD62L− splenocytes. These studies suggest a mechanism in which lactoferrin may exert adjuvant activity by enhancing DC function to promote generation of antigen-specific T cells. PMID:19692539

Functional Module Search in Protein Networks based on Semantic Similarity Improves the Analysis of Proteomics Data*

PubMed Central

Boyanova, Desislava; Nilla, Santosh; Klau, Gunnar W.; Dandekar, Thomas; Müller, Tobias; Dittrich, Marcus

2014-01-01

The continuously evolving field of proteomics produces increasing amounts of data while improving the quality of protein identifications. Albeit quantitative measurements are becoming more popular, many proteomic studies are still based on non-quantitative methods for protein identification. These studies result in potentially large sets of identified proteins, where the biological interpretation of proteins can be challenging. Systems biology develops innovative network-based methods, which allow an integrated analysis of these data. Here we present a novel approach, which combines prior knowledge of protein-protein interactions (PPI) with proteomics data using functional similarity measurements of interacting proteins. This integrated network analysis exactly identifies network modules with a maximal consistent functional similarity reflecting biological processes of the investigated cells. We validated our approach on small (H9N2 virus-infected gastric cells) and large (blood constituents) proteomic data sets. Using this novel algorithm, we identified characteristic functional modules in virus-infected cells, comprising key signaling proteins (e.g. the stress-related kinase RAF1) and demonstrate that this method allows a module-based functional characterization of cell types. Analysis of a large proteome data set of blood constituents resulted in clear separation of blood cells according to their developmental origin. A detailed investigation of the T-cell proteome further illustrates how the algorithm partitions large networks into functional subnetworks each representing specific cellular functions. These results demonstrate that the integrated network approach not only allows a detailed analysis of proteome networks but also yields a functional decomposition of complex proteomic data sets and thereby provides deeper insights into the underlying cellular processes of the investigated system. PMID:24807868

Motor imagery learning modulates functional connectivity of multiple brain systems in resting state.

PubMed

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

2014-01-01

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

A translational systems biology approach in both animals and humans identifies a functionally related module of accumbal genes involved in the regulation of reward processing and binge drinking in males.

PubMed

Stacey, David; Lourdusamy, Anbarasu; Ruggeri, Barbara; Maroteaux, Matthieu; Jia, Tianye; Cattrell, Anna; Nymberg, Charlotte; Banaschewski, Tobias; Bhattacharyya, Sohinee; Band, Hamid; Barker, Gareth; Bokde, Arun; Buchel, Christian; Carvalho, Fabiana; Conrod, Patricia; Desrivieres, Sylvane; Easton, Alanna; Fauth-Buehler, Mira; Fernandez-Medarde, Alberto; Flor, Herta; Frouin, Vincent; Gallinat, Jurgen; Garavanh, Hugh; Heinz, Andreas; Ittermann, Bernd; Lathrop, Mark; Lawrence, Claire; Loth, Eva; Mann, Karl; Martinot, Jean-Luc; Nees, Frauke; Paus, Tomas; Pausova, Zdenka; Rietschel, Marcella; Rotter, Andrea; Santos, Eugenio; Smolka, Michael; Sommer, Wolfgang; Mameli, Manuel; Spanagel, Rainer; Girault, Jean-Antoine; Mueller, Christian; Schumann, Gunter

2016-04-01

function in the NAcc. Taken together, our findings indicate that the accumbal M5 module, initially identified as being dysregulated in male Rasgrf2(-/-) mice, is also relevant for human alcohol-related phenotypes potentially through the modulation of reinforcement mechanisms in the NAcc. We therefore propose that the genes comprising this module represent important candidates for further elucidation within the context of alcohol-related phenotypes.

Carrier Modulation Via Waveform Probability Density Function

NASA Technical Reports Server (NTRS)

Williams, Glenn L.

2006-01-01

Beyond the classic modes of carrier modulation by varying amplitude (AM), phase (PM), or frequency (FM), we extend the modulation domain of an analog carrier signal to include a class of general modulations which are distinguished by their probability density function histogram. Separate waveform states are easily created by varying the pdf of the transmitted waveform. Individual waveform states are assignable as proxies for digital one's or zero's. At the receiver, these states are easily detected by accumulating sampled waveform statistics and performing periodic pattern matching, correlation, or statistical filtering. No fundamental physical laws are broken in the detection process. We show how a typical modulation scheme would work in the digital domain and suggest how to build an analog version. We propose that clever variations of the modulating waveform (and thus the histogram) can provide simple steganographic encoding.

Carrier Modulation Via Waveform Probability Density Function

NASA Technical Reports Server (NTRS)

Williams, Glenn L.

2004-01-01

Beyond the classic modes of carrier modulation by varying amplitude (AM), phase (PM), or frequency (FM), we extend the modulation domain of an analog carrier signal to include a class of general modulations which are distinguished by their probability density function histogram. Separate waveform states are easily created by varying the pdf of the transmitted waveform. Individual waveform states are assignable as proxies for digital ONEs or ZEROs. At the receiver, these states are easily detected by accumulating sampled waveform statistics and performing periodic pattern matching, correlation, or statistical filtering. No fundamental natural laws are broken in the detection process. We show how a typical modulation scheme would work in the digital domain and suggest how to build an analog version. We propose that clever variations of the modulating waveform (and thus the histogram) can provide simple steganographic encoding.

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

PubMed Central

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

2014-01-01

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

A translational systems biology approach in both animals and humans identifies a functionally related module of accumbal genes involved in the regulation of reward processing and binge drinking in males

PubMed Central

Stacey, David; Lourdusamy, Anbarasu; Ruggeri, Barbara; Maroteaux, Matthieu; Jia, Tianye; Cattrell, Anna; Nymberg, Charlotte; Banaschewski, Tobias; Bhattacharyya, Sohinee; Band, Hamid; Barker, Gareth; Bokde, Arun; Buchel, Christian; Carvalho, Fabiana; Conrod, Patricia; Desrivieres, Sylvane; Easton, Alanna; Fauth-Buehler, Mira; Fernandez-Medarde, Alberto; Flor, Herta; Frouin, Vincent; Gallinat, Jurgen; Garavanh, Hugh; Heinz, Andreas; Ittermann, Bernd; Lathrop, Mark; Lawrence, Claire; Loth, Eva; Mann, Karl; Martinot, Jean-Luc; Nees, Frauke; Paus, Tomas; Pausova, Zdenka; Rietschel, Marcella; Rotter, Andrea; Santos, Eugenio; Smolka, Michael; Sommer, Wolfgang; Mameli, Manuel; Spanagel, Rainer; Girault, Jean-Antoine; Mueller, Christian; Schumann, Gunter

2016-01-01

dopamine signalling or by the loss of Rasgrf2 function in the NAcc. Conclusion Taken together, our findings indicate that the accumbal M5 module, initially identified as being dysregulated in male Rasgrf2−/− mice, is also relevant for human alcohol-related phenotypes potentially through the modulation of reinforcement mechanisms in the NAcc. We therefore propose that the genes comprising this module represent important candidates for further elucidation within the context of alcohol-related phenotypes. PMID:26679926

Using scale and feather traits for module construction provides a functional approach to chicken epidermal development.

PubMed

Bao, Weier; Greenwold, Matthew J; Sawyer, Roger H

2017-11-01

Gene co-expression network analysis has been a research method widely used in systematically exploring gene function and interaction. Using the Weighted Gene Co-expression Network Analysis (WGCNA) approach to construct a gene co-expression network using data from a customized 44K microarray transcriptome of chicken epidermal embryogenesis, we have identified two distinct modules that are highly correlated with scale or feather development traits. Signaling pathways related to feather development were enriched in the traditional KEGG pathway analysis and functional terms relating specifically to embryonic epidermal development were also enriched in the Gene Ontology analysis. Significant enrichment annotations were discovered from customized enrichment tools such as Modular Single-Set Enrichment Test (MSET) and Medical Subject Headings (MeSH). Hub genes in both trait-correlated modules showed strong specific functional enrichment toward epidermal development. Also, regulatory elements, such as transcription factors and miRNAs, were targeted in the significant enrichment result. This work highlights the advantage of this methodology for functional prediction of genes not previously associated with scale- and feather trait-related modules.

A Multiplexed High-Content Screening Approach Using the Chromobody Technology to Identify Cell Cycle Modulators in Living Cells.

PubMed

Schorpp, Kenji; Rothenaigner, Ina; Maier, Julia; Traenkle, Bjoern; Rothbauer, Ulrich; Hadian, Kamyar

2016-10-01

Many screening hits show relatively poor quality regarding later efficacy and safety. Therefore, small-molecule screening efforts shift toward high-content analysis providing more detailed information. Here, we describe a novel screening approach to identify cell cycle modulators with low toxicity by combining the Cell Cycle Chromobody (CCC) technology with the CytoTox-Glo (CTG) cytotoxicity assay. The CCC technology employs intracellularly functional single-domain antibodies coupled to a fluorescent protein (chromobodies) to visualize the cell cycle-dependent redistribution of the proliferating cell nuclear antigen (PCNA) in living cells. This image-based cell cycle analysis was combined with determination of dead-cell protease activity in cell culture supernatants by the CTG assay. We adopted this multiplex approach to high-throughput format and screened 960 Food and Drug Administration (FDA)-approved drugs. By this, we identified nontoxic compounds, which modulate different cell cycle stages, and validated selected hits in diverse cell lines stably expressing CCC. Additionally, we independently validated these hits by flow cytometry as the current state-of-the-art format for cell cycle analysis. This study demonstrates that CCC imaging is a versatile high-content screening approach to identify cell cycle modulators, which can be multiplexed with cytotoxicity assays for early elimination of toxic compounds during screening. © 2016 Society for Laboratory Automation and Screening.

Gene Network Construction from Microarray Data Identifies a Key Network Module and Several Candidate Hub Genes in Age-Associated Spatial Learning Impairment

PubMed Central

Uddin, Raihan; Singh, Shiva M.

2017-01-01

As humans age many suffer from a decrease in normal brain functions including spatial learning impairments. This study aimed to better understand the molecular mechanisms in age-associated spatial learning impairment (ASLI). We used a mathematical modeling approach implemented in Weighted Gene Co-expression Network Analysis (WGCNA) to create and compare gene network models of young (learning unimpaired) and aged (predominantly learning impaired) brains from a set of exploratory datasets in rats in the context of ASLI. The major goal was to overcome some of the limitations previously observed in the traditional meta- and pathway analysis using these data, and identify novel ASLI related genes and their networks based on co-expression relationship of genes. This analysis identified a set of network modules in the young, each of which is highly enriched with genes functioning in broad but distinct GO functional categories or biological pathways. Interestingly, the analysis pointed to a single module that was highly enriched with genes functioning in “learning and memory” related functions and pathways. Subsequent differential network analysis of this “learning and memory” module in the aged (predominantly learning impaired) rats compared to the young learning unimpaired rats allowed us to identify a set of novel ASLI candidate hub genes. Some of these genes show significant repeatability in networks generated from independent young and aged validation datasets. These hub genes are highly co-expressed with other genes in the network, which not only show differential expression but also differential co-expression and differential connectivity across age and learning impairment. The known function of these hub genes indicate that they play key roles in critical pathways, including kinase and phosphatase signaling, in functions related to various ion channels, and in maintaining neuronal integrity relating to synaptic plasticity and memory formation. Taken

Gene Network Construction from Microarray Data Identifies a Key Network Module and Several Candidate Hub Genes in Age-Associated Spatial Learning Impairment.

PubMed

Uddin, Raihan; Singh, Shiva M

2017-01-01

As humans age many suffer from a decrease in normal brain functions including spatial learning impairments. This study aimed to better understand the molecular mechanisms in age-associated spatial learning impairment (ASLI). We used a mathematical modeling approach implemented in Weighted Gene Co-expression Network Analysis (WGCNA) to create and compare gene network models of young (learning unimpaired) and aged (predominantly learning impaired) brains from a set of exploratory datasets in rats in the context of ASLI. The major goal was to overcome some of the limitations previously observed in the traditional meta- and pathway analysis using these data, and identify novel ASLI related genes and their networks based on co-expression relationship of genes. This analysis identified a set of network modules in the young, each of which is highly enriched with genes functioning in broad but distinct GO functional categories or biological pathways. Interestingly, the analysis pointed to a single module that was highly enriched with genes functioning in "learning and memory" related functions and pathways. Subsequent differential network analysis of this "learning and memory" module in the aged (predominantly learning impaired) rats compared to the young learning unimpaired rats allowed us to identify a set of novel ASLI candidate hub genes. Some of these genes show significant repeatability in networks generated from independent young and aged validation datasets. These hub genes are highly co-expressed with other genes in the network, which not only show differential expression but also differential co-expression and differential connectivity across age and learning impairment. The known function of these hub genes indicate that they play key roles in critical pathways, including kinase and phosphatase signaling, in functions related to various ion channels, and in maintaining neuronal integrity relating to synaptic plasticity and memory formation. Taken together, they

On Functional Module Detection in Metabolic Networks

PubMed Central

Koch, Ina; Ackermann, Jörg

2013-01-01

Functional modules of metabolic networks are essential for understanding the metabolism of an organism as a whole. With the vast amount of experimental data and the construction of complex and large-scale, often genome-wide, models, the computer-aided identification of functional modules becomes more and more important. Since steady states play a key role in biology, many methods have been developed in that context, for example, elementary flux modes, extreme pathways, transition invariants and place invariants. Metabolic networks can be studied also from the point of view of graph theory, and algorithms for graph decomposition have been applied for the identification of functional modules. A prominent and currently intensively discussed field of methods in graph theory addresses the Q-modularity. In this paper, we recall known concepts of module detection based on the steady-state assumption, focusing on transition-invariants (elementary modes) and their computation as minimal solutions of systems of Diophantine equations. We present the Fourier-Motzkin algorithm in detail. Afterwards, we introduce the Q-modularity as an example for a useful non-steady-state method and its application to metabolic networks. To illustrate and discuss the concepts of invariants and Q-modularity, we apply a part of the central carbon metabolism in potato tubers (Solanum tuberosum) as running example. The intention of the paper is to give a compact presentation of known steady-state concepts from a graph-theoretical viewpoint in the context of network decomposition and reduction and to introduce the application of Q-modularity to metabolic Petri net models. PMID:24958145

Identification of functional modules using network topology and high-throughput data.

PubMed

Ulitsky, Igor; Shamir, Ron

2007-01-26

With the advent of systems biology, biological knowledge is often represented today by networks. These include regulatory and metabolic networks, protein-protein interaction networks, and many others. At the same time, high-throughput genomics and proteomics techniques generate very large data sets, which require sophisticated computational analysis. Usually, separate and different analysis methodologies are applied to each of the two data types. An integrated investigation of network and high-throughput information together can improve the quality of the analysis by accounting simultaneously for topological network properties alongside intrinsic features of the high-throughput data. We describe a novel algorithmic framework for this challenge. We first transform the high-throughput data into similarity values, (e.g., by computing pairwise similarity of gene expression patterns from microarray data). Then, given a network of genes or proteins and similarity values between some of them, we seek connected sub-networks (or modules) that manifest high similarity. We develop algorithms for this problem and evaluate their performance on the osmotic shock response network in S. cerevisiae and on the human cell cycle network. We demonstrate that focused, biologically meaningful and relevant functional modules are obtained. In comparison with extant algorithms, our approach has higher sensitivity and higher specificity. We have demonstrated that our method can accurately identify functional modules. Hence, it carries the promise to be highly useful in analysis of high throughput data.

Auditory sensitivity to spectral modulation phase reversal as a function of modulation depth

PubMed Central

Grose, John

2018-01-01

The present study evaluated auditory sensitivity to spectral modulation by determining the modulation depth required to detect modulation phase reversal. This approach may be preferable to spectral modulation detection with a spectrally flat standard, since listeners appear unable to perform the task based on the detection of temporal modulation. While phase reversal thresholds are often evaluated by holding modulation depth constant and adjusting modulation rate, holding rate constant and adjusting modulation depth supports rate-specific assessment of modulation processing. Stimuli were pink noise samples, filtered into seven octave-wide bands (0.125–8 kHz) and spectrally modulated in dB. Experiment 1 measured performance as a function of modulation depth to determine appropriate units for adaptive threshold estimation. Experiment 2 compared thresholds in dB for modulation detection with a flat standard and modulation phase reversal; results supported the idea that temporal cues were available at high rates for the former but not the latter. Experiment 3 evaluated spectral modulation phase reversal thresholds for modulation that was restricted to either one or two neighboring bands. Flanking bands of unmodulated noise had a larger detrimental effect on one-band than two-band targets. Thresholds for high-rate modulation improved with increasing carrier frequency up to 2 kHz, whereas low-rate modulation appeared more consistent across frequency, particularly in the two-band condition. Experiment 4 measured spectral weights for spectral modulation phase reversal detection and found higher weights for bands in the spectral center of the stimulus than for the lowest (0.125 kHz) or highest (8 kHz) band. Experiment 5 compared performance for highly practiced and relatively naïve listeners, and found weak evidence of a larger practice effect at high than low spectral modulation rates. These results provide preliminary data for a task that may provide a better estimate

A Forward Genetic Screen in Zebrafish Identifies the G-Protein-Coupled Receptor CaSR as a Modulator of Sensorimotor Decision Making.

PubMed

Jain, Roshan A; Wolman, Marc A; Marsden, Kurt C; Nelson, Jessica C; Shoenhard, Hannah; Echeverry, Fabio A; Szi, Christina; Bell, Hannah; Skinner, Julianne; Cobbs, Emilia N; Sawada, Keisuke; Zamora, Amy D; Pereda, Alberto E; Granato, Michael

2018-05-07

Animals continuously integrate sensory information and select contextually appropriate responses. Here, we show that zebrafish larvae select a behavioral response to acoustic stimuli from a pre-existing choice repertoire in a context-dependent manner. We demonstrate that this sensorimotor choice is modulated by stimulus quality and history, as well as by neuromodulatory systems-all hallmarks of more complex decision making. Moreover, from a genetic screen coupled with whole-genome sequencing, we identified eight mutants with deficits in this sensorimotor choice, including mutants of the vertebrate-specific G-protein-coupled extracellular calcium-sensing receptor (CaSR), whose function in the nervous system is not well understood. We demonstrate that CaSR promotes sensorimotor decision making acutely through Gα i/o and Gα q/11 signaling, modulated by clathrin-mediated endocytosis. Combined, our results identify the first set of genes critical for behavioral choice modulation in a vertebrate and reveal an unexpected critical role for CaSR in sensorimotor decision making. Copyright © 2018 Elsevier Ltd. All rights reserved.

Membrane proteins bind lipids selectively to modulate their structure and function.

PubMed

Laganowsky, Arthur; Reading, Eamonn; Allison, Timothy M; Ulmschneider, Martin B; Degiacomi, Matteo T; Baldwin, Andrew J; Robinson, Carol V

2014-06-05

Previous studies have established that the folding, structure and function of membrane proteins are influenced by their lipid environments and that lipids can bind to specific sites, for example, in potassium channels. Fundamental questions remain however regarding the extent of membrane protein selectivity towards lipids. Here we report a mass spectrometry approach designed to determine the selectivity of lipid binding to membrane protein complexes. We investigate the mechanosensitive channel of large conductance (MscL) from Mycobacterium tuberculosis and aquaporin Z (AqpZ) and the ammonia channel (AmtB) from Escherichia coli, using ion mobility mass spectrometry (IM-MS), which reports gas-phase collision cross-sections. We demonstrate that folded conformations of membrane protein complexes can exist in the gas phase. By resolving lipid-bound states, we then rank bound lipids on the basis of their ability to resist gas phase unfolding and thereby stabilize membrane protein structure. Lipids bind non-selectively and with high avidity to MscL, all imparting comparable stability; however, the highest-ranking lipid is phosphatidylinositol phosphate, in line with its proposed functional role in mechanosensation. AqpZ is also stabilized by many lipids, with cardiolipin imparting the most significant resistance to unfolding. Subsequently, through functional assays we show that cardiolipin modulates AqpZ function. Similar experiments identify AmtB as being highly selective for phosphatidylglycerol, prompting us to obtain an X-ray structure in this lipid membrane-like environment. The 2.3 Å resolution structure, when compared with others obtained without lipid bound, reveals distinct conformational changes that re-position AmtB residues to interact with the lipid bilayer. Our results demonstrate that resistance to unfolding correlates with specific lipid-binding events, enabling a distinction to be made between lipids that merely bind from those that modulate membrane

Protein complexes and functional modules in molecular networks

NASA Astrophysics Data System (ADS)

Spirin, Victor; Mirny, Leonid A.

2003-10-01

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

GOMA: functional enrichment analysis tool based on GO modules

PubMed Central

Huang, Qiang; Wu, Ling-Yun; Wang, Yong; Zhang, Xiang-Sun

2013-01-01

Analyzing the function of gene sets is a critical step in interpreting the results of high-throughput experiments in systems biology. A variety of enrichment analysis tools have been developed in recent years, but most output a long list of significantly enriched terms that are often redundant, making it difficult to extract the most meaningful functions. In this paper, we present GOMA, a novel enrichment analysis method based on the new concept of enriched functional Gene Ontology (GO) modules. With this method, we systematically revealed functional GO modules, i.e., groups of functionally similar GO terms, via an optimization model and then ranked them by enrichment scores. Our new method simplifies enrichment analysis results by reducing redundancy, thereby preventing inconsistent enrichment results among functionally similar terms and providing more biologically meaningful results. PMID:23237213

Response functions for sine- and square-wave modulations of disparity.

NASA Technical Reports Server (NTRS)

Richards, W.

1972-01-01

Depth sensations cannot be elicited by modulations of disparity that are more rapid than about 6 Hz, regardless of the modulation amplitude. Vergence tracking also fails at similar modulation rates, suggesting that this portion of the oculomotor system is limited by the behavior of disparity detectors. For sinusoidal modulations of disparity between 1/2 to 2 deg of disparity, most depth-response functions exhibit a low-frequency decrease that is not observed with square-wave modulations of disparity.

Modulation of ionotropic glutamate receptor function by vertebrate galectins

PubMed Central

Copits, Bryan A; Vernon, Claire G; Sakai, Ryuichi; Swanson, Geoffrey T

2014-01-01

AMPA and kainate receptors are glutamate-gated ion channels whose function is known to be altered by a variety of plant oligosaccharide-binding proteins, or lectins, but the physiological relevance of this activity has been uncertain because no lectins with analogous allosteric modulatory effects have been identified in animals. We report here that members of the prototype galectin family, which are β-galactoside-binding lectins, exhibit subunit-specific allosteric modulation of desensitization of recombinant homomeric and heteromeric AMPA and kainate receptors. Galectin modulation of GluK2 kainate receptors was dependent upon complex oligosaccharide processing of N-glycosylation sites in the amino-terminal domain and downstream linker region. The sensitivity of GluA4 AMPA receptors to human galectin-1 could be enhanced by supplementation of culture media with uridine and N-acetylglucosamine (GlcNAc), precursors for the hexosamine pathway that supplies UDP-GlcNAc for synthesis of complex oligosaccharides. Neuronal kainate receptors in dorsal root ganglia were sensitive to galectin modulation, whereas AMPA receptors in cultured hippocampal neurons were insensitive, which could be a reflection of differential N-glycan processing or receptor subunit selectivity. Because glycan content of integral proteins can be modified dynamically, we postulate that physiological or pathological conditions in the CNS could arise in which galectins alter excitatory neurotransmission or neuronal excitability through their actions on AMPA or kainate receptors. PMID:24614744

Dynamic Network-Based Relevance Score Reveals Essential Proteins and Functional Modules in Directed Differentiation

PubMed Central

Wu, Chia-Chou; Lin, Che

2015-01-01

The induction of stem cells toward a desired differentiation direction is required for the advancement of stem cell-based therapies. Despite successful demonstrations of the control of differentiation direction, the effective use of stem cell-based therapies suffers from a lack of systematic knowledge regarding the mechanisms underlying directed differentiation. Using dynamic modeling and the temporal microarray data of three differentiation stages, three dynamic protein-protein interaction networks were constructed. The interaction difference networks derived from the constructed networks systematically delineated the evolution of interaction variations and the underlying mechanisms. A proposed relevance score identified the essential components in the directed differentiation. Inspection of well-known proteins and functional modules in the directed differentiation showed the plausibility of the proposed relevance score, with the higher scores of several proteins and function modules indicating their essential roles in the directed differentiation. During the differentiation process, the proteins and functional modules with higher relevance scores also became more specific to the neuronal identity. Ultimately, the essential components revealed by the relevance scores may play a role in controlling the direction of differentiation. In addition, these components may serve as a starting point for understanding the systematic mechanisms of directed differentiation and for increasing the efficiency of stem cell-based therapies. PMID:25977693

Overview Article: Identifying transcriptional cis-regulatory modules in animal genomes

PubMed Central

Suryamohan, Kushal; Halfon, Marc S.

2014-01-01

Gene expression is regulated through the activity of transcription factors and chromatin modifying proteins acting on specific DNA sequences, referred to as cis-regulatory elements. These include promoters, located at the transcription initiation sites of genes, and a variety of distal cis-regulatory modules (CRMs), the most common of which are transcriptional enhancers. Because regulated gene expression is fundamental to cell differentiation and acquisition of new cell fates, identifying, characterizing, and understanding the mechanisms of action of CRMs is critical for understanding development. CRM discovery has historically been challenging, as CRMs can be located far from the genes they regulate, have few readily-identifiable sequence characteristics, and for many years were not amenable to high-throughput discovery methods. However, the recent availability of complete genome sequences and the development of next-generation sequencing methods has led to an explosion of both computational and empirical methods for CRM discovery in model and non-model organisms alike. Experimentally, CRMs can be identified through chromatin immunoprecipitation directed against transcription factors or histone post-translational modifications, identification of nucleosome-depleted “open” chromatin regions, or sequencing-based high-throughput functional screening. Computational methods include comparative genomics, clustering of known or predicted transcription factor binding sites, and supervised machine-learning approaches trained on known CRMs. All of these methods have proven effective for CRM discovery, but each has its own considerations and limitations, and each is subject to a greater or lesser number of false-positive identifications. Experimental confirmation of predictions is essential, although shortcomings in current methods suggest that additional means of validation need to be developed. PMID:25704908

Increased Global Interaction Across Functional Brain Modules During Cognitive Emotion Regulation.

PubMed

Brandl, Felix; Mulej Bratec, Satja; Xie, Xiyao; Wohlschläger, Afra M; Riedl, Valentin; Meng, Chun; Sorg, Christian

2017-07-13

Cognitive emotion regulation (CER) enables humans to flexibly modulate their emotions. While local theories of CER neurobiology suggest interactions between specialized local brain circuits underlying CER, e.g., in subparts of amygdala and medial prefrontal cortices (mPFC), global theories hypothesize global interaction increases among larger functional brain modules comprising local circuits. We tested the global CER hypothesis using graph-based whole-brain network analysis of functional MRI data during aversive emotional processing with and without CER. During CER, global between-module interaction across stable functional network modules increased. Global interaction increase was particularly driven by subregions of amygdala and cuneus-nodes of highest nodal participation-that overlapped with CER-specific local activations, and by mPFC and posterior cingulate as relevant connector hubs. Results provide evidence for the global nature of human CER, complementing functional specialization of embedded local brain circuits during successful CER. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

MINE: Module Identification in Networks

PubMed Central

2011-01-01

Background Graphical models of network associations are useful for both visualizing and integrating multiple types of association data. Identifying modules, or groups of functionally related gene products, is an important challenge in analyzing biological networks. However, existing tools to identify modules are insufficient when applied to dense networks of experimentally derived interaction data. To address this problem, we have developed an agglomerative clustering method that is able to identify highly modular sets of gene products within highly interconnected molecular interaction networks. Results MINE outperforms MCODE, CFinder, NEMO, SPICi, and MCL in identifying non-exclusive, high modularity clusters when applied to the C. elegans protein-protein interaction network. The algorithm generally achieves superior geometric accuracy and modularity for annotated functional categories. In comparison with the most closely related algorithm, MCODE, the top clusters identified by MINE are consistently of higher density and MINE is less likely to designate overlapping modules as a single unit. MINE offers a high level of granularity with a small number of adjustable parameters, enabling users to fine-tune cluster results for input networks with differing topological properties. Conclusions MINE was created in response to the challenge of discovering high quality modules of gene products within highly interconnected biological networks. The algorithm allows a high degree of flexibility and user-customisation of results with few adjustable parameters. MINE outperforms several popular clustering algorithms in identifying modules with high modularity and obtains good overall recall and precision of functional annotations in protein-protein interaction networks from both S. cerevisiae and C. elegans. PMID:21605434

Aerodynamic parameter estimation via Fourier modulating function techniques

NASA Technical Reports Server (NTRS)

Pearson, A. E.

1995-01-01

Parameter estimation algorithms are developed in the frequency domain for systems modeled by input/output ordinary differential equations. The approach is based on Shinbrot's method of moment functionals utilizing Fourier based modulating functions. Assuming white measurement noises for linear multivariable system models, an adaptive weighted least squares algorithm is developed which approximates a maximum likelihood estimate and cannot be biased by unknown initial or boundary conditions in the data owing to a special property attending Shinbrot-type modulating functions. Application is made to perturbation equation modeling of the longitudinal and lateral dynamics of a high performance aircraft using flight-test data. Comparative studies are included which demonstrate potential advantages of the algorithm relative to some well established techniques for parameter identification. Deterministic least squares extensions of the approach are made to the frequency transfer function identification problem for linear systems and to the parameter identification problem for a class of nonlinear-time-varying differential system models.

System identification and model reduction using modulating function techniques

NASA Technical Reports Server (NTRS)

Shen, Yan

1993-01-01

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

Monoaminergic Modulation of Motor Cortex Function

PubMed Central

Vitrac, Clément; Benoit-Marand, Marianne

2017-01-01

Elaboration of appropriate responses to behavioral situations rests on the ability of selecting appropriate motor outcomes in accordance to specific environmental inputs. To this end, the primary motor cortex (M1) is a key structure for the control of voluntary movements and motor skills learning. Subcortical loops regulate the activity of the motor cortex and thus contribute to the selection of appropriate motor plans. Monoamines are key mediators of arousal, attention and motivation. Their firing pattern enables a direct encoding of different states thus promoting or repressing the selection of actions adapted to the behavioral context. Monoaminergic modulation of motor systems has been extensively studied in subcortical circuits. Despite evidence of converging projections of multiple neurotransmitters systems in the motor cortex pointing to a direct modulation of local circuits, their contribution to the execution and learning of motor skills is still poorly understood. Monoaminergic dysregulation leads to impaired plasticity and motor function in several neurological and psychiatric conditions, thus it is critical to better understand how monoamines modulate neural activity in the motor cortex. This review aims to provide an update of our current understanding on the monoaminergic modulation of the motor cortex with an emphasis on motor skill learning and execution under physiological conditions. PMID:29062274

A DEK Domain-Containing Protein Modulates Chromatin Structure and Function in Arabidopsis[W][OPEN

PubMed Central

Waidmann, Sascha; Kusenda, Branislav; Mayerhofer, Juliane; Mechtler, Karl; Jonak, Claudia

2014-01-01

Chromatin is a major determinant in the regulation of virtually all DNA-dependent processes. Chromatin architectural proteins interact with nucleosomes to modulate chromatin accessibility and higher-order chromatin structure. The evolutionarily conserved DEK domain-containing protein is implicated in important chromatin-related processes in animals, but little is known about its DNA targets and protein interaction partners. In plants, the role of DEK has remained elusive. In this work, we identified DEK3 as a chromatin-associated protein in Arabidopsis thaliana. DEK3 specifically binds histones H3 and H4. Purification of other proteins associated with nuclear DEK3 also established DNA topoisomerase 1α and proteins of the cohesion complex as in vivo interaction partners. Genome-wide mapping of DEK3 binding sites by chromatin immunoprecipitation followed by deep sequencing revealed enrichment of DEK3 at protein-coding genes throughout the genome. Using DEK3 knockout and overexpressor lines, we show that DEK3 affects nucleosome occupancy and chromatin accessibility and modulates the expression of DEK3 target genes. Furthermore, functional levels of DEK3 are crucial for stress tolerance. Overall, data indicate that DEK3 contributes to modulation of Arabidopsis chromatin structure and function. PMID:25387881

The relative vertex clustering value - a new criterion for the fast discovery of functional modules in protein interaction networks

PubMed Central

2015-01-01

Background Cellular processes are known to be modular and are realized by groups of proteins implicated in common biological functions. Such groups of proteins are called functional modules, and many community detection methods have been devised for their discovery from protein interaction networks (PINs) data. In current agglomerative clustering approaches, vertices with just a very few neighbors are often classified as separate clusters, which does not make sense biologically. Also, a major limitation of agglomerative techniques is that their computational efficiency do not scale well to large PINs. Finally, PIN data obtained from large scale experiments generally contain many false positives, and this makes it hard for agglomerative clustering methods to find the correct clusters, since they are known to be sensitive to noisy data. Results We propose a local similarity premetric, the relative vertex clustering value, as a new criterion allowing to decide when a node can be added to a given node's cluster and which addresses the above three issues. Based on this criterion, we introduce a novel and very fast agglomerative clustering technique, FAC-PIN, for discovering functional modules and protein complexes from a PIN data. Conclusions Our proposed FAC-PIN algorithm is applied to nine PIN data from eight different species including the yeast PIN, and the identified functional modules are validated using Gene Ontology (GO) annotations from DAVID Bioinformatics Resources. Identified protein complexes are also validated using experimentally verified complexes. Computational results show that FAC-PIN can discover functional modules or protein complexes from PINs more accurately and more efficiently than HC-PIN and CNM, the current state-of-the-art approaches for clustering PINs in an agglomerative manner. PMID:25734691

Efficient and accurate Greedy Search Methods for mining functional modules in protein interaction networks.

PubMed

He, Jieyue; Li, Chaojun; Ye, Baoliu; Zhong, Wei

2012-06-25

Most computational algorithms mainly focus on detecting highly connected subgraphs in PPI networks as protein complexes but ignore their inherent organization. Furthermore, many of these algorithms are computationally expensive. However, recent analysis indicates that experimentally detected protein complexes generally contain Core/attachment structures. In this paper, a Greedy Search Method based on Core-Attachment structure (GSM-CA) is proposed. The GSM-CA method detects densely connected regions in large protein-protein interaction networks based on the edge weight and two criteria for determining core nodes and attachment nodes. The GSM-CA method improves the prediction accuracy compared to other similar module detection approaches, however it is computationally expensive. Many module detection approaches are based on the traditional hierarchical methods, which is also computationally inefficient because the hierarchical tree structure produced by these approaches cannot provide adequate information to identify whether a network belongs to a module structure or not. In order to speed up the computational process, the Greedy Search Method based on Fast Clustering (GSM-FC) is proposed in this work. The edge weight based GSM-FC method uses a greedy procedure to traverse all edges just once to separate the network into the suitable set of modules. The proposed methods are applied to the protein interaction network of S. cerevisiae. Experimental results indicate that many significant functional modules are detected, most of which match the known complexes. Results also demonstrate that the GSM-FC algorithm is faster and more accurate as compared to other competing algorithms. Based on the new edge weight definition, the proposed algorithm takes advantages of the greedy search procedure to separate the network into the suitable set of modules. Experimental analysis shows that the identified modules are statistically significant. The algorithm can reduce the

Modulation of ionotropic glutamate receptor function by vertebrate galectins.

PubMed

Copits, Bryan A; Vernon, Claire G; Sakai, Ryuichi; Swanson, Geoffrey T

2014-05-15

AMPA and kainate receptors are glutamate-gated ion channels whose function is known to be altered by a variety of plant oligosaccharide-binding proteins, or lectins, but the physiological relevance of this activity has been uncertain because no lectins with analogous allosteric modulatory effects have been identified in animals. We report here that members of the prototype galectin family, which are β-galactoside-binding lectins, exhibit subunit-specific allosteric modulation of desensitization of recombinant homomeric and heteromeric AMPA and kainate receptors. Galectin modulation of GluK2 kainate receptors was dependent upon complex oligosaccharide processing of N-glycosylation sites in the amino-terminal domain and downstream linker region. The sensitivity of GluA4 AMPA receptors to human galectin-1 could be enhanced by supplementation of culture media with uridine and N-acetylglucosamine (GlcNAc), precursors for the hexosamine pathway that supplies UDP-GlcNAc for synthesis of complex oligosaccharides. Neuronal kainate receptors in dorsal root ganglia were sensitive to galectin modulation, whereas AMPA receptors in cultured hippocampal neurons were insensitive, which could be a reflection of differential N-glycan processing or receptor subunit selectivity. Because glycan content of integral proteins can be modified dynamically, we postulate that physiological or pathological conditions in the CNS could arise in which galectins alter excitatory neurotransmission or neuronal excitability through their actions on AMPA or kainate receptors. © 2014 The Authors. The Journal of Physiology © 2014 The Physiological Society.

Thin-Film Module Reverse-Bias Breakdown Sites Identified by Thermal Imaging

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

Johnston, Steven; Sulas, Dana; Guthrey, Harvey L

Thin-film module sections are stressed under reverse bias to simulate partial shading conditions. Such stresses can cause permanent damage in the form of 'wormlike' defects due to thermal runaway. When large reverse biases with limited current are applied to the cells, dark lock-in thermography (DLIT) can detect where spatially-localized breakdown initiates before thermal runaway leads to permanent damage. Predicted breakdown defect sites have been identified in both CIGS and CdTe modules using DLIT. These defects include small pinholes, craters, or voids in the absorber layer of the film that lead to built-in areas of weakness where high current densities maymore » cause thermal damage in a partial-shading event.« less

Functional Evolution of a cis-Regulatory Module

PubMed Central

Palsson, Arnar; Alekseeva, Elena; Bergman, Casey M; Nathan, Janaki; Kreitman, Martin

2005-01-01

Lack of knowledge about how regulatory regions evolve in relation to their structure–function may limit the utility of comparative sequence analysis in deciphering cis-regulatory sequences. To address this we applied reverse genetics to carry out a functional genetic complementation analysis of a eukaryotic cis-regulatory module—the even-skipped stripe 2 enhancer—from four Drosophila species. The evolution of this enhancer is non-clock-like, with important functional differences between closely related species and functional convergence between distantly related species. Functional divergence is attributable to differences in activation levels rather than spatiotemporal control of gene expression. Our findings have implications for understanding enhancer structure–function, mechanisms of speciation and computational identification of regulatory modules. PMID:15757364

Methylphenidate Modulates Functional Network Connectivity to Enhance Attention

PubMed Central

Zhang, Sheng; Hsu, Wei-Ting; Scheinost, Dustin; Finn, Emily S.; Shen, Xilin; Constable, R. Todd; Li, Chiang-Shan R.; Chun, Marvin M.

2016-01-01

Recent work has demonstrated that human whole-brain functional connectivity patterns measured with fMRI contain information about cognitive abilities, including sustained attention. To derive behavioral predictions from connectivity patterns, our group developed a connectome-based predictive modeling (CPM) approach (Finn et al., 2015; Rosenberg et al., 2016). Previously using CPM, we defined a high-attention network, comprising connections positively correlated with performance on a sustained attention task, and a low-attention network, comprising connections negatively correlated with performance. Validating the networks as generalizable biomarkers of attention, models based on network strength at rest predicted attention-deficit/hyperactivity disorder (ADHD) symptoms in an independent group of individuals (Rosenberg et al., 2016). To investigate whether these networks play a causal role in attention, here we examined their strength in healthy adults given methylphenidate (Ritalin), a common ADHD treatment, compared with unmedicated controls. As predicted, individuals given methylphenidate showed patterns of connectivity associated with better sustained attention: higher high-attention and lower low-attention network strength than controls. There was significant overlap between the high-attention network and a network with greater strength in the methylphenidate group, and between the low-attention network and a network with greater strength in the control group. Network strength also predicted behavior on a stop-signal task, such that participants with higher go response rates showed higher high-attention and lower low-attention network strength. These results suggest that methylphenidate acts by modulating functional brain networks related to sustained attention, and that changing whole-brain connectivity patterns may help improve attention. SIGNIFICANCE STATEMENT Recent work identified a promising neuromarker of sustained attention based on whole

Methylphenidate Modulates Functional Network Connectivity to Enhance Attention.

PubMed

Rosenberg, Monica D; Zhang, Sheng; Hsu, Wei-Ting; Scheinost, Dustin; Finn, Emily S; Shen, Xilin; Constable, R Todd; Li, Chiang-Shan R; Chun, Marvin M

2016-09-14

Recent work has demonstrated that human whole-brain functional connectivity patterns measured with fMRI contain information about cognitive abilities, including sustained attention. To derive behavioral predictions from connectivity patterns, our group developed a connectome-based predictive modeling (CPM) approach (Finn et al., 2015; Rosenberg et al., 2016). Previously using CPM, we defined a high-attention network, comprising connections positively correlated with performance on a sustained attention task, and a low-attention network, comprising connections negatively correlated with performance. Validating the networks as generalizable biomarkers of attention, models based on network strength at rest predicted attention-deficit/hyperactivity disorder (ADHD) symptoms in an independent group of individuals (Rosenberg et al., 2016). To investigate whether these networks play a causal role in attention, here we examined their strength in healthy adults given methylphenidate (Ritalin), a common ADHD treatment, compared with unmedicated controls. As predicted, individuals given methylphenidate showed patterns of connectivity associated with better sustained attention: higher high-attention and lower low-attention network strength than controls. There was significant overlap between the high-attention network and a network with greater strength in the methylphenidate group, and between the low-attention network and a network with greater strength in the control group. Network strength also predicted behavior on a stop-signal task, such that participants with higher go response rates showed higher high-attention and lower low-attention network strength. These results suggest that methylphenidate acts by modulating functional brain networks related to sustained attention, and that changing whole-brain connectivity patterns may help improve attention. Recent work identified a promising neuromarker of sustained attention based on whole-brain functional connectivity

A conserved BDNF, glutamate- and GABA-enriched gene module related to human depression identified by coexpression meta-analysis and DNA variant genome-wide association studies.

PubMed

Chang, Lun-Ching; Jamain, Stephane; Lin, Chien-Wei; Rujescu, Dan; Tseng, George C; Sibille, Etienne

2014-01-01

Large scale gene expression (transcriptome) analysis and genome-wide association studies (GWAS) for single nucleotide polymorphisms have generated a considerable amount of gene- and disease-related information, but heterogeneity and various sources of noise have limited the discovery of disease mechanisms. As systematic dataset integration is becoming essential, we developed methods and performed meta-clustering of gene coexpression links in 11 transcriptome studies from postmortem brains of human subjects with major depressive disorder (MDD) and non-psychiatric control subjects. We next sought enrichment in the top 50 meta-analyzed coexpression modules for genes otherwise identified by GWAS for various sets of disorders. One coexpression module of 88 genes was consistently and significantly associated with GWAS for MDD, other neuropsychiatric disorders and brain functions, and for medical illnesses with elevated clinical risk of depression, but not for other diseases. In support of the superior discriminative power of this novel approach, we observed no significant enrichment for GWAS-related genes in coexpression modules extracted from single studies or in meta-modules using gene expression data from non-psychiatric control subjects. Genes in the identified module encode proteins implicated in neuronal signaling and structure, including glutamate metabotropic receptors (GRM1, GRM7), GABA receptors (GABRA2, GABRA4), and neurotrophic and development-related proteins [BDNF, reelin (RELN), Ephrin receptors (EPHA3, EPHA5)]. These results are consistent with the current understanding of molecular mechanisms of MDD and provide a set of putative interacting molecular partners, potentially reflecting components of a functional module across cells and biological pathways that are synchronously recruited in MDD, other brain disorders and MDD-related illnesses. Collectively, this study demonstrates the importance of integrating transcriptome data, gene coexpression modules

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

NASA Technical Reports Server (NTRS)

Stocklin, F.

1973-01-01

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

Screening with an NMNAT2-MSD platform identifies small molecules that modulate NMNAT2 levels in cortical neurons.

PubMed

Ali, Yousuf O; Bradley, Gillian; Lu, Hui-Chen

2017-03-07

Nicotinamide mononucleotide adenylyl transferase 2 (NMNAT2) is a key neuronal maintenance factor and provides potent neuroprotection in numerous preclinical models of neurological disorders. NMNAT2 is significantly reduced in Alzheimer's, Huntington's, Parkinson's diseases. Here we developed a Meso Scale Discovery (MSD)-based screening platform to quantify endogenous NMNAT2 in cortical neurons. The high sensitivity and large dynamic range of this NMNAT2-MSD platform allowed us to screen the Sigma LOPAC library consisting of 1280 compounds. This library had a 2.89% hit rate, with 24 NMNAT2 positive and 13 negative modulators identified. Western analysis was conducted to validate and determine the dose-dependency of identified modulators. Caffeine, one identified NMNAT2 positive-modulator, when systemically administered restored NMNAT2 expression in rTg4510 tauopathy mice to normal levels. We confirmed in a cell culture model that four selected positive-modulators exerted NMNAT2-specific neuroprotection against vincristine-induced cell death while four selected NMNAT2 negative modulators reduced neuronal viability in an NMNAT2-dependent manner. Many of the identified NMNAT2 positive modulators are predicted to increase cAMP concentration, suggesting that neuronal NMNAT2 levels are tightly regulated by cAMP signaling. Taken together, our findings indicate that the NMNAT2-MSD platform provides a sensitive phenotypic screen to detect NMNAT2 in neurons.

Screening with an NMNAT2-MSD platform identifies small molecules that modulate NMNAT2 levels in cortical neurons

PubMed Central

Ali, Yousuf O.; Bradley, Gillian; Lu, Hui-Chen

2017-01-01

Nicotinamide mononucleotide adenylyl transferase 2 (NMNAT2) is a key neuronal maintenance factor and provides potent neuroprotection in numerous preclinical models of neurological disorders. NMNAT2 is significantly reduced in Alzheimer’s, Huntington’s, Parkinson’s diseases. Here we developed a Meso Scale Discovery (MSD)-based screening platform to quantify endogenous NMNAT2 in cortical neurons. The high sensitivity and large dynamic range of this NMNAT2-MSD platform allowed us to screen the Sigma LOPAC library consisting of 1280 compounds. This library had a 2.89% hit rate, with 24 NMNAT2 positive and 13 negative modulators identified. Western analysis was conducted to validate and determine the dose-dependency of identified modulators. Caffeine, one identified NMNAT2 positive-modulator, when systemically administered restored NMNAT2 expression in rTg4510 tauopathy mice to normal levels. We confirmed in a cell culture model that four selected positive-modulators exerted NMNAT2-specific neuroprotection against vincristine-induced cell death while four selected NMNAT2 negative modulators reduced neuronal viability in an NMNAT2-dependent manner. Many of the identified NMNAT2 positive modulators are predicted to increase cAMP concentration, suggesting that neuronal NMNAT2 levels are tightly regulated by cAMP signaling. Taken together, our findings indicate that the NMNAT2-MSD platform provides a sensitive phenotypic screen to detect NMNAT2 in neurons. PMID:28266613

Tracking the Reorganization of Module Structure in Time-Varying Weighted Brain Functional Connectivity Networks.

PubMed

Schmidt, Christoph; Piper, Diana; Pester, Britta; Mierau, Andreas; Witte, Herbert

2018-05-01

Identification of module structure in brain functional networks is a promising way to obtain novel insights into neural information processing, as modules correspond to delineated brain regions in which interactions are strongly increased. Tracking of network modules in time-varying brain functional networks is not yet commonly considered in neuroscience despite its potential for gaining an understanding of the time evolution of functional interaction patterns and associated changing degrees of functional segregation and integration. We introduce a general computational framework for extracting consensus partitions from defined time windows in sequences of weighted directed edge-complete networks and show how the temporal reorganization of the module structure can be tracked and visualized. Part of the framework is a new approach for computing edge weight thresholds for individual networks based on multiobjective optimization of module structure quality criteria as well as an approach for matching modules across time steps. By testing our framework using synthetic network sequences and applying it to brain functional networks computed from electroencephalographic recordings of healthy subjects that were exposed to a major balance perturbation, we demonstrate the framework's potential for gaining meaningful insights into dynamic brain function in the form of evolving network modules. The precise chronology of the neural processing inferred with our framework and its interpretation helps to improve the currently incomplete understanding of the cortical contribution for the compensation of such balance perturbations.

Quantitative High-Throughput Luciferase Screening in Identifying CAR Modulators.

PubMed

Lynch, Caitlin; Zhao, Jinghua; Wang, Hongbing; Xia, Menghang

2016-01-01

The constitutive androstane receptor (CAR, NR1I3) is responsible for the transcription of multiple drug metabolizing enzymes and transporters. There are two possible methods of activation for CAR, direct ligand binding and a ligand-independent method, which makes this a unique nuclear receptor. Both of these mechanisms require translocation of CAR from the cytoplasm into the nucleus. Interestingly, CAR is constitutively active in immortalized cell lines due to the basal nuclear location of this receptor. This creates an important challenge in most in vitro assay models because immortalized cells cannot be used without inhibiting the high basal activity. In this book chapter, we go into detail of how to perform quantitative high-throughput screens to identify hCAR1 modulators through the employment of a double stable cell line. Using this line, we are able to identify activators, as well as deactivators, of the challenging nuclear receptor, CAR.

Intranasal oxytocin modulates neural functional connectivity during human social interaction.

PubMed

Rilling, James K; Chen, Xiangchuan; Chen, Xu; Haroon, Ebrahim

2018-02-10

Oxytocin (OT) modulates social behavior in primates and many other vertebrate species. Studies in non-primate animals have demonstrated that, in addition to influencing activity within individual brain areas, OT influences functional connectivity across networks of areas involved in social behavior. Previously, we used fMRI to image brain function in human subjects during a dyadic social interaction task following administration of either intranasal oxytocin (INOT) or placebo, and analyzed the data with a standard general linear model. Here, we conduct an extensive re-analysis of these data to explore how OT modulates functional connectivity across a neural network that animal studies implicate in social behavior. OT induced widespread increases in functional connectivity in response to positive social interactions among men and widespread decreases in functional connectivity in response to negative social interactions among women. Nucleus basalis of Meynert, an important regulator of selective attention and motivation with a particularly high density of OT receptors, had the largest number of OT-modulated connections. Regions known to receive mesolimbic dopamine projections such as the nucleus accumbens and lateral septum were also hubs for OT effects on functional connectivity. Our results suggest that the neural mechanism by which OT influences primate social cognition may include changes in patterns of activity across neural networks that regulate social behavior in other animals. © 2018 Wiley Periodicals, Inc.

Integrated analysis of microRNA and gene expression profiles reveals a functional regulatory module associated with liver fibrosis.

PubMed

Chen, Wei; Zhao, Wenshan; Yang, Aiting; Xu, Anjian; Wang, Huan; Cong, Min; Liu, Tianhui; Wang, Ping; You, Hong

2017-12-15

Liver fibrosis, characterized with the excessive accumulation of extracellular matrix (ECM) proteins, represents the final common pathway of chronic liver inflammation. Ever-increasing evidence indicates microRNAs (miRNAs) dysregulation has important implications in the different stages of liver fibrosis. However, our knowledge of miRNA-gene regulation details pertaining to such disease remains unclear. The publicly available Gene Expression Omnibus (GEO) datasets of patients suffered from cirrhosis were extracted for integrated analysis. Differentially expressed miRNAs (DEMs) and genes (DEGs) were identified using GEO2R web tool. Putative target gene prediction of DEMs was carried out using the intersection of five major algorithms: DIANA-microT, TargetScan, miRanda, PICTAR5 and miRWalk. Functional miRNA-gene regulatory network (FMGRN) was constructed based on the computational target predictions at the sequence level and the inverse expression relationships between DEMs and DEGs. DAVID web server was selected to perform KEGG pathway enrichment analysis. Functional miRNA-gene regulatory module was generated based on the biological interpretation. Internal connections among genes in liver fibrosis-related module were determined using String database. MiRNA-gene regulatory modules related to liver fibrosis were experimentally verified in recombinant human TGFβ1 stimulated and specific miRNA inhibitor treated LX-2 cells. We totally identified 85 and 923 dysregulated miRNAs and genes in liver cirrhosis biopsy samples compared to their normal controls. All evident miRNA-gene pairs were identified and assembled into FMGRN which consisted of 990 regulations between 51 miRNAs and 275 genes, forming two big sub-networks that were defined as down-network and up-network, respectively. KEGG pathway enrichment analysis revealed that up-network was prominently involved in several KEGG pathways, in which "Focal adhesion", "PI3K-Akt signaling pathway" and "ECM

Cholinergic modulation of hippocampal network function

PubMed Central

Teles-Grilo Ruivo, Leonor M.; Mellor, Jack R.

2013-01-01

Cholinergic septohippocampal projections from the medial septal area to the hippocampus are proposed to have important roles in cognition by modulating properties of the hippocampal network. However, the precise spatial and temporal profile of acetylcholine release in the hippocampus remains unclear making it difficult to define specific roles for cholinergic transmission in hippocampal dependent behaviors. This is partly due to a lack of tools enabling specific intervention in, and recording of, cholinergic transmission. Here, we review the organization of septohippocampal cholinergic projections and hippocampal acetylcholine receptors as well as the role of cholinergic transmission in modulating cellular excitability, synaptic plasticity, and rhythmic network oscillations. We point to a number of open questions that remain unanswered and discuss the potential for recently developed techniques to provide a radical reappraisal of the function of cholinergic inputs to the hippocampus. PMID:23908628

Temporal modulation transfer functions for listeners with real and simulated hearing loss

PubMed Central

Desloge, Joseph G.; Reed, Charlotte M.; Braida, Louis D.; Perez, Zachary D.; Delhorne, Lorraine A.

2011-01-01

A functional simulation of hearing loss was evaluated in its ability to reproduce the temporal modulation transfer functions (TMTFs) for nine listeners with mild to profound sensorineural hearing loss. Each hearing loss was simulated in a group of three age-matched normal-hearing listeners through spectrally shaped masking noise or a combination of masking noise and multiband expansion. TMTFs were measured for both groups of listeners using a broadband noise carrier as a function of modulation rate in the range 2 to 1024 Hz. The TMTFs were fit with a lowpass filter function that provided estimates of overall modulation-depth sensitivity and modulation cutoff frequency. Although the simulations were capable of accurately reproducing the threshold elevations of the hearing-impaired listeners, they were not successful in reproducing the TMTFs. On average, the simulations resulted in lower sensitivity and higher cutoff frequency than were observed in the TMTFs of the hearing-impaired listeners. Discrepancies in performance between listeners with real and simulated hearing loss are possibly related to inaccuracies in the simulation of recruitment. PMID:21682411

Nanotopographical Modulation of Cell Function through Nuclear Deformation

PubMed Central

Wang, Kai; Bruce, Allison; Mezan, Ryan; Kadiyala, Anand; Wang, Liying; Dawson, Jeremy; Rojanasakul, Yon; Yang, Yong

2016-01-01

Although nanotopography has been shown to be a potent modulator of cell behavior, it is unclear how the nanotopographical cue, through focal adhesions, affects the nucleus, eventually influencing cell phenotype and function. Thus, current methods to apply nanotopography to regulate cell behavior are basically empirical. We, herein, engineered nanotopographies of various shapes (gratings and pillars) and dimensions (feature size, spacing and height), and thoroughly investigated cell spreading, focal adhesion organization and nuclear deformation of human primary fibroblasts as the model cell grown on the nanotopographies. We examined the correlation between nuclear deformation and cell functions such as cell proliferation, transfection and extracellular matrix protein type I collagen production. It was found that the nanoscale gratings and pillars could facilitate focal adhesion elongation by providing anchoring sites, and the nanogratings could orient focal adhesions and nuclei along the nanograting direction, depending on not only the feature size but also the spacing of the nanogratings. Compared with continuous nanogratings, discrete nanopillars tended to disrupt the formation and growth of focal adhesions and thus had less profound effects on nuclear deformation. Notably, nuclear volume could be effectively modulated by the height of nanotopography. Further, we demonstrated that cell proliferation, transfection, and type I collagen production were strongly associated with the nuclear volume, indicating that the nucleus serves as a critical mechanosensor for cell regulation. Our study delineated the relationships between focal adhesions, nucleus and cell function and highlighted that the nanotopography could regulate cell phenotype and function by modulating nuclear deformation. This study provides insight into the rational design of nanotopography for new biomaterials and the cell–substrate interfaces of implants and medical devices. PMID:26844365

Cytokine Signaling Modulates Blood-Brain Barrier Function

PubMed Central

Pan, Weihong; Stone, Kirsten P.; Hsuchou, Hung; Manda, Vamshi K.; Zhang, Yan; Kastin, Abba J.

2014-01-01

The blood-brain barrier (BBB) provides a vast interface for cytokines to affect CNS function. The BBB is a target for therapeutic intervention. It is essential, therefore, to understand how cytokines interact with each other at the level of the BBB and how secondary signals modulate CNS functions beyond the BBB. The interactions between cytokines and lipids, however, have not been fully addressed at the level of the BBB. Here, we summarize current understanding of the localization of cytokine receptors and transporters in specific membrane microdomains, particularly lipid rafts, on the luminal (apical) surface of the microvascular endothelial cells composing the BBB. We then illustrate the clinical context of cytokine effects on the BBB by neuroendocrine regulation and amplification of inflammatory signals. Two unusual aspects discussed are signaling crosstalk by different classes of cytokines and genetic regulation of drug efflux transporters. We also introduce a novel area of focus on how cytokines may act through nuclear hormone receptors to modulate efflux transporters and other targets. A specific example discussed is the ATP-binding cassette transporter-1 (ABCA-1) that regulates lipid metabolism. Overall, cytokine signaling at the level of the BBB is a crucial feature of the dynamic regulation that can rapidly change BBB function and affect brain health and disease. PMID:21834767

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

PubMed Central

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

2009-01-01

For normal-hearing listeners, masked speech recognition can improve with the introduction of masker amplitude modulation. The present experiments tested the hypothesis that this masking release is due in part to an interaction between the temporal distribution of cues necessary to perform the task and the probability of those cues temporally coinciding with masker modulation minima. Stimuli were monosyllabic words masked by speech-shaped noise, and masker modulation was introduced via multiplication with a raised sinusoid of 2.5–40 Hz. Tasks included detection, three-alternative forced-choice identification, and open-set identification. Overall, there was more masking release associated with the closed than the open-set tasks. The best rate of modulation also differed as a function of task; whereas low modulation rates were associated with best performance for the detection and three-alternative identification tasks, performance improved with modulation rate in the open-set task. This task-by-rate interaction was also observed when amplitude-modulated speech was presented in a steady masker, and for low- and high-pass filtered speech presented in modulated noise. These results were interpreted as showing that the optimal rate of amplitude modulation depends on the temporal distribution of speech cues and the information required to perform a particular task. PMID:19603883

Plasmid Replicons from Pseudomonas Are Natural Chimeras of Functional, Exchangeable Modules

PubMed Central

Bardaji, Leire; Añorga, Maite; Ruiz-Masó, José A.; del Solar, Gloria; Murillo, Jesús

2017-01-01

Plasmids are a main factor for the evolution of bacteria through horizontal gene exchange, including the dissemination of pathogenicity genes, resistance to antibiotics and degradation of pollutants. Their capacity to duplicate is dependent on their replication determinants (replicon), which also define their bacterial host range and the inability to coexist with related replicons. We characterize a second replicon from the virulence plasmid pPsv48C, from Pseudomonas syringae pv. savastanoi, which appears to be a natural chimera between the gene encoding a newly described replication protein and a putative replication control region present in the widespread family of PFP virulence plasmids. We present extensive evidence of this type of chimerism in structurally similar replicons from species of Pseudomonas, including environmental bacteria as well as plant, animal and human pathogens. We establish that these replicons consist of two functional modules corresponding to putative control (REx-C module) and replication (REx-R module) regions. These modules are functionally separable, do not show specificity for each other, and are dynamically exchanged among replicons of four distinct plasmid families. Only the REx-C module displays strong incompatibility, which is overcome by a few nucleotide changes clustered in a stem-and-loop structure of a putative antisense RNA. Additionally, a REx-C module from pPsv48C conferred replication ability to a non-replicative chromosomal DNA region containing features associated to replicons. Thus, the organization of plasmid replicons as independent and exchangeable functional modules is likely facilitating rapid replicon evolution, fostering their diversification and survival, besides allowing the potential co-option of appropriate genes into novel replicons and the artificial construction of new replicon specificities. PMID:28243228

MiRNA-miRNA synergistic network: construction via co-regulating functional modules and disease miRNA topological features.

PubMed

Xu, Juan; Li, Chuan-Xing; Li, Yong-Sheng; Lv, Jun-Ying; Ma, Ye; Shao, Ting-Ting; Xu, Liang-De; Wang, Ying-Ying; Du, Lei; Zhang, Yun-Peng; Jiang, Wei; Li, Chun-Quan; Xiao, Yun; Li, Xia

2011-02-01

Synergistic regulations among multiple microRNAs (miRNAs) are important to understand the mechanisms of complex post-transcriptional regulations in humans. Complex diseases are affected by several miRNAs rather than a single miRNA. So, it is a challenge to identify miRNA synergism and thereby further determine miRNA functions at a system-wide level and investigate disease miRNA features in the miRNA-miRNA synergistic network from a new view. Here, we constructed a miRNA-miRNA functional synergistic network (MFSN) via co-regulating functional modules that have three features: common targets of corresponding miRNA pairs, enriched in the same gene ontology category and close proximity in the protein interaction network. Predicted miRNA synergism is validated by significantly high co-expression of functional modules and significantly negative regulation to functional modules. We found that the MFSN exhibits a scale free, small world and modular architecture. Furthermore, the topological features of disease miRNAs in the MFSN are distinct from non-disease miRNAs. They have more synergism, indicating their higher complexity of functions and are the global central cores of the MFSN. In addition, miRNAs associated with the same disease are close to each other. The structure of the MFSN and the features of disease miRNAs are validated to be robust using different miRNA target data sets.

Quantitative High-throughput Luciferase Screening in Identifying CAR Modulators

PubMed Central

Lynch, Caitlin; Zhao, Jinghua; Wang, Hongbing; Xia, Menghang

2017-01-01

Summary The constitutive androstane receptor (CAR, NR1I3) is responsible for the transcription of multiple drug metabolizing enzymes and transporters. There are two possible methods of activation for CAR, direct ligand binding and a ligand-independent method, which makes this a unique nuclear receptor. Both of these mechanisms require translocation of CAR from the cytoplasm into the nucleus. Interestingly, CAR is constitutively active in immortalized cell lines due to the basal nuclear location of this receptor. This creates an important challenge in most in vitro assay models because immortalized cells cannot be used without inhibiting the basal activity. In this book chapter, we go into detail of how to perform quantitative high-throughput screens to identify hCAR1 modulators through the employment of a double stable cell line. Using this line, we are able to identify activators, as well as deactivators, of the challenging nuclear receptor, CAR. PMID:27518621

Thin-Film Module Reverse-Bias Breakdown Sites Identified by Thermal Imaging: Preprint

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

Johnston, Steven; Sulas, Dana; Guthrey, Harvey L

Thin-film module sections are stressed under reverse bias to simulate partial shading conditions. Such stresses can cause permanent damage in the form of 'wormlike' defects due to thermal runaway. When large reverse biases with limited current are applied to the cells, dark lock-in thermography (DLIT) can detect where spatially-localized breakdown initiates before thermal runaway leads to permanent damage. Predicted breakdown defect sites have been identified in both CIGS and CdTe modules using DLIT. These defects include small pinholes, craters, or voids in the absorber layer of the film that lead to built-in areas of weakness where high current densities maymore » cause thermal damage in a partial-shading event.« less

Identifying modules of coexpressed transcript units and their organization of Saccharopolyspora erythraea from time series gene expression profiles.

PubMed

Chang, Xiao; Liu, Shuai; Yu, Yong-Tao; Li, Yi-Xue; Li, Yuan-Yuan

2010-08-12

The Saccharopolyspora erythraea genome sequence was released in 2007. In order to look at the gene regulations at whole transcriptome level, an expression microarray was specifically designed on the S. erythraea strain NRRL 2338 genome sequence. Based on these data, we set out to investigate the potential transcriptional regulatory networks and their organization. In view of the hierarchical structure of bacterial transcriptional regulation, we constructed a hierarchical coexpression network at whole transcriptome level. A total of 27 modules were identified from 1255 differentially expressed transcript units (TUs) across time course, which were further classified in to four groups. Functional enrichment analysis indicated the biological significance of our hierarchical network. It was indicated that primary metabolism is activated in the first rapid growth phase (phase A), and secondary metabolism is induced when the growth is slowed down (phase B). Among the 27 modules, two are highly correlated to erythromycin production. One contains all genes in the erythromycin-biosynthetic (ery) gene cluster and the other seems to be associated with erythromycin production by sharing common intermediate metabolites. Non-concomitant correlation between production and expression regulation was observed. Especially, by calculating the partial correlation coefficients and building the network based on Gaussian graphical model, intrinsic associations between modules were found, and the association between those two erythromycin production-correlated modules was included as expected. This work created a hierarchical model clustering transcriptome data into coordinated modules, and modules into groups across the time course, giving insight into the concerted transcriptional regulations especially the regulation corresponding to erythromycin production of S. erythraea. This strategy may be extendable to studies on other prokaryotic microorganisms.

Excavation of attractor modules for nasopharyngeal carcinoma via integrating systemic module inference with attract method.

PubMed

Jiang, T; Jiang, C-Y; Shu, J-H; Xu, Y-J

2017-07-10

The molecular mechanism of nasopharyngeal carcinoma (NPC) is poorly understood and effective therapeutic approaches are needed. This research aimed to excavate the attractor modules involved in the progression of NPC and provide further understanding of the underlying mechanism of NPC. Based on the gene expression data of NPC, two specific protein-protein interaction networks for NPC and control conditions were re-weighted using Pearson correlation coefficient. Then, a systematic tracking of candidate modules was conducted on the re-weighted networks via cliques algorithm, and a total of 19 and 38 modules were separately identified from NPC and control networks, respectively. Among them, 8 pairs of modules with similar gene composition were selected, and 2 attractor modules were identified via the attract method. Functional analysis indicated that these two attractor modules participate in one common bioprocess of cell division. Based on the strategy of integrating systemic module inference with the attract method, we successfully identified 2 attractor modules. These attractor modules might play important roles in the molecular pathogenesis of NPC via affecting the bioprocess of cell division in a conjunct way. Further research is needed to explore the correlations between cell division and NPC.

Gene Network for Identifying the Entropy Changes of Different Modules in Pediatric Sepsis.

PubMed

Yang, Jing; Zhang, Pingli; Wang, Lumin

2016-01-01

Pediatric sepsis is a disease that threatens life of children. The incidence of pediatric sepsis is higher in developing countries due to various reasons, such as insufficient immunization and nutrition, water and air pollution, etc. Exploring the potential genes via different methods is of significance for the prevention and treatment of pediatric sepsis. This study aimed to identify potential genes associated with pediatric sepsis utilizing analysis of gene network and entropy. The mRNA expression in the blood samples collected from 20 septic children and 30 healthy controls was quantified by using Affymetrix HG-U133A microarray. Two condition-specific protein-protein interaction networks (PINs), one for the healthy control and the other one for the children with sepsis, were deduced by combining the fundamental human PINs with gene expression profiles in the two phenotypes. Subsequently, distinct modules from the two conditional networks were extracted by adopting a maximal clique-merging approach. Delta entropy (ΔS) was calculated between sepsis and control modules. Then, key genes displaying changes in gene composition were identified by matching the control and sepsis modules. Two objective modules were obtained, in which ribosomal protein RPL4 and RPL9 as well as TOP2A were probably considered as the key genes differentiating sepsis from healthy controls. According to previous reports and this work, TOP2A is the potential gene therapy target for pediatric sepsis. The relationship between pediatric sepsis and RPL4 and RPL9 needs further investigation. © 2016 The Author(s) Published by S. Karger AG, Basel.

Functional cis-regulatory modules encoded by mouse-specific endogenous retrovirus

PubMed Central

Sundaram, Vasavi; Choudhary, Mayank N. K.; Pehrsson, Erica; Xing, Xiaoyun; Fiore, Christopher; Pandey, Manishi; Maricque, Brett; Udawatta, Methma; Ngo, Duc; Chen, Yujie; Paguntalan, Asia; Ray, Tammy; Hughes, Ava; Cohen, Barak A.; Wang, Ting

2017-01-01

Cis-regulatory modules contain multiple transcription factor (TF)-binding sites and integrate the effects of each TF to control gene expression in specific cellular contexts. Transposable elements (TEs) are uniquely equipped to deposit their regulatory sequences across a genome, which could also contain cis-regulatory modules that coordinate the control of multiple genes with the same regulatory logic. We provide the first evidence of mouse-specific TEs that encode a module of TF-binding sites in mouse embryonic stem cells (ESCs). The majority (77%) of the individual TEs tested exhibited enhancer activity in mouse ESCs. By mutating individual TF-binding sites within the TE, we identified a module of TF-binding motifs that cooperatively enhanced gene expression. Interestingly, we also observed the same motif module in the in silico constructed ancestral TE that also acted cooperatively to enhance gene expression. Our results suggest that ancestral TE insertions might have brought in cis-regulatory modules into the mouse genome. PMID:28348391

Detection of CFTR function and modulation in primary human nasal cell spheroids.

PubMed

Brewington, John J; Filbrandt, Erin T; LaRosa, F J; Ostmann, Alicia J; Strecker, Lauren M; Szczesniak, Rhonda D; Clancy, John P

2018-01-01

Expansion of CFTR modulators to patients with rare/undescribed mutations will be facilitated by patient-derived models quantifying CFTR function and restoration. We aimed to generate a personalized model system of CFTR function and modulation using non-surgically obtained nasal epithelial cells (NECs). NECs obtained by curettage from healthy volunteers and CF patients were expanded and grown in 3-dimensional culture as spheroids, characterized, and stimulated with cAMP-inducing agents to activate CFTR. Spheroid swelling was quantified as a proxy for CFTR function. NEC spheroids recapitulated characteristics of pseudostratified respiratory epithelia. When stimulated with forskolin/IBMX, spheroids swelled in the presence of functional CFTR, and shrank in its absence. Spheroid swelling quantified mutant CFTR restoration in F508del homozygous cells using clinically available CFTR modulators. NEC spheroids hold promise for understanding rare CFTR mutations and personalized modulator testing to drive evaluation for CF patients with common, rare or undescribed mutations. Portions of this data have previously been presented in abstract form at the 2016 meetings of the American Thoracic Society and the 2016 North American Cystic Fibrosis Conference. Copyright © 2017 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

Method and system for providing precise multi-function modulation

NASA Technical Reports Server (NTRS)

Davarian, Faramaz (Inventor); Sumida, Joe T. (Inventor)

1989-01-01

A method and system is disclosed which provides precise multi-function digitally implementable modulation for a communication system. The invention provides a modulation signal for a communication system in response to an input signal from a data source. A digitized time response is generated from samples of a time domain representation of a spectrum profile of a selected modulation scheme. The invention generates and stores coefficients for each input symbol in accordance with the selected modulation scheme. The output signal is provided by a plurality of samples, each sample being generated by summing the products of a predetermined number of the coefficients and a predetermined number of the samples of the digitized time response. In a specific illustrative implementation, the samples of the output signals are converted to analog signals, filtered and used to modulate a carrier in a conventional manner. The invention is versatile in that it allows for the storage of the digitized time responses and corresponding coefficient lookup table of a number of modulation schemes, any of which may then be selected for use in accordance with the teachings of the invention.

Algorithm to Identify Frequent Coupled Modules from Two-Layered Network Series: Application to Study Transcription and Splicing Coupling

PubMed Central

Li, Wenyuan; Dai, Chao; Liu, Chun-Chi

2012-01-01

Abstract Current network analysis methods all focus on one or multiple networks of the same type. However, cells are organized by multi-layer networks (e.g., transcriptional regulatory networks, splicing regulatory networks, protein-protein interaction networks), which interact and influence each other. Elucidating the coupling mechanisms among those different types of networks is essential in understanding the functions and mechanisms of cellular activities. In this article, we developed the first computational method for pattern mining across many two-layered graphs, with the two layers representing different types yet coupled biological networks. We formulated the problem of identifying frequent coupled clusters between the two layers of networks into a tensor-based computation problem, and proposed an efficient solution to solve the problem. We applied the method to 38 two-layered co-transcription and co-splicing networks, derived from 38 RNA-seq datasets. With the identified atlas of coupled transcription-splicing modules, we explored to what extent, for which cellular functions, and by what mechanisms transcription-splicing coupling takes place. PMID:22697243

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

PubMed

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

2013-03-01

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

Nonlinear modulation of interacting between COMT and depression on brain function.

PubMed

Gong, L; He, C; Yin, Y; Ye, Q; Bai, F; Yuan, Y; Zhang, H; Lv, L; Zhang, H; Zhang, Z; Xie, C

2017-09-01

The catechol-O-methyltransferase (COMT) gene is related to dopamine degradation and has been suggested to be involved in the pathogenesis of major depressive disorder (MDD). However, how this gene affects brain function properties in MDD is still unclear. Fifty patients with MDD and 35 cognitively normal participants underwent a resting-state functional magnetic resonance imaging scan. A voxelwise and data-drive global functional connectivity density (gFCD) analysis was used to investigate the main effects and the interactions of disease states and COMT rs4680 gene polymorphism on brain function. We found significant group differences of the gFCD in bilateral fusiform area (FFA), post-central and pre-central cortex, left superior temporal gyrus (STG), rectal and superior temporal gyrus and right ventrolateral prefrontal cortex (vlPFC); abnormal gFCDs in left STG were positively correlated with severity of depression in MDD group. Significant disease×COMT interaction effects were found in the bilateral calcarine gyrus, right vlPFC, hippocampus and thalamus, and left SFG and FFA. Further post-hoc tests showed a nonlinear modulation effect of COMT on gFCD in the development of MDD. Interestingly, an inverted U-shaped modulation was found in the prefrontal cortex (control system) but U-shaped modulations were found in the hippocampus, thalamus and occipital cortex (processing system). Our study demonstrated nonlinear modulation of the interaction between COMT and depression on brain function. These findings expand our understanding of the COMT effect underlying the pathophysiology of MDD. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Bilingual Skills Training Program. Meat Cutting. Module 3.0: Identifying and Cutting Meat and By-Products.

ERIC Educational Resources Information Center

Northern New Mexico Community Coll., El Rito.

This module on identifying and cutting of meat and by-products is the third of three (CE 028 291-293) in the meat cutting course of a bilingual skills training program. The course is designed to furnish theoretical and laboratory experience in the cutting of beef, pork, poultry, lamb, and mutton. Module objectives are for students to develop…

Proper Analytic Point Spread Function for Lateral Modulation

NASA Astrophysics Data System (ADS)

Chikayoshi Sumi,; Kunio Shimizu,; Norihiko Matsui,

2010-07-01

For ultrasonic lateral modulation for the imaging and measurement of tissue motion, better envelope shapes of the point spread function (PSF) than of a parabolic function are searched for within analytic functions or windows on the basis of the knowledge of the ideal shape of PSF previously obtained, i.e., having a large full width at half maximum and short feet. Through simulation of displacement vector measurement, better shapes are determined. As a better shape, a new window is obtained from a Turkey window by changing Hanning windows by power functions with an order larger than the second order. The order of measurement accuracies obtained is as follows, the new window > rectangular window > power function with a higher order > parabolic function > Akaike window.

Residential photovoltaic module and array requirements study

NASA Technical Reports Server (NTRS)

Nearhoof, S. L.; Oster, J. R.

1979-01-01

Design requirements for photovoltaic modules and arrays used in residential applications were identified. Building codes and referenced standards were reviewed for their applicability to residential photovoltaic array installations. Four installation types were identified - integral (replaces roofing), direct (mounted on top of roofing), stand-off (mounted away from roofing), and rack (for flat or low slope roofs, or ground mounted). Installation costs were developed for these mounting types as a function of panel/module size. Studies were performed to identify optimum module shapes and sizes and operating voltage cost drivers. It is concluded that there are no perceived major obstacles to the use of photovoltaic modules in residential arrays. However, there is no applicable building code category for residential photovoltaic modules and arrays and additional work with standards writing organizations is needed to develop residential module and array requirements.

Physiological modulation of eustachian tube function.

PubMed

Leclerc, J E; Doyle, W J; Karnavas, W

1987-01-01

The effect of changing body position on the Eustachian tube opening time (TOT) and nasal conductance (NC) was investigated in 5 subjects. Eustachian tube function was evaluated using a sonotubometric technique and NC was determined by anterior or posterior rhinomanometry. The results showed that both the TOT and NC were decreased by changing the body position from erect to recumbent. On a different day, Eustachian tube function and rhinomanometry tests were repeated every 30 min over a 5-7 h period. The results documented a nasal cycle in all subjects. Moreover, TOT tracked the ipsilateral NC in 3 subjects and the contralateral NC in 2 subjects. Since TOT measures mucosal venous congestion, these findings suggest that the tubal mucosa also experiences autonomically modulated cyclic fluctuations.

Genomic locus modulating corneal thickness in the mouse identifies POU6F2 as a potential risk of developing glaucoma

PubMed Central

Li, Ying; Wang, Jiaxing; Allingham, R. Rand; Hauser, Michael A.; Wiggs, Janey L.; Geisert, Eldon E.

2018-01-01

Central corneal thickness (CCT) is one of the most heritable ocular traits and it is also a phenotypic risk factor for primary open angle glaucoma (POAG). The present study uses the BXD Recombinant Inbred (RI) strains to identify novel quantitative trait loci (QTLs) modulating CCT in the mouse with the potential of identifying a molecular link between CCT and risk of developing POAG. The BXD RI strain set was used to define mammalian genomic loci modulating CCT, with a total of 818 corneas measured from 61 BXD RI strains (between 60–100 days of age). The mice were anesthetized and the eyes were positioned in front of the lens of the Phoenix Micron IV Image-Guided OCT system or the Bioptigen OCT system. CCT data for each strain was averaged and used to QTLs modulating this phenotype using the bioinformatics tools on GeneNetwork (www.genenetwork.org). The candidate genes and genomic loci identified in the mouse were then directly compared with the summary data from a human POAG genome wide association study (NEIGHBORHOOD) to determine if any genomic elements modulating mouse CCT are also risk factors for POAG.This analysis revealed one significant QTL on Chr 13 and a suggestive QTL on Chr 7. The significant locus on Chr 13 (13 to 19 Mb) was examined further to define candidate genes modulating this eye phenotype. For the Chr 13 QTL in the mouse, only one gene in the region (Pou6f2) contained nonsynonymous SNPs. Of these five nonsynonymous SNPs in Pou6f2, two resulted in changes in the amino acid proline which could result in altered secondary structure affecting protein function. The 7 Mb region under the mouse Chr 13 peak distributes over 2 chromosomes in the human: Chr 1 and Chr 7. These genomic loci were examined in the NEIGHBORHOOD database to determine if they are potential risk factors for human glaucoma identified using meta-data from human GWAS. The top 50 hits all resided within one gene (POU6F2), with the highest significance level of p = 10−6 for SNP

N-Terminomics TAILS Identifies Host Cell Substrates of Poliovirus and Coxsackievirus B3 3C Proteinases That Modulate Virus Infection.

PubMed

Jagdeo, Julienne M; Dufour, Antoine; Klein, Theo; Solis, Nestor; Kleifeld, Oded; Kizhakkedathu, Jayachandran; Luo, Honglin; Overall, Christopher M; Jan, Eric

2018-04-15

Enteroviruses encode proteinases that are essential for processing of the translated viral polyprotein. In addition, viral proteinases also target host proteins to manipulate cellular processes and evade innate antiviral responses to promote replication and infection. Although some host protein substrates of enterovirus proteinases have been identified, the full repertoire of targets remains unknown. We used a novel quantitative in vitro proteomics-based approach, termed t erminal a mine i sotopic l abeling of s ubstrates (TAILS), to identify with high confidence 72 and 34 new host protein targets of poliovirus and coxsackievirus B3 (CVB3) 3C proteinases (3C pro s) in HeLa cell and cardiomyocyte HL-1 cell lysates, respectively. We validated a subset of candidate substrates that are targets of poliovirus 3C pro in vitro including three common protein targets, phosphoribosylformylglycinamidine synthetase (PFAS), hnRNP K, and hnRNP M, of both proteinases. 3C pro -targeted substrates were also cleaved in virus-infected cells but not noncleavable mutant proteins designed from the TAILS-identified cleavage sites. Knockdown of TAILS-identified target proteins modulated infection both negatively and positively, suggesting that cleavage by 3C pro promotes infection. Indeed, expression of a cleavage-resistant mutant form of the endoplasmic reticulum (ER)-Golgi vesicle-tethering protein p115 decreased viral replication and yield. As the first comprehensive study to identify and validate functional enterovirus 3C pro substrates in vivo , we conclude that N-terminomics by TAILS is an effective strategy to identify host targets of viral proteinases in a nonbiased manner. IMPORTANCE Enteroviruses are positive-strand RNA viruses that encode proteases that cleave the viral polyprotein into the individual mature viral proteins. In addition, viral proteases target host proteins in order to modulate cellular pathways and block antiviral responses in order to facilitate virus infection

N-Terminomics TAILS Identifies Host Cell Substrates of Poliovirus and Coxsackievirus B3 3C Proteinases That Modulate Virus Infection

PubMed Central

Jagdeo, Julienne M.; Dufour, Antoine; Klein, Theo; Solis, Nestor; Kleifeld, Oded; Kizhakkedathu, Jayachandran; Luo, Honglin; Overall, Christopher M.

2018-01-01

ABSTRACT Enteroviruses encode proteinases that are essential for processing of the translated viral polyprotein. In addition, viral proteinases also target host proteins to manipulate cellular processes and evade innate antiviral responses to promote replication and infection. Although some host protein substrates of enterovirus proteinases have been identified, the full repertoire of targets remains unknown. We used a novel quantitative in vitro proteomics-based approach, termed terminal amine isotopic labeling of substrates (TAILS), to identify with high confidence 72 and 34 new host protein targets of poliovirus and coxsackievirus B3 (CVB3) 3C proteinases (3Cpros) in HeLa cell and cardiomyocyte HL-1 cell lysates, respectively. We validated a subset of candidate substrates that are targets of poliovirus 3Cpro in vitro including three common protein targets, phosphoribosylformylglycinamidine synthetase (PFAS), hnRNP K, and hnRNP M, of both proteinases. 3Cpro-targeted substrates were also cleaved in virus-infected cells but not noncleavable mutant proteins designed from the TAILS-identified cleavage sites. Knockdown of TAILS-identified target proteins modulated infection both negatively and positively, suggesting that cleavage by 3Cpro promotes infection. Indeed, expression of a cleavage-resistant mutant form of the endoplasmic reticulum (ER)-Golgi vesicle-tethering protein p115 decreased viral replication and yield. As the first comprehensive study to identify and validate functional enterovirus 3Cpro substrates in vivo, we conclude that N-terminomics by TAILS is an effective strategy to identify host targets of viral proteinases in a nonbiased manner. IMPORTANCE Enteroviruses are positive-strand RNA viruses that encode proteases that cleave the viral polyprotein into the individual mature viral proteins. In addition, viral proteases target host proteins in order to modulate cellular pathways and block antiviral responses in order to facilitate virus infection

Nutritional modulation of immune function in broilers.

PubMed

Kidd, M T

2004-04-01

Collaborative research efforts across disciplines typically result in more insight toward the hypothesis being tested due to the omnibus nature of the projects. For example, nutritional experiments evaluating a nutrient response will benefit greatly by incorporating biochemical, physiological, and immunological endpoints for measurement. Clearly, commercial poultry producers do not have the luxury of focusing on specific disciplines when field problems occur. Hence, in practice interplay exists among nutrition, genetics, management, and diseases. Dietary composition impacts immune function of the chicken. As research in the area of nutritional immunology has increased, it is becoming apparent that nutrient needs for immunity do not coincide with those for growth or skeletal tissue accretion. This review is not a comprehensive assessment of nutrient needs for immunity in the chicken. Rather, this review is concerned with nutritional modulation of immunity in broilers that offers insight for nutritionists and researchers to implement nutritional regimens to reduce the severity of disease and to test or validate nutritional regimens that heighten immunity. Nutritional modulation of the hen diet and in ovo nutrient modulation to improve chick immunity and disease resistance are discussed.

Editor's Highlight: High-Throughput Functional Genomics Identifies Modulators of TCE Metabolite Genotoxicity and Candidate Susceptibility Genes.

PubMed

De La Rosa, Vanessa Y; Asfaha, Jonathan; Fasullo, Michael; Loguinov, Alex; Li, Peng; Moore, Lee E; Rothman, Nathaniel; Nakamura, Jun; Swenberg, James A; Scelo, Ghislaine; Zhang, Luoping; Smith, Martyn T; Vulpe, Chris D

2017-11-01

Trichloroethylene (TCE), an industrial chemical and environmental contaminant, is a human carcinogen. Reactive metabolites are implicated in renal carcinogenesis associated with TCE exposure, yet the toxicity mechanisms of these metabolites and their contribution to cancer and other adverse effects remain unclear. We employed an integrated functional genomics approach that combined functional profiling studies in yeast and avian DT40 cell models to provide new insights into the specific mechanisms contributing to toxicity associated with TCE metabolites. Genome-wide profiling studies in yeast identified the error-prone translesion synthesis (TLS) pathway as an import mechanism in response to TCE metabolites. The role of TLS DNA repair was further confirmed by functional profiling in DT40 avian cell lines, but also revealed that TLS and homologous recombination DNA repair likely play competing roles in cellular susceptibility to TCE metabolites in higher eukaryotes. These DNA repair pathways are highly conserved between yeast, DT40, and humans. We propose that in humans, mutagenic TLS is favored over homologous recombination repair in response to TCE metabolites. The results of these studies contribute to the body of evidence supporting a mutagenic mode of action for TCE-induced renal carcinogenesis mediated by reactive metabolites in humans. Our approach illustrates the potential for high-throughput in vitro functional profiling in yeast to elucidate toxicity pathways (molecular initiating events, key events) and candidate susceptibility genes for focused study. © The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Multifunctional ferromagnetic disks for modulating cell function

PubMed Central

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

2013-01-01

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

An algorithm to identify functional groups in organic molecules.

PubMed

Ertl, Peter

2017-06-07

The concept of functional groups forms a basis of organic chemistry, medicinal chemistry, toxicity assessment, spectroscopy and also chemical nomenclature. All current software systems to identify functional groups are based on a predefined list of substructures. We are not aware of any program that can identify all functional groups in a molecule automatically. The algorithm presented in this article is an attempt to solve this scientific challenge. An algorithm to identify functional groups in a molecule based on iterative marching through its atoms is described. The procedure is illustrated by extracting functional groups from the bioactive portion of the ChEMBL database, resulting in identification of 3080 unique functional groups. A new algorithm to identify all functional groups in organic molecules is presented. The algorithm is relatively simple and full details with examples are provided, therefore implementation in any cheminformatics toolkit should be relatively easy. The new method allows the analysis of functional groups in large chemical databases in a way that was not possible using previous approaches. Graphical abstract .

Modulation Based on Probability Density Functions

NASA Technical Reports Server (NTRS)

Williams, Glenn L.

2009-01-01

A proposed method of modulating a sinusoidal carrier signal to convey digital information involves the use of histograms representing probability density functions (PDFs) that characterize samples of the signal waveform. The method is based partly on the observation that when a waveform is sampled (whether by analog or digital means) over a time interval at least as long as one half cycle of the waveform, the samples can be sorted by frequency of occurrence, thereby constructing a histogram representing a PDF of the waveform during that time interval.

Cholinergic modulation of cognition: Insights from human pharmacological functional neuroimaging

PubMed Central

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

2011-01-01

Evidence from lesion and cortical-slice studies implicate the neocortical cholinergic system in the modulation of sensory, attentional and memory processing. In this review we consider findings from sixty-three healthy human cholinergic functional neuroimaging studies that probe interactions of cholinergic drugs with brain activation profiles, and relate these to contemporary neurobiological models. Consistent patterns that emerge are: (1) the direction of cholinergic modulation of sensory cortex activations depends upon top-down influences; (2) cholinergic hyperstimulation reduces top-down selective modulation of sensory cortices; (3) cholinergic hyperstimulation interacts with task-specific frontoparietal activations according to one of several patterns, including: suppression of parietal-mediated reorienting; decreasing ‘effort’-associated activations in prefrontal regions; and deactivation of a ‘resting-state network’ in medial cortex, with reciprocal recruitment of dorsolateral frontoparietal regions during performance-challenging conditions; (4) encoding-related activations in both neocortical and hippocampal regions are disrupted by cholinergic blockade, or enhanced with cholinergic stimulation, while the opposite profile is observed during retrieval; (5) many examples exist of an ‘inverted-U shaped’ pattern of cholinergic influences by which the direction of functional neural activation (and performance) depends upon both task (e.g. relative difficulty) and subject (e.g. age) factors. Overall, human cholinergic functional neuroimaging studies both corroborate and extend physiological accounts of cholinergic function arising from other experimental contexts, while providing mechanistic insights into cholinergic-acting drugs and their potential clinical applications. PMID:21708219

Dopaminergic modulation of hemodynamic signal variability and the functional connectome during cognitive performance.

PubMed

Alavash, Mohsen; Lim, Sung-Joo; Thiel, Christiane; Sehm, Bernhard; Deserno, Lorenz; Obleser, Jonas

2018-05-15

Dopamine underlies important aspects of cognition, and has been suggested to boost cognitive performance. However, how dopamine modulates the large-scale cortical dynamics during cognitive performance has remained elusive. Using functional MRI during a working memory task in healthy young human listeners, we investigated the effect of levodopa (l-dopa) on two aspects of cortical dynamics, blood oxygen-level-dependent (BOLD) signal variability and the functional connectome of large-scale cortical networks. We here show that enhanced dopaminergic signaling modulates the two potentially interrelated aspects of large-scale cortical dynamics during cognitive performance, and the degree of these modulations is able to explain inter-individual differences in l-dopa-induced behavioral benefits. Relative to placebo, l-dopa increased BOLD signal variability in task-relevant temporal, inferior frontal, parietal and cingulate regions. On the connectome level, however, l-dopa diminished functional integration across temporal and cingulo-opercular regions. This hypo-integration was expressed as a reduction in network efficiency and modularity in more than two thirds of the participants and to different degrees. Hypo-integration co-occurred with relative hyper-connectivity in paracentral lobule and precuneus, as well as posterior putamen. Both, l-dopa-induced BOLD signal variability modulation and functional connectome modulations proved predictive of an individual's l-dopa-induced benefits in behavioral performance, namely response speed and perceptual sensitivity. Lastly, l-dopa-induced modulations of BOLD signal variability were correlated with l-dopa-induced modulation of nodal connectivity and network efficiency. Our findings underline the role of dopamine in maintaining the dynamic range of, and communication between, cortical systems, and their explanatory power for inter-individual differences in benefits from dopamine during cognitive performance. Copyright © 2018

Dysbindin modulates brain function during visual processing in children.

PubMed

Mechelli, A; Viding, E; Kumar, A; Pettersson-Yeo, W; Fusar-Poli, P; Tognin, S; O'Donovan, M C; McGuire, P

2010-01-01

Schizophrenia is a neurodevelopmental disorder, and risk genes are thought to act through disruption of brain development. Several genetic studies have identified dystrobrevin binding protein 1 (DTNBP1, also known as dysbindin) as a potential susceptibility gene for schizophrenia, but its impact on brain function is poorly understood. It has been proposed that DTNBP1 may be associated with differences in visual processing. To test this, we examined the impact on visual processing in 61 healthy children aged 10-12 years of a genetic variant in DTNBP1 (rs2619538) that was common to all schizophrenia associated haplotypes in an earlier UK-Irish study. We tested the hypothesis that carriers of the risk allele would show altered occipital cortical function relative to noncarriers. Functional Magnetic Resonance Imaging (fMRI) was used to measure brain responses during a visual matching task. The data were analysed using statistical parametric mapping and statistical inferences were made at p<0.05 (corrected for multiple comparisons). Relative to noncarriers, carriers of the risk allele had greater activation in the lingual, fusiform gyrus and inferior occipital gyri. In these regions DTNBP1 genotype accounted for 19%, 20% and 14% of the inter-individual variance, respectively. Our results suggest that that genetic variation in DTNBP1 is associated with differences in the function of brain areas that mediate visual processing, and that these effects are evident in young children. These findings are consistent with the notion that the DTNBP1 gene influences brain development and can thereby modulate vulnerability to schizophrenia.

Functional measures developed for clinical populations identified impairment among active workers with upper extremity disorders

PubMed Central

Gardner, Bethany T.; Dale, Ann Marie; Buckner-Petty, Skye; Rachford, Robert; Strickland, Jaime; Kaskutas, Vicki; Evanoff, Bradley

2017-01-01

Purpose Few studies have explored measures of function across a range of health outcomes in a general working population. Using four upper extremity (UE) case definitions from the scientific literature, we described the performance of functional measures of work, activities of daily living, and overall health. Methods A sample of 573 workers completed several functional measures: modified recall versions of the QuickDASH, Levine Functional Status Scale (FSS), DASH Work module (DASH-W), and standard SF-8 physical component score. We determined case status based on four UE case definitions: 1) UE symptoms, 2) UE musculoskeletal disorders (MSD), 3) carpal tunnel syndrome (CTS), and 4) work limitations due to UE symptoms. We calculated effect sizes for each case definition to show the magnitude of the differences that were detected between cases and non-cases for each case definition on each functional measure. Sensitivity and specificity analyses showed how well each measure identified functional impairments across the UE case definitions. Results All measures discriminated between cases and non-cases for each case definition with the largest effect sizes for CTS and work limitations, particularly for the modified FSS and DASH-W measures. Specificity was high and sensitivity was low for outcomes of UE symptoms and UE MSD in all measures. Sensitivity was high for CTS and work limitations. Conclusions Functional measures developed specifically for use in clinical, treatment-seeking populations may identify mild levels of impairment in relatively healthy, active working populations, but measures performed better among workers with CTS or those reporting limitations at work. PMID:26091980

Functional characterization and cellular dynamics of the CDC-42 - RAC - CDC-24 module in Neurospora crassa.

PubMed

Araujo-Palomares, Cynthia L; Richthammer, Corinna; Seiler, Stephan; Castro-Longoria, Ernestina

2011-01-01

Rho-type GTPases are key regulators that control eukaryotic cell polarity, but their role in fungal morphogenesis is only beginning to emerge. In this study, we investigate the role of the CDC-42 - RAC - CDC-24 module in Neurospora crassa. rac and cdc-42 deletion mutants are viable, but generate highly compact colonies with severe morphological defects. Double mutants carrying conditional and loss of function alleles of rac and cdc-42 are lethal, indicating that both GTPases share at least one common essential function. The defects of the GTPase mutants are phenocopied by deletion and conditional alleles of the guanine exchange factor (GEF) cdc-24, and in vitro GDP-GTP exchange assays identify CDC-24 as specific GEF for both CDC-42 and RAC. In vivo confocal microscopy shows that this module is organized as membrane-associated cap that covers the hyphal apex. However, the specific localization patterns of the three proteins are distinct, indicating different functions of RAC and CDC-42 within the hyphal tip. CDC-42 localized as confined apical membrane-associated crescent, while RAC labeled a membrane-associated ring excluding the region labeled by CDC42. The GEF CDC-24 occupied a strategic position, localizing as broad apical membrane-associated crescent and in the apical cytosol excluding the Spitzenkörper. RAC and CDC-42 also display distinct localization patterns during branch initiation and germ tube formation, with CDC-42 accumulating at the plasma membrane before RAC. Together with the distinct cellular defects of rac and cdc-42 mutants, these localizations suggest that CDC-42 is more important for polarity establishment, while the primary function of RAC may be maintaining polarity. In summary, this study identifies CDC-24 as essential regulator for RAC and CDC-42 that have common and distinct functions during polarity establishment and maintenance of cell polarity in N. crassa.

Functional modules of sigma factor regulons guarantee adaptability and evolvability

PubMed Central

Binder, Sebastian C.; Eckweiler, Denitsa; Schulz, Sebastian; Bielecka, Agata; Nicolai, Tanja; Franke, Raimo; Häussler, Susanne; Meyer-Hermann, Michael

2016-01-01

The focus of modern molecular biology turns from assigning functions to individual genes towards understanding the expression and regulation of complex sets of molecules. Here, we provide evidence that alternative sigma factor regulons in the pathogen Pseudomonas aeruginosa largely represent insulated functional modules which provide a critical level of biological organization involved in general adaptation and survival processes. Analysis of the operational state of the sigma factor network revealed that transcription factors functionally couple the sigma factor regulons and significantly modulate the transcription levels in the face of challenging environments. The threshold quality of newly evolved transcription factors was reached faster and more robustly in in silico testing when the structural organization of sigma factor networks was taken into account. These results indicate that the modular structures of alternative sigma factor regulons provide P. aeruginosa with a robust framework to function adequately in its environment and at the same time facilitate evolutionary change. Our data support the view that widespread modularity guarantees robustness of biological networks and is a key driver of evolvability. PMID:26915971

Dynamic range of frontoparietal functional modulation is associated with working memory capacity limitations in older adults.

PubMed

Hakun, Jonathan G; Johnson, Nathan F

2017-11-01

Older adults tend to over-activate regions throughout frontoparietal cortices and exhibit a reduced range of functional modulation during WM task performance compared to younger adults. While recent evidence suggests that reduced functional modulation is associated with poorer task performance, it remains unclear whether reduced range of modulation is indicative of general WM capacity-limitations. In the current study, we examined whether the range of functional modulation observed over multiple levels of WM task difficulty (N-Back) predicts in-scanner task performance and out-of-scanner psychometric estimates of WM capacity. Within our sample (60-77years of age), age was negatively associated with frontoparietal modulation range. Individuals with greater modulation range exhibited more accurate N-Back performance. In addition, despite a lack of significant relationships between N-Back and complex span task performance, range of frontoparietal modulation during the N-Back significantly predicted domain-general estimates of WM capacity. Consistent with previous cross-sectional findings, older individuals with less modulation range exhibited greater activation at the lowest level of task difficulty but less activation at the highest levels of task difficulty. Our results are largely consistent with existing theories of neurocognitive aging (e.g. CRUNCH) but focus attention on dynamic range of functional modulation asa novel marker of WM capacity-limitations in older adults. Copyright © 2017 Elsevier Inc. All rights reserved.

Development and Evaluation of the SUMIT Microcomputer Module Entitled 'Predator Functional Response'.

ERIC Educational Resources Information Center

Shaltz, Mark B.

An experiment was conducted that compared the teaching effectiveness of a computer assisted instructional module and a lecture-discussion. The module, Predator Functional Response (PFR), was developed as part of the SUMIT (Single-concept User-adaptable Microcomputer-based Instructional Technique) project. A class of 30 students was randomly…

Comparison of Modules of Wild Type and Mutant Huntingtin and TP53 Protein Interaction Networks: Implications in Biological Processes and Functions

PubMed Central

Basu, Mahashweta; Bhattacharyya, Nitai P.; Mohanty, Pradeep K.

2013-01-01

Disease-causing mutations usually change the interacting partners of mutant proteins. In this article, we propose that the biological consequences of mutation are directly related to the alteration of corresponding protein protein interaction networks (PPIN). Mutation of Huntingtin (HTT) which causes Huntington's disease (HD) and mutations to TP53 which is associated with different cancers are studied as two example cases. We construct the PPIN of wild type and mutant proteins separately and identify the structural modules of each of the networks. The functional role of these modules are then assessed by Gene Ontology (GO) enrichment analysis for biological processes (BPs). We find that a large number of significantly enriched () GO terms in mutant PPIN were absent in the wild type PPIN indicating the gain of BPs due to mutation. Similarly some of the GO terms enriched in wild type PPIN cease to exist in the modules of mutant PPIN, representing the loss. GO terms common in modules of mutant and wild type networks indicate both loss and gain of BPs. We further assign relevant biological function(s) to each module by classifying the enriched GO terms associated with it. It turns out that most of these biological functions in HTT networks are already known to be altered in HD and those of TP53 networks are altered in cancers. We argue that gain of BPs, and the corresponding biological functions, are due to new interacting partners acquired by mutant proteins. The methodology we adopt here could be applied to genetic diseases where mutations alter the ability of the protein to interact with other proteins. PMID:23741403

Assessing upper limb function in nonambulant SMA patients: development of a new module.

PubMed

Mazzone, Elena; Bianco, Flaviana; Martinelli, Diego; Glanzman, Allan M; Messina, Sonia; De Sanctis, Roberto; Main, Marion; Eagle, Michelle; Florence, Julaine; Krosschell, Kristin; Vasco, Gessica; Pelliccioni, Marco; Lombardo, Marilena; Pane, Marika; Finkel, Richard; Muntoni, Francesco; Bertini, Enrico; Mercuri, Eugenio

2011-06-01

We report the development of a module specifically designed for assessing upper limb function in nonambulant SMA patients, including young children and those with severe contractures. The application of the module to a preschool cohort of 40 children (age 30-48 months) showed that all the items could be completed by 30 months. The module was also used in 45 nonambulant SMA patients (age 30 months to 27 years). Their scores were more variable than in the preschool cohort, ranging from 0 to 18. The magnitude of scores was not related to age (r=-0.19). The upper limb scores had a good correlation with the Hammersmith Functional Motor Scale, r=0.75, but the upper limb function did not always strictly follow the overall gross motor function. These findings suggest that even some of the very weak nonambulant children possess upper limb skills that can be measured. Copyright © 2011 Elsevier B.V. All rights reserved.

Identification and functional analysis of a core gene module associated with hepatitis C virus-induced human hepatocellular carcinoma progression.

PubMed

Bai, Gaobo; Zheng, Wenling; Ma, Wenli

2018-05-01

Hepatitis C virus (HCV)-induced human hepatocellular carcinoma (HCC) progression may be due to a complex multi-step processes. The developmental mechanism of these processes is worth investigating for the prevention, diagnosis and therapy of HCC. The aim of the present study was to investigate the molecular mechanism underlying the progression of HCV-induced hepatocarcinogenesis. First, the dynamic gene module, consisting of key genes associated with progression between the normal stage and HCC, was identified using the Weighted Gene Co-expression Network Analysis tool from R language. By defining those genes in the module as seeds, the change of co-expression in differentially expressed gene sets in two consecutive stages of pathological progression was examined. Finally, interaction pairs of HCV viral proteins and their directly targeted proteins in the identified module were extracted from the literature and a comprehensive interaction dataset from yeast two-hybrid experiments. By combining the interactions between HCV and their targets, and protein-protein interactions in the Search Tool for the Retrieval of Interacting Genes database (STRING), the HCV-key genes interaction network was constructed and visualized using Cytoscape software 3.2. As a result, a module containing 44 key genes was identified to be associated with HCC progression, due to the dynamic features and functions of those genes in the module. Several important differentially co-expressed gene pairs were identified between non-HCC and HCC stages. In the key genes, cyclin dependent kinase 1 (CDK1), NDC80, cyclin A2 (CCNA2) and rac GTPase activating protein 1 (RACGAP1) were shown to be targeted by the HCV nonstructural proteins NS5A, NS3 and NS5B, respectively. The four genes perform an intermediary role between the HCV viral proteins and the dysfunctional module in the HCV key genes interaction network. These findings provided valuable information for understanding the mechanism of HCV

Prior knowledge guided active modules identification: an integrated multi-objective approach.

PubMed

Chen, Weiqi; Liu, Jing; He, Shan

2017-03-14

Active module, defined as an area in biological network that shows striking changes in molecular activity or phenotypic signatures, is important to reveal dynamic and process-specific information that is correlated with cellular or disease states. A prior information guided active module identification approach is proposed to detect modules that are both active and enriched by prior knowledge. We formulate the active module identification problem as a multi-objective optimisation problem, which consists two conflicting objective functions of maximising the coverage of known biological pathways and the activity of the active module simultaneously. Network is constructed from protein-protein interaction database. A beta-uniform-mixture model is used to estimate the distribution of p-values and generate scores for activity measurement from microarray data. A multi-objective evolutionary algorithm is used to search for Pareto optimal solutions. We also incorporate a novel constraints based on algebraic connectivity to ensure the connectedness of the identified active modules. Application of proposed algorithm on a small yeast molecular network shows that it can identify modules with high activities and with more cross-talk nodes between related functional groups. The Pareto solutions generated by the algorithm provides solutions with different trade-off between prior knowledge and novel information from data. The approach is then applied on microarray data from diclofenac-treated yeast cells to build network and identify modules to elucidate the molecular mechanisms of diclofenac toxicity and resistance. Gene ontology analysis is applied to the identified modules for biological interpretation. Integrating knowledge of functional groups into the identification of active module is an effective method and provides a flexible control of balance between pure data-driven method and prior information guidance.

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

ERIC Educational Resources Information Center

Wasel, Ed; Espy, John

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

Event related desynchronization-modulated functional electrical stimulation system for stroke rehabilitation: a feasibility study.

PubMed

Takahashi, Mitsuru; Takeda, Kotaro; Otaka, Yohei; Osu, Rieko; Hanakawa, Takashi; Gouko, Manabu; Ito, Koji

2012-08-16

We developed an electroencephalogram-based brain computer interface system to modulate functional electrical stimulation (FES) to the affected tibialis anterior muscle in a stroke patient. The intensity of FES current increased in a stepwise manner when the event-related desynchronization (ERD) reflecting motor intent was continuously detected from the primary cortical motor area. We tested the feasibility of the ERD-modulated FES system in comparison with FES without ERD modulation. The stroke patient who presented with severe hemiparesis attempted to perform dorsiflexion of the paralyzed ankle during which FES was applied either with or without ERD modulation. After 20 minutes of training, the range of movement at the ankle joint and the electromyography amplitude of the affected tibialis anterior muscle were significantly increased following the ERD-modulated FES compared with the FES alone. The proposed rehabilitation technique using ERD-modulated FES for stroke patients was feasible. The system holds potentials to improve the limb function and to benefit stroke patients.

Selective androgen receptor modulators as function promoting therapies.

PubMed

Bhasin, Shalender; Jasuja, Ravi

2009-05-01

The past decade has witnessed an unprecedented discovery effort to develop selective androgen receptor modulators (SARMs) that improve physical function and bone health without adversely affecting the prostate and cardiovascular outcomes. This review describes the historical evolution, the rationale for SARM development, and the mechanisms of testosterone action and SARM selectivity. Although steroidal SARMs have been around since the 1940s, a number of nonsteroidal SARMs that do not serve as substrates for CYP19 aromatase or 5alpha-reductase, act as full agonists in muscle and bone and as partial agonists in prostate are in development. The differing interactions of steroidal and nonsteroidal compounds with androgen receptor (AR) contribute to their unique pharmacologic actions. Ligand binding induces specific conformational changes in the ligand-binding domain, which could modulate surface topology and protein-protein interactions between AR and coregulators, resulting in tissue-specific gene regulation. Preclinical studies have demonstrated the ability of SARMs to increase muscle and bone mass in preclinical rodent models with varying degree of prostate sparing. Phase I trials of SARMs in humans have reported modest increments in fat-free mass. SARMs hold promise as a new class of function promoting anabolic therapies for a number of clinical indications, including functional limitations associated with aging and chronic disease, frailty, cancer cachexia, and osteoporosis.

Response function of modulated grid Faraday cup plasma instruments

NASA Technical Reports Server (NTRS)

Barnett, A.; Olbert, S.

1986-01-01

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

Abiotic regulation: a common way for proteins to modulate their functions.

PubMed

Zou, Zhi; Fu, Xinmiao

2015-01-01

Modulation of protein intrinsic activity in cells is generally carried out via a combination of four common ways, i.e., allosteric regulation, covalent modification, proteolytic cleavage and association of other regulatory proteins. Accumulated evidence indicate that changes of certain abiotic factors (e.g., temperature, pH, light and mechanical force) within or outside the cells directly influence protein structure and thus profoundly modulate the functions of a wide range of proteins, termed as abiotic regulatory proteins (e.g., heat shock factor, small heat shock protein, hemoglobin, zymogen, integrin, rhodopsin). Such abiotic regulation apparently differs from the four classic ways in perceiving and response to the signals. Importantly, it enables cells to directly and also immediately response to extracellular stimuli, thus facilitating the ability of organisms to resist against and adapt to the abiotic stress and thereby playing crucial roles in life evolution. Altogether, abiotic regulation may be considered as a common way for proteins to modulate their functions.

Evolutionary and Developmental Modules

PubMed Central

Lacquaniti, Francesco; Ivanenko, Yuri P.; d’Avella, Andrea; Zelik, Karl E.; Zago, Myrka

2013-01-01

The identification of biological modules at the systems level often follows top-down decomposition of a task goal, or bottom-up decomposition of multidimensional data arrays into basic elements or patterns representing shared features. These approaches traditionally have been applied to mature, fully developed systems. Here we review some results from two other perspectives on modularity, namely the developmental and evolutionary perspective. There is growing evidence that modular units of development were highly preserved and recombined during evolution. We first consider a few examples of modules well identifiable from morphology. Next we consider the more difficult issue of identifying functional developmental modules. We dwell especially on modular control of locomotion to argue that the building blocks used to construct different locomotor behaviors are similar across several animal species, presumably related to ancestral neural networks of command. A recurrent theme from comparative studies is that the developmental addition of new premotor modules underlies the postnatal acquisition and refinement of several different motor behaviors in vertebrates. PMID:23730285

Evolutionary and developmental modules.

PubMed

Lacquaniti, Francesco; Ivanenko, Yuri P; d'Avella, Andrea; Zelik, Karl E; Zago, Myrka

2013-01-01

The identification of biological modules at the systems level often follows top-down decomposition of a task goal, or bottom-up decomposition of multidimensional data arrays into basic elements or patterns representing shared features. These approaches traditionally have been applied to mature, fully developed systems. Here we review some results from two other perspectives on modularity, namely the developmental and evolutionary perspective. There is growing evidence that modular units of development were highly preserved and recombined during evolution. We first consider a few examples of modules well identifiable from morphology. Next we consider the more difficult issue of identifying functional developmental modules. We dwell especially on modular control of locomotion to argue that the building blocks used to construct different locomotor behaviors are similar across several animal species, presumably related to ancestral neural networks of command. A recurrent theme from comparative studies is that the developmental addition of new premotor modules underlies the postnatal acquisition and refinement of several different motor behaviors in vertebrates.

OrbView-3 Technical Performance Evaluation 2005: Modulation Transfer Function

NASA Technical Reports Server (NTRS)

Cole, Aaron

2007-01-01

The Technical performance evaluation of OrbView-3 using the Modulation Transfer Function (MTF) is presented. The contents include: 1) MTF Results and Methodology; 2) Radiometric Calibration Methodology; and 3) Relative Radiometric Assessment Results

Temporal modulation transfer functions in cochlear implantees using a method that limits overall loudness cues

PubMed Central

Fraser, Matthew; McKay, Colette M.

2012-01-01

Temporal modulation transfer functions (TMTFs) were measured for six users of cochlear implants, using different carrier rates and levels. Unlike most previous studies investigating modulation detection, the experimental design limited potential effects of overall loudness cues. Psychometric functions (percent correct discrimination of modulated from unmodulated stimuli versus modulation depth) were obtained. For each modulation depth, each modulated stimulus was loudness balanced to the unmodulated reference stimulus, and level jitter was applied in the discrimination task. The loudness-balance data showed that the modulated stimuli were louder than the unmodulated reference stimuli with the same average current, thus confirming the need to limit loudness cues when measuring modulation detection. TMTFs measured in this way had a low-pass characteristic, with a cut-off frequency (at comfortably loud levels) similar to that for normal-hearing listeners. A reduction in level caused degradation in modulation detection efficiency and a lower-cut-off frequency (i.e. poorer temporal resolution). An increase in carrier rate also led to a degradation in modulation detection efficiency, but only at lower levels or higher modulation frequencies. When detection thresholds were expressed as a proportion of dynamic range, there was no effect of carrier rate for the lowest modulation frequency (50 Hz) at either level. PMID:22146425

Allosteric Modulation of Chemoattractant Receptors

PubMed Central

Allegretti, Marcello; Cesta, Maria Candida; Locati, Massimo

2016-01-01

Chemoattractants control selective leukocyte homing via interactions with a dedicated family of related G protein-coupled receptor (GPCR). Emerging evidence indicates that the signaling activity of these receptors, as for other GPCR, is influenced by allosteric modulators, which interact with the receptor in a binding site distinct from the binding site of the agonist and modulate the receptor signaling activity in response to the orthosteric ligand. Allosteric modulators have a number of potential advantages over orthosteric agonists/antagonists as therapeutic agents and offer unprecedented opportunities to identify extremely selective drug leads. Here, we resume evidence of allosterism in the context of chemoattractant receptors, discussing in particular its functional impact on functional selectivity and probe/concentration dependence of orthosteric ligands activities. PMID:27199992

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

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

Pakhomov, A.G.; Dubovick, B.V.; Degtyariov, I.G.

1995-09-01

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

The partial coherence modulation transfer function in testing lithography lens

NASA Astrophysics Data System (ADS)

Huang, Jiun-Woei

2018-03-01

Due to the lithography demanding high performance in projection of semiconductor mask to wafer, the lens has to be almost free in spherical and coma aberration, thus, in situ optical testing for diagnosis of lens performance has to be established to verify the performance and to provide the suggesting for further improvement of the lens, before the lens has been build and integrated with light source. The measurement of modulation transfer function of critical dimension (CD) is main performance parameter to evaluate the line width of semiconductor platform fabricating ability for the smallest line width of producing tiny integrated circuits. Although the modulation transfer function (MTF) has been popularly used to evaluation the optical system, but in lithography, the contrast of each line-pair is in one dimension or two dimensions, analytically, while the lens stand along in the test bench integrated with the light source coherent or near coherent for the small dimension near the optical diffraction limit, the MTF is not only contributed by the lens, also by illumination of platform. In the study, the partial coherence modulation transfer function (PCMTF) for testing a lithography lens is suggested by measuring MTF in the high spatial frequency of in situ lithography lens, blended with the illumination of partial and in coherent light source. PCMTF can be one of measurement to evaluate the imperfect lens of lithography lens for further improvement in lens performance.

Validation of Skeletal Muscle cis-Regulatory Module Predictions Reveals Nucleotide Composition Bias in Functional Enhancers

PubMed Central

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

2011-01-01

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

Novel subgroups of attention-deficit/hyperactivity disorder identified by topological data analysis and their functional network modular organizations

PubMed Central

Kyeong, Sunghyon; Kim, Jae-Jin; Kim, Eunjoo

2017-01-01

Attention-deficit/hyperactivity disorder (ADHD) is a clinically heterogeneous condition and identification of clinically meaningful subgroups would open up a new window for personalized medicine. Thus, we aimed to identify new clinical phenotypes in children and adolescents with ADHD and to investigate whether neuroimaging findings validate the identified phenotypes. Neuroimaging and clinical data from 67 children with ADHD and 62 typically developing controls (TDCs) from the ADHD-200 database were selected. Clinical measures of ADHD symptoms and intelligence quotient (IQ) were used as input features into a topological data analysis (TDA) to identify ADHD subgroups within our sample. As external validators, graph theoretical measures obtained from the functional connectome were compared to address the biological meaningfulness of the identified subtypes. The TDA identified two unique subgroups of ADHD, labelled as mild symptom ADHD (mADHD) and severe symptom ADHD (sADHD). The output topology shape was repeatedly observed in the independent validation dataset. The graph theoretical analysis showed a decrease in the degree centrality and PageRank in the bilateral posterior cingulate cortex in the sADHD group compared with the TDC group. The mADHD group showed similar patterns of intra- and inter-module connectivity to the sADHD group. Relative to the TDC group, the inter-module connectivity between the default mode network and executive control network were significantly increased in the sADHD group but not in the mADHD group. Taken together, our results show that the data-driven TDA is potentially useful in identifying objective and biologically relevant disease phenotypes in children and adolescents with ADHD. PMID:28829775

Garlic compounds modulate macrophage and T-lymphocyte functions.

PubMed

Lau, B H; Yamasaki, T; Gridley, D S

1991-06-01

Organosulfur compounds of garlic have been shown to inhibit growth of animal tumors and to modulate the activity of diverse chemical carcinogens. There is also evidence that garlic may modulate antitumor immunity. In this study, we determined the effects of an aqueous garlic extract and a protein fraction isolated from the extract on the chemiluminescent oxidative burst of the murine J774 macrophage cell line and thioglycollate-elicited peritoneal macrophages obtained from BALB/c mice. T-lymphocyte activity was determined using mouse splenocytes incubated with phytohemagglutinin, labeled with [3H]-thymidine and assayed for lymphoproliferation. Significant dose-related augmentation of oxidative burst was observed with garlic extract and the protein fraction. The protein fraction also enhanced the T-lymphocyte blastogenesis. The data suggest that garlic compounds may serve as biological response modifiers by augmenting macrophage and T-lymphocyte functions.

Cholinergic modulation of the hippocampal region and memory function.

PubMed

Haam, Juhee; Yakel, Jerrel L

2017-08-01

Acetylcholine (ACh) plays an important role in memory function and has been implicated in aging-related dementia, in which the impairment of hippocampus-dependent learning strongly manifests. Cholinergic neurons densely innervate the hippocampus, mediating the formation of episodic as well as semantic memory. Here, we will review recent findings on acetylcholine's modulation of memory function, with a particular focus on hippocampus-dependent learning, and the circuits involved. In addition, we will discuss the complexity of ACh actions in memory function to better understand the physiological role of ACh in memory. This is an article for the special issue XVth International Symposium on Cholinergic Mechanisms. © 2017 International Society for Neurochemistry.

A Western diet ecological module identified from the 'humanized' mouse microbiota predicts diet in adults and formula feeding in children.

PubMed

Siddharth, Jay; Holway, Nicholas; Parkinson, Scott J

2013-01-01

The interplay between diet and the microbiota has been implicated in the growing frequency of chronic diseases associated with the Western lifestyle. However, the complexity and variability of microbial ecology in humans and preclinical models has hampered identification of the molecular mechanisms underlying the association of the microbiota in this context. We sought to address two key questions. Can the microbial ecology of preclinical models predict human populations? And can we identify underlying principles that surpass the plasticity of microbial ecology in humans? To do this, we focused our study on diet; perhaps the most influential factor determining the composition of the gut microbiota. Beginning with a study in 'humanized' mice we identified an interactive module of 9 genera allied with Western diet intake. This module was applied to a controlled dietary study in humans. The abundance of the Western ecological module correctly predicted the dietary intake of 19/21 top and 21/21 of the bottom quartile samples inclusive of all 5 Western and 'low-fat' diet subjects, respectively. In 98 volunteers the abundance of the Western module correlated appropriately with dietary intake of saturated fatty acids, fat-soluble vitamins and fiber. Furthermore, it correlated with the geographical location and dietary habits of healthy adults from the Western, developing and third world. The module was also coupled to dietary intake in children (and piglets) correlating with formula (vs breast) feeding and associated with a precipitous development of the ecological module in young children. Our study provides a conceptual platform to translate microbial ecology from preclinical models to humans and identifies an ecological network module underlying the association of the gut microbiota with Western dietary habits.

Using Functional Signatures to Identify Repositioned Drugs for Breast, Myelogenous Leukemia and Prostate Cancer

PubMed Central

Shigemizu, Daichi; Hu, Zhenjun; Hung, Jui-Hung; Huang, Chia-Ling; Wang, Yajie; DeLisi, Charles

2012-01-01

The cost and time to develop a drug continues to be a major barrier to widespread distribution of medication. Although the genomic revolution appears to have had little impact on this problem, and might even have exacerbated it because of the flood of additional and usually ineffective leads, the emergence of high throughput resources promises the possibility of rapid, reliable and systematic identification of approved drugs for originally unintended uses. In this paper we develop and apply a method for identifying such repositioned drug candidates against breast cancer, myelogenous leukemia and prostate cancer by looking for inverse correlations between the most perturbed gene expression levels in human cancer tissue and the most perturbed expression levels induced by bioactive compounds. The method uses variable gene signatures to identify bioactive compounds that modulate a given disease. This is in contrast to previous methods that use small and fixed signatures. This strategy is based on the observation that diseases stem from failed/modified cellular functions, irrespective of the particular genes that contribute to the function, i.e., this strategy targets the functional signatures for a given cancer. This function-based strategy broadens the search space for the effective drugs with an impressive hit rate. Among the 79, 94 and 88 candidate drugs for breast cancer, myelogenous leukemia and prostate cancer, 32%, 13% and 17% respectively are either FDA-approved/in-clinical-trial drugs, or drugs with suggestive literature evidences, with an FDR of 0.01. These findings indicate that the method presented here could lead to a substantial increase in efficiency in drug discovery and development, and has potential application for the personalized medicine. PMID:22346740

Discovering functional modules by topic modeling RNA-Seq based toxicogenomic data.

PubMed

Yu, Ke; Gong, Binsheng; Lee, Mikyung; Liu, Zhichao; Xu, Joshua; Perkins, Roger; Tong, Weida

2014-09-15

Toxicogenomics (TGx) endeavors to elucidate the underlying molecular mechanisms through exploring gene expression profiles in response to toxic substances. Recently, RNA-Seq is increasingly regarded as a more powerful alternative to microarrays in TGx studies. However, realizing RNA-Seq's full potential requires novel approaches to extracting information from the complex TGx data. Considering read counts as the number of times a word occurs in a document, gene expression profiles from RNA-Seq are analogous to a word by document matrix used in text mining. Topic modeling aiming at to discover the latent structures in text corpora would be helpful to explore RNA-Seq based TGx data. In this study, topic modeling was applied on a typical RNA-Seq based TGx data set to discover hidden functional modules. The RNA-Seq based gene expression profiles were transformed into "documents", on which latent Dirichlet allocation (LDA) was used to build a topic model. We found samples treated by the compounds with the same modes of actions (MoAs) could be clustered based on topic similarities. The topic most relevant to each cluster was identified as a "marker" topic, which was interpreted by gene enrichment analysis with MoAs then confirmed by compound and pathways associations mined from literature. To further validate the "marker" topics, we tested topic transferability from RNA-Seq to microarrays. The RNA-Seq based gene expression profile of a topic specifically associated with peroxisome proliferator-activated receptors (PPAR) signaling pathway was used to query samples with similar expression profiles in two different microarray data sets, yielding accuracy of about 85%. This proof-of-concept study demonstrates the applicability of topic modeling to discover functional modules in RNA-Seq data and suggests a valuable computational tool for leveraging information within TGx data in RNA-Seq era.

Multiple components of surround modulation in primary visual cortex: multiple neural circuits with multiple functions?

PubMed Central

Nurminen, Lauri; Angelucci, Alessandra

2014-01-01

The responses of neurons in primary visual cortex (V1) to stimulation of their receptive field (RF) are modulated by stimuli in the RF surround. This modulation is suppressive when the stimuli in the RF and surround are of similar orientation, but less suppressive or facilitatory when they are cross-oriented. Similarly, in human vision surround stimuli selectively suppress the perceived contrast of a central stimulus. Although the properties of surround modulation have been thoroughly characterized in many species, cortical areas and sensory modalities, its role in perception remains unknown. Here we argue that surround modulation in V1 consists of multiple components having different spatio-temporal and tuning properties, generated by different neural circuits and serving different visual functions. One component arises from LGN afferents, is fast, untuned for orientation, and spatially restricted to the surround region nearest to the RF (the near-surround); its function is to normalize V1 cell responses to local contrast. Intra-V1 horizontal connections contribute a slower, narrowly orientation-tuned component to near-surround modulation, whose function is to increase the coding efficiency of natural images in manner that leads to the extraction of object boundaries. The third component is generated by topdown feedback connections to V1, is fast, broadly orientation-tuned, and extends into the far-surround; its function is to enhance the salience of behaviorally relevant visual features. Far- and near-surround modulation, thus, act as parallel mechanisms: the former quickly detects and guides saccades/attention to salient visual scene locations, the latter segments object boundaries in the scene. PMID:25204770

Selective Androgen Receptor Modulators (SARMs) as Function Promoting Therapies

PubMed Central

Bhasin, Shalender; Jasuja, Ravi

2010-01-01

Purpose of review The last decade has witnessed unprecedented discovery effort to develop selective androgen receptor modulators (SARMs) that improve physical function and bone health without adversely affecting the prostate and cardiovascular outcomes. This review describes the historical evolution, the rationale for SARM development, and the mechanisms of testosterone action and SARM selectivity. Recent Findings While steroidal SARMs have been around since the 1940s, a number of nonsteroidal SARMs that do not serve as substrates for CYP19 aromatase or 5α-reductase, act as full agonists in muscle and bone and as partial agonists in prostate are in development. The differing interactions of steroidal and nonsteroidal compounds with AR contribute to their unique pharmacologic actions. Ligand binding induces specific conformational changes in the ligand binding domain, which could modulate surface topology and protein-protein interactions between AR and coregulators, resulting in tissue-specific gene regulation. Preclinical studies have demonstrated the ability of SARMs to increase muscle and bone mass in preclinical rodent models with varying degree of prostate sparing. Phase I trials of SARMs in humans have reported modest increments in fat-free mass. Summary SARMs hold promise as a new class of function promoting anabolic therapies for a number of clinical indications, including functional limitations associated with aging and chronic disease, frailty, cancer cachexia, and osteoporosis. PMID:19357508

Ocean wave-radar modulation transfer functions from the West Coast experiment

NASA Technical Reports Server (NTRS)

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

1980-01-01

Short gravity-capillary waves, the equilibrium, or the steady state excitations of the ocean surface are modulated by longer ocean waves. These short waves are the predominant microwave scatterers on the ocean surface under many viewing conditions so that the modulation is readily measured with CW Doppler radar used as a two-scale wave probe. Modulation transfer functions (the ratio of the cross spectrum of the line-of-sight orbital speed and backscattered microwave power to the autospectrum of the line-of-sight orbital speed) were measured at 9.375 and 1.5 GHz (Bragg wavelengths of 2.3 and 13 cm) for winds up to 10 m/s and ocean wave periods from 2-18 s. The measurements were compared with the relaxation-time model; the principal result is that a source of modulation other than straining by the horizontal component of orbital speed, possibly the wave-induced airflow, is responsible for most of the modulation by waves of typical ocean wave period (10 s). The modulations are large; for unit coherence, spectra of radar images of deep-water waves should be proportional to the quotient of the slope spectra of the ocean waves by the ocean wave frequency.

The Thickness Effect of the Functional Film for the Fabrication of Photovoltaic Module.

PubMed

Shan, Bowen; Kim, Jung Hyun; Choi, Wonseok

2018-09-01

In this study, a functional coating technology to improve the anti-fouling properties of the photo-voltaic module is introduced. The coating was applied on the cover glass, which is the same material as the photovoltaic module. After coating the cover glass once, twice, and three times in the horizontal and vertical directions respectively, the anti-fouling properties was tested according to the coating times and the thickness of the coating film. To ensure the durability of the coating film, the annealing process was performed for 1 hour at 200 °C in a furnace after coating. Finally, the photovoltaic module will be coated with the best coating method. Compared to uncoated modules, the coated photovoltaic modules showed significantly improved anti-fouling properties and also good performance in hardness and adhesion.

Parametric dependence of ocean wave-radar modulation transfer functions

NASA Technical Reports Server (NTRS)

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

1983-01-01

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

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

NASA Astrophysics Data System (ADS)

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

2011-06-01

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

An integrative approach to inferring biologically meaningful gene modules.

PubMed

Cho, Ji-Hoon; Wang, Kai; Galas, David J

2011-07-26

The ability to construct biologically meaningful gene networks and modules is critical for contemporary systems biology. Though recent studies have demonstrated the power of using gene modules to shed light on the functioning of complex biological systems, most modules in these networks have shown little association with meaningful biological function. We have devised a method which directly incorporates gene ontology (GO) annotation in construction of gene modules in order to gain better functional association. We have devised a method, Semantic Similarity-Integrated approach for Modularization (SSIM) that integrates various gene-gene pairwise similarity values, including information obtained from gene expression, protein-protein interactions and GO annotations, in the construction of modules using affinity propagation clustering. We demonstrated the performance of the proposed method using data from two complex biological responses: 1. the osmotic shock response in Saccharomyces cerevisiae, and 2. the prion-induced pathogenic mouse model. In comparison with two previously reported algorithms, modules identified by SSIM showed significantly stronger association with biological functions. The incorporation of semantic similarity based on GO annotation with gene expression and protein-protein interaction data can greatly enhance the functional relevance of inferred gene modules. In addition, the SSIM approach can also reveal the hierarchical structure of gene modules to gain a broader functional view of the biological system. Hence, the proposed method can facilitate comprehensive and in-depth analysis of high throughput experimental data at the gene network level.

An integrative approach to inferring biologically meaningful gene modules

PubMed Central

2011-01-01

Background The ability to construct biologically meaningful gene networks and modules is critical for contemporary systems biology. Though recent studies have demonstrated the power of using gene modules to shed light on the functioning of complex biological systems, most modules in these networks have shown little association with meaningful biological function. We have devised a method which directly incorporates gene ontology (GO) annotation in construction of gene modules in order to gain better functional association. Results We have devised a method, Semantic Similarity-Integrated approach for Modularization (SSIM) that integrates various gene-gene pairwise similarity values, including information obtained from gene expression, protein-protein interactions and GO annotations, in the construction of modules using affinity propagation clustering. We demonstrated the performance of the proposed method using data from two complex biological responses: 1. the osmotic shock response in Saccharomyces cerevisiae, and 2. the prion-induced pathogenic mouse model. In comparison with two previously reported algorithms, modules identified by SSIM showed significantly stronger association with biological functions. Conclusions The incorporation of semantic similarity based on GO annotation with gene expression and protein-protein interaction data can greatly enhance the functional relevance of inferred gene modules. In addition, the SSIM approach can also reveal the hierarchical structure of gene modules to gain a broader functional view of the biological system. Hence, the proposed method can facilitate comprehensive and in-depth analysis of high throughput experimental data at the gene network level. PMID:21791051

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

PubMed

Prinz, P; Ronacher, B

2002-08-01

The temporal resolution of auditory receptors of locusts was investigated by applying noise stimuli with sinusoidal amplitude modulations and by computing temporal modulation transfer functions. These transfer functions showed mostly bandpass characteristics, which are rarely found in other species at the level of receptors. From the upper cut-off frequencies of the modulation transfer functions the minimum integration times were calculated. Minimum integration times showed no significant correlation to the receptor spike rates but depended strongly on the body temperature. At 20 degrees C the average minimum integration time was 1.7 ms, dropping to 0.95 ms at 30 degrees C. The values found in this study correspond well to the range of minimum integration times found in birds and mammals. Gap detection is another standard paradigm to investigate temporal resolution. In locusts and other grasshoppers application of this paradigm yielded values of the minimum detectable gap widths that are approximately twice as large than the minimum integration times reported here.

Selective chemical detection by energy modulation of sensors

DOEpatents

Stetter, J.R.; Otagawa, T.

1985-05-20

A portable instrument for use in the field in detecting, identifying, and quantifying a component of a sampled fluid includes a sensor which chemically reacts with the component of interest or a derivative thereof, an electrical heating filament for heating the sample before it is applied to the sensor, and modulating means for continuously varying the temperature of the filament (and hence the reaction rate) between two values sufficient to produce the chemical reaction. In response to this thermal modulation, the sensor produces a modulated output signal, the modulation of which is a function of the activation energy of the chemical reaction, which activation energy is specific to the particular component of interest and its concentration. Microprocessor means compares the modulated output signal with standard responses for a plurality of components to identify and quantify the particular component of interest. 4 figs.

Differential network analysis reveals the genome-wide landscape of estrogen receptor modulation in hormonal cancers

PubMed Central

Hsiao, Tzu-Hung; Chiu, Yu-Chiao; Hsu, Pei-Yin; Lu, Tzu-Pin; Lai, Liang-Chuan; Tsai, Mong-Hsun; Huang, Tim H.-M.; Chuang, Eric Y.; Chen, Yidong

2016-01-01

Several mutual information (MI)-based algorithms have been developed to identify dynamic gene-gene and function-function interactions governed by key modulators (genes, proteins, etc.). Due to intensive computation, however, these methods rely heavily on prior knowledge and are limited in genome-wide analysis. We present the modulated gene/gene set interaction (MAGIC) analysis to systematically identify genome-wide modulation of interaction networks. Based on a novel statistical test employing conjugate Fisher transformations of correlation coefficients, MAGIC features fast computation and adaption to variations of clinical cohorts. In simulated datasets MAGIC achieved greatly improved computation efficiency and overall superior performance than the MI-based method. We applied MAGIC to construct the estrogen receptor (ER) modulated gene and gene set (representing biological function) interaction networks in breast cancer. Several novel interaction hubs and functional interactions were discovered. ER+ dependent interaction between TGFβ and NFκB was further shown to be associated with patient survival. The findings were verified in independent datasets. Using MAGIC, we also assessed the essential roles of ER modulation in another hormonal cancer, ovarian cancer. Overall, MAGIC is a systematic framework for comprehensively identifying and constructing the modulated interaction networks in a whole-genome landscape. MATLAB implementation of MAGIC is available for academic uses at https://github.com/chiuyc/MAGIC. PMID:26972162

Preservation of tissue microstructure and functionality during freezing by modulation of cytoskeletal structure

PubMed Central

Park, Seungman; Seawright, Angela; Park, Sinwook; Dutton, J Craig; Grinnell, Frederick; Han, Bumsoo

2015-01-01

Cryopreservation is one of the key enabling technologies for tissue engineering and regenerative medicine, which can provide a reliable long-term storage of engineered tissues (ETs) without losing their functionality. However, it is still extremely difficult to design and develop cryopreservation protocols guaranteeing the post-thaw tissue functionality. One of the major challenges in cryopreservation is associated with the difficulty of identifying effective and less toxic cryoprotective agents (CPAs) to guarantee the post-thaw tissue functionality. In this study, thus, a hypothesis was tested that the modulation of the cytoskeletal structure of cells embedded in the extracellular matrix (ECM) can mitigate the freezing-induced changes of the functionality and can reduce the amount of CPA necessary to preserve the functionality of ETs during cryopreservation. In order to test this hypothesis, we prepared dermal equivalents by seeding fibroblasts in type I collagen matrices resulting in three different cytoskeletal structures. These ETs were exposed to various freeze/thaw (F/T) conditions with and without CPAs. The freezing-induced cell-fluid-matrix interactions and subsequent functional properties of the ETs were assessed. The results showed that the cytoskeletal structure and the use of CPA were strongly correlated to the preservation of the post-thaw functional properties. As the cytoskeletal structure became stronger via stress fiber formation, the ETs functionality was preserved better. It also reduced the necessary CPA concentration to preserve the post-thaw functionality. However, if the extent of the freezing-induced cell-fluid-matrix interaction was too excessive, the cytoskeletal structure was completely destroyed and the beneficial effects became minimal. PMID:25679482

Genome-wide RNAi Screening to Identify Host Factors That Modulate Oncolytic Virus Therapy.

PubMed

Allan, Kristina J; Mahoney, Douglas J; Baird, Stephen D; Lefebvre, Charles A; Stojdl, David F

2018-04-03

High-throughput genome-wide RNAi (RNA interference) screening technology has been widely used for discovering host factors that impact virus replication. Here we present the application of this technology to uncovering host targets that specifically modulate the replication of Maraba virus, an oncolytic rhabdovirus, and vaccinia virus with the goal of enhancing therapy. While the protocol has been tested for use with oncolytic Maraba virus and oncolytic vaccinia virus, this approach is applicable to other oncolytic viruses and can also be utilized for identifying host targets that modulate virus replication in mammalian cells in general. This protocol describes the development and validation of an assay for high-throughput RNAi screening in mammalian cells, the key considerations and preparation steps important for conducting a primary high-throughput RNAi screen, and a step-by-step guide for conducting a primary high-throughput RNAi screen; in addition, it broadly outlines the methods for conducting secondary screen validation and tertiary validation studies. The benefit of high-throughput RNAi screening is that it allows one to catalogue, in an extensive and unbiased fashion, host factors that modulate any aspect of virus replication for which one can develop an in vitro assay such as infectivity, burst size, and cytotoxicity. It has the power to uncover biotherapeutic targets unforeseen based on current knowledge.

Graph coarse-graining reveals differences in the module-level structure of functional brain networks.

PubMed

Kujala, Rainer; Glerean, Enrico; Pan, Raj Kumar; Jääskeläinen, Iiro P; Sams, Mikko; Saramäki, Jari

2016-11-01

Networks have become a standard tool for analyzing functional magnetic resonance imaging (fMRI) data. In this approach, brain areas and their functional connections are mapped to the nodes and links of a network. Even though this mapping reduces the complexity of the underlying data, it remains challenging to understand the structure of the resulting networks due to the large number of nodes and links. One solution is to partition networks into modules and then investigate the modules' composition and relationship with brain functioning. While this approach works well for single networks, understanding differences between two networks by comparing their partitions is difficult and alternative approaches are thus necessary. To this end, we present a coarse-graining framework that uses a single set of data-driven modules as a frame of reference, enabling one to zoom out from the node- and link-level details. As a result, differences in the module-level connectivity can be understood in a transparent, statistically verifiable manner. We demonstrate the feasibility of the method by applying it to networks constructed from fMRI data recorded from 13 healthy subjects during rest and movie viewing. While independently partitioning the rest and movie networks is shown to yield little insight, the coarse-graining framework enables one to pinpoint differences in the module-level structure, such as the increased number of intra-module links within the visual cortex during movie viewing. In addition to quantifying differences due to external stimuli, the approach could also be applied in clinical settings, such as comparing patients with healthy controls. © 2016 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

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

NASA Astrophysics Data System (ADS)

Bell, L.

2002-01-01

The Sasakawa International Center for Space Architecture (SICSA) has a long history of projects that involve design of space structures, including habitats for low-Earth orbit (LEO) and planetary applications. Most of these facilities and component systems are planned to comply with size, geometry and mass restrictions imposed by the Space Shuttle Orbiter's payload and lift/landing abort restrictions. These constraints limit launch elements to approximately 15 ft. diameter, 40 ft. long cylindrical dimensions weighing no more than approximately 25 metric tons. It is clear that future success of commercial space programs such as tourism will hinge upon the availability of bigger and more efficient Earth to LEO launch vehicles which can greatly reduce transportation and operational costs. This will enable development and utilization of larger habitat modules and other infrastructure elements which can be deployed with fewer launches and on-orbit assembly procedures. The sizing of these new heavy lift launchers should be scaled to optimize habitat functionality and efficiency, just as the habitat designs must consider optimization of launch vehicle economy. SICSA's planning studies address these vehicle and habitat optimization priorities as parallel and interdependent considerations. The allowable diameter of habitat modules established by launch vehicle capacity dictates functionally acceptable internal configuration options. Analyses of these options relative to practical dimensions for Earth-to-orbit launch vehicle scaling were conducted for two general schemes. The "bologna slice" configuration stacks the floors within a predominately cylindrical or spherical envelope, producing circular areas. The "banana split" approach divides a cylindrical module longitudinally, creating floors that are generally rectangular in shape. The assessments established minimum sizes for reasonable utility and efficiency. The bologna slice option. This configuration is only acceptable

Which functional unit to identify sustainable foods?

PubMed

Masset, Gabriel; Vieux, Florent; Darmon, Nicole

2015-09-01

In life-cycle assessment, the functional unit defines the unit for calculation of environmental indicators. The objective of the present study was to assess the influence of two functional units, 100 g and 100 kcal (420 kJ), on the associations between three dimensions for identifying sustainable foods, namely environmental impact (via greenhouse gas emissions (GHGE)), nutritional quality (using two distinct nutrient profiling systems) and price. GHGE and price data were collected for individual foods, and were each expressed per 100 g and per 100 kcal. Two nutrient profiling models, SAIN,LIM and UK Ofcom, were used to assess foods' nutritional quality. Spearman correlations were used to assess associations between variables. Sustainable foods were identified as those having more favourable values for all three dimensions. The French Individual and National Dietary Survey (INCA2), 2006-2007. Three hundred and seventy-three foods highly consumed in INCA2, covering 65 % of total energy intake of adult participants. When GHGE and price were expressed per 100 g, low-GHGE foods had a lower price and higher SAIN,LIM and Ofcom scores (r=0·59, -0·34 and -0·43, respectively), suggesting a compatibility between the three dimensions; 101 and 100 sustainable foods were identified with SAIN,LIM and Ofcom, respectively. When GHGE and price were expressed per 100 kcal, low-GHGE foods had a lower price but also lower SAIN,LIM and Ofcom scores (r=0·67, 0·51 and 0·47, respectively), suggesting that more environment-friendly foods were less expensive but also less healthy; thirty-four sustainable foods were identified with both SAIN,LIM and Ofcom. The choice of functional unit strongly influenced the compatibility between the sustainability dimensions and the identification of sustainable foods.

Benchmark data for identifying multi-functional types of membrane proteins.

PubMed

Wan, Shibiao; Mak, Man-Wai; Kung, Sun-Yuan

2016-09-01

Identifying membrane proteins and their multi-functional types is an indispensable yet challenging topic in proteomics and bioinformatics. In this article, we provide data that are used for training and testing Mem-ADSVM (Wan et al., 2016. "Mem-ADSVM: a two-layer multi-label predictor for identifying multi-functional types of membrane proteins" [1]), a two-layer multi-label predictor for predicting multi-functional types of membrane proteins.

Strategies to identify natural antisense transcripts.

PubMed

Sun, Yulong; Li, Dijie; Zhang, Ru; Peng, Shang; Zhang, Ge; Yang, Tuanmin; Qian, Airong

2017-01-01

Natural antisense transcripts, originally considered as transcriptional noises arising from so-called "junk DNA″, are recently recognized as important modulators for gene regulation. They are prevalent in nearly all realms of life and have been found to modulate gene expression positively or negatively. By affecting almost all stages of gene expression range from pre-transcriptional, transcriptional and post-transcriptional to translation, NATs are fundamentally involved in various biological processes. However, compared to increasing huge data from transcriptional analysis especially high-throughput sequencing technologies (such as RNA-seq), limited functional NATs (around 70) are so far reported, which hinder our advanced comprehensive understanding for this field. Hence, efficient strategies for identifying NATs are urgently desired. In this review, we discussed the current strategies for identifying NATs, with a focus on the advantages, disadvantages, and applications of methods isolating functional NATs. Moreover, publicly available databases for NATs were also discussed. Copyright © 2016 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

Identification of Unstable Network Modules Reveals Disease Modules Associated with the Progression of Alzheimer’s Disease

PubMed Central

Kikuchi, Masataka; Ogishima, Soichi; Miyamoto, Tadashi; Miyashita, Akinori; Kuwano, Ryozo; Nakaya, Jun; Tanaka, Hiroshi

2013-01-01

Alzheimer’s disease (AD), the most common cause of dementia, is associated with aging, and it leads to neuron death. Deposits of amyloid β and aberrantly phosphorylated tau protein are known as pathological hallmarks of AD, but the underlying mechanisms have not yet been revealed. A high-throughput gene expression analysis previously showed that differentially expressed genes accompanying the progression of AD were more down-regulated than up-regulated in the later stages of AD. This suggested that the molecular networks and their constituent modules collapsed along with AD progression. In this study, by using gene expression profiles and protein interaction networks (PINs), we identified the PINs expressed in three brain regions: the entorhinal cortex (EC), hippocampus (HIP) and superior frontal gyrus (SFG). Dividing the expressed PINs into modules, we examined the stability of the modules with AD progression and with normal aging. We found that in the AD modules, the constituent proteins, interactions and cellular functions were not maintained between consecutive stages through all brain regions. Interestingly, the modules were collapsed with AD progression, specifically in the EC region. By identifying the modules that were affected by AD pathology, we found the transcriptional regulation-associated modules that interact with the proteasome-associated module via UCHL5 hub protein, which is a deubiquitinating enzyme. Considering PINs as a system made of network modules, we found that the modules relevant to the transcriptional regulation are disrupted in the EC region, which affects the ubiquitin-proteasome system. PMID:24348898

The modulation of visceral functions by somatic afferent activity.

PubMed

Sato, A; Schmidt, R F

1987-01-01

We began by briefly reviewing the historical background of neurophysiological studies of the somato-autonomic reflexes and then discussed recent studies on somatic-visceral reflexes in combination with autonomic efferent nerve activity and effector organ responses. Most of the studies that have advanced our knowledge in this area have been carried out on anesthetized animals, thus eliminating emotional factors. We would like to emphasize again that the functions of many, or perhaps all visceral organs can be modulated by somato-sympathetic or somato-parasympathetic reflex activity induced by a appropriate somatic afferent stimulation in anesthetized animals. As mentioned previously, some autonomic nervous outflow, e.g. the adrenal sympathetic nerve activity, is involved in the control of hormonal secretion. John F. Fulton wrote in his famous textbook "Physiology of the Nervous System" (1949) that the posterior pituitary neurosecretion system (i.e. for oxytocin and vasopressin) could be considered a part of the parasympathetic nervous system. In the study of body homeostasis and environmental adaptation it would seem very important to further analyze the contribution of somatic afferent input to the autonomic nervous and hormonal regulation of visceral organ activity. Also, some immunological functions have been found to be influenced by autonomic nerves or hormones (e.g. adrenal cortical hormone and catecholamines). Finally, we must take into account, as we have briefly discussed, that visceral functions can be modulated by somatic afferent input via various degrees of integration of autonomic nerves, hormones, and immunological processes. We trust that such research will be expanded to higher species of mammals, and that ultimately this knowledge of somato-visceral reflexes obtained in the physiological laboratory will become clinically useful in influencing visceral functions.

Functional Redundancy Between Canonical Endocannabinoid Signaling Systems in the Modulation of Anxiety.

PubMed

Bedse, Gaurav; Hartley, Nolan D; Neale, Emily; Gaulden, Andrew D; Patrick, Toni A; Kingsley, Philip J; Uddin, Md Jashim; Plath, Niels; Marnett, Lawrence J; Patel, Sachin

2017-10-01

Increasing the available repertoire of effective treatments for mood and anxiety disorders represents a critical unmet need. Pharmacological augmentation of endogenous cannabinoid (eCB) signaling has been suggested to represent a novel approach to the treatment of anxiety disorders; however, the functional interactions between two canonical eCB pathways mediated via anandamide (N-arachidonylethanolamine [AEA]) and 2-arachidonoylglycerol (2-AG) in the regulation of anxiety are not well understood. We utilized pharmacological augmentation and depletion combined with behavioral and electrophysiological approaches to probe the role of 2-AG signaling in the modulation of stress-induced anxiety and the functional redundancy between AEA and 2-AG signaling in the modulation of anxiety-like behaviors in mice. Selective 2-AG augmentation reduced anxiety in the light/dark box assay and prevented stress-induced increases in anxiety associated with limbic AEA deficiency. In contrast, acute 2-AG depletion increased anxiety-like behaviors, which was normalized by selective pharmacological augmentation of AEA signaling and via direct cannabinoid receptor 1 stimulation with Δ 9 -tetrahydrocannabinol. Electrophysiological studies revealed 2-AG modulation of amygdala glutamatergic transmission as a key synaptic correlate of the anxiolytic effects of 2-AG augmentation. Although AEA and 2-AG likely subserve distinct physiological roles, a pharmacological and functional redundancy between these canonical eCB signaling pathways exists in the modulation of anxiety-like behaviors. These data support development of eCB-based treatment approaches for mood and anxiety disorders and suggest a potentially wider therapeutic overlap between AEA and 2-AG augmentation approaches than was previously appreciated. Copyright © 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Microarray and network-based identification of functional modules and pathways of active tuberculosis.

PubMed

Bian, Zhong-Rui; Yin, Juan; Sun, Wen; Lin, Dian-Jie

2017-04-01

Diagnose of active tuberculosis (TB) is challenging and treatment response is also difficult to efficiently monitor. The aim of this study was to use an integrated analysis of microarray and network-based method to the samples from publically available datasets to obtain a diagnostic module set and pathways in active TB. Towards this goal, background protein-protein interactions (PPI) network was generated based on global PPI information and gene expression data, following by identification of differential expression network (DEN) from the background PPI network. Then, ego genes were extracted according to the degree features in DEN. Next, module collection was conducted by ego gene expansion based on EgoNet algorithm. After that, differential expression of modules between active TB and controls was evaluated using random permutation test. Finally, biological significance of differential modules was detected by pathways enrichment analysis based on Reactome database, and Fisher's exact test was implemented to extract differential pathways for active TB. Totally, 47 ego genes and 47 candidate modules were identified from the DEN. By setting the cutoff-criteria of gene size >5 and classification accuracy ≥0.9, 7 ego modules (Module 4, Module 7, Module 9, Module 19, Module 25, Module 38 and Module 43) were extracted, and all of them had the statistical significance between active TB and controls. Then, Fisher's exact test was conducted to capture differential pathways for active TB. Interestingly, genes in Module 4, Module 25, Module 38, and Module 43 were enriched in the same pathway, formation of a pool of free 40S subunits. Significant pathway for Module 7 and Module 9 was eukaryotic translation termination, and for Module 19 was nonsense mediated decay enhanced by the exon junction complex (EJC). Accordingly, differential modules and pathways might be potential biomarkers for treating active TB, and provide valuable clues for better understanding of molecular

Selective chemical detection by energy modulation of sensors

DOEpatents

Stetter, Joseph R.; Otagawa, Takaaki

1991-01-01

A portable instrument for use in the field in detecting, identifying, and quantifying a component of a sampled fluid includes a sensor which chemically reacts with the component of interest or a derivative thereof, an electrical heating filament for heating the sample before it is applied to the sensor, and modulator for continuously varying the temperature of the filament (and hence the reaction rate) between two values sufficient to produce the chemical reaction. In response to this thermal modulation, the sensor produces a modulated output signal, the modulation of which is a function of the activation energy of the chemical reaction, which activation energy is specific to the particular component of interest and its concentration. Microprocessor which compares the modulated output signal with standard responses for a plurality of components to identify and quantify the particular component of interest. In particular, the concentration of the component of interest is proportional to the amplitude of the modulated output signal, while the identifying activation output energy of the chemical interaction indicative of that component is proportional to a normalized parameter equal to the peak-to-peak amplitude divided by the height of the upper peaks above a base line signal level.

Modulation transfer function measurement technique for small-pixel detectors

NASA Technical Reports Server (NTRS)

Marchywka, Mike; Socker, Dennis G.

1992-01-01

A modulation transfer function (MTF) measurement technique suitable for large-format, small-pixel detector characterization has been investigated. A volume interference grating is used as a test image instead of the bar or sine wave target images normally used. This technique permits a high-contrast, large-area, sinusoidal intensity distribution to illuminate the device being tested, avoiding the need to deconvolve raw data with imaging system characteristics. A high-confidence MTF result at spatial frequencies near 200 cycles/mm is obtained. We present results at several visible light wavelengths with a 6.8-micron-pixel CCD. Pixel response functions are derived from the MTF results.

A Western Diet Ecological Module Identified from the ‘Humanized’ Mouse Microbiota Predicts Diet in Adults and Formula Feeding in Children

PubMed Central

Siddharth, Jay; Holway, Nicholas; Parkinson, Scott J.

2013-01-01

The interplay between diet and the microbiota has been implicated in the growing frequency of chronic diseases associated with the Western lifestyle. However, the complexity and variability of microbial ecology in humans and preclinical models has hampered identification of the molecular mechanisms underlying the association of the microbiota in this context. We sought to address two key questions. Can the microbial ecology of preclinical models predict human populations? And can we identify underlying principles that surpass the plasticity of microbial ecology in humans? To do this, we focused our study on diet; perhaps the most influential factor determining the composition of the gut microbiota. Beginning with a study in ‘humanized’ mice we identified an interactive module of 9 genera allied with Western diet intake. This module was applied to a controlled dietary study in humans. The abundance of the Western ecological module correctly predicted the dietary intake of 19/21 top and 21/21 of the bottom quartile samples inclusive of all 5 Western and ‘low-fat’ diet subjects, respectively. In 98 volunteers the abundance of the Western module correlated appropriately with dietary intake of saturated fatty acids, fat-soluble vitamins and fiber. Furthermore, it correlated with the geographical location and dietary habits of healthy adults from the Western, developing and third world. The module was also coupled to dietary intake in children (and piglets) correlating with formula (vs breast) feeding and associated with a precipitous development of the ecological module in young children. Our study provides a conceptual platform to translate microbial ecology from preclinical models to humans and identifies an ecological network module underlying the association of the gut microbiota with Western dietary habits. PMID:24391809

Postnatal Experience Modulates Functional Properties of Mouse Olfactory Sensory Neurons

PubMed Central

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

2012-01-01

Early experience considerably modulates the organization and function of all sensory systems. In the mammalian olfactory system, deprivation of the sensory inputs via neonatal, unilateral naris closure has been shown to induce structural, molecular, and functional changes from the olfactory epithelium to the olfactory bulb and cortex. However, it remains unknown how early experience shapes functional properties of individual olfactory sensory neurons (OSNs), the primary odor detectors in the nose. To address this question, we examined odorant response properties of mouse OSNs in both the closed and open nostril after four weeks of unilateral naris closure with age-matched untreated animals as control. Using patch-clamp technique on genetically-tagged OSNs with defined odorant receptors (ORs), we found that sensory deprivation increased the sensitivity of MOR23 neurons in the closed side while overexposure caused the opposite effect in the open side. We next analyzed the response properties including rise time, decay time, and adaptation induced by repeated stimulation in MOR23 and M71 neurons. Even though these two types of neurons showed distinct properties in dynamic range and response kinetics, sensory deprivation significantly slowed down the decay phase of odorant-induced transduction events in both types. Using western blotting and antibody staining, we confirmed upregulation of several signaling proteins in the closed side as compared with the open side. This study suggests that early experience modulates functional properties of OSNs, probably via modifying the signal transduction cascade. PMID:22703547

The response function of modulated grid Faraday cup plasma instruments

NASA Technical Reports Server (NTRS)

Barnett, A.; Olbert, S.

1986-01-01

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

Functional description of the FAA's Aviation Environmental Design Tool's aircraft acoustics module

DOT National Transportation Integrated Search

2008-07-28

This paper presents architectural and functional descriptions of the Aircraft Acoustics Module : (AAM) in the Federal Aviation Administrations Aviation Environmental Design Tool (AEDT) : for modeling aircraft noise in the vicinity of airports. Whi...

Evidence of Rentian Scaling of Functional Modules in Diverse Biological Networks.

PubMed

How, Javier J; Navlakha, Saket

2018-06-12

Biological networks have long been known to be modular, containing sets of nodes that are highly connected internally. Less emphasis, however, has been placed on understanding how intermodule connections are distributed within a network. Here, we borrow ideas from engineered circuit design and study Rentian scaling, which states that the number of external connections between nodes in different modules is related to the number of nodes inside the modules by a power-law relationship. We tested this property in a broad class of molecular networks, including protein interaction networks for six species and gene regulatory networks for 41 human and 25 mouse cell types. Using evolutionarily defined modules corresponding to known biological processes in the cell, we found that all networks displayed Rentian scaling with a broad range of exponents. We also found evidence for Rentian scaling in functional modules in the Caenorhabditis elegans neural network, but, interestingly, not in three different social networks, suggesting that this property does not inevitably emerge. To understand how such scaling may have arisen evolutionarily, we derived a new graph model that can generate Rentian networks given a target Rent exponent and a module decomposition as inputs. Overall, our work uncovers a new principle shared by engineered circuits and biological networks.

Weighted gene co-expression network analysis of expression data of monozygotic twins identifies specific modules and hub genes related to BMI.

PubMed

Wang, Weijing; Jiang, Wenjie; Hou, Lin; Duan, Haiping; Wu, Yili; Xu, Chunsheng; Tan, Qihua; Li, Shuxia; Zhang, Dongfeng

2017-11-13

The therapeutic management of obesity is challenging, hence further elucidating the underlying mechanisms of obesity development and identifying new diagnostic biomarkers and therapeutic targets are urgent and necessary. Here, we performed differential gene expression analysis and weighted gene co-expression network analysis (WGCNA) to identify significant genes and specific modules related to BMI based on gene expression profile data of 7 discordant monozygotic twins. In the differential gene expression analysis, it appeared that 32 differentially expressed genes (DEGs) were with a trend of up-regulation in twins with higher BMI when compared to their siblings. Categories of positive regulation of nitric-oxide synthase biosynthetic process, positive regulation of NF-kappa B import into nucleus, and peroxidase activity were significantly enriched within GO database and NF-kappa B signaling pathway within KEGG database. DEGs of NAMPT, TLR9, PTGS2, HBD, and PCSK1N might be associated with obesity. In the WGCNA, among the total 20 distinct co-expression modules identified, coral1 module (68 genes) had the strongest positive correlation with BMI (r = 0.56, P = 0.04) and disease status (r = 0.56, P = 0.04). Categories of positive regulation of phospholipase activity, high-density lipoprotein particle clearance, chylomicron remnant clearance, reverse cholesterol transport, intermediate-density lipoprotein particle, chylomicron, low-density lipoprotein particle, very-low-density lipoprotein particle, voltage-gated potassium channel complex, cholesterol transporter activity, and neuropeptide hormone activity were significantly enriched within GO database for this module. And alcoholism and cell adhesion molecules pathways were significantly enriched within KEGG database. Several hub genes, such as GAL, ASB9, NPPB, TBX2, IL17C, APOE, ABCG4, and APOC2 were also identified. The module eigengene of saddlebrown module (212 genes) was also significantly

Career Education. Administrators and Counselors Implementation Model. Module III--Teacher Information and Orientation for Administrators. (3.1) Identify Change Strategy.

ERIC Educational Resources Information Center

Thompson, John A.; Chock, Mona K.O.

Part of a 13-volume series designed to be used as a group inservice or a self-learning system to train school administrators and counselors for their role in career education, this section of module 3 is designed to identify change strategies to help the principal motivate teachers to accept the concept of career education. (Module 3 is one of six…

Life span and structure of ephemeral root modules of different functional groups from a desert system.

PubMed

Liu, Bo; He, Junxia; Zeng, Fanjiang; Lei, Jiaqiang; Arndt, Stefan K

2016-07-01

The terminal branch orders of plant root systems have been proposed as short-lived 'ephemeral' modules specialized for resource absorption. The occurrence of ephemeral root modules has so far only been reported for a temperate tree species and it is unclear if the concept also applies to other woody (shrub, tree) and herb species. Fine roots of 12 perennial dicotyledonous herb, shrub and tree species were monitored for two growing seasons using a branch-order classification, sequential sampling and rhizotrons in the Taklamakan desert. Two root modules existed in all three plant functional groups. Among the first five branch orders, the first two (perennial herbs, shrubs) or three (trees) root orders were ephemeral and had a primary anatomical structure, high nitrogen (N) concentrations, high respiration rates and very short life spans of 1-4 months, whereas the last two branch orders in all functional groups were perennial, with thicker diameters, no or collapsed cortex, distinct secondary growth, low N concentrations, low respiration rates, but much longer life spans. Ephemeral, short-lived root modules and long-lived, persistent root modules seem to be a general feature across many plant functional groups and could represent a basic root system design. © 2016 The Authors. New Phytologist © 2016 New Phytologist Trust.

Modulation of α power and functional connectivity during facial affect recognition.

PubMed

Popov, Tzvetan; Miller, Gregory A; Rockstroh, Brigitte; Weisz, Nathan

2013-04-03

Research has linked oscillatory activity in the α frequency range, particularly in sensorimotor cortex, to processing of social actions. Results further suggest involvement of sensorimotor α in the processing of facial expressions, including affect. The sensorimotor face area may be critical for perception of emotional face expression, but the role it plays is unclear. The present study sought to clarify how oscillatory brain activity contributes to or reflects processing of facial affect during changes in facial expression. Neuromagnetic oscillatory brain activity was monitored while 30 volunteers viewed videos of human faces that changed their expression from neutral to fearful, neutral, or happy expressions. Induced changes in α power during the different morphs, source analysis, and graph-theoretic metrics served to identify the role of α power modulation and cross-regional coupling by means of phase synchrony during facial affect recognition. Changes from neutral to emotional faces were associated with a 10-15 Hz power increase localized in bilateral sensorimotor areas, together with occipital power decrease, preceding reported emotional expression recognition. Graph-theoretic analysis revealed that, in the course of a trial, the balance between sensorimotor power increase and decrease was associated with decreased and increased transregional connectedness as measured by node degree. Results suggest that modulations in α power facilitate early registration, with sensorimotor cortex including the sensorimotor face area largely functionally decoupled and thereby protected from additional, disruptive input and that subsequent α power decrease together with increased connectedness of sensorimotor areas facilitates successful facial affect recognition.

Modulation transfer function of a triangular pixel array detector.

PubMed

Karimzadeh, Ayatollah

2014-07-01

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

Protein kinase inhibitor peptide (PKI): a family of endogenous neuropeptides that modulate neuronal cAMP-dependent protein kinase function.

PubMed

Dalton, George D; Dewey, William L

2006-02-01

Signal transduction cascades involving cAMP-dependent protein kinase are highly conserved among a wide variety of organisms. Given the universal nature of this enzyme it is not surprising that cAMP-dependent protein kinase plays a critical role in numerous cellular processes. This is particularly evident in the nervous system where cAMP-dependent protein kinase is involved in neurotransmitter release, gene transcription, and synaptic plasticity. Protein kinase inhibitor peptide (PKI) is an endogenous thermostable peptide that modulates cAMP-dependent protein kinase function. PKI contains two distinct functional domains within its amino acid sequence that allow it to: (1) potently and specifically inhibit the activity of the free catalytic subunit of cAMP-dependent protein kinase and (2) export the free catalytic subunit of cAMP-dependent protein kinase from the nucleus. Three distinct PKI isoforms (PKIalpha, PKIbeta, PKIgamma) have been identified and each isoform is expressed in the brain. PKI modulates neuronal synaptic activity, while PKI also is involved in morphogenesis and symmetrical left-right axis formation. In addition, PKI also plays a role in regulating gene expression induced by cAMP-dependent protein kinase. Future studies should identify novel physiological functions for endogenous PKI both in the nervous system and throughout the body. Most interesting will be the determination whether functional differences exist between individual PKI isoforms which is an intriguing possibility since these isoforms exhibit: (1) cell-type specific tissue expression patterns, (2) different potencies for the inhibition of cAMP-dependent protein kinase activity, and (3) expression patterns that are hormonally, developmentally and cell-cycle regulated. Finally, synthetic peptide analogs of endogenous PKI will continue to be invaluable tools that are used to elucidate the role of cAMP-dependent protein kinase in a variety of cellular processes throughout the nervous

Relationships between self-reported ankle function and modulation of Hoffmann reflex in patients with chronic ankle instability.

PubMed

Kim, Kyung-Min; Hart, Joseph M; Saliba, Susan A; Hertel, Jay

2016-01-01

To examine relationships between self-reported ankle function and Hoffmann (H) reflex modulation during changes in body positions in patients with chronic ankle instability (CAI). Observational. Laboratory. Thirty-one young adults with CAI (19 males, 12 females) participated. There were two subscales of Foot and Ankle Ability Measure (FAAM) to quantify self-reported ankle function during activities of daily living (ADL) and sports activities. Maximum H-reflexes (H-max) and motor waves (M-max) from soleus and fibularis longus were recorded while participants lied prone and stood in bipedal and unipedal stances. For each muscle, percent change scores in Hmax:Mmax ratios were calculated between each pair of positions: prone-to-bipedal, bipedal-to-unipedal, and prone-to-unipedal, and used as a measure of H-reflex modulation. Pearson correlation coefficients were calculated between FAAM and H-reflex modulation measures. There were significant correlations between: (1) FAAM-ADL and soleus prone-to-unipedal modulation (r = 0.384, p = 0.04), (2) FAAM-Sport and soleus prone-to-unipedal modulation (r = 0.505, p = 0.005), (3) FAAM-Sport and fibular bipedal-to-unipedal modulation (r = 0.377, p = 0.05), and (4) FAAM-Sport and fibular prone-to-unipedal modulation (r = 0.396, p = 0.04). CAI patients presented moderate, positive relationships between self-reported ankle function and H-reflex modulation during changes in body positions. Copyright © 2015 Elsevier Ltd. All rights reserved.

A-7E Software Module Guide.

DTIC Science & Technology

1981-12-08

o 14 A& B:2.1 Function Driver Module.. ..... .... 14’ ’: B:2.2 Shared Services Module . . . o o . 0 -15 M’ 5:3 Software Decision Module...2.1.13 Weapon Release Functions... ........24 C:2.l.14 Ground Test Functions .. ........... 24 C:2.2 Shared Services Module Decomposition. ........24 C...Driver (FD) Module supported by a Shared Services (SS) Module. B:2.1 FUNCTION DRIVER MODULE The Function Driver Module consists of a set of individual

Selective chemical detection by energy modulation of sensors

DOEpatents

Stetter, J.R.; Otagawa, T.

1991-09-10

A portable instrument for use in the field in detecting, identifying, and quantifying a component of a sampled fluid includes a sensor which chemically reacts with the component of interest or a derivative thereof, an electrical heating filament for heating the sample before it is applied to the sensor, and modulator for continuously varying the temperature of the filament (and hence the reaction rate) between two values sufficient to produce the chemical reaction. In response to this thermal modulation, the sensor produces a modulated output signal, the modulation of which is a function of the activation energy of the chemical reaction, which activation energy is specific to the particular component of interest and its concentration. Microprocessor which compares the modulated output signal with standard responses for a plurality of components to identify and quantify the particular component of interest. In particular, the concentration of the component of interest is proportional to the amplitude of the modulated output signal, while the identifying activation output energy of the chemical interaction indicative of that component is proportional to a normalized parameter equal to the peak-to-peak amplitude divided by the height of the upper peaks above a base line signal level. 5 figures.

A strategy to identify linker-based modules for the allosteric regulation of antibody-antigen binding affinities of different scFvs

PubMed Central

Thie, Holger

2017-01-01

ABSTRACT Antibody single-chain variable fragments (scFvs) are used in a variety of applications, such as for research, diagnosis and therapy. Essential for these applications is the extraordinary specificity, selectivity and affinity of antibody paratopes, which can also be used for efficient protein purification. However, this use is hampered by the high affinity for the protein to be purified because harsh elution conditions, which may impair folding, integrity or viability of the eluted biomaterials, are typically required. In this study, we developed a strategy to obtain structural elements that provide allosteric modulation of the affinities of different antibody scFvs for their antigen. To identify suitable allosteric modules, a complete set of cyclic permutations of calmodulin variants was generated and tested for modulation of the affinity when substituting the linker between VH and VL. Modulation of affinity induced by addition of different calmodulin-binding peptides at physiologic conditions was demonstrated for 5 of 6 tested scFvs of different specificities and antigens ranging from cell surface proteins to haptens. In addition, a variety of different modulator peptides were tested. Different structural solutions were found in respect of the optimal calmodulin permutation, the optimal peptide and the allosteric effect for scFvs binding to different antigen structures. Significantly, effective linker modules were identified for scFvs with both VH-VL and VL-VH architecture. The results suggest that this approach may offer a rapid, paratope-independent strategy to provide allosteric regulation of affinity for many other antibody scFvs. PMID:28055297

Phonological experience modulates voice discrimination: Evidence from functional brain networks analysis.

PubMed

Hu, Xueping; Wang, Xiangpeng; Gu, Yan; Luo, Pei; Yin, Shouhang; Wang, Lijun; Fu, Chao; Qiao, Lei; Du, Yi; Chen, Antao

2017-10-01

Numerous behavioral studies have found a modulation effect of phonological experience on voice discrimination. However, the neural substrates underpinning this phenomenon are poorly understood. Here we manipulated language familiarity to test the hypothesis that phonological experience affects voice discrimination via mediating the engagement of multiple perceptual and cognitive resources. The results showed that during voice discrimination, the activation of several prefrontal regions was modulated by language familiarity. More importantly, the same effect was observed concerning the functional connectivity from the fronto-parietal network to the voice-identity network (VIN), and from the default mode network to the VIN. Our findings indicate that phonological experience could bias the recruitment of cognitive control and information retrieval/comparison processes during voice discrimination. Therefore, the study unravels the neural substrates subserving the modulation effect of phonological experience on voice discrimination, and provides new insights into studying voice discrimination from the perspective of network interactions. Copyright © 2017. Published by Elsevier Inc.

Remote Synchronization Reveals Network Symmetries and Functional Modules

NASA Astrophysics Data System (ADS)

Nicosia, Vincenzo; Valencia, Miguel; Chavez, Mario; Díaz-Guilera, Albert; Latora, Vito

2013-04-01

We study a Kuramoto model in which the oscillators are associated with the nodes of a complex network and the interactions include a phase frustration, thus preventing full synchronization. The system organizes into a regime of remote synchronization where pairs of nodes with the same network symmetry are fully synchronized, despite their distance on the graph. We provide analytical arguments to explain this result, and we show how the frustration parameter affects the distribution of phases. An application to brain networks suggests that anatomical symmetry plays a role in neural synchronization by determining correlated functional modules across distant locations.

Sperm-binding fibronectin type II-module proteins are genetically linked and functionally related.

PubMed

Ekhlasi-Hundrieser, Mahnaz; Schäfer, Bettina; Philipp, Ute; Kuiper, Heidi; Leeb, Tosso; Mehta, Meenal; Kirchhoff, Christiane; Töpfer-Petersen, Edda

2007-05-01

Fibronectin type II (Fn2) module-containing proteins in the male genital tract are characterized by different numbers of Fn2 modules. Predominantly two classes exist which are distinct by having either two or four Fn2 modules. Minor variants with three Fn2 modules were also found in the human and the porcine epididymis. To reveal their relationship, mRNAs and proteins of representatives of these classes were studied in human, in Sus scrofa, and in rodents. Adult boars expressed members of both classes, i.e. ELSPBP1 and pB1, in subsequent regions of the epididymis, and both were under androgenic control. Human and rodent epididymides, on the other hand, alternatively contained only representatives of one of these two classes, i.e. ELSPBP1 in the human and two different pB1-related counterparts in rodents. ELSPBP1 and pB1-related genomic sequences were closely linked in chromosomal regions HSA 19q and SSC 6 q11-q21; conserved synteny between these regions is well established. On the other hand, in a syntenic region on mouse chromosome 7, ELSPBP1-related sequences were lacking. Tight binding to the sperm membrane via a choline-mediated mechanism was a common feature of the two classes of Fn2-module proteins, suggesting related function(s). However, differences in their regionalized expression patterns along the male genital tract as well as in association sites on the sperm surface suggested a species-specific sequential order in sperm binding.

Functional specification of the Performance Measurement (PM) module

NASA Technical Reports Server (NTRS)

Berliner, J. E.

1980-01-01

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

Conical : An extended module for computing a numerically satisfactory pair of solutions of the differential equation for conical functions

NASA Astrophysics Data System (ADS)

Dunster, T. M.; Gil, A.; Segura, J.; Temme, N. M.

2017-08-01

Conical functions appear in a large number of applications in physics and engineering. In this paper we describe an extension of our module Conical (Gil et al., 2012) for the computation of conical functions. Specifically, the module includes now a routine for computing the function R-1/2+ iτ m (x) , a real-valued numerically satisfactory companion of the function P-1/2+ iτ m (x) for x > 1. In this way, a natural basis for solving Dirichlet problems bounded by conical domains is provided. The module also improves the performance of our previous algorithm for the conical function P-1/2+ iτ m (x) and it includes now the computation of the first order derivative of the function. This is also considered for the function R-1/2+ iτ m (x) in the extended algorithm.

Phosducin-like protein: an ethanol-responsive potential modulator of guanine nucleotide-binding protein function.

PubMed

Miles, M F; Barhite, S; Sganga, M; Elliott, M

1993-11-15

Acute and chronic exposure to ethanol produces specific changes in several signal transduction cascades. Such alterations in signaling are thought to be a crucial aspect of the central nervous system's adaptive response, which occurs with chronic exposure to ethanol. We have recently identified and isolated several genes whose expression is specifically induced by ethanol in neural cell cultures. The product of one of these genes has extensive sequence homology to phosducin, a phosphoprotein expressed in retina and pineal gland that modulates trimeric guanine nucleotide-binding protein (G protein) function by binding to G-protein beta gamma subunits. We identified from a rat brain cDNA library an isolate encoding the phosducin-like protein (PhLP), which has 41% identity and 65% amino acid homology to phosducin. PhLP cDNA is expressed in all tissues screened by RNA blot-hybridization analysis and shows marked evolutionary conservation on Southern hybridization. We have identified four forms of PhLP cDNA varying only in their 5' ends, probably due to alternative splicing. This 5'-end variation generates two predicted forms of PhLP protein that differ by 79 aa at the NH2 terminus. Treatment of NG108-15 cells for 24 hr with concentrations of ethanol seen in actively drinking alcoholics (25-100 mM) causes up to a 3-fold increase in PhLP mRNA levels. Induction of PhLP by ethanol could account for at least some of the widespread alterations in signal transduction and G-protein function that are known to occur with chronic exposure to ethanol.

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

PubMed Central

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

1999-01-01

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

Simulation verification techniques study. Task report 4: Simulation module performance parameters and performance standards

NASA Technical Reports Server (NTRS)

1974-01-01

Shuttle simulation software modules in the environment, crew station, vehicle configuration and vehicle dynamics categories are discussed. For each software module covered, a description of the module functions and operational modes, its interfaces with other modules, its stored data, inputs, performance parameters and critical performance parameters is given. Reference data sources which provide standards of performance are identified for each module. Performance verification methods are also discussed briefly.

Performance of SEM scintillation detector evaluated by modulation transfer function and detective quantum efficiency function.

PubMed

Bok, Jan; Schauer, Petr

2014-01-01

In the paper, the SEM detector is evaluated by the modulation transfer function (MTF) which expresses the detector's influence on the SEM image contrast. This is a novel approach, since the MTF was used previously to describe only the area imaging detectors, or whole imaging systems. The measurement technique and calculation of the MTF for the SEM detector are presented. In addition, the measurement and calculation of the detective quantum efficiency (DQE) as a function of the spatial frequency for the SEM detector are described. In this technique, the time modulated e-beam is used in order to create well-defined input signal for the detector. The MTF and DQE measurements are demonstrated on the Everhart-Thornley scintillation detector. This detector was alternated using the YAG:Ce, YAP:Ce, and CRY18 single-crystal scintillators. The presented MTF and DQE characteristics show good imaging properties of the detectors with the YAP:Ce or CRY18 scintillator, especially for a specific type of the e-beam scan. The results demonstrate the great benefit of the description of SEM detectors using the MTF and DQE. In addition, point-by-point and continual-sweep e-beam scans in SEM were discussed and their influence on the image quality was revealed using the MTF. © 2013 Wiley Periodicals, Inc.

MODULATION OF RAT LEYDIG CELL STEROIDOGENIC FUNCTION BY DI(2-ETHYLHEXYL)PHTHALATE

EPA Science Inventory

Modulation of rat Leydig cell steroidogenic function by di(2-ethylhexyl)phthalate.

Akingbemi BT, Youker RT, Sottas CM, Ge R, Katz E, Klinefelter GR, Zirkin BR, Hardy MP.

Center for Biomedical Research, Population Council, New York, New York 10021, USA. benson@popcbr...

Kidneys: Key Modulators of HDL Levels and Function

PubMed Central

Yang, Haichun; Fogo, Agnes B.; Kon, Valentina

2016-01-01

Purpose of review This review will examine advances in our understanding of the role kidneys play in HDL metabolism and the effect on levels, composition, and function of HDL particles. Recent findings Components of the HDL particles can cross the glomerular filtration barrier. Some of these components, including apolipoproteins and enzymes involved in lipid metabolism, are taken up by the proximal tubule and degraded, modified, salvaged/returned to the circulation, or lost in the urine. Injury of the glomerular capillaries or tubules can affect these intrarenal processes and modify HDL. Changes in the plasma and urine levels of HDL may be novel markers of kidney damage and/or mechanism(s) of kidney disease. Summary The kidneys have a significant role in metabolism of individual HDL components, which in turn modulate HDL levels, composition and functionality of HDL particles. These intrarenal effects may be useful markers of kidney damage and have consequences on kidney-related perturbations in HDL. PMID:27008596

Definition of a core module for the nuclear retrograde response to altered organellar gene expression identifies GLK overexpressors as gun mutants.

PubMed

Leister, Dario; Kleine, Tatjana

2016-07-01

Retrograde signaling can be triggered by changes in organellar gene expression (OGE) induced by inhibitors such as lincomycin (LIN) or mutations that perturb OGE. Thus, an insufficiency of the organelle-targeted prolyl-tRNA synthetase PRORS1 in Arabidopsis thaliana activates retrograde signaling and reduces the expression of nuclear genes for photosynthetic proteins. Recently, we showed that mTERF6, a member of the so-called mitochondrial transcription termination factor (mTERF) family, is involved in the formation of chloroplast (cp) isoleucine-tRNA. To obtain further insights into its functions, co-expression analysis of MTERF6, PRORS1 and two other genes for organellar aminoacyl-tRNA synthetases was conducted. The results suggest a prominent role of mTERF6 in aminoacylation activity, light signaling and seed storage. Analysis of changes in whole-genome transcriptomes in the mterf6-1 mutant showed that levels of nuclear transcripts for cp OGE proteins were particularly affected. Comparison of the mterf6-1 transcriptome with that of prors1-2 showed that reduced aminoacylation of proline (prors1-2) and isoleucine (mterf6-1) tRNAs alters retrograde signaling in similar ways. Database analyses indicate that comparable gene expression changes are provoked by treatment with LIN, norflurazon or high light. A core OGE response module was defined by identifying genes that were differentially expressed under at least four of six conditions relevant to OGE signaling. Based on this module, overexpressors of the Golden2-like transcription factors GLK1 and GLK2 were identified as genomes uncoupled mutants. © 2016 Scandinavian Plant Physiology Society.

Modulation of Immune Function by Polyphenols: Possible Contribution of Epigenetic Factors

PubMed Central

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

2013-01-01

Several biological activities have been described for polyphenolic compounds, including a modulator effect on the immune system. The effects of these biologically active compounds on the immune system are associated to processes as differentiation and activation of immune cells. Among the mechanisms associated to immune regulation are epigenetic modifications as DNA methylation of regulatory sequences, histone modifications and posttranscriptional repression by microRNAs that influences the gene expression of key players involved in the immune response. Considering that polyphenols are able to regulate the immune function and has been also demonstrated an effect on epigenetic mechanisms, it is possible to hypothesize that there exists a mediator role of epigenetic mechanisms in the modulation of the immune response by polyphenols. PMID:23812304

Modulation of the pupil function of microscope objective lens for multifocal multi-photon microscopy using a spatial light modulator

NASA Astrophysics Data System (ADS)

Matsumoto, Naoya; Okazaki, Shigetoshi; Takamoto, Hisayoshi; Inoue, Takashi; Terakawa, Susumu

2014-02-01

We propose a method for high precision modulation of the pupil function of a microscope objective lens to improve the performance of multifocal multi-photon microscopy (MMM). To modulate the pupil function, we adopt a spatial light modulator (SLM) and place it at the conjugate position of the objective lens. The SLM can generate an arbitrary number of spots to excite the multiple fluorescence spots (MFS) at the desired positions and intensities by applying an appropriate computer-generated hologram (CGH). This flexibility allows us to control the MFS according to the photobleaching level of a fluorescent protein and phototoxicity of a specimen. However, when a large number of excitation spots are generated, the intensity distribution of the MFS is significantly different from the one originally designed due to misalignment of the optical setup and characteristics of the SLM. As a result, the image of a specimen obtained using laser scanning for the MFS has block noise segments because the SLM could not generate a uniform MFS. To improve the intensity distribution of the MFS, we adaptively redesigned the CGH based on the observed MFS. We experimentally demonstrate an improvement in the uniformity of a 10 × 10 MFS grid using a dye solution. The simplicity of the proposed method will allow it to be applied for calibration of MMM before observing living tissue. After the MMM calibration, we performed laser scanning with two-photon excitation to observe a real specimen without detecting block noise segments.

Structure-Based Approach To Identify 5-[4-Hydroxyphenyl]pyrrole-2-carbonitrile Derivatives as Potent and Tissue Selective Androgen Receptor Modulators.

PubMed

Unwalla, Ray; Mousseau, James J; Fadeyi, Olugbeminiyi O; Choi, Chulho; Parris, Kevin; Hu, Baihua; Kenney, Thomas; Chippari, Susan; McNally, Christopher; Vishwanathan, Karthick; Kilbourne, Edward; Thompson, Catherine; Nagpal, Sunil; Wrobel, Jay; Yudt, Matthew; Morris, Carl A; Powell, Dennis; Gilbert, Adam M; Chekler, Eugene L Piatnitski

2017-07-27

In an effort to find new and safer treatments for osteoporosis and frailty, we describe a novel series of selective androgen receptor modulators (SARMs). Using a structure-based approach, we identified compound 7, a potent AR (ARE EC 50 = 0.34 nM) and selective (N/C interaction EC 50 = 1206 nM) modulator. In vivo data, an AR LBD X-ray structure of 7, and further insights from modeling studies of ligand receptor interactions are also presented.

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

PubMed Central

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

2007-01-01

The Arabidopsis thaliana basic helix-loop-helix Leu zipper transcription factor (TF) MYC2/JIN1 differentially regulates jasmonate (JA)-responsive pathogen defense (e.g., PDF1.2) and wound response (e.g., VSP) genes. In this study, genome-wide transcriptional profiling of wild type and mutant myc2/jin1 plants followed by functional analyses has revealed new roles for MYC2 in the modulation of diverse JA functions. We found that MYC2 negatively regulates Trp and Trp-derived secondary metabolism such as indole glucosinolate biosynthesis during JA signaling. Furthermore, MYC2 positively regulates JA-mediated resistance to insect pests, such as Helicoverpa armigera, and tolerance to oxidative stress, possibly via enhanced ascorbate redox cycling and flavonoid biosynthesis. Analyses of MYC2 cis binding elements and expression of MYC2-regulated genes in T-DNA insertion lines of a subset of MYC2–regulated TFs suggested that MYC2 might modulate JA responses via differential regulation of an intermediate spectrum of TFs with activating or repressing roles in JA signaling. MYC2 also negatively regulates its own expression, and this may be one of the mechanisms used in fine-tuning JA signaling. Overall, these results provide new insights into the function of MYC2 and the transcriptional coordination of the JA signaling pathway. PMID:17616737

Sparing functional anatomical structures during intensity-modulated radiotherapy: an old problem, a new solution.

PubMed

Tan, Wenyong; Han, Guang; Wei, Shaozhong; Hu, Desheng

2014-08-01

During intensity-modulated radiotherapy, an organ is usually assumed to be functionally homogeneous and, generally, its anatomical and spatial heterogeneity with respect to radiation response are not taken into consideration. However, advances in imaging and radiation techniques as well as an improved understanding of the radiobiological response of organs have raised the possibility of sparing the critical functional structures within various organs at risk during intensity-modulated radiotherapy. Here, we discuss these structures, which include the critical brain structure, or neural nuclei, and the nerve fiber tracts in the CNS, head and neck structures related to radiation-induced salivary and swallowing dysfunction, and functional structures in the heart and lung. We suggest that these structures can be used as potential surrogate organs at risk in order to minimize their radiation dose and/or irradiated volume without compromising the dose coverage of the target volume during radiation treatment.

Global analysis of glycoproteins identifies markers of endotoxin tolerant monocytes and GPR84 as a modulator of TNFα expression.

PubMed

Müller, Mario M; Lehmann, Roland; Klassert, Tilman E; Reifenstein, Stella; Conrad, Theresia; Moore, Christoph; Kuhn, Anna; Behnert, Andrea; Guthke, Reinhard; Driesch, Dominik; Slevogt, Hortense

2017-04-12

Exposure of human monocytes to lipopolysaccharide (LPS) induces a temporary insensitivity to subsequent LPS challenges, a cellular state called endotoxin tolerance. In this study, we investigated the LPS-induced global glycoprotein expression changes of tolerant human monocytes and THP-1 cells to identify markers and glycoprotein targets capable to modulate the immunosuppressive state. Using hydrazide chemistry and LC-MS/MS analysis, we analyzed glycoprotein expression changes during a 48 h LPS time course. The cellular snapshots at different time points identified 1491 glycoproteins expressed by monocytes and THP-1 cells. Label-free quantitative analysis revealed transient or long-lasting LPS-induced expression changes of secreted or membrane-anchored glycoproteins derived from intracellular membrane coated organelles or from the plasma membrane. Monocytes and THP-1 cells demonstrated marked differences in glycoproteins differentially expressed in the tolerant state. Among the shared differentially expressed glycoproteins G protein-coupled receptor 84 (GPR84) was identified as being capable of modulating pro-inflammatory TNFα mRNA expression in the tolerant cell state when activated with its ligand Decanoic acid.

Characterizing 3D sensors using the 3D modulation transfer function

NASA Astrophysics Data System (ADS)

Kellner, Timo; Breitbarth, Andreas; Zhang, Chen; Notni, Gunther

2018-03-01

The fields of optical 3D measurement system applications are continuously expanding and becoming more and more diverse. To evaluate appropriate systems for various measurement tasks, comparable parameters are necessary, whereas the 3D modulation transfer function (3D-MTF) has been established as a further criterion. Its aim is the determination of the system response between the measurement of a straight, sharp-edged cube and its opposite ideal calculated one. Within the scope of this work simulations and practical investigations regarding the 3D-MTF’s influences and its main issues are specifically investigated. Therefore, different determined edge radii representing the high-frequency spectra lead to various decreasing 3D-MTF characteristics. Furthermore, rising sampling frequencies improve its maximum transfer value to a saturation point in dependence of the radius. To approve these results of previous simulations, three fringe projection scanners were selected to determine the diversity. As the best 3D-MTF characteristic, a saturated transfer value of H_3D( f_N, 3D) = 0.79 has been identified at a sufficient sampling frequency, which is reached at four times the Nyquist limit. This high 3D resolution can mainly be achieved due to an improved camera projector interaction. Additionally, too small sampling ratios lead to uncertainties in the edge function determination, while higher ratios do not show major improvements. In conclusion, the 3D-MTF algorithm has thus been practically verified and its repeatability as well as its robustness have been confirmed.

MO detector (MOD): a dual-function optical modulator-detector for on-chip communication

NASA Astrophysics Data System (ADS)

Sun, Shuai; Zhang, Ruoyu; Peng, Jiaxin; Narayana, Vikram K.; Dalir, Hamed; El-Ghazawi, Tarek; Sorger, Volker J.

2018-04-01

Physical challenges at the device and interconnect level limit both network and computing energy efficiency. While photonics is being considered to address interconnect bottlenecks, optical routing is still limited by electronic circuitry, requiring substantial overhead for optical-electrical-optical conversion. Here we show a novel design of an integrated broadband photonic-plasmonic hybrid device termed MODetector featuring dual light modulation and detection function to act as an optical transceiver in the photonic network-on-chip. With over 10 dB extinction ratio and 0.8 dB insertion loss at the modulation state, this MODetector provides 0.7 W/A responsivity in the detection state with 36 ps response time. This multi-functional device: (i) eliminates OEO conversion, (ii) reduces optical losses from photodetectors when not needed, and (iii) enables cognitive routing strategies for network-on-chips.

Proteomic Profiling in the Brain of CLN1 Disease Model Reveals Affected Functional Modules.

PubMed

Tikka, Saara; Monogioudi, Evanthia; Gotsopoulos, Athanasios; Soliymani, Rabah; Pezzini, Francesco; Scifo, Enzo; Uusi-Rauva, Kristiina; Tyynelä, Jaana; Baumann, Marc; Jalanko, Anu; Simonati, Alessandro; Lalowski, Maciej

2016-03-01

Neuronal ceroid lipofuscinoses (NCL) are the most commonly inherited progressive encephalopathies of childhood. Pathologically, they are characterized by endolysosomal storage with different ultrastructural features and biochemical compositions. The molecular mechanisms causing progressive neurodegeneration and common molecular pathways linking expression of different NCL genes are largely unknown. We analyzed proteome alterations in the brains of a mouse model of human infantile CLN1 disease-palmitoyl-protein thioesterase 1 (Ppt1) gene knockout and its wild-type age-matched counterpart at different stages: pre-symptomatic, symptomatic and advanced. For this purpose, we utilized a combination of laser capture microdissection-based quantitative liquid chromatography tandem mass spectrometry (MS) and matrix-assisted laser desorption/ionization time-of-flight MS imaging to quantify/visualize the changes in protein expression in disease-affected brain thalamus and cerebral cortex tissue slices, respectively. Proteomic profiling of the pre-symptomatic stage thalamus revealed alterations mostly in metabolic processes and inhibition of various neuronal functions, i.e., neuritogenesis. Down-regulation in dynamics associated with growth of plasma projections and cellular protrusions was further corroborated by findings from RNA sequencing of CLN1 patients' fibroblasts. Changes detected at the symptomatic stage included: mitochondrial functions, synaptic vesicle transport, myelin proteome and signaling cascades, such as RhoA signaling. Considerable dysregulation of processes related to mitochondrial cell death, RhoA/Huntington's disease signaling and myelin sheath breakdown were observed at the advanced stage of the disease. The identified changes in protein levels were further substantiated by bioinformatics and network approaches, immunohistochemistry on brain tissues and literature knowledge, thus identifying various functional modules affected in the CLN1 childhood

Complement factor H family proteins in their non-canonical role as modulators of cellular functions.

PubMed

Józsi, Mihály; Schneider, Andrea E; Kárpáti, Éva; Sándor, Noémi

2018-01-04

Complement factor H is a major regulator of the alternative pathway of the complement system. The factor H-related proteins are less characterized, but recent data indicate that they rather promote complement activation. These proteins have some common ligands with factor H and have both overlapping and distinct functions depending on domain composition and the degree of conservation of amino acid sequence. Factor H and some of the factor H-related proteins also appear in a non-canonical function that is beyond their role in the modulation of complement activation. This review covers our current understanding on this emerging role of factor H family proteins in modulating the activation and function of various cells by binding to receptors or receptor ligands. Copyright © 2018 Elsevier Ltd. All rights reserved.

Degree of bioresorbable vascular scaffold expansion modulates loss of essential function.

PubMed

Ferdous, Jahid; Kolachalama, Vijaya B; Kolandaivelu, Kumaran; Shazly, Tarek

2015-10-01

Drug-eluting bioresorbable vascular scaffolds (BVSs) have the potential to restore lumen patency, enable recovery of the native vascular environment, and circumvent late complications associated with permanent endovascular devices. To ensure therapeutic effects persist for sufficient times prior to scaffold resorption and resultant functional loss, many factors dictating BVS performance must be identified, characterized and optimized. While some factors relate to BVS design and manufacturing, others depend on device deployment and intrinsic vascular properties. Importantly, these factors interact and cannot be considered in isolation. The objective of this study is to quantify the extent to which degree of radial expansion modulates BVS performance, specifically in the context of modifying device erosion kinetics and evolution of structural mechanics and local drug elution. We systematically varied degree of radial expansion in model BVS constructs composed of poly dl-lactide-glycolide and generated in vitro metrics of device microstructure, degradation, erosion, mechanics and drug release. Experimental data permitted development of computational models that predicted transient concentrations of scaffold-derived soluble species and drug in the arterial wall, thus enabling speculation on the short- and long-term effects of differential expansion. We demonstrate that degree of expansion significantly affects scaffold properties critical to functionality, underscoring its relevance in BVS design and optimization. Bioresorbable vascular scaffold (BVS) therapy is beginning to transform the treatment of obstructive artery disease, owing to effective treatment of short term vessel closure while avoiding long term consequences such as in situ, late stent thrombosis - a fatal event associated with permanent implants such as drug-eluting stents. As device scaffolding and drug elution are temporary for BVS, the notion of using this therapy in lieu of existing, clinically

Community Landscapes: An Integrative Approach to Determine Overlapping Network Module Hierarchy, Identify Key Nodes and Predict Network Dynamics

PubMed Central

Kovács, István A.; Palotai, Robin; Szalay, Máté S.; Csermely, Peter

2010-01-01

Background Network communities help the functional organization and evolution of complex networks. However, the development of a method, which is both fast and accurate, provides modular overlaps and partitions of a heterogeneous network, has proven to be rather difficult. Methodology/Principal Findings Here we introduce the novel concept of ModuLand, an integrative method family determining overlapping network modules as hills of an influence function-based, centrality-type community landscape, and including several widely used modularization methods as special cases. As various adaptations of the method family, we developed several algorithms, which provide an efficient analysis of weighted and directed networks, and (1) determine pervasively overlapping modules with high resolution; (2) uncover a detailed hierarchical network structure allowing an efficient, zoom-in analysis of large networks; (3) allow the determination of key network nodes and (4) help to predict network dynamics. Conclusions/Significance The concept opens a wide range of possibilities to develop new approaches and applications including network routing, classification, comparison and prediction. PMID:20824084

Translational informatics approach for identifying the functional molecular communicators linking coronary artery disease, infection and inflammation

PubMed Central

SHARMA, ANKIT; GHATGE, MADANKUMAR; MUNDKUR, LAKSHMI; VANGALA, RAJANI KANTH

2016-01-01

Translational informatics approaches are required for the integration of diverse and accumulating data to enable the administration of effective translational medicine specifically in complex diseases such as coronary artery disease (CAD). In the current study, a novel approach for elucidating the association between infection, inflammation and CAD was used. Genes for CAD were collected from the CAD-gene database and those for infection and inflammation were collected from the UniProt database. The cytomegalovirus (CMV)-induced genes were identified from the literature and the CAD-associated clinical phenotypes were obtained from the Unified Medical Language System. A total of 55 gene ontologies (GO) termed functional communicator ontologies were identifed in the gene sets linking clinical phenotypes in the diseasome network. The network topology analysis suggested that important functions including viral entry, cell adhesion, apoptosis, inflammatory and immune responses networked with clinical phenotypes. Microarray data was extracted from the Gene Expression Omnibus (dataset: GSE48060) for highly networked disease myocardial infarction. Further analysis of differentially expressed genes and their GO terms suggested that CMV infection may trigger a xenobiotic response, oxidative stress, inflammation and immune modulation. Notably, the current study identified γ-glutamyl transferase (GGT)-5 as a potential biomarker with an odds ratio of 1.947, which increased to 2.561 following the addition of CMV and CMV-neutralizing antibody (CMV-NA) titers. The C-statistics increased from 0.530 for conventional risk factors (CRFs) to 0.711 for GGT in combination with the above mentioned infections and CRFs. Therefore, the translational informatics approach used in the current study identified a potential molecular mechanism for CMV infection in CAD, and a potential biomarker for risk prediction. PMID:27035874

Cell cholesterol modulates metalloproteinase-dependent shedding of low-density lipoprotein receptor-related protein-1 (LRP-1) and clearance function

PubMed Central

Selvais, Charlotte; D'Auria, Ludovic; Tyteca, Donatienne; Perrot, Gwenn; Lemoine, Pascale; Troeberg, Linda; Dedieu, Stéphane; Noël, Agnès; Nagase, Hideaki; Henriet, Patrick; Courtoy, Pierre J.; Marbaix, Etienne; Emonard, Hervé

2011-01-01

Low-density lipoprotein receptor-related protein-1 (LRP-1) is a plasma membrane scavenger and signaling receptor, composed of a large ligand-binding subunit (515-kDa α-chain) linked to a shorter transmembrane subunit (85-kDa β-chain). LRP-1 cell-surface level and function are controlled by proteolytic shedding of its ectodomain. Here, we identified ectodomain sheddases in human HT1080 cells and demonstrated regulation of the cleavage by cholesterol by comparing the classical fibroblastoid type with a spontaneous epithelioid variant, enriched ∼2-fold in cholesterol. Two membrane-associated metalloproteinases were involved in LRP-1 shedding: a disintegrin and metalloproteinase-12 (ADAM-12) and membrane-type 1 matrix metalloproteinase (MT1-MMP). Although both variants expressed similar levels of LRP-1, ADAM-12, MT1-MMP, and specific tissue inhibitor of metalloproteinases-2 (TIMP-2), LRP-1 shedding from epithelioid cells was ∼4-fold lower than from fibroblastoid cells. Release of the ectodomain was triggered by cholesterol depletion in epithelioid cells and impaired by cholesterol overload in fibroblastoid cells. Modulation of LRP-1 shedding on clearance was reflected by accumulation of gelatinases (MMP-2 and MMP-9) in the medium. We conclude that cholesterol exerts an important control on LRP-1 levels and function at the plasma membrane by modulating shedding of its ectodomain, and therefore represents a novel regulator of extracellular proteolytic activities.—Selvais, C., D'Auria, L., Tyteca, D., Perrot, G, Lemoine, P., Troeberg, L., Dedieu, S., Noël, A., Nagase, H., Henriet, P., Courtoy, P. J., Marbaix, E., Emonard, H. Cell cholesterol modulates metalloproteinase-dependent shedding of low-density lipoprotein receptor-related protein-1 (LRP-1) and clearance function. PMID:21518850

Norepinephrine versus Dopamine and their Interaction in Modulating Synaptic Function in the Prefrontal Cortex

PubMed Central

Xing, Bo; Li, Yan-Chun; Gao, Wen-Jun

2016-01-01

Among the neuromodulators that regulate prefrontal cortical circuit function, the catecholamine transmitters norepinephrine (NE) and dopamine (DA) stand out as powerful players in working memory and attention. Perturbation of either NE or DA signaling is implicated in the pathogenesis of several neuropsychiatric disorders, including attention deficit hyperactivity disorder (ADHD), post-traumatic stress disorder (PTSD), schizophrenia, and drug addiction. Although the precise mechanisms employed by NE and DA to cooperatively control prefrontal functions are not fully understood, emerging research indicates that both transmitters regulate electrical and biochemical aspects of neuronal function by modulating convergent ionic and synaptic signaling in the prefrontal cortex (PFC). This review summarizes previous studies that investigated the effects of both NE and DA on excitatory and inhibitory transmissions in the prefrontal cortical circuitry. Specifically, we focus on the functional interaction between NE and DA in prefrontal cortical local circuitry, synaptic integration, signaling pathways, and receptor properties. Although it is clear that both NE and DA innervate the PFC extensively and modulate synaptic function by activating distinctly different receptor subtypes and signaling pathways, it remains unclear how these two systems coordinate their actions to optimize PFC function for appropriate behavior. Throughout this review, we provide perspectives and highlight several critical topics for future studies. PMID:26790349

Peroxisome proliferator-activated receptor α ligands and modulators from dietary compounds: Types, screening methods and functions.

PubMed

Yang, Haixia; Xiao, Lei; Wang, Nanping

2017-04-01

Peroxisome proliferator-activated receptor α (PPARα) plays a key role in lipid metabolism and glucose homeostasis and a crucial role in the prevention and treatment of metabolic diseases. Natural dietary compounds, including nutrients and phytochemicals, are PPARα ligands or modulators. High-throughput screening assays have been developed to screen for PPARα ligands and modulators in our diet. In the present review, we discuss recent advances in our knowledge of PPARα, including its structure, function, and ligand and modulator screening assays, and summarize the different types of dietary PPARα ligands and modulators. © 2016 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.

CommWalker: correctly evaluating modules in molecular networks in light of annotation bias.

PubMed

Luecken, M D; Page, M J T; Crosby, A J; Mason, S; Reinert, G; Deane, C M

2018-03-15

Detecting novel functional modules in molecular networks is an important step in biological research. In the absence of gold standard functional modules, functional annotations are often used to verify whether detected modules/communities have biological meaning. However, as we show, the uneven distribution of functional annotations means that such evaluation methods favor communities of well-studied proteins. We propose a novel framework for the evaluation of communities as functional modules. Our proposed framework, CommWalker, takes communities as inputs and evaluates them in their local network environment by performing short random walks. We test CommWalker's ability to overcome annotation bias using input communities from four community detection methods on two protein interaction networks. We find that modules accepted by CommWalker are similarly co-expressed as those accepted by current methods. Crucially, CommWalker performs well not only in well-annotated regions, but also in regions otherwise obscured by poor annotation. CommWalker community prioritization both faithfully captures well-validated communities and identifies functional modules that may correspond to more novel biology. The CommWalker algorithm is freely available at opig.stats.ox.ac.uk/resources or as a docker image on the Docker Hub at hub.docker.com/r/lueckenmd/commwalker/. deane@stats.ox.ac.uk. Supplementary data are available at Bioinformatics online.

Dual-function photonic integrated circuit for frequency octo-tupling or single-side-band modulation.

PubMed

Hasan, Mehedi; Maldonado-Basilio, Ramón; Hall, Trevor J

2015-06-01

A dual-function photonic integrated circuit for microwave photonic applications is proposed. The circuit consists of four linear electro-optic phase modulators connected optically in parallel within a generalized Mach-Zehnder interferometer architecture. The photonic circuit is arranged to have two separate output ports. A first port provides frequency up-conversion of a microwave signal from the electrical to the optical domain; equivalently single-side-band modulation. A second port provides tunable millimeter wave carriers by frequency octo-tupling of an appropriate amplitude RF carrier. The circuit exploits the intrinsic relative phases between the ports of multi-mode interference couplers to provide substantially all the static optical phases needed. The operation of the proposed dual-function photonic integrated circuit is verified by computer simulations. The performance of the frequency octo-tupling and up-conversion functions is analyzed in terms of the electrical signal to harmonic distortion ratio and the optical single side band to unwanted harmonics ratio, respectively.

Honey Bee Allatostatins Target Galanin/Somatostatin-Like Receptors and Modulate Learning: A Conserved Function?

PubMed Central

Urlacher, Elodie; Soustelle, Laurent; Parmentier, Marie-Laure; Verlinden, Heleen; Gherardi, Marie-Julie; Fourmy, Daniel; Mercer, Alison R.

2016-01-01

Sequencing of the honeybee genome revealed many neuropeptides and putative neuropeptide receptors, yet functional characterization of these peptidic systems is scarce. In this study, we focus on allatostatins, which were first identified as inhibitors of juvenile hormone synthesis, but whose role in the adult honey bee (Apis mellifera) brain remains to be determined. We characterize the bee allatostatin system, represented by two families: allatostatin A (Apime-ASTA) and its receptor (Apime-ASTA-R); and C-type allatostatins (Apime-ASTC and Apime-ASTCC) and their common receptor (Apime-ASTC-R). Apime-ASTA-R and Apime-ASTC-R are the receptors in bees most closely related to vertebrate galanin and somatostatin receptors, respectively. We examine the functional properties of the two honeybee receptors and show that they are transcriptionally expressed in the adult brain, including in brain centers known to be important for learning and memory processes. Thus we investigated the effects of exogenously applied allatostatins on appetitive olfactory learning in the bee. Our results show that allatostatins modulate learning in this insect, and provide important insights into the evolution of somatostatin/allatostatin signaling. PMID:26741132

Mercury exposure induces cytoskeleton disruption and loss of renal function through epigenetic modulation of MMP9 expression.

PubMed

Khan, Hafizurrahman; Singh, Radha Dutt; Tiwari, Ratnakar; Gangopadhyay, Siddhartha; Roy, Somendu Kumar; Singh, Dhirendra; Srivastava, Vikas

2017-07-01

Mercury is one of the major heavy metal pollutants occurring in elemental, inorganic and organic forms. Due to ban on most inorganic mercury containing products, human exposure to mercury generally occurs as methylmercury (MeHg) by consumption of contaminated fish and other sea food. Animal and epidemiological studies indicate that MeHg affects neural and renal function. Our study is focused on nephrotoxic potential of MeHg. In this study, we have shown for the first time how MeHg could epigenetically modulate matrix metalloproteinase 9(MMP9) to promote nephrotoxicity using an animal model of sub chronic MeHg exposure. MeHg caused renal toxicity as was seen by increased levels of serum creatinine and expression of early nephrotoxicity markers (KIM-1, Clusterin, IP-10, and TIMP). MeHg exposure also correlated strongly with induction of MMP9 mRNA and protein in a dose dependent manner. Further, while induction of MMP9 promoted cytoskeleton disruption and loss of cell-cell adhesion (loss of F-actin, Vimentin and Fibronectin), inhibition of MMP9 was found to reduce these disruptions. Mechanistic studies by ChIP analysis showed that MeHg modulated MMP9 by promoting demethylation of its regulatory region to increase its expression. Bisulfite sequencing identified critical CpGs in the first exon of MMP9 which were demethylated following MeHg exposure. ChIP studies also showed loss of methyl binding protein, MeCP2 and transcription factor PEA3 at the demethylated site confirming decreased CpG methylation. Our studies thus show how MeHg could epigenetically modulate MMP9 to promote cytoskeleton disruption leading to loss of renal function. Copyright © 2017 Elsevier B.V. All rights reserved.

Functional Proteomics to Identify Moderators of CD8+ T Cell Function in Melanoma

DTIC Science & Technology

2015-05-01

identified 17 phage that selectively bind TIL rather than effector cells. However, none of these phage influenced CD8+ TIL expansion or function in vitro...Using a novel NextGeneration sequencing approach, we have further defined another 1,000,000 phage that selectively bind TIL , of which 100,000 are unique...Using the original approach outlined in the application, we identified a total of 17 unique phage that selectively bind CD8+ TIL but not effector or

How emotional abilities modulate the influence of early life stress on hippocampal functioning.

PubMed

Aust, Sabine; Alkan Härtwig, Elif; Koelsch, Stefan; Heekeren, Hauke R; Heuser, Isabella; Bajbouj, Malek

2014-07-01

Early life stress (ELS) is known to have considerable influence on brain development, mental health and affective functioning. Previous investigations have shown that alexithymia, a prevalent personality trait associated with difficulties experiencing and verbalizing emotions, is particularly related to ELS. The aim of the present study was to investigate how neural correlates of emotional experiences in alexithymia are altered in the presence and absence of ELS. Therefore, 50 healthy individuals with different levels of alexithymia were matched regarding ELS and investigated with respect to neural correlates of audio-visually induced emotional experiences via functional magnetic resonance imaging. The main finding was that ELS modulated hippocampal responses to pleasant (>neutral) stimuli in high-alexithymic individuals, whereas there was no such modulation in low-alexithymic individuals matched for ELS. Behavioral and psychophysiological results followed a similar pattern. When considered independent of ELS, alexithymia was associated with decreased responses in insula (pleasant > neutral) and temporal pole (unpleasant > neutral). Our results show that the influence of ELS on emotional brain responses seems to be modulated by an individual's degree of alexithymia. Potentially, protective and adverse effects of emotional abilities on brain responses to emotional experiences are discussed. © The Author (2013). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

Functional Polymorphisms in Dopaminergic Genes Modulate Neurobehavioral and Neurophysiological Consequences of Sleep Deprivation.

PubMed

Holst, Sebastian C; Müller, Thomas; Valomon, Amandine; Seebauer, Britta; Berger, Wolfgang; Landolt, Hans-Peter

2017-04-10

Sleep deprivation impairs cognitive performance and reliably alters brain activation in wakefulness and sleep. Nevertheless, the molecular regulators of prolonged wakefulness remain poorly understood. Evidence from genetic, behavioral, pharmacologic and imaging studies suggest that dopaminergic signaling contributes to the behavioral and electroencephalographic (EEG) consequences of sleep loss, although direct human evidence thereof is missing. We tested whether dopamine neurotransmission regulate sustained attention and evolution of EEG power during prolonged wakefulness. Here, we studied the effects of functional genetic variation in the dopamine transporter (DAT1) and the dopamine D 2 receptor (DRD2) genes, on psychomotor performance and standardized waking EEG oscillations during 40 hours of wakefulness in 64 to 82 healthy volunteers. Sleep deprivation consistently enhanced sleepiness, lapses of attention and the theta-to-alpha power ratio (TAR) in the waking EEG. Importantly, DAT1 and DRD2 genotypes distinctly modulated sleep loss-induced changes in subjective sleepiness, PVT lapses and TAR, according to inverted U-shaped relationships. Together, the data suggest that genetically determined differences in DAT1 and DRD2 expression modulate functional consequences of sleep deprivation, supporting the hypothesis that striato-thalamo-cortical dopaminergic pathways modulate the neurobehavioral and neurophysiological consequences of sleep loss in humans.

Mitochondrial functions modulate neuroendocrine, metabolic, inflammatory, and transcriptional responses to acute psychological stress

PubMed Central

Picard, Martin; McManus, Meagan J.; Gray, Jason D.; Nasca, Carla; Moffat, Cynthia; Kopinski, Piotr K.; Seifert, Erin L.; McEwen, Bruce S.; Wallace, Douglas C.

2015-01-01

The experience of psychological stress triggers neuroendocrine, inflammatory, metabolic, and transcriptional perturbations that ultimately predispose to disease. However, the subcellular determinants of this integrated, multisystemic stress response have not been defined. Central to stress adaptation is cellular energetics, involving mitochondrial energy production and oxidative stress. We therefore hypothesized that abnormal mitochondrial functions would differentially modulate the organism’s multisystemic response to psychological stress. By mutating or deleting mitochondrial genes encoded in the mtDNA [NADH dehydrogenase 6 (ND6) and cytochrome c oxidase subunit I (COI)] or nuclear DNA [adenine nucleotide translocator 1 (ANT1) and nicotinamide nucleotide transhydrogenase (NNT)], we selectively impaired mitochondrial respiratory chain function, energy exchange, and mitochondrial redox balance in mice. The resulting impact on physiological reactivity and recovery from restraint stress were then characterized. We show that mitochondrial dysfunctions altered the hypothalamic–pituitary–adrenal axis, sympathetic adrenal–medullary activation and catecholamine levels, the inflammatory cytokine IL-6, circulating metabolites, and hippocampal gene expression responses to stress. Each mitochondrial defect generated a distinct whole-body stress-response signature. These results demonstrate the role of mitochondrial energetics and redox balance as modulators of key pathophysiological perturbations previously linked to disease. This work establishes mitochondria as stress-response modulators, with implications for understanding the mechanisms of stress pathophysiology and mitochondrial diseases. PMID:26627253

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

Non-Invasive Electrical Brain Stimulation Montages for Modulation of Human Motor Function.

PubMed

Curado, Marco; Fritsch, Brita; Reis, Janine

2016-02-04

Non-invasive electrical brain stimulation (NEBS) is used to modulate brain function and behavior, both for research and clinical purposes. In particular, NEBS can be applied transcranially either as direct current stimulation (tDCS) or alternating current stimulation (tACS). These stimulation types exert time-, dose- and in the case of tDCS polarity-specific effects on motor function and skill learning in healthy subjects. Lately, tDCS has been used to augment the therapy of motor disabilities in patients with stroke or movement disorders. This article provides a step-by-step protocol for targeting the primary motor cortex with tDCS and transcranial random noise stimulation (tRNS), a specific form of tACS using an electrical current applied randomly within a pre-defined frequency range. The setup of two different stimulation montages is explained. In both montages the emitting electrode (the anode for tDCS) is placed on the primary motor cortex of interest. For unilateral motor cortex stimulation the receiving electrode is placed on the contralateral forehead while for bilateral motor cortex stimulation the receiving electrode is placed on the opposite primary motor cortex. The advantages and disadvantages of each montage for the modulation of cortical excitability and motor function including learning are discussed, as well as safety, tolerability and blinding aspects.

Stereotypical modulations in dynamic functional connectivity explained by changes in BOLD variance.

PubMed

Glomb, Katharina; Ponce-Alvarez, Adrián; Gilson, Matthieu; Ritter, Petra; Deco, Gustavo

2018-05-01

Spontaneous activity measured in human subject under the absence of any task exhibits complex patterns of correlation that largely correspond to large-scale functional topographies obtained with a wide variety of cognitive and perceptual tasks. These "resting state networks" (RSNs) fluctuate over time, forming and dissolving on the scale of seconds to minutes. While these fluctuations, most prominently those of the default mode network, have been linked to cognitive function, it remains unclear whether they result from random noise or whether they index a nonstationary process which could be described as state switching. In this study, we use a sliding windows-approach to relate temporal dynamics of RSNs to global modulations in correlation and BOLD variance. We compare empirical data, phase-randomized surrogate data, and data simulated with a stationary model. We find that RSN time courses exhibit a large amount of coactivation in all three cases, and that the modulations in their activity are closely linked to global dynamics of the underlying BOLD signal. We find that many properties of the observed fluctuations in FC and BOLD, including their ranges and their correlations amongst each other, are explained by fluctuations around the average FC structure. However, we also report some interesting characteristics that clearly support nonstationary features in the data. In particular, we find that the brain spends more time in the troughs of modulations than can be expected from stationary dynamics. Copyright © 2018 Elsevier Inc. All rights reserved.

Replacement Behaviors for Identified Functions of Challenging Behaviors

ERIC Educational Resources Information Center

Matson, Johnny L.; Shoemaker, Mary E.; Sipes, Megan; Horovitz, Max; Worley, Julie A.; Kozlowski, Alison M.

2011-01-01

Functional assessment has become a major feature of learning-based research. A critical element of the majority of these studies includes not only methods and procedures to identify the cause of the challenging behavior, but to establish replacement treatment methods. By far the most common intervention in the 176 studies we reviewed was…

Modulation of vascular function by diet and exercise.

PubMed

Jennings, G L; Chin-Dusting, J P; Kingwell, B A; Dart, A M; Cameron, J; Esler, M; Lewis, T V

1997-01-01

Clinical research is conducted in free living individuals who are always subject to the influences on vascular function and the major cardiovascular regulators of their lifestyle. The purpose of this paper is to review some lifestyle influences on cardiovascular function, particularly the sympathetic nervous system and endothelially mediated vasodilatation. There are highly differentiated sympathetic responses to feeding, and to acute exercise. Over a longer period obesity has a typical pattern of sympathetic activity. Reduced dietary salt intake elicits profound localised increases in sympathetic activity to the kidney. Marine oil supplementation attenuates the sympathetic responses to psychological stress and improves endothelially mediated vasodilatation in hypercholesterolaemics. Exercise training reduced total noradrenaline spillover, the major beds affected being the renal and skeletal muscle. These examples illustrate the dynamic nature of vascular dilatation and that, like the sympathetic nervous system, it is modulated by short, medium and long term influences. In both cases there is regulation both at a local and systemic level. Habitual, and recent, lifestyle can exert important cardiovascular effects which must be taken into account in clinical and epidemiological research.

Oxytocin And Vasopressin Modulation Of The Neural Correlates Of Motivation And Emotion: Results From Functional MRI Studies In Awake Rats

PubMed Central

Febo, Marcelo; Ferris, Craig F.

2014-01-01

Oxytocin and vasopressin modulate a range of species typical behavioral functions that include social recognition, maternal-infant attachment, and modulation of memory, offensive aggression, defensive fear reactions, and reward seeking. We have employed novel functional magnetic resonance mapping techniques in awake rats to explore the roles of these neuropeptides in the maternal and non-maternal brain. Results from the functional neuroimaging studies that are summarized here have directly and indirectly confirmed and supported previous findings. Oxytocin is released within the lactating rat brain during suckling stimulation and activates specific subcortical networks in the maternal brain. Both vasopressin and oxytocin modulate brain regions involved unconditioned fear, processing of social stimuli and the expression of agonistic behaviors. Across studies there are relatively consistent brain networks associated with internal motivational drives and emotional states that are modulated by oxytocin and vasopressin. PMID:24486356

Identifying taxonomic and functional surrogates for spring biodiversity conservation.

PubMed

Jyväsjärvi, Jussi; Virtanen, Risto; Ilmonen, Jari; Paasivirta, Lauri; Muotka, Timo

2018-02-27

Surrogate approaches are widely used to estimate overall taxonomic diversity for conservation planning. Surrogate taxa are frequently selected based on rarity or charisma, whereas selection through statistical modeling has been applied rarely. We used boosted-regression-tree models (BRT) fitted to biological data from 165 springs to identify bryophyte and invertebrate surrogates for taxonomic and functional diversity of boreal springs. We focused on these 2 groups because they are well known and abundant in most boreal springs. The best indicators of taxonomic versus functional diversity differed. The bryophyte Bryum weigelii and the chironomid larva Paratrichocladius skirwithensis best indicated taxonomic diversity, whereas the isopod Asellus aquaticus and the chironomid Macropelopia spp. were the best surrogates of functional diversity. In a scoring algorithm for priority-site selection, taxonomic surrogates performed only slightly better than random selection for all spring-dwelling taxa, but they were very effective in representing spring specialists, providing a distinct improvement over random solutions. However, the surrogates for taxonomic diversity represented functional diversity poorly and vice versa. When combined with cross-taxon complementarity analyses, surrogate selection based on statistical modeling provides a promising approach for identifying groundwater-dependent ecosystems of special conservation value, a key requirement of the EU Water Framework Directive. © 2018 Society for Conservation Biology.

TAAR1 Modulates Cortical Glutamate NMDA Receptor Function

PubMed Central

Espinoza, Stefano; Lignani, Gabriele; Caffino, Lucia; Maggi, Silvia; Sukhanov, Ilya; Leo, Damiana; Mus, Liudmila; Emanuele, Marco; Ronzitti, Giuseppe; Harmeier, Anja; Medrihan, Lucian; Sotnikova, Tatyana D; Chieregatti, Evelina; Hoener, Marius C; Benfenati, Fabio; Tucci, Valter; Fumagalli, Fabio; Gainetdinov, Raul R

2015-01-01

Trace Amine-Associated Receptor 1 (TAAR1) is a G protein-coupled receptor expressed in the mammalian brain and known to influence subcortical monoaminergic transmission. Monoamines, such as dopamine, also play an important role within the prefrontal cortex (PFC) circuitry, which is critically involved in high-o5rder cognitive processes. TAAR1-selective ligands have shown potential antipsychotic, antidepressant, and pro-cognitive effects in experimental animal models; however, it remains unclear whether TAAR1 can affect PFC-related processes and functions. In this study, we document a distinct pattern of expression of TAAR1 in the PFC, as well as altered subunit composition and deficient functionality of the glutamate N-methyl-D-aspartate (NMDA) receptors in the pyramidal neurons of layer V of PFC in mice lacking TAAR1. The dysregulated cortical glutamate transmission in TAAR1-KO mice was associated with aberrant behaviors in several tests, indicating a perseverative and impulsive phenotype of mutants. Conversely, pharmacological activation of TAAR1 with selective agonists reduced premature impulsive responses observed in the fixed-interval conditioning schedule in normal mice. Our study indicates that TAAR1 plays an important role in the modulation of NMDA receptor-mediated glutamate transmission in the PFC and related functions. Furthermore, these data suggest that the development of TAAR1-based drugs could provide a novel therapeutic approach for the treatment of disorders related to aberrant cortical functions. PMID:25749299

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

PubMed Central

Siep, Nicolette; Markus, C. Rob

2013-01-01

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

Deep sequencing identifies circulating mouse miRNAs that are functionally implicated in manifestations of aging and responsive to calorie restriction.

PubMed

Dhahbi, Joseph M; Spindler, Stephen R; Atamna, Hani; Yamakawa, Amy; Guerrero, Noel; Boffelli, Dario; Mote, Patricia; Martin, David I K

2013-02-01

MicroRNAs (miRNAs) function to modulate gene expression, and through this property they regulate a broad spectrum of cellular processes. They can circulate in blood and thereby mediate cell-to-cell communication. Aging involves changes in many cellular processes that are potentially regulated by miRNAs, and some evidence has implicated circulating miRNAs in the aging process. In order to initiate a comprehensive assessment of the role of circulating miRNAs in aging, we have used deep sequencing to characterize circulating miRNAs in the serum of young mice, old mice, and old mice maintained on calorie restriction (CR). Deep sequencing identifies a set of novel miRNAs, and also accurately measures all known miRNAs present in serum. This analysis demonstrates that the levels of many miRNAs circulating in the mouse are increased with age, and that the increases can be antagonized by CR. The genes targeted by this set of age-modulated miRNAs are predicted to regulate biological processes directly relevant to the manifestations of aging including metabolic changes, and the miRNAs themselves have been linked to diseases associated with old age. This finding implicates circulating miRNAs in the aging process, raising questions about their tissues of origin, their cellular targets, and their functional role in metabolic changes that occur with aging.

Modulation transfer function cascade model for a sampled IR imaging system.

PubMed

de Luca, L; Cardone, G

1991-05-01

The performance of the infrared scanning radiometer (IRSR) is strongly stressed in convective heat transfer applications where high spatial frequencies in the signal that describes the thermal image are present. The need to characterize more deeply the system spatial resolution has led to the formulation of a cascade model for the evaluation of the actual modulation transfer function of a sampled IR imaging system. The model can yield both the aliasing band and the averaged modulation response for a general sampling subsystem. For a line scan imaging system, which is the case of a typical IRSR, a rule of thumb that states whether the combined sampling-imaging system is either imaging-dependent or sampling-dependent is proposed. The model is tested by comparing it with other noncascade models as well as by ad hoc measurements performed on a commercial digitized IRSR.

The FUN of identifying gene function in bacterial pathogens; insights from Salmonella functional genomics.

PubMed

Hammarlöf, Disa L; Canals, Rocío; Hinton, Jay C D

2013-10-01

The availability of thousands of genome sequences of bacterial pathogens poses a particular challenge because each genome contains hundreds of genes of unknown function (FUN). How can we easily discover which FUN genes encode important virulence factors? One solution is to combine two different functional genomic approaches. First, transcriptomics identifies bacterial FUN genes that show differential expression during the process of mammalian infection. Second, global mutagenesis identifies individual FUN genes that the pathogen requires to cause disease. The intersection of these datasets can reveal a small set of candidate genes most likely to encode novel virulence attributes. We demonstrate this approach with the Salmonella infection model, and propose that a similar strategy could be used for other bacterial pathogens. Copyright © 2013 Elsevier Ltd. All rights reserved.

Norepinephrine versus dopamine and their interaction in modulating synaptic function in the prefrontal cortex.

PubMed

Xing, Bo; Li, Yan-Chun; Gao, Wen-Jun

2016-06-15

Among the neuromodulators that regulate prefrontal cortical circuit function, the catecholamine transmitters norepinephrine (NE) and dopamine (DA) stand out as powerful players in working memory and attention. Perturbation of either NE or DA signaling is implicated in the pathogenesis of several neuropsychiatric disorders, including attention deficit hyperactivity disorder (ADHD), post-traumatic stress disorder (PTSD), schizophrenia, and drug addiction. Although the precise mechanisms employed by NE and DA to cooperatively control prefrontal functions are not fully understood, emerging research indicates that both transmitters regulate electrical and biochemical aspects of neuronal function by modulating convergent ionic and synaptic signaling in the prefrontal cortex (PFC). This review summarizes previous studies that investigated the effects of both NE and DA on excitatory and inhibitory transmissions in the prefrontal cortical circuitry. Specifically, we focus on the functional interaction between NE and DA in prefrontal cortical local circuitry, synaptic integration, signaling pathways, and receptor properties. Although it is clear that both NE and DA innervate the PFC extensively and modulate synaptic function by activating distinctly different receptor subtypes and signaling pathways, it remains unclear how these two systems coordinate their actions to optimize PFC function for appropriate behavior. Throughout this review, we provide perspectives and highlight several critical topics for future studies. This article is part of a Special Issue entitled SI: Noradrenergic System. Copyright © 2016 Elsevier B.V. All rights reserved.

Extraversion modulates functional connectivity hubs of resting-state brain networks.

PubMed

Pang, Yajing; Cui, Qian; Duan, Xujun; Chen, Heng; Zeng, Ling; Zhang, Zhiqiang; Lu, Guangming; Chen, Huafu

2017-09-01

Personality dimension extraversion describes individual differences in social behaviour and socio-emotional functioning. The intrinsic functional connectivity patterns of the brain are reportedly associated with extraversion. However, whether or not extraversion is associated with functional hubs warrants clarification. Functional hubs are involved in the rapid integration of neural processing, and their dysfunction contributes to the development of neuropsychiatric disorders. In this study, we employed the functional connectivity density (FCD) method for the first time to distinguish the energy-efficient hubs associated with extraversion. The resting-state functional magnetic resonance imaging data of 71 healthy subjects were used in the analysis. Short-range FCD was positively correlated with extraversion in the left cuneus, revealing a link between the local functional activity of this region and extraversion in risk-taking. Long-range FCD was negatively correlated with extraversion in the right superior frontal gyrus and the inferior frontal gyrus. Seed-based resting-state functional connectivity (RSFC) analyses revealed that a decreased long-range FCD in individuals with high extraversion scores showed a low long-range functional connectivity pattern between the medial and dorsolateral prefrontal cortex, middle temporal gyrus, and anterior cingulate cortex. This result suggests that decreased RSFC patterns are responsible for self-esteem, self-evaluation, and inhibitory behaviour system that account for the modulation and shaping of extraversion. Overall, our results emphasize specific brain hubs, and reveal long-range functional connections in relation to extraversion, thereby providing a neurobiological basis of extraversion. © 2015 The British Psychological Society.

An extensive investigation of work function modulated trapezoidal recessed channel MOSFET

NASA Astrophysics Data System (ADS)

Lenka, Annada Shankar; Mishra, Sikha; Mishra, Satyaranjan; Bhanja, Urmila; Mishra, Guru Prasad

2017-11-01

The concept of silicon on insulator (SOI) and grooved gate help to lessen the short channel effects (SCEs). Again the work function modulation along the metal gate gives a better drain current due to the uniform electric field along the channel. So all these concepts are combined and used in the proposed MOSFET structure for more improved performance. In this work, trapezoidal recessed channel silicon on insulator (TRC-SOI) MOSFET and work function modulated trapezoidal recessed channel silicon on insulator (WFM-TRC-SOI) MOSFET are compared with DC and RF parameters and later linearity of both the devices is tested. An analytical model is formulated by using a 2-D Poisson's equation and develops a compact equation for threshold voltage using minimum surface potential. In this work we analyze the effect of negative junction depth and the corner angle on various device parameters such as minimum surface potential, sub-threshold slope (SS), drain induced barrier lowering (DIBL) and threshold voltage. The analysis interprets that the switching performance of WFM-TRC-SOI MOSFET surpasses TRC-SOI MOSFET in terms of high Ion/Ioff ratio and also the proposed structure can minimize the short channel effects (SCEs) in RF application. The validity of proposed model has been verified with simulation result performed on Sentaurus TCAD device simulator.

An Analysis of the Cost and Performance of Photovoltaic Systems as a Function of Module Area

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

Horowitz, Kelsey A.W.; Fu, Ran; Silverman, Tim

We investigate the potential effects of module area on the cost and performance of photovoltaic systems. Applying a bottom-up methodology, we analyzed the costs associated with mc-Si and thin-film modules and systems as a function of module area. We calculate a potential for savings of up to $0.04/W, $0.10/W, and $0.13/W in module manufacturing costs for mc-Si, CdTe, and CIGS respectively, with large area modules. We also find that an additional $0.05/W savings in balance-of-systems costs may be achieved. However, these savings are dependent on the ability to maintain efficiency and manufacturing yield as area scales. Lifetime energy yield mustmore » also be maintained to realize reductions in the levelized cost of energy. We explore the possible effects of module size on efficiency and energy production, and find that more research is required to understand these issues for each technology. Sensitivity of the $/W cost savings to module efficiency and manufacturing yield is presented. We also discuss non-cost barriers to adoption of large area modules.« less

A computational module assembled from different protease family motifs identifies PI PLC from Bacillus cereus as a putative prolyl peptidase with a serine protease scaffold.

PubMed

Rendón-Ramírez, Adela; Shukla, Manish; Oda, Masataka; Chakraborty, Sandeep; Minda, Renu; Dandekar, Abhaya M; Ásgeirsson, Bjarni; Goñi, Félix M; Rao, Basuthkar J

2013-01-01

Proteolytic enzymes have evolved several mechanisms to cleave peptide bonds. These distinct types have been systematically categorized in the MEROPS database. While a BLAST search on these proteases identifies homologous proteins, sequence alignment methods often fail to identify relationships arising from convergent evolution, exon shuffling, and modular reuse of catalytic units. We have previously established a computational method to detect functions in proteins based on the spatial and electrostatic properties of the catalytic residues (CLASP). CLASP identified a promiscuous serine protease scaffold in alkaline phosphatases (AP) and a scaffold recognizing a β-lactam (imipenem) in a cold-active Vibrio AP. Subsequently, we defined a methodology to quantify promiscuous activities in a wide range of proteins. Here, we assemble a module which encapsulates the multifarious motifs used by protease families listed in the MEROPS database. Since APs and proteases are an integral component of outer membrane vesicles (OMV), we sought to query other OMV proteins, like phospholipase C (PLC), using this search module. Our analysis indicated that phosphoinositide-specific PLC from Bacillus cereus is a serine protease. This was validated by protease assays, mass spectrometry and by inhibition of the native phospholipase activity of PI-PLC by the well-known serine protease inhibitor AEBSF (IC50 = 0.018 mM). Edman degradation analysis linked the specificity of the protease activity to a proline in the amino terminal, suggesting that the PI-PLC is a prolyl peptidase. Thus, we propose a computational method of extending protein families based on the spatial and electrostatic congruence of active site residues.

Identifying a gene expression signature of cluster headache in blood

PubMed Central

Eising, Else; Pelzer, Nadine; Vijfhuizen, Lisanne S.; Vries, Boukje de; Ferrari, Michel D.; ‘t Hoen, Peter A. C.; Terwindt, Gisela M.; van den Maagdenberg, Arn M. J. M.

2017-01-01

Cluster headache is a relatively rare headache disorder, typically characterized by multiple daily, short-lasting attacks of excruciating, unilateral (peri-)orbital or temporal pain associated with autonomic symptoms and restlessness. To better understand the pathophysiology of cluster headache, we used RNA sequencing to identify differentially expressed genes and pathways in whole blood of patients with episodic (n = 19) or chronic (n = 20) cluster headache in comparison with headache-free controls (n = 20). Gene expression data were analysed by gene and by module of co-expressed genes with particular attention to previously implicated disease pathways including hypocretin dysregulation. Only moderate gene expression differences were identified and no associations were found with previously reported pathogenic mechanisms. At the level of functional gene sets, associations were observed for genes involved in several brain-related mechanisms such as GABA receptor function and voltage-gated channels. In addition, genes and modules of co-expressed genes showed a role for intracellular signalling cascades, mitochondria and inflammation. Although larger study samples may be required to identify the full range of involved pathways, these results indicate a role for mitochondria, intracellular signalling and inflammation in cluster headache. PMID:28074859

Walking the interactome to identify human miRNA-disease associations through the functional link between miRNA targets and disease genes

PubMed Central

2013-01-01

Background MicroRNAs (miRNAs) are important post-transcriptional regulators that have been demonstrated to play an important role in human diseases. Elucidating the associations between miRNAs and diseases at the systematic level will deepen our understanding of the molecular mechanisms of diseases. However, miRNA-disease associations identified by previous computational methods are far from completeness and more effort is needed. Results We developed a computational framework to identify miRNA-disease associations by performing random walk analysis, and focused on the functional link between miRNA targets and disease genes in protein-protein interaction (PPI) networks. Furthermore, a bipartite miRNA-disease network was constructed, from which several miRNA-disease co-regulated modules were identified by hierarchical clustering analysis. Our approach achieved satisfactory performance in identifying known cancer-related miRNAs for nine human cancers with an area under the ROC curve (AUC) ranging from 71.3% to 91.3%. By systematically analyzing the global properties of the miRNA-disease network, we found that only a small number of miRNAs regulated genes involved in various diseases, genes associated with neurological diseases were preferentially regulated by miRNAs and some immunological diseases were associated with several specific miRNAs. We also observed that most diseases in the same co-regulated module tended to belong to the same disease category, indicating that these diseases might share similar miRNA regulatory mechanisms. Conclusions In this study, we present a computational framework to identify miRNA-disease associations, and further construct a bipartite miRNA-disease network for systematically analyzing the global properties of miRNA regulation of disease genes. Our findings provide a broad perspective on the relationships between miRNAs and diseases and could potentially aid future research efforts concerning miRNA involvement in disease pathogenesis

Pain perception and hypnosis: findings from recent functional neuroimaging studies.

PubMed

Del Casale, Antonio; Ferracuti, Stefano; Rapinesi, Chiara; Serata, Daniele; Caltagirone, Saverio Simone; Savoja, Valeria; Piacentino, Daria; Callovini, Gemma; Manfredi, Giovanni; Sani, Gabriele; Kotzalidis, Georgios D; Girardi, Paolo

2015-01-01

Hypnosis modulates pain perception and tolerance by affecting cortical and subcortical activity in brain regions involved in these processes. By reviewing functional neuroimaging studies focusing on pain perception under hypnosis, the authors aimed to identify brain activation-deactivation patterns occurring in hypnosis-modulated pain conditions. Different changes in brain functionality occurred throughout all components of the pain network and other brain areas. The anterior cingulate cortex appears to be central in modulating pain circuitry activity under hypnosis. Most studies also showed that the neural functions of the prefrontal, insular, and somatosensory cortices are consistently modified during hypnosis-modulated pain conditions. Functional neuroimaging studies support the clinical use of hypnosis in the management of pain conditions.

From Saccharomyces cerevisiae to human: The important gene co-expression modules.

PubMed

Liu, Wei; Li, Li; Ye, Hua; Chen, Haiwei; Shen, Weibiao; Zhong, Yuexian; Tian, Tian; He, Huaqin

2017-08-01

Network-based systems biology has become an important method for analyzing high-throughput gene expression data and gene function mining. Yeast has long been a popular model organism for biomedical research. In the current study, a weighted gene co-expression network analysis algorithm was applied to construct a gene co-expression network in Saccharomyces cerevisiae . Seventeen stable gene co-expression modules were detected from 2,814 S. cerevisiae microarray data. Further characterization of these modules with the Database for Annotation, Visualization and Integrated Discovery tool indicated that these modules were associated with certain biological processes, such as heat response, cell cycle, translational regulation, mitochondrion oxidative phosphorylation, amino acid metabolism and autophagy. Hub genes were also screened by intra-modular connectivity. Finally, the module conservation was evaluated in a human disease microarray dataset. Functional modules were identified in budding yeast, some of which are associated with patient survival. The current study provided a paradigm for single cell microorganisms and potentially other organisms.

Modulation Transfer Function (MTF) measurement techniques for lenses and linear detector arrays

NASA Technical Reports Server (NTRS)

Schnabel, J. J., Jr.; Kaishoven, J. E., Jr.; Tom, D.

1984-01-01

Application is the determination of the Modulation Transfer Function (MTF) for linear detector arrays. A system set up requires knowledge of the MTF of the imaging lens. Procedure for this measurement is described for standard optical lab equipment. Given this information, various possible approaches to MTF measurement for linear arrays is described. The knife edge method is then described in detail.

Identifying the molecular functions of electron transport proteins using radial basis function networks and biochemical properties.

PubMed

Le, Nguyen-Quoc-Khanh; Nguyen, Trinh-Trung-Duong; Ou, Yu-Yen

2017-05-01

The electron transport proteins have an important role in storing and transferring electrons in cellular respiration, which is the most proficient process through which cells gather energy from consumed food. According to the molecular functions, the electron transport chain components could be formed with five complexes with several different electron carriers and functions. Therefore, identifying the molecular functions in the electron transport chain is vital for helping biologists understand the electron transport chain process and energy production in cells. This work includes two phases for discriminating electron transport proteins from transport proteins and classifying categories of five complexes in electron transport proteins. In the first phase, the performances from PSSM with AAIndex feature set were successful in identifying electron transport proteins in transport proteins with achieved sensitivity of 73.2%, specificity of 94.1%, and accuracy of 91.3%, with MCC of 0.64 for independent data set. With the second phase, our method can approach a precise model for identifying of five complexes with different molecular functions in electron transport proteins. The PSSM with AAIndex properties in five complexes achieved MCC of 0.51, 0.47, 0.42, 0.74, and 1.00 for independent data set, respectively. We suggest that our study could be a power model for determining new proteins that belongs into which molecular function of electron transport proteins. Copyright © 2017 Elsevier Inc. All rights reserved.

Hypocretin neuron-specific transcriptome profiling identifies the sleep modulator Kcnh4a.

PubMed

Yelin-Bekerman, Laura; Elbaz, Idan; Diber, Alex; Dahary, Dvir; Gibbs-Bar, Liron; Alon, Shahar; Lerer-Goldshtein, Tali; Appelbaum, Lior

2015-10-01

Sleep has been conserved throughout evolution; however, the molecular and neuronal mechanisms of sleep are largely unknown. The hypothalamic hypocretin/orexin (Hcrt) neurons regulate sleep\\wake states, feeding, stress, and reward. To elucidate the mechanism that enables these various functions and to identify sleep regulators, we combined fluorescence cell sorting and RNA-seq in hcrt:EGFP zebrafish. Dozens of Hcrt-neuron-specific transcripts were identified and comprehensive high-resolution imaging revealed gene-specific localization in all or subsets of Hcrt neurons. Clusters of Hcrt-neuron-specific genes are predicted to be regulated by shared transcription factors. These findings show that Hcrt neurons are heterogeneous and that integrative molecular mechanisms orchestrate their diverse functions. The voltage-gated potassium channel Kcnh4a, which is expressed in all Hcrt neurons, was silenced by the CRISPR-mediated gene inactivation system. The mutant kcnh4a (kcnh4a(-/-)) larvae showed reduced sleep time and consolidation, specifically during the night, suggesting that Kcnh4a regulates sleep.

Indicators of ecosystem function identify alternate states in the sagebrush steppe.

PubMed

Kachergis, Emily; Rocca, Monique E; Fernandez-Gimenez, Maria E

2011-10-01

Models of ecosystem change that incorporate nonlinear dynamics and thresholds, such as state-and-transition models (STMs), are increasingly popular tools for land management decision-making. However, few models are based on systematic collection and documentation of ecological data, and of these, most rely solely on structural indicators (species composition) to identify states and transitions. As STMs are adopted as an assessment framework throughout the United States, finding effective and efficient ways to create data-driven models that integrate ecosystem function and structure is vital. This study aims to (1) evaluate the utility of functional indicators (indicators of rangeland health, IRH) as proxies for more difficult ecosystem function measurements and (2) create a data-driven STM for the sagebrush steppe of Colorado, USA, that incorporates both ecosystem structure and function. We sampled soils, plant communities, and IRH at 41 plots with similar clayey soils but different site histories to identify potential states and infer the effects of management practices and disturbances on transitions. We found that many IRH were correlated with quantitative measures of functional indicators, suggesting that the IRH can be used to approximate ecosystem function. In addition to a reference state that functions as expected for this soil type, we identified four biotically and functionally distinct potential states, consistent with the theoretical concept of alternate states. Three potential states were related to management practices (chemical and mechanical shrub treatments and seeding history) while one was related only to ecosystem processes (erosion). IRH and potential states were also related to environmental variation (slope, soil texture), suggesting that there are environmental factors within areas with similar soils that affect ecosystem dynamics and should be noted within STMs. Our approach generated an objective, data-driven model of ecosystem dynamics

Spleen lymphocyte function modulated by a cocoa-enriched diet.

PubMed

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

2007-09-01

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

Spleen lymphocyte function modulated by a cocoa-enriched diet

PubMed Central

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

2007-01-01

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

Assessment Tools for Identifying Functional Limitations Associated With Functional Ankle Instability

PubMed Central

Ross, Scott E; Guskiewicz, Kevin M; Gross, Michael T; Yu, Bing

2008-01-01

Context: Assessment tools should identify functional limitations associated with functional ankle instability (FAI) by discriminating unstable from stable ankles. Objective: To identify assessment tools that discriminated FAI from stable ankles and determine the most accurate assessment tool for discriminating between FAI and stable ankles. Design: Case-control study. Setting: Research laboratory. Patients or Other Participants: Fifteen individuals with FAI and 15 healthy individuals; participants with unilateral FAI reported “giving-way” sensations and ankle sprains, whereas healthy participants did not. Intervention(s): Participants answered 12 questions on the Ankle Joint Functional Assessment Tool (AJFAT). They also performed a single-leg jump landing, which required them to jump to half their maximum jump height, land on a single leg, and stabilize quickly on a force plate. Main Outcome Measure(s): Receiver operating characteristic curves determined cutoff scores for discriminating between ankle groups for AJFAT total score and resultant vector (RV) time to stabilization. Accuracy values for discriminating between groups were determined by calculating the area under the receiver operating characteristic curves. Results: The cutoff score for discriminating between FAI and stable ankles was ≥26 (sensitivity  =  1, specificity  =  1) and ≥1.58 seconds (sensitivity  =  0.67, specificity  =  0.73) for the AJFAT total score and RV time to stabilization, respectively. The area under the curve for the AJFAT was 1.0 (asymptotic significance <.05), whereas the RV time to stabilization had an area under the curve of 0.72 (asymptotic significance <.05). Conclusions: The AJFAT was an excellent assessment tool for discriminating between ankle groups, whereas RV time to stabilization was a fair assessment tool. Although both assessments discriminated between ankle groups, the AJFAT more accurately discriminated between groups than the RV time to

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

PubMed Central

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

2010-01-01

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

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

PubMed Central

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

2011-01-01

Human corticosteroid-binding globulin (CBG), a heavily glycosylated protein containing six N-linked glycosylation sites, transports cortisol and other corticosteroids in blood circulation. Here, we investigate the biological importance of the N-glycans of CBG derived from human serum by performing a structural and functional characterization of CBG N-glycosylation. Liquid chromatography-tandem MS-based glycoproteomics and glycomics combined with exoglycosidase treatment revealed 26 complex type N-glycoforms, all of which were terminated with α2,3-linked neuraminic acid (NeuAc) residues. The CBG N-glycans showed predominantly bi- and tri-antennary branching, but higher branching was also observed. N-glycans from all six N-glycosylation sites were identified with high site occupancies (70.5–99.5%) and glycoforms from all sites contained a relatively low degree of core-fucosylation (0–34.9%). CBG showed site-specific glycosylation and the site-to-site differences in core-fucosylation and branching could be in silico correlated with the accessibility to the individual glycosylation sites on the maturely folded protein. Deglycosylated and desialylated CBG analogs were generated to investigate the biological importance of CBG N-glycans. As a functional assay, MCF-7 cells were challenged with native and glycan-modified CBG and the amount of cAMP, which is produced as a quantitative response upon CBG binding to its cell surface receptor, was used to evaluate the CBG:receptor interaction. The removal of both CBG N-glycans and NeuAc residues increased the production of cAMP significantly. This confirms that N-glycans are involved in the CBG:receptor interaction and indicates that the modulation is performed by steric and/or electrostatic means through the terminal NeuAc residues. PMID:21558494

Past Strategies and Future Directions for Identifying AMP-Activated Protein Kinase (AMPK) Modulators

PubMed Central

Sinnett, Sarah E.; Brenman, Jay E.

2014-01-01

AMP-activated protein kinase (AMPK) is a promising therapeutic target for cancer, type II diabetes, and other illnesses characterized by abnormal energy utilization. During the last decade, numerous labs have published a range of methods for identifying novel AMPK modulators. The current understanding of AMPK structure and regulation, however, has propelled a paradigm shift in which many researchers now consider ADP to be an additional regulatory nucleotide of AMPK. How can the AMPK community apply this new understanding of AMPK signaling to translational research? Recent insights into AMPK structure, regulation, and holoenzyme-sensitive signaling may provide the hindsight needed to clearly evaluate the strengths and weaknesses of past AMPK drug discovery efforts. Improving future strategies for AMPK drug discovery will require pairing the current understanding of AMPK signaling with improved experimental designs. PMID:24583089

The modulation rate transfer function of a harbour porpoise (Phocoena phocoena).

PubMed

Linnenschmidt, Meike; Wahlberg, Magnus; Damsgaard Hansen, Janni

2013-02-01

During echolocation, toothed whales produce ultrasonic clicks at extremely rapid rates and listen for the returning echoes. The auditory brainstem response (ABR) duration was evaluated in terms of latency between single peaks: 5.5 ms (from peak I to VII), 3.4 ms (I-VI), and 1.4 ms (II-IV). In comparison to the killer whale and the bottlenose dolphin, the ABR of the harbour porpoise has shorter intervals between the peaks and consequently a shorter ABR duration. This indicates that the ABR duration and peak latencies are possibly related to the relative size of the auditory structures of the central nervous system and thus to the animal's size. The ABR to a sinusoidal amplitude modulated stimulus at 125 kHz (sensitivity threshold 63 dB re 1 μPa rms) was evaluated to determine the modulation rate transfer function of a harbour porpoise. The ABR showed distinct envelope following responses up to a modulation rate of 1,900 Hz. The corresponding calculated equivalent rectangular duration of 263 μs indicates a good temporal resolution in the harbour porpoise auditory system similar to the one for the bottlenose dolphin. The results explain how the harbour porpoise can follow clicks and echoes during echolocation with very short inter click intervals.

Oxytocin and vasopressin modulation of the neural correlates of motivation and emotion: results from functional MRI studies in awake rats.

PubMed

Febo, Marcelo; Ferris, Craig F

2014-09-11

Oxytocin and vasopressin modulate a range of species typical behavioral functions that include social recognition, maternal-infant attachment, and modulation of memory, offensive aggression, defensive fear reactions, and reward seeking. We have employed novel functional magnetic resonance mapping techniques in awake rats to explore the roles of these neuropeptides in the maternal and non-maternal brain. Results from the functional neuroimaging studies that are summarized here have directly and indirectly confirmed and supported previous findings. Oxytocin is released within the lactating rat brain during suckling stimulation and activates specific subcortical networks in the maternal brain. Both vasopressin and oxytocin modulate brain regions involved unconditioned fear, processing of social stimuli and the expression of agonistic behaviors. Across studies there are relatively consistent brain networks associated with internal motivational drives and emotional states that are modulated by oxytocin and vasopressin. This article is part of a Special Issue entitled Oxytocin and Social Behav. Copyright © 2014 Elsevier B.V. All rights reserved.

Design of small-molecule epigenetic modulators

PubMed Central

Pachaiyappan, Boobalan

2013-01-01

The field of epigenetics has expanded rapidly to reveal multiple new targets for drug discovery. The functional elements of the epigenomic machinery can be catagorized as writers, erasers and readers, and together these elements control cellular gene expression and homeostasis. It is increasingly clear that aberrations in the epigenome can underly a variety of diseases, and thus discovery of small molecules that modulate the epigenome in a specific manner is a viable approach to the discovery of new therapeutic agents. In this Digest, the components of epigenetic control of gene expression will be briefly summarized, and efforts to identify small molecules that modulate epigenetic processes will be described. PMID:24300735

Organic cation transporter 3 modulates murine basophil functions by controlling intracellular histamine levels

PubMed Central

Schneider, Elke; Machavoine, François; Pléau, Jean-Marie; Bertron, Anne-France; Thurmond, Robin L.; Ohtsu, Hiroshi; Watanabe, Takehiko; Schinkel, Alfred H.; Dy, Michel

2005-01-01

In this study, we identify the bidirectional organic cation transporter 3 (OCT3/Slc22a3) as the molecule responsible for histamine uptake by murine basophils. We demonstrate that OCT3 participates in the control of basophil functions because exogenous histamine can inhibit its own synthesis—and that of interleukin (IL)-4, IL-6, and IL-13—through this means of transport. Furthermore, ligands of H3/H4 histamine receptors or OCT3 inhibit histamine uptake, and outward transport of newly synthesized histamine. By doing so, they increase the histamine content of basophils, which explains why they mimic the effect of exogenous histamine. These drugs were no longer effective in histamine-free histidine decarboxylase (HDC)-deficient mice, in contrast with histamine itself. Histamine was not taken up and lost its inhibitory effect in mice deficient for OCT3, which proved its specific involvement. Intracellular histamine levels were increased strongly in IL-3–induced OCT3 −/− bone marrow basophils, and explained why they generated fewer cytokines than their wild-type counterpart. Their production was enhanced when histamine synthesis was blocked by the specific HDC inhibitor α-fluoro-methyl histidine, and underscored the determinant role of histamine in the inhibitory effect. We postulate that pharmacologic modulation of histamine transport might become instrumental in the control of basophil functions during allergic diseases. PMID:16061728

A whole organism screen identifies novel regulators of fat storage

PubMed Central

Lemieux, George A.; Liu, Jason; Mayer, Nasima; Bainton, Roland J.; Ashrafi, Kaveh; Werb, Zena

2011-01-01

The regulation of energy homeostasis integrates diverse biological processes ranging from behavior to metabolism and is linked fundamentally to numerous disease states. To identify new molecules that can bypass homeostatic compensatory mechanisms of energy balance in intact animals, we screened for small molecule modulators of C. elegans fat content. We report on several molecules that modulate fat storage without obvious deleterious effects on feeding, growth, and reproduction. A subset of these compounds also altered fat storage in mammalian and insect cell culture. We found that one of the newly identified compounds exerts its effects in C. elegans through a pathway that requires novel functions of an AMP-activated kinase catalytic subunit and a transcription factor previously unassociated with fat regulation. Thus, our strategy identifies small molecules that are effective within the context of intact animals and reveals relationships between new pathways that operate across phyla to influence energy homeostasis. PMID:21390037

Sex, hormones and neurogenesis in the hippocampus: hormonal modulation of neurogenesis and potential functional implications.

PubMed

Galea, L A M; Wainwright, S R; Roes, M M; Duarte-Guterman, P; Chow, C; Hamson, D K

2013-11-01

The hippocampus is an area of the brain that undergoes dramatic plasticity in response to experience and hormone exposure. The hippocampus retains the ability to produce new neurones in most mammalian species and is a structure that is targeted in a number of neurodegenerative and neuropsychiatric diseases, many of which are influenced by both sex and sex hormone exposure. Intriguingly, gonadal and adrenal hormones affect the structure and function of the hippocampus differently in males and females. Adult neurogenesis in the hippocampus is regulated by both gonadal and adrenal hormones in a sex- and experience-dependent way. Sex differences in the effects of steroid hormones to modulate hippocampal plasticity should not be completely unexpected because the physiology of males and females is different, with the most notable difference being that females gestate and nurse the offspring. Furthermore, reproductive experience (i.e. pregnancy and mothering) results in permanent changes to the maternal brain, including the hippocampus. This review outlines the ability of gonadal and stress hormones to modulate multiple aspects of neurogenesis (cell proliferation and cell survival) in both male and female rodents. The function of adult neurogenesis in the hippocampus is linked to spatial memory and depression, and the present review provides early evidence of the functional links between the hormonal modulation of neurogenesis that may contribute to the regulation of cognition and stress. © 2013 British Society for Neuroendocrinology.

Commercial/industrial photovoltaic module and array requirement study. Low-cost solar array project engineering area

NASA Technical Reports Server (NTRS)

1981-01-01

Design requirements for photovoltaic modules and arrays used in commercial and industrial applications were identified. Building codes and referenced standards were reviewed for their applicability to commercial and industrial photovoltaic array installation. Four general installation types were identified - integral (replaces roofing), direct (mounted on top of roofing), stand-off (mounted away from roofing), and rack (for flat or low slope roofs, or ground mounted). Each of the generic mounting types can be used in vertical wall mounting systems. This implies eight mounting types exist in the commercial/industrial sector. Installation costs were developed for these mounting types as a function of panel/module size. Cost drivers were identified. Studies were performed to identify optimum module shapes and sizes and operating voltage cost drivers. The general conclusion is that there are no perceived major obstacles to the use of photovoltaic modules in commercial/industrial arrays.

Multi-processor including data flow accelerator module

DOEpatents

Davidson, George S.; Pierce, Paul E.

1990-01-01

An accelerator module for a data flow computer includes an intelligent memory. The module is added to a multiprocessor arrangement and uses a shared tagged memory architecture in the data flow computer. The intelligent memory module assigns locations for holding data values in correspondence with arcs leading to a node in a data dependency graph. Each primitive computation is associated with a corresponding memory cell, including a number of slots for operands needed to execute a primitive computation, a primitive identifying pointer, and linking slots for distributing the result of the cell computation to other cells requiring that result as an operand. Circuitry is provided for utilizing tag bits to determine automatically when all operands required by a processor are available and for scheduling the primitive for execution in a queue. Each memory cell of the module may be associated with any of the primitives, and the particular primitive to be executed by the processor associated with the cell is identified by providing an index, such as the cell number for the primitive, to the primitive lookup table of starting addresses. The module thus serves to perform functions previously performed by a number of sections of data flow architectures and coexists with conventional shared memory therein. A multiprocessing system including the module operates in a hybrid mode, wherein the same processing modules are used to perform some processing in a sequential mode, under immediate control of an operating system, while performing other processing in a data flow mode.

Therapeutic Strategies for Modulating the Extracellular Matrix to Improve Pancreatic Islet Function and Survival After Transplantation.

PubMed

Smink, Alexandra M; de Vos, Paul

2018-05-19

Extracellular matrix (ECM) components modulate the interaction between pancreatic islet cells. During the islet isolation prior to transplantation as treatment for type 1 diabetes, the ECM is disrupted impacting functional graft survival. Recently, strategies for restoring ECM have shown to improve transplantation outcomes. This review discusses the current therapeutic strategies to modulate ECM components to improve islet engraftment. Approaches applied are seeding islets in ECM of decellularized organs, supplementation of specific ECM components in polymeric scaffolds or immunoisolating capsules, and stimulating islet ECM production with specific growth factors or ECM-producing cells. These strategies have shown success in improving functional islet survival. However, the same experiments show that caution should be taken as some ECM components may negatively impact islet function and engraftment. ECM restoration resulted in improved transplantation outcomes, but careful selection of beneficial ECM components and strategies is warranted.

ORF phage display to identify cellular proteins with different functions.

PubMed

Li, Wei

2012-09-01

Open reading frame (ORF) phage display is a new branch of phage display aimed at improving its efficiency to identify cellular proteins with specific binding or functional activities. Despite the success of phage display with antibody libraries and random peptide libraries, phage display with cDNA libraries of cellular proteins identifies a high percentage of non-ORF clones encoding unnatural short peptides with minimal biological implications. This is mainly because of the uncontrollable reading frames of cellular proteins in conventional cDNA libraries. ORF phage display solves this problem by eliminating non-ORF clones to generate ORF cDNA libraries. Here I summarize the procedures of ORF phage display, discuss the factors influencing its efficiency, present examples of its versatile applications, and highlight evidence of its capability of identifying biologically relevant cellular proteins. ORF phage display coupled with different selection strategies is capable of delineating diverse functions of cellular proteins with unique advantages. Copyright © 2012 Elsevier Inc. All rights reserved.

Allosteric Modulation of Metabotropic Glutamate Receptors

PubMed Central

Sheffler, Douglas J.; Gregory, Karen J.; Rook, Jerri M.; Conn, P. Jeffrey

2013-01-01

The development of receptor subtype-selective ligands by targeting allosteric sites of G protein-coupled receptors (GPCRs) has proven highly successful in recent years. One GPCR family that has greatly benefited from this approach is the metabotropic glutamate receptors (mGlus). These family C GPCRs participate in the neuromodulatory actions of glutamate throughout the CNS, where they play a number of key roles in regulating synaptic transmission and neuronal excitability. A large number of mGlu subtype-selective allosteric modulators have been identified, the majority of which are thought to bind within the transmembrane regions of the receptor. These modulators can either enhance or inhibit mGlu functional responses and, together with mGlu knockout mice, have furthered the establishment of the physiologic roles of many mGlu subtypes. Numerous pharmacological and receptor mutagenesis studies have been aimed at providing a greater mechanistic understanding of the interaction of mGlu allosteric modulators with the receptor, which have revealed evidence for common allosteric binding sites across multiple mGlu subtypes and the presence for multiple allosteric sites within a single mGlu subtype. Recent data have also revealed that mGlu allosteric modulators can display functional selectivity toward particular signal transduction cascades downstream of an individual mGlu subtype. Studies continue to validate the therapeutic utility of mGlu allosteric modulators as a potential therapeutic approach for a number of disorders including anxiety, schizophrenia, Parkinson’s disease, and Fragile X syndrome. PMID:21907906

Differential activation of an identified motor neuron and neuromodulation provide Aplysia's retractor muscle an additional function.

PubMed

McManus, Jeffrey M; Lu, Hui; Cullins, Miranda J; Chiel, Hillel J

2014-08-15

To survive, animals must use the same peripheral structures to perform a variety of tasks. How does a nervous system employ one muscle to perform multiple functions? We addressed this question through work on the I3 jaw muscle of the marine mollusk Aplysia californica's feeding system. This muscle mediates retraction of Aplysia's food grasper in multiple feeding responses and is innervated by a pool of identified neurons that activate different muscle regions. One I3 motor neuron, B38, is active in the protraction phase, rather than the retraction phase, suggesting the muscle has an additional function. We used intracellular, extracellular, and muscle force recordings in several in vitro preparations as well as recordings of nerve and muscle activity from intact, behaving animals to characterize B38's activation of the muscle and its activity in different behavior types. We show that B38 specifically activates the anterior region of I3 and is specifically recruited during one behavior, swallowing. The function of this protraction-phase jaw muscle contraction is to hold food; thus the I3 muscle has an additional function beyond mediating retraction. We additionally show that B38's typical activity during in vivo swallowing is insufficient to generate force in an unmodulated muscle and that intrinsic and extrinsic modulation shift the force-frequency relationship to allow contraction. Using methods that traverse levels from individual neuron to muscle to intact animal, we show how regional muscle activation, differential motor neuron recruitment, and neuromodulation are key components in Aplysia's generation of multifunctionality. Copyright © 2014 the American Physiological Society.

Insights into the Modulation of Dopamine Transporter Function by Amphetamine, Orphenadrine, and Cocaine Binding

PubMed Central

Cheng, Mary Hongying; Block, Ethan; Hu, Feizhuo; Cobanoglu, Murat Can; Sorkin, Alexander; Bahar, Ivet

2015-01-01

Human dopamine (DA) transporter (hDAT) regulates dopaminergic signaling in the central nervous system by maintaining the synaptic concentration of DA at physiological levels, upon reuptake of DA into presynaptic terminals. DA translocation involves the co-transport of two sodium ions and the channeling of a chloride ion, and it is achieved via alternating access between outward-facing (OF) and inward-facing states of DAT. hDAT is a target for addictive drugs, such as cocaine, amphetamine (AMPH), and therapeutic antidepressants. Our recent quantitative systems pharmacology study suggested that orphenadrine (ORPH), an anticholinergic agent and anti-Parkinson drug, might be repurposable as a DAT drug. Previous studies have shown that DAT-substrates like AMPH or -blockers like cocaine modulate the function of DAT in different ways. However, the molecular mechanisms of modulation remained elusive due to the lack of structural data on DAT. The newly resolved DAT structure from Drosophila melanogaster opens the way to a deeper understanding of the mechanism and time evolution of DAT–drug/ligand interactions. Using a combination of homology modeling, docking analysis, molecular dynamics simulations, and molecular biology experiments, we performed a comparative study of the binding properties of DA, AMPH, ORPH, and cocaine and their modulation of hDAT function. Simulations demonstrate that binding DA or AMPH drives a structural transition toward a functional form predisposed to translocate the ligand. In contrast, ORPH appears to inhibit DAT function by arresting it in the OF open conformation. The analysis shows that cocaine and ORPH competitively bind DAT, with the binding pose and affinity dependent on the conformational state of DAT. Further assays show that the effect of ORPH on DAT uptake and endocytosis is comparable to that of cocaine. PMID:26106364

Predicting invasive species impacts: a community module functional response approach reveals context dependencies.

PubMed

Paterson, Rachel A; Dick, Jaimie T A; Pritchard, Daniel W; Ennis, Marilyn; Hatcher, Melanie J; Dunn, Alison M

2015-03-01

Predatory functional responses play integral roles in predator-prey dynamics, and their assessment promises greater understanding and prediction of the predatory impacts of invasive species. Other interspecific interactions, however, such as parasitism and higher-order predation, have the potential to modify predator-prey interactions and thus the predictive capability of the comparative functional response approach. We used a four-species community module (higher-order predator; focal native or invasive predators; parasites of focal predators; native prey) to compare the predatory functional responses of native Gammarus duebeni celticus and invasive Gammarus pulex amphipods towards three invertebrate prey species (Asellus aquaticus, Simulium spp., Baetis rhodani), thus, quantifying the context dependencies of parasitism and a higher-order fish predator on these functional responses. Our functional response experiments demonstrated that the invasive amphipod had a higher predatory impact (lower handling time) on two of three prey species, which reflects patterns of impact observed in the field. The community module also revealed that parasitism had context-dependent influences, for one prey species, with the potential to further reduce the predatory impact of the invasive amphipod or increase the predatory impact of the native amphipod in the presence of a higher-order fish predator. Partial consumption of prey was similar for both predators and occurred increasingly in the order A. aquaticus, Simulium spp. and B. rhodani. This was associated with increasing prey densities, but showed no context dependencies with parasitism or higher-order fish predator. This study supports the applicability of comparative functional responses as a tool to predict and assess invasive species impacts incorporating multiple context dependencies. © 2014 The Authors. Journal of Animal Ecology © 2014 British Ecological Society.

Measurements of ocean wave spectra and modulation transfer function with the airborne two frequency scatterometer

NASA Technical Reports Server (NTRS)

Weissman, D. E.; Johnson, J. W.

1984-01-01

The directional spectrum and the microwave modulation transfer function of ocean waves can be measured with the airborne two frequency scatterometer technique. Similar to tower based observations, the aircraft measurements of the Modulation Transfer Function (MTF) show that it is strongly affected by both wind speed and sea state. Also detected are small differences in the magnitudes of the MTF between downwind and upwind radar look directions, and variations with ocean wavenumber. The MTF inferred from the two frequency radar is larger than that measured using single frequency, wave orbital velocity techniques such as tower based radars or ROWS measurements from low altitude aircraft. Possible reasons for this are discussed. The ability to measure the ocean directional spectrum with the two frequency scatterometer, with supporting MTF data, is demonstrated.

Measurements of ocean wave spectra and modulation transfer function with the airborne two-frequency scatterometer

NASA Technical Reports Server (NTRS)

Weissman, D. E.; Johnson, J. W.

1986-01-01

The directional spectrum and the microwave modulation transfer function of ocean waves can be measured with the airborne two frequency scatterometer technique. Similar to tower based observations, the aircraft measurements of the Modulation Transfer Function (MTF) show that it is strongly affected by both wind speed and sea state. Also detected are small differences in the magnitudes of the MTF between downwind and upwind radar look directions, and variations with ocean wavenumber. The MTF inferred from the two frequency radar is larger than that measured using single frequency, wave orbital velocity techniques such as tower based radars or ROWS measurements from low altitude aircraft. Possible reasons for this are discussed. The ability to measure the ocean directional spectrum with the two frequency scatterometer, with supporting MTF data, is demonstrated.

Selective GABA(A) α5 positive allosteric modulators improve cognitive function in aged rats with memory impairment.

PubMed

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

2013-01-01

A condition of excess activity in the hippocampal formation is observed in the aging brain and in conditions that confer additional risk during aging for Alzheimer's disease. Compounds that act as positive allosteric modulators at GABA(A) α5 receptors might be useful in targeting this condition because GABA(A) α5 receptors mediate tonic inhibition of principal neurons in the affected network. While agents to improve cognitive function in the past focused on inverse agonists, which are negative allosteric modulators at GABA(A) α5 receptors, research supporting that approach used only young animals and predated current evidence for excessive hippocampal activity in age-related conditions of cognitive impairment. Here, we used two compounds, Compound 44 [6,6-dimethyl-3-(3-hydroxypropyl)thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one] and Compound 6 [methyl 3,5-diphenylpyridazine-4-carboxylate], with functional activity as potentiators of γ-aminobutyric acid at GABA(A) α5 receptors, to test their ability to improve hippocampal-dependent memory in aged rats with identified cognitive impairment. Improvement was obtained in aged rats across protocols differing in motivational and performance demands and across varying retention intervals. Significant memory improvement occurred after either intracereboventricular infusion with Compound 44 (100 μg) in a water maze task or systemic administration with Compound 6 (3 mg/kg) in a radial arm maze task. Furthermore, systemic administration improved behavioral performance at dosing shown to provide drug exposure in the brain and in vivo receptor occupancy in the hippocampus. These data suggest a novel approach to improve neural network function in clinical conditions of excess hippocampal activity. This article is part of a Special Issue entitled 'Cognitive Enhancers'. Copyright © 2012 Elsevier Ltd. All rights reserved.

Evolution of functional specialization and division of labor.

PubMed

Rueffler, Claus; Hermisson, Joachim; Wagner, Günter P

2012-02-07

Division of labor among functionally specialized modules occurs at all levels of biological organization in both animals and plants. Well-known examples include the evolution of specialized enzymes after gene duplication, the evolution of specialized cell types, limb diversification in arthropods, and the evolution of specialized colony members in many taxa of marine invertebrates and social insects. Here, we identify conditions favoring the evolution of division of labor by means of a general mathematical model. Our starting point is the assumption that modules contribute to two different biological tasks and that the potential of modules to contribute to these tasks is traded off. Our results are phrased in terms of properties of performance functions that map the phenotype of modules to measures of performance. We show that division of labor is favored by three factors: positional effects that predispose modules for one of the tasks, accelerating performance functions, and synergistic interactions between modules. If modules can be lost or damaged, selection for robustness can counteract selection for functional specialization. To illustrate our theory we apply it to the evolution of specialized enzymes coded by duplicated genes.

Analogy of transistor function with modulating photonic band gap in electromagnetically induced grating

PubMed Central

Wang, Zhiguo; Ullah, Zakir; Gao, Mengqin; Zhang, Dan; Zhang, Yiqi; Gao, Hong; Zhang, Yanpeng

2015-01-01

Optical transistor is a device used to amplify and switch optical signals. Many researchers focus on replacing current computer components with optical equivalents, resulting in an optical digital computer system processing binary data. Electronic transistor is the fundamental building block of modern electronic devices. To replace electronic components with optical ones, an equivalent optical transistor is required. Here we compare the behavior of an optical transistor with the reflection from a photonic band gap structure in an electromagnetically induced transparency medium. A control signal is used to modulate the photonic band gap structure. Power variation of the control signal is used to provide an analogy between the reflection behavior caused by modulating the photonic band gap structure and the shifting of Q-point (Operation point) as well as amplification function of optical transistor. By means of the control signal, the switching function of optical transistor has also been realized. Such experimental schemes could have potential applications in making optical diode and optical transistor used in quantum information processing. PMID:26349444

Analogy of transistor function with modulating photonic band gap in electromagnetically induced grating

NASA Astrophysics Data System (ADS)

Wang, Zhiguo; Ullah, Zakir; Gao, Mengqin; Zhang, Dan; Zhang, Yiqi; Gao, Hong; Zhang, Yanpeng

2015-09-01

Optical transistor is a device used to amplify and switch optical signals. Many researchers focus on replacing current computer components with optical equivalents, resulting in an optical digital computer system processing binary data. Electronic transistor is the fundamental building block of modern electronic devices. To replace electronic components with optical ones, an equivalent optical transistor is required. Here we compare the behavior of an optical transistor with the reflection from a photonic band gap structure in an electromagnetically induced transparency medium. A control signal is used to modulate the photonic band gap structure. Power variation of the control signal is used to provide an analogy between the reflection behavior caused by modulating the photonic band gap structure and the shifting of Q-point (Operation point) as well as amplification function of optical transistor. By means of the control signal, the switching function of optical transistor has also been realized. Such experimental schemes could have potential applications in making optical diode and optical transistor used in quantum information processing.

Interhemispheric modulation of dual-mode, noninvasive brain stimulation on motor function.

PubMed

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

2014-06-01

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

STRS SpaceWire FPGA Module

NASA Technical Reports Server (NTRS)

Lux, James P.; Taylor, Gregory H.; Lang, Minh; Stern, Ryan A.

2011-01-01

An FPGA module leverages the previous work from Goddard Space Flight Center (GSFC) relating to NASA s Space Telecommunications Radio System (STRS) project. The STRS SpaceWire FPGA Module is written in the Verilog Register Transfer Level (RTL) language, and it encapsulates an unmodified GSFC core (which is written in VHDL). The module has the necessary inputs/outputs (I/Os) and parameters to integrate seamlessly with the SPARC I/O FPGA Interface module (also developed for the STRS operating environment, OE). Software running on the SPARC processor can access the configuration and status registers within the SpaceWire module. This allows software to control and monitor the SpaceWire functions, but it is also used to give software direct access to what is transmitted and received through the link. SpaceWire data characters can be sent/received through the software interface, as well as through the dedicated interface on the GSFC core. Similarly, SpaceWire time codes can be sent/received through the software interface or through a dedicated interface on the core. This innovation is designed for plug-and-play integration in the STRS OE. The SpaceWire module simplifies the interfaces to the GSFC core, and synchronizes all I/O to a single clock. An interrupt output (with optional masking) identifies time-sensitive events within the module. Test modes were added to allow internal loopback of the SpaceWire link and internal loopback of the client-side data interface.

Impaired conditioned pain modulation in youth with functional abdominal pain

PubMed Central

Morris, Matthew C.; Walker, Lynn S.; Bruehl, Stephen; Stone, Amanda L.; Mielock, Alyssa S.; Rao, Uma

2016-01-01

Functional abdominal pain (FAP) is associated with enhanced pain responsiveness. Although impaired conditioned pain modulation (CPM) characterizes adults with a variety of chronic pain conditions, relatively little is known about CPM in youth with FAP. The present study assessed CPM to evoked thermal pain in 140 youth (ages 10 to 17), 63 of whom had FAP and 77 of whom were healthy controls. Multilevel models demonstrated weaker CPM effects in FAP than healthy youth, as evident in slower within-person decreases in pain ratings during the conditioning phase. Weaker CPM effects were associated with greater somatic symptom severity and functional disability. Pain responses in FAP youth were heterogeneous, with 43% of youth showing an unexpected increase in pain ratings during the conditioning phase, suggesting sensitization rather than CPM-related pain inhibition. These findings highlight directions for future research on the emergence and maintenance of FAP in youth. PMID:27389918

Impaired conditioned pain modulation in youth with functional abdominal pain.

PubMed

Morris, Matthew C; Walker, Lynn S; Bruehl, Stephen; Stone, Amanda L; Mielock, Alyssa S; Rao, Uma

2016-10-01

Functional abdominal pain (FAP) is associated with enhanced pain responsiveness. Although impaired conditioned pain modulation (CPM) characterizes adults with a variety of chronic pain conditions, relatively little is known about CPM in youth with FAP. This study assessed CPM to evoked thermal pain in 140 youth (ages 10-17), 63 of whom had FAP and 77 of whom were healthy controls. Multilevel models demonstrated weaker CPM effects in youth with FAP than in healthy youth, as evident in slower within-person decreases in pain ratings during the conditioning phase. Weaker CPM effects were associated with greater somatic symptom severity and functional disability. Pain responses in youth with FAP were heterogeneous, with 43% of youth showing an unexpected increase in pain ratings during the conditioning phase, suggesting sensitization rather than CPM-related pain inhibition. These findings highlight directions for future research on the emergence and maintenance of FAP in youth.

Multiple Novel Functions of Henipavirus O-glycans: The First O-glycan Functions Identified in the Paramyxovirus Family.

PubMed

Stone, Jacquelyn A; Nicola, Anthony V; Baum, Linda G; Aguilar, Hector C

2016-02-01

O-linked glycosylation is a ubiquitous protein modification in organisms belonging to several kingdoms. Both microbial and host protein glycans are used by many pathogens for host invasion and immune evasion, yet little is known about the roles of O-glycans in viral pathogenesis. Reportedly, there is no single function attributed to O-glycans for the significant paramyxovirus family. The paramyxovirus family includes many important pathogens, such as measles, mumps, parainfluenza, metapneumo- and the deadly Henipaviruses Nipah (NiV) and Hendra (HeV) viruses. Paramyxoviral cell entry requires the coordinated actions of two viral membrane glycoproteins: the attachment (HN/H/G) and fusion (F) glycoproteins. O-glycan sites in HeV G were recently identified, facilitating use of the attachment protein of this deadly paramyxovirus as a model to study O-glycan functions. We mutated the identified HeV G O-glycosylation sites and found mutants with altered cell-cell fusion, G conformation, G/F association, viral entry in a pseudotyped viral system, and, quite unexpectedly, pseudotyped viral F protein incorporation and processing phenotypes. These are all important functions of viral glycoproteins. These phenotypes were broadly conserved for equivalent NiV mutants. Thus our results identify multiple novel and pathologically important functions of paramyxoviral O-glycans, paving the way to study O-glycan functions in other paramyxoviruses and enveloped viruses.

Teller Training Module: Off-Line Banking System. High-Technology Training Module.

ERIC Educational Resources Information Center

Lund, Candyce J.

This teller training module on offline banking systems is intended to be part of a postsecondary financial applications course. The module contains the following sections: module objective; specific objective; content--electronic audit machine key functions, practice packet--sample bank transactions and practicing procedures, and…

Two-dimensional, phase modulated lattice sums with application to the Helmholtz Green’s function

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

Linton, C. M., E-mail: C.M.Linton@lboro.ac.uk

2015-01-15

A class of two-dimensional phase modulated lattice sums in which the denominator is an indefinite quadratic polynomial Q is expressed in terms of a single, exponentially convergent series of elementary functions. This expression provides an extremely efficient method for the computation of the quasi-periodic Green’s function for the Helmholtz equation that arises in a number of physical contexts when studying wave propagation through a doubly periodic medium. For a class of sums in which Q is positive definite, our new result can be used to generate representations in terms of θ-functions which are significant generalisations of known results.

Dopamine negatively modulates the NCA ion channels in C. elegans

PubMed Central

Topalidou, Irini; Pereira, Laura

2017-01-01

The NALCN/NCA ion channel is a cation channel related to voltage-gated sodium and calcium channels. NALCN has been reported to be a sodium leak channel with a conserved role in establishing neuronal resting membrane potential, but its precise cellular role and regulation are unclear. The Caenorhabditis elegans orthologs of NALCN, NCA-1 and NCA-2, act in premotor interneurons to regulate motor circuit activity that sustains locomotion. Recently we found that NCA-1 and NCA-2 are activated by a signal transduction pathway acting downstream of the heterotrimeric G protein Gq and the small GTPase Rho. Through a forward genetic screen, here we identify the GPCR kinase GRK-2 as a new player affecting signaling through the Gq-Rho-NCA pathway. Using structure-function analysis, we find that the GPCR phosphorylation and membrane association domains of GRK-2 are required for its function. Genetic epistasis experiments suggest that GRK-2 acts on the D2-like dopamine receptor DOP-3 to inhibit Go signaling and positively modulate NCA-1 and NCA-2 activity. Through cell-specific rescuing experiments, we find that GRK-2 and DOP-3 act in premotor interneurons to modulate NCA channel function. Finally, we demonstrate that dopamine, through DOP-3, negatively regulates NCA activity. Thus, this study identifies a pathway by which dopamine modulates the activity of the NCA channels. PMID:28968387

Dopamine negatively modulates the NCA ion channels in C. elegans.

PubMed

Topalidou, Irini; Cooper, Kirsten; Pereira, Laura; Ailion, Michael

2017-10-01

The NALCN/NCA ion channel is a cation channel related to voltage-gated sodium and calcium channels. NALCN has been reported to be a sodium leak channel with a conserved role in establishing neuronal resting membrane potential, but its precise cellular role and regulation are unclear. The Caenorhabditis elegans orthologs of NALCN, NCA-1 and NCA-2, act in premotor interneurons to regulate motor circuit activity that sustains locomotion. Recently we found that NCA-1 and NCA-2 are activated by a signal transduction pathway acting downstream of the heterotrimeric G protein Gq and the small GTPase Rho. Through a forward genetic screen, here we identify the GPCR kinase GRK-2 as a new player affecting signaling through the Gq-Rho-NCA pathway. Using structure-function analysis, we find that the GPCR phosphorylation and membrane association domains of GRK-2 are required for its function. Genetic epistasis experiments suggest that GRK-2 acts on the D2-like dopamine receptor DOP-3 to inhibit Go signaling and positively modulate NCA-1 and NCA-2 activity. Through cell-specific rescuing experiments, we find that GRK-2 and DOP-3 act in premotor interneurons to modulate NCA channel function. Finally, we demonstrate that dopamine, through DOP-3, negatively regulates NCA activity. Thus, this study identifies a pathway by which dopamine modulates the activity of the NCA channels.

High-Throughput Screens To Identify Autophagy Inducers That Function by Disrupting Beclin 1/Bcl-2 Binding.

PubMed

Chiang, Wei-Chung; Wei, Yongjie; Kuo, Yi-Chun; Wei, Shuguang; Zhou, Anwu; Zou, Zhongju; Yehl, Jenna; Ranaghan, Matthew J; Skepner, Adam; Bittker, Joshua A; Perez, Jose R; Posner, Bruce A; Levine, Beth

2018-06-21

Autophagy, a lysosomal degradation pathway, plays a crucial role in cellular homeostasis, development, immunity, tumor suppression, metabolism, prevention of neurodegeneration, and lifespan extension. Thus, pharmacological stimulation of autophagy may be an effective approach for preventing or treating certain human diseases and/or aging. We sought to establish a method for developing new chemical compounds that specifically induce autophagy. To do this, we developed two assays to identify compounds that target a key regulatory node of autophagy induction-specifically, the binding of Bcl-2 (a negative regulator of autophagy) to Beclin 1 (an allosteric modulator of the Beclin 1/VPS34 lipid kinase complex that functions in autophagy initiation). These assays use either a split-luciferase assay to measure Beclin 1/Bcl-2 binding in cells or an AlphaLISA assay to directly measure direct Beclin 1/Bcl-2 binding in vitro. We screened two different chemical compound libraries, comprising ∼300 K compounds, to identify small molecules that disrupt Beclin 1/Bcl-2 binding and induce autophagy. Three novel compounds were identified that directly inhibit Beclin 1/Bcl-2 interaction with an IC 50 in the micromolar range and increase autophagic flux. These compounds do not demonstrate significant cytotoxicity, and they exert selectivity for disruption of Bcl-2 binding to the BH3 domain of Beclin 1 compared with the BH3 domain of the pro-apoptotic Bcl-2 family members, Bax and Bim. Thus, we have identified candidate molecules that serve as lead templates for developing potent and selective Beclin 1/Bcl-2 inhibitors that may be clinically useful as autophagy-inducing agents.

Aerosol scattering and absorption modulation transfer function

NASA Astrophysics Data System (ADS)

Sadot, Dan; Kopeika, Norman S.

1993-08-01

Recent experimental measurements of overall atmospheric modulation transfer function (MTF) indicate significant difference between the turbulence and overall atmospheric MTFs, except often at midday when turbulence is strong. We suggest here a physical explanation for those results which essentially relates to what we call a practical instrumentation-based atmospheric aerosol MTF which is a modification of the classical aerosol MTF theory. It is shown that system field-of-view and dynamic range affect strongly aerosol and overall atmospheric MTFs. It is often necessary to choose between MTF and SNR depending upon dynamic range requirements. Also, a new approach regarding aerosol absorption is presented. It is shown that aerosol-absorbed irradiance is spatial frequency dependent and enhances the degradation in image quality arising from received scattered light. This is most relevant for thermal imaging. An analytically corrected model for the aerosol MTF is presented which is relevant for imaging. An important conclusion is that the aerosol MTF is often the dominant part in the actual overall atmospheric MTF all across the optical spectral region.

Expression of versican 3'-untranslated region modulates endogenous microRNA functions.

PubMed

Lee, Daniel Y; Jeyapalan, Zina; Fang, Ling; Yang, Jennifer; Zhang, Yaou; Yee, Albert Y; Li, Minhui; Du, William W; Shatseva, Tatiana; Yang, Burton B

2010-10-25

Mature microRNAs (miRNAs) are single-stranded RNAs that regulate post-transcriptional gene expression. In our previous study, we have shown that versican 3'UTR, a fragment of non-coding transcript, has the ability to antagonize miR-199a-3p function thereby regulating expression of the matrix proteins versican and fibronectin, and thus resulting in enhanced cell-cell adhesion and organ adhesion. However, the impact of this non-coding fragment on tumorigenesis is yet to be determined. Using computational prediction confirmed with in vitro and in vivo experiments, we report that the expression of versican 3'UTR not only antagonizes miR-199a-3p but can also lower its steady state expression. We found that expression of versican 3'UTR in a mouse breast carcinoma cell line, 4T1, decreased miR-199a-3p levels. The decrease in miRNA activity consequently translated into differences in tumor growth. Computational analysis indicated that both miR-199a-3p and miR-144 targeted a cell cycle regulator, Rb1. In addition, miR-144 and miR-136, which have also been shown to interact with versican 3'UTR, was found to target PTEN. Expression of Rb1 and PTEN were up-regulated synergistically in vitro and in vivo, suggesting that the 3'UTR binds and modulates miRNA activities, freeing Rb1 and PTEN mRNAs for translation. In tumor formation assays, cells transfected with the 3'UTR formed smaller tumors compared with cells transfected with a control vector. Our results demonstrated that a 3'UTR fragment can be used to modulate miRNA functions. Our study also suggests that miRNAs in the cancer cells are more susceptible to degradation, due to its interaction with a non-coding 3'UTR. This non-coding component of mRNA may be used retrospectively to modulate miRNA activities.

LANDSAT-4 Thematic Mapper Modulation Transfer Function (MTF) evaluation

NASA Technical Reports Server (NTRS)

Schowengerdt, R. (Principal Investigator)

1985-01-01

The Modulation Transfer Function (MTF) for thematic mapping (TM) bands 3, 4, 5 and 7 is reliably estimated with the San Mateo Bridge target in the 12/31/82 scene. These results are to be compared with those from the 8/12/83 scene. Bands 1, 2 and 6 are to be analyzed with a different target possessing greater contrast. This may be possible with the underflight data comparison currently underway. The registration of this data to the TM image of 8/12/83 for a region arround the Stockton sewage pond east of San Francisco has begun. This particular approach has the advantage that the full two-dimensional MFT will be measured instead of the MFT in only one azimuth as reported.

Analyses of germline variants associated with ovarian cancer survival identify functional candidates at the 1q22 and 19p12 outcome loci

PubMed Central

Glubb, Dylan M.; Johnatty, Sharon E.; Quinn, Michael C.J.; O’Mara, Tracy A.; Tyrer, Jonathan P.; Gao, Bo; Fasching, Peter A.; Beckmann, Matthias W.; Lambrechts, Diether; Vergote, Ignace; Velez Edwards, Digna R.; Beeghly-Fadiel, Alicia; Benitez, Javier; Garcia, Maria J.; Goodman, Marc T.; Thompson, Pamela J.; Dörk, Thilo; Dürst, Matthias; Modungo, Francesmary; Moysich, Kirsten; Heitz, Florian; du Bois, Andreas; Pfisterer, Jacobus; Hillemanns, Peter; Karlan, Beth Y.; Lester, Jenny; Goode, Ellen L.; Cunningham, Julie M.; Winham, Stacey J.; Larson, Melissa C.; McCauley, Bryan M.; Kjær, Susanne Krüger; Jensen, Allan; Schildkraut, Joellen M.; Berchuck, Andrew; Cramer, Daniel W.; Terry, Kathryn L.; Salvesen, Helga B.; Bjorge, Line; Webb, Penny M.; Grant, Peter; Pejovic, Tanja; Moffitt, Melissa; Hogdall, Claus K.; Hogdall, Estrid; Paul, James; Glasspool, Rosalind; Bernardini, Marcus; Tone, Alicia; Huntsman, David; Woo, Michelle; Group, AOCS; deFazio, Anna; Kennedy, Catherine J.; Pharoah, Paul D.P.; MacGregor, Stuart; Chenevix-Trench, Georgia

2017-01-01

We previously identified associations with ovarian cancer outcome at five genetic loci. To identify putatively causal genetic variants and target genes, we prioritized two ovarian outcome loci (1q22 and 19p12) for further study. Bioinformatic and functional genetic analyses indicated that MEF2D and ZNF100 are targets of candidate outcome variants at 1q22 and 19p12, respectively. At 19p12, the chromatin interaction of a putative regulatory element with the ZNF100 promoter region correlated with candidate outcome variants. At 1q22, putative regulatory elements enhanced MEF2D promoter activity and haplotypes containing candidate outcome variants modulated these effects. In a public dataset, MEF2D and ZNF100 expression were both associated with ovarian cancer progression-free or overall survival time. In an extended set of 6,162 epithelial ovarian cancer patients, we found that functional candidates at the 1q22 and 19p12 loci, as well as other regional variants, were nominally associated with patient outcome; however, no associations reached our threshold for statistical significance (p<1×10-5). Larger patient numbers will be needed to convincingly identify any true associations at these loci. PMID:29029385

Short-term estriol administration modulates hypothalamo-pituitary function in patients with functional hypothalamic amenorrhea (FHA).

PubMed

Genazzani, Alessandro D; Podfigurna-Stopa, Agnieszka; Czyzyk, Adam; Katulski, Krzysztof; Prati, Alessia; Despini, Giulia; Angioni, Stefano; Simoncini, Tommaso; Meczekalski, Blazej

2016-01-01

To evaluate the influence of short-term estriol administration (10 d) on the hypothalamus-pituitary function and gonadotropins secretion in patients affected by functional hypothalamic amenorrhea (FHA). Controlled clinical study on patients with FHA (n = 12) in a clinical research environment. Hormonal determinations and gonadotropin (luteinizing hormone [LH] and FSH) response to a gonadotropin-releasing hormone (GnRH) bolus (10 μg) at baseline condition and after 10 d of therapy with 2 mg/d of estriol per os. Measurements of plasma LH, FSH, prolactin, estradiol, androstenedione, 17α-hydroxyprogesterone, insulin, cortisol, thyroid-stimulating hormone, free triiodothyronine, and free thyroxine. After treatment, the FHA patients showed a statistically significant increase of both LH and FSH plasma levels and the significant increase of their responses to the GnRH bolus. Estriol short-term therapy modulates within 10 d of administration the neuroendocrine control of the hypothalamus-pituitary unit and induces the recovery of both gonadotropins synthesis and secretion in hypogonadotropic patients with FHA.

Word Frequency As a Cue For Identifying Function Words In Infancy

ERIC Educational Resources Information Center

Hochmann, Jean-Remy; Endress, Ansgar D.; Mehler, Jacques

2010-01-01

While content words (e.g., 'dog') tend to carry meaning, function words (e.g., 'the') mainly serve syntactic purposes. Here, we ask whether 17-month old infants can use one language-universal cue to identify function word candidates: their high frequency of occurrence. In Experiment 1, infants listened to a series of short, naturally recorded…

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

PubMed

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

2014-11-01

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

Large Work Function Modulation of Monolayer MoS2 by Ambient Gases.

PubMed

Lee, Si Young; Kim, Un Jeong; Chung, JaeGwan; Nam, Honggi; Jeong, Hye Yun; Han, Gang Hee; Kim, Hyun; Oh, Hye Min; Lee, Hyangsook; Kim, Hyochul; Roh, Young-Geun; Kim, Jineun; Hwang, Sung Woo; Park, Yeonsang; Lee, Young Hee

2016-06-28

Although two-dimensional monolayer transition-metal dichalcogenides reveal numerous unique features that are inaccessible in bulk materials, their intrinsic properties are often obscured by environmental effects. Among them, work function, which is the energy required to extract an electron from a material to vacuum, is one critical parameter in electronic/optoelectronic devices. Here, we report a large work function modulation in MoS2 via ambient gases. The work function was measured by an in situ Kelvin probe technique and further confirmed by ultraviolet photoemission spectroscopy and theoretical calculations. A measured work function of 4.04 eV in vacuum was converted to 4.47 eV with O2 exposure, which is comparable with a large variation in graphene. The homojunction diode by partially passivating a transistor reveals an ideal junction with an ideality factor of almost one and perfect electrical reversibility. The estimated depletion width obtained from photocurrent mapping was ∼200 nm, which is much narrower than bulk semiconductors.

Differential Modulation of Functional Dynamics and Allosteric Interactions in the Hsp90-Cochaperone Complexes with p23 and Aha1: A Computational Study

PubMed Central

Blacklock, Kristin; Verkhivker, Gennady M.

2013-01-01

Allosteric interactions of the molecular chaperone Hsp90 with a large cohort of cochaperones and client proteins allow for molecular communication and event coupling in signal transduction networks. The integration of cochaperones into the Hsp90 system is driven by the regulatory mechanisms that modulate the progression of the ATPase cycle and control the recruitment of the Hsp90 clientele. In this work, we report the results of computational modeling of allosteric regulation in the Hsp90 complexes with the cochaperones p23 and Aha1. By integrating protein docking, biophysical simulations, modeling of allosteric communications, protein structure network analysis and the energy landscape theory we have investigated dynamics and stability of the Hsp90-p23 and Hsp90-Aha1 interactions in direct comparison with the extensive body of structural and functional experiments. The results have revealed that functional dynamics and allosteric interactions of Hsp90 can be selectively modulated by these cochaperones via specific targeting of the regulatory hinge regions that could restrict collective motions and stabilize specific chaperone conformations. The protein structure network parameters have quantified the effects of cochaperones on conformational stability of the Hsp90 complexes and identified dynamically stable communities of residues that can contribute to the strengthening of allosteric interactions. According to our results, p23-mediated changes in the Hsp90 interactions may provide “molecular brakes” that could slow down an efficient transmission of the inter-domain allosteric signals, consistent with the functional role of p23 in partially inhibiting the ATPase cycle. Unlike p23, Aha1-mediated acceleration of the Hsp90-ATPase cycle may be achieved via modulation of the equilibrium motions that facilitate allosteric changes favoring a closed dimerized form of Hsp90. The results of our study have shown that Aha1 and p23 can modulate the Hsp90-ATPase activity

Quetiapine modulates functional connectivity in brain aggression networks.

PubMed

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

2013-07-15

Aggressive behavior is associated with dysfunctions in an affective regulation network encompassing amygdala and prefrontal areas such as orbitofrontal (OFC), anterior cingulate (ACC), and dorsolateral prefrontal cortex (DLPFC). In particular, prefrontal regions have been postulated to control amygdala activity by inhibitory projections, and this process may be disrupted in aggressive individuals. The atypical antipsychotic quetiapine successfully attenuates aggressive behavior in various disorders; the underlying neural processes, however, are unknown. A strengthened functional coupling in the prefrontal-amygdala system may account for these anti-aggressive effects. An inhibition of this network has been reported for virtual aggression in violent video games as well. However, there have been so far no in-vivo observations of pharmacological influences on corticolimbic projections during human aggressive behavior. In a double-blind, placebo-controlled study, quetiapine and placebo were administered for three successive days prior to an fMRI experiment. In this experiment, functional brain connectivity was assessed during virtual aggressive behavior in a violent video game and an aggression-free control task in a non-violent modification. Quetiapine increased the functional connectivity of ACC and DLPFC with the amygdala during virtual aggression, whereas OFC-amygdala coupling was attenuated. These effects were observed neither for placebo nor for the non-violent control. These results demonstrate for the first time a pharmacological modification of aggression-related human brain networks in a naturalistic setting. The violence-specific modulation of prefrontal-amygdala networks appears to control aggressive behavior and provides a neurobiological model for the anti-aggressive effects of quetiapine. Copyright © 2013 Elsevier Inc. All rights reserved.

Analysis of evolutionary conservation patterns and their influence on identifying protein functional sites.

PubMed

Fang, Chun; Noguchi, Tamotsu; Yamana, Hayato

2014-10-01

Evolutionary conservation information included in position-specific scoring matrix (PSSM) has been widely adopted by sequence-based methods for identifying protein functional sites, because all functional sites, whether in ordered or disordered proteins, are found to be conserved at some extent. However, different functional sites have different conservation patterns, some of them are linear contextual, some of them are mingled with highly variable residues, and some others seem to be conserved independently. Every value in PSSMs is calculated independently of each other, without carrying the contextual information of residues in the sequence. Therefore, adopting the direct output of PSSM for prediction fails to consider the relationship between conservation patterns of residues and the distribution of conservation scores in PSSMs. In order to demonstrate the importance of combining PSSMs with the specific conservation patterns of functional sites for prediction, three different PSSM-based methods for identifying three kinds of functional sites have been analyzed. Results suggest that, different PSSM-based methods differ in their capability to identify different patterns of functional sites, and better combining PSSMs with the specific conservation patterns of residues would largely facilitate the prediction.

Respiratory modulation of human autonomic function: long-term neuroplasticity in space.

PubMed

Eckberg, Dwain L; Diedrich, André; Cooke, William H; Biaggioni, Italo; Buckey, Jay C; Pawelczyk, James A; Ertl, Andrew C; Cox, James F; Kuusela, Tom A; Tahvanainen, Kari U O; Mano, Tadaaki; Iwase, Satoshi; Baisch, Friedhelm J; Levine, Benjamin D; Adams-Huet, Beverley; Robertson, David; Blomqvist, C Gunnar

2016-10-01

We studied healthy astronauts before, during and after the Neurolab Space Shuttle mission with controlled breathing and apnoea, to identify autonomic changes that might contribute to postflight orthostatic intolerance. Measurements included the electrocardiogram, finger photoplethysmographic arterial pressure, respiratory carbon dioxide levels, tidal volume and peroneal nerve muscle sympathetic activity. Arterial pressure fell and then rose in space, and drifted back to preflight levels after return to Earth. Vagal metrics changed in opposite directions: vagal baroreflex gain and two indices of vagal fluctuations rose and then fell in space, and descended to preflight levels upon return to Earth. Sympathetic burst frequencies (but not areas) were greater than preflight in space and on landing day, and astronauts' abilities to modulate both burst areas and frequencies during apnoea were sharply diminished. Spaceflight triggers long-term neuroplastic changes reflected by reciptocal sympathetic and vagal motoneurone responsiveness to breathing changes. We studied six healthy astronauts five times, on Earth, in space on the first and 12th or 13th day of the 16 day Neurolab Space Shuttle mission, on landing day, and 5-6 days later. Astronauts followed a fixed protocol comprising controlled and random frequency breathing and apnoea, conceived to perturb their autonomic function and identify changes, if any, provoked by microgravity exposure. We recorded the electrocardiogram, finger photoplethysmographic arterial pressure, tidal carbon dioxide concentrations and volumes, and peroneal nerve muscle sympathetic activity on Earth (in the supine position) and in space. (Sympathetic nerve recordings were made during three sessions: preflight, late mission and landing day.) Arterial pressure changed systematically from preflight levels: pressure fell during early microgravity exposure, rose as microgravity exposure continued, and drifted back to preflight levels after return

Respiratory modulation of human autonomic function: long‐term neuroplasticity in space

PubMed Central

Diedrich, André; Cooke, William H.; Biaggioni, Italo; Buckey, Jay C.; Pawelczyk, James A.; Ertl, Andrew C.; Cox, James F.; Kuusela, Tom A.; Tahvanainen, Kari U.O.; Mano, Tadaaki; Iwase, Satoshi; Baisch, Friedhelm J.; Levine, Benjamin D.; Adams‐Huet, Beverley; Robertson, David; Blomqvist, C. Gunnar

2016-01-01

Key points We studied healthy astronauts before, during and after the Neurolab Space Shuttle mission with controlled breathing and apnoea, to identify autonomic changes that might contribute to postflight orthostatic intolerance.Measurements included the electrocardiogram, finger photoplethysmographic arterial pressure, respiratory carbon dioxide levels, tidal volume and peroneal nerve muscle sympathetic activity.Arterial pressure fell and then rose in space, and drifted back to preflight levels after return to Earth.Vagal metrics changed in opposite directions: vagal baroreflex gain and two indices of vagal fluctuations rose and then fell in space, and descended to preflight levels upon return to Earth.Sympathetic burst frequencies (but not areas) were greater than preflight in space and on landing day, and astronauts’ abilities to modulate both burst areas and frequencies during apnoea were sharply diminished.Spaceflight triggers long‐term neuroplastic changes reflected by reciptocal sympathetic and vagal motoneurone responsiveness to breathing changes. Abstract We studied six healthy astronauts five times, on Earth, in space on the first and 12th or 13th day of the 16 day Neurolab Space Shuttle mission, on landing day, and 5–6 days later. Astronauts followed a fixed protocol comprising controlled and random frequency breathing and apnoea, conceived to perturb their autonomic function and identify changes, if any, provoked by microgravity exposure. We recorded the electrocardiogram, finger photoplethysmographic arterial pressure, tidal carbon dioxide concentrations and volumes, and peroneal nerve muscle sympathetic activity on Earth (in the supine position) and in space. (Sympathetic nerve recordings were made during three sessions: preflight, late mission and landing day.) Arterial pressure changed systematically from preflight levels: pressure fell during early microgravity exposure, rose as microgravity exposure continued, and drifted back to preflight

In Silico Docking and Electrophysiological Characterization of Lacosamide Binding Sites on Collapsin Response Mediator Protein-2 Identifies a Pocket Important in Modulating Sodium Channel Slow Inactivation*

PubMed Central

Wang, Yuying; Brittain, Joel M.; Jarecki, Brian W.; Park, Ki Duk; Wilson, Sarah M.; Wang, Bo; Hale, Rachel; Meroueh, Samy O.; Cummins, Theodore R.; Khanna, Rajesh

2010-01-01

The anti-epileptic drug (R)-lacosamide ((2R)-2-(acetylamino)-N-benzyl-3-methoxypropanamide (LCM)) modulates voltage-gated sodium channels (VGSCs) by preferentially interacting with slow inactivated sodium channels, but the observation that LCM binds to collapsin response mediator protein 2 (CRMP-2) suggests additional mechanisms of action for LCM. We postulated that CRMP-2 levels affects the actions of LCM on VGSCs. CRMP-2 labeling by LCM analogs was competitively displaced by excess LCM in rat brain lysates. Manipulation of CRMP-2 levels in the neuronal model system CAD cells affected slow inactivation of VGSCs without any effects on other voltage-dependent properties. In silico docking was performed to identify putative binding sites in CRMP-2 that may modulate the effects of LCM on VGSCs. These studies identified five cavities in CRMP-2 that can accommodate LCM. CRMP-2 alanine mutants of key residues within these cavities were functionally similar to wild-type CRMP-2 as assessed by similar levels of enhancement in dendritic complexity of cortical neurons. Next, we examined the effects of expression of wild-type and mutant CRMP-2 constructs on voltage-sensitive properties of VGSCs in CAD cells: 1) steady-state voltage-dependent activation and fast-inactivation properties were not affected by LCM, 2) CRMP-2 single alanine mutants reduced the LCM-mediated effects on the ability of endogenous Na+ channels to transition to a slow inactivated state, and 3) a quintuplicate CRMP-2 alanine mutant further decreased this slow inactivated fraction. Collectively, these results identify key CRMP-2 residues that can coordinate LCM binding thus making it more effective on its primary clinical target. PMID:20538611

Crystal Structure of an Integron Gene Cassette-Associated Protein from Vibrio cholerae Identifies a Cationic Drug-Binding Module

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

Deshpande, Chandrika N.; Harrop, Stephen J.; Boucher, Yan

2012-02-15

The direct isolation of integron gene cassettes from cultivated and environmental microbial sources allows an assessment of the impact of the integron/gene cassette system on the emergence of new phenotypes, such as drug resistance or virulence. A structural approach is being exploited to investigate the modularity and function of novel integron gene cassettes. We report the 1.8 {angstrom} crystal structure of Cass2, an integron-associated protein derived from an environmental V. cholerae. The structure defines a monomeric beta-barrel protein with a fold related to the effector-binding portion of AraC/XylS transcription activators. The closest homologs of Cass2 are multi-drug binding proteins, suchmore » as BmrR. Consistent with this, a binding pocket made up of hydrophobic residues and a single glutamate side chain is evident in Cass2, occupied in the crystal form by polyethylene glycol. Fluorescence assays demonstrate that Cass2 is capable of binding cationic drug compounds with submicromolar affinity. The Cass2 module possesses a protein interaction surface proximal to its drug-binding cavity with features homologous to those seen in multi-domain transcriptional regulators. Genetic analysis identifies Cass2 to be representative of a larger family of independent effector-binding proteins associated with lateral gene transfer within Vibrio and closely-related species. We propose that the Cass2 family not only has capacity to form functional transcription regulator complexes, but represents possible evolutionary precursors to multi-domain regulators associated with cationic drug compounds.« less

Interrogator system for identifying electrical circuits

DOEpatents

Jatko, W.B.; McNeilly, D.R.

1988-04-12

A system for interrogating electrical leads to correctly ascertain the identity of equipment attached to remote ends of the leads is disclosed. The system includes a source of a carrier signal generated in a controller/receiver to be sent over the leads and an identifier unit at the equipment. The identifier is activated by command of the carrier and uses a portion of the carrier to produce a supply voltage. Each identifier is uniquely programmed for a specific piece of equipment, and causes the impedance of the circuit to be modified whereby the carrier signal is modulated according to that program. The modulation can be amplitude, frequency or phase modulation. A demodulator in the controller/receiver analyzes the modulated carrier signal, and if a verified signal is recognized displays and/or records the information. This information can be utilized in a computer system to prepare a wiring diagram of the electrical equipment attached to specific leads. Specific circuit values are given for amplitude modulation, and the system is particularly described for use with thermocouples. 6 figs.

Interrogator system for identifying electrical circuits

DOEpatents

Jatko, William B.; McNeilly, David R.

1988-01-01

A system for interrogating electrical leads to correctly ascertain the identity of equipment attached to remote ends of the leads. The system includes a source of a carrier signal generated in a controller/receiver to be sent over the leads and an identifier unit at the equipment. The identifier is activated by command of the carrier and uses a portion of the carrier to produce a supply voltage. Each identifier is uniquely programmed for a specific piece of equipment, and causes the impedance of the circuit to be modified whereby the carrier signal is modulated according to that program. The modulation can be amplitude, frequency or phase modulation. A demodulator in the controller/receiver analyzes the modulated carrier signal, and if a verified signal is recognized displays and/or records the information. This information can be utilized in a computer system to prepare a wiring diagram of the electrical equipment attached to specific leads. Specific circuit values are given for amplitude modulation, and the system is particularly described for use with thermocouples.

Function, dynamics and evolution of network motif modules in integrated gene regulatory networks of worm and plant.

PubMed

Defoort, Jonas; Van de Peer, Yves; Vermeirssen, Vanessa

2018-06-05

Gene regulatory networks (GRNs) consist of different molecular interactions that closely work together to establish proper gene expression in time and space. Especially in higher eukaryotes, many questions remain on how these interactions collectively coordinate gene regulation. We study high quality GRNs consisting of undirected protein-protein, genetic and homologous interactions, and directed protein-DNA, regulatory and miRNA-mRNA interactions in the worm Caenorhabditis elegans and the plant Arabidopsis thaliana. Our data-integration framework integrates interactions in composite network motifs, clusters these in biologically relevant, higher-order topological network motif modules, overlays these with gene expression profiles and discovers novel connections between modules and regulators. Similar modules exist in the integrated GRNs of worm and plant. We show how experimental or computational methodologies underlying a certain data type impact network topology. Through phylogenetic decomposition, we found that proteins of worm and plant tend to functionally interact with proteins of a similar age, while at the regulatory level TFs favor same age, but also older target genes. Despite some influence of the duplication mode difference, we also observe at the motif and module level for both species a preference for age homogeneity for undirected and age heterogeneity for directed interactions. This leads to a model where novel genes are added together to the GRNs in a specific biological functional context, regulated by one or more TFs that also target older genes in the GRNs. Overall, we detected topological, functional and evolutionary properties of GRNs that are potentially universal in all species.

Information sensitivity functions to assess parameter information gain and identifiability of dynamical systems.

PubMed

Pant, Sanjay

2018-05-01

A new class of functions, called the 'information sensitivity functions' (ISFs), which quantify the information gain about the parameters through the measurements/observables of a dynamical system are presented. These functions can be easily computed through classical sensitivity functions alone and are based on Bayesian and information-theoretic approaches. While marginal information gain is quantified by decrease in differential entropy, correlations between arbitrary sets of parameters are assessed through mutual information. For individual parameters, these information gains are also presented as marginal posterior variances, and, to assess the effect of correlations, as conditional variances when other parameters are given. The easy to interpret ISFs can be used to (a) identify time intervals or regions in dynamical system behaviour where information about the parameters is concentrated; (b) assess the effect of measurement noise on the information gain for the parameters; (c) assess whether sufficient information in an experimental protocol (input, measurements and their frequency) is available to identify the parameters; (d) assess correlation in the posterior distribution of the parameters to identify the sets of parameters that are likely to be indistinguishable; and (e) assess identifiability problems for particular sets of parameters. © 2018 The Authors.

Cannabinoid Modulation of Functional Connectivity within Regions Processing Attentional Salience

PubMed Central

Bhattacharyya, Sagnik; Falkenberg, Irina; Martin-Santos, Rocio; Atakan, Zerrin; Crippa, Jose A; Giampietro, Vincent; Brammer, Mick; McGuire, Philip

2015-01-01

There is now considerable evidence to support the hypothesis that psychotic symptoms are the result of abnormal salience attribution, and that the attribution of salience is largely mediated through the prefrontal cortex, the striatum, and the hippocampus. Although these areas show differential activation under the influence of delta-9-tetrahydrocannabinol (delta-9-THC) and cannabidiol (CBD), the two major derivatives of cannabis sativa, little is known about the effects of these cannabinoids on the functional connectivity between these regions. We investigated this in healthy occasional cannabis users by employing event-related functional magnetic resonance imaging (fMRI) following oral administration of delta-9-THC, CBD, or a placebo capsule. Employing a seed cluster-based functional connectivity analysis that involved using the average time series from each seed cluster for a whole-brain correlational analysis, we investigated the effect of drug condition on functional connectivity between the seed clusters and the rest of the brain during an oddball salience processing task. Relative to the placebo condition, delta-9-THC and CBD had opposite effects on the functional connectivity between the dorsal striatum, the prefrontal cortex, and the hippocampus. Delta-9-THC reduced fronto-striatal connectivity, which was related to its effect on task performance, whereas this connection was enhanced by CBD. Conversely, mediotemporal-prefrontal connectivity was enhanced by delta-9-THC and reduced by CBD. Our results suggest that the functional integration of brain regions involved in salience processing is differentially modulated by single doses of delta-9-THC and CBD and that this relates to the processing of salient stimuli. PMID:25249057

Cannabinoid modulation of functional connectivity within regions processing attentional salience.

PubMed

Bhattacharyya, Sagnik; Falkenberg, Irina; Martin-Santos, Rocio; Atakan, Zerrin; Crippa, Jose A; Giampietro, Vincent; Brammer, Mick; McGuire, Philip

2015-05-01

There is now considerable evidence to support the hypothesis that psychotic symptoms are the result of abnormal salience attribution, and that the attribution of salience is largely mediated through the prefrontal cortex, the striatum, and the hippocampus. Although these areas show differential activation under the influence of delta-9-tetrahydrocannabinol (delta-9-THC) and cannabidiol (CBD), the two major derivatives of cannabis sativa, little is known about the effects of these cannabinoids on the functional connectivity between these regions. We investigated this in healthy occasional cannabis users by employing event-related functional magnetic resonance imaging (fMRI) following oral administration of delta-9-THC, CBD, or a placebo capsule. Employing a seed cluster-based functional connectivity analysis that involved using the average time series from each seed cluster for a whole-brain correlational analysis, we investigated the effect of drug condition on functional connectivity between the seed clusters and the rest of the brain during an oddball salience processing task. Relative to the placebo condition, delta-9-THC and CBD had opposite effects on the functional connectivity between the dorsal striatum, the prefrontal cortex, and the hippocampus. Delta-9-THC reduced fronto-striatal connectivity, which was related to its effect on task performance, whereas this connection was enhanced by CBD. Conversely, mediotemporal-prefrontal connectivity was enhanced by delta-9-THC and reduced by CBD. Our results suggest that the functional integration of brain regions involved in salience processing is differentially modulated by single doses of delta-9-THC and CBD and that this relates to the processing of salient stimuli.

Subgenual anterior cingulate cortex controls sadness-induced modulations of cognitive and emotional network hubs.

PubMed

Ramirez-Mahaluf, Juan P; Perramon, Joan; Otal, Begonya; Villoslada, Pablo; Compte, Albert

2018-06-04

The regulation of cognitive and emotional processes is critical for proper executive functions and social behavior, but its specific mechanisms remain unknown. Here, we addressed this issue by studying with functional magnetic resonance imaging the changes in network topology that underlie competitive interactions between emotional and cognitive networks in healthy participants. Our behavioral paradigm contrasted periods with high emotional and cognitive demands by including a sadness provocation task followed by a spatial working memory task. The sharp contrast between successive tasks was designed to enhance the separability of emotional and cognitive networks and reveal areas that regulate the flow of information between them (hubs). By applying graph analysis methods on functional connectivity between 20 regions of interest in 22 participants we identified two main brain network modules, one dorsal and one ventral, and their hub areas: the left dorsolateral prefrontal cortex (dlPFC) and the left medial frontal pole (mFP). These hub areas did not modulate their mutual functional connectivity following sadness but they did so through an interposed area, the subgenual anterior cingulate cortex (sACC). Our results identify dlPFC and mFP as areas regulating interactions between emotional and cognitive networks, and suggest that their modulation by sadness experience is mediated by sACC.

Design of small molecule epigenetic modulators.

PubMed

Pachaiyappan, Boobalan; Woster, Patrick M

2014-01-01

The field of epigenetics has expanded rapidly to reveal multiple new targets for drug discovery. The functional elements of the epigenomic machinery can be categorized as writers, erasers and readers, and together these elements control cellular gene expression and homeostasis. It is increasingly clear that aberrations in the epigenome can underly a variety of diseases, and thus discovery of small molecules that modulate the epigenome in a specific manner is a viable approach to the discovery of new therapeutic agents. In this Digest, the components of epigenetic control of gene expression will be briefly summarized, and efforts to identify small molecules that modulate epigenetic processes will be described. Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

Low frequency steady-state brain responses modulate large scale functional networks in a frequency-specific means.

PubMed

Wang, Yi-Feng; Long, Zhiliang; Cui, Qian; Liu, Feng; Jing, Xiu-Juan; Chen, Heng; Guo, Xiao-Nan; Yan, Jin H; Chen, Hua-Fu

2016-01-01

Neural oscillations are essential for brain functions. Research has suggested that the frequency of neural oscillations is lower for more integrative and remote communications. In this vein, some resting-state studies have suggested that large scale networks function in the very low frequency range (<1 Hz). However, it is difficult to determine the frequency characteristics of brain networks because both resting-state studies and conventional frequency tagging approaches cannot simultaneously capture multiple large scale networks in controllable cognitive activities. In this preliminary study, we aimed to examine whether large scale networks can be modulated by task-induced low frequency steady-state brain responses (lfSSBRs) in a frequency-specific pattern. In a revised attention network test, the lfSSBRs were evoked in the triple network system and sensory-motor system, indicating that large scale networks can be modulated in a frequency tagging way. Furthermore, the inter- and intranetwork synchronizations as well as coherence were increased at the fundamental frequency and the first harmonic rather than at other frequency bands, indicating a frequency-specific modulation of information communication. However, there was no difference among attention conditions, indicating that lfSSBRs modulate the general attention state much stronger than distinguishing attention conditions. This study provides insights into the advantage and mechanism of lfSSBRs. More importantly, it paves a new way to investigate frequency-specific large scale brain activities. © 2015 Wiley Periodicals, Inc.

Regulatory Snapshots: integrative mining of regulatory modules from expression time series and regulatory networks.

PubMed

Gonçalves, Joana P; Aires, Ricardo S; Francisco, Alexandre P; Madeira, Sara C

2012-01-01

Explaining regulatory mechanisms is crucial to understand complex cellular responses leading to system perturbations. Some strategies reverse engineer regulatory interactions from experimental data, while others identify functional regulatory units (modules) under the assumption that biological systems yield a modular organization. Most modular studies focus on network structure and static properties, ignoring that gene regulation is largely driven by stimulus-response behavior. Expression time series are key to gain insight into dynamics, but have been insufficiently explored by current methods, which often (1) apply generic algorithms unsuited for expression analysis over time, due to inability to maintain the chronology of events or incorporate time dependency; (2) ignore local patterns, abundant in most interesting cases of transcriptional activity; (3) neglect physical binding or lack automatic association of regulators, focusing mainly on expression patterns; or (4) limit the discovery to a predefined number of modules. We propose Regulatory Snapshots, an integrative mining approach to identify regulatory modules over time by combining transcriptional control with response, while overcoming the above challenges. Temporal biclustering is first used to reveal transcriptional modules composed of genes showing coherent expression profiles over time. Personalized ranking is then applied to prioritize prominent regulators targeting the modules at each time point using a network of documented regulatory associations and the expression data. Custom graphics are finally depicted to expose the regulatory activity in a module at consecutive time points (snapshots). Regulatory Snapshots successfully unraveled modules underlying yeast response to heat shock and human epithelial-to-mesenchymal transition, based on regulations documented in the YEASTRACT and JASPAR databases, respectively, and available expression data. Regulatory players involved in functionally enriched

Regulatory Snapshots: Integrative Mining of Regulatory Modules from Expression Time Series and Regulatory Networks

PubMed Central

Gonçalves, Joana P.; Aires, Ricardo S.; Francisco, Alexandre P.; Madeira, Sara C.

2012-01-01

Explaining regulatory mechanisms is crucial to understand complex cellular responses leading to system perturbations. Some strategies reverse engineer regulatory interactions from experimental data, while others identify functional regulatory units (modules) under the assumption that biological systems yield a modular organization. Most modular studies focus on network structure and static properties, ignoring that gene regulation is largely driven by stimulus-response behavior. Expression time series are key to gain insight into dynamics, but have been insufficiently explored by current methods, which often (1) apply generic algorithms unsuited for expression analysis over time, due to inability to maintain the chronology of events or incorporate time dependency; (2) ignore local patterns, abundant in most interesting cases of transcriptional activity; (3) neglect physical binding or lack automatic association of regulators, focusing mainly on expression patterns; or (4) limit the discovery to a predefined number of modules. We propose Regulatory Snapshots, an integrative mining approach to identify regulatory modules over time by combining transcriptional control with response, while overcoming the above challenges. Temporal biclustering is first used to reveal transcriptional modules composed of genes showing coherent expression profiles over time. Personalized ranking is then applied to prioritize prominent regulators targeting the modules at each time point using a network of documented regulatory associations and the expression data. Custom graphics are finally depicted to expose the regulatory activity in a module at consecutive time points (snapshots). Regulatory Snapshots successfully unraveled modules underlying yeast response to heat shock and human epithelial-to-mesenchymal transition, based on regulations documented in the YEASTRACT and JASPAR databases, respectively, and available expression data. Regulatory players involved in functionally enriched

Genome-Wide Survey and Expression Profiling of CCCH-Zinc Finger Family Reveals a Functional Module in Macrophage Activation

PubMed Central

Liang, Jian; Song, Wenjun; Tromp, Gail; Kolattukudy, Pappachan E.; Fu, Mingui

2008-01-01

Previously, we have identified a novel CCCH zinc finger protein family as negative regulators of macrophage activation. To gain an overall insight into the entire CCCH zinc finger gene family and to evaluate their potential role in macrophage activation, here we performed a genome-wide survey of CCCH zinc finger genes in mouse and human. Totally 58 CCCH zinc finger genes in mouse and 55 in human were identified and most of them have not been reported previously. Phylogenetic analysis revealed that the mouse CCCH family was divided into 6 groups. Meanwhile, we employed quantitative real-time PCR to profile their tissue expression patterns in adult mice. Clustering analysis showed that most of CCCH genes were broadly expressed in all of tissues examined with various levels. Interestingly, several CCCH genes Mbnl3, Zfp36l2, Zfp36, Zc3h12a, Zc3h12d, Zc3h7a and Leng9 were enriched in macrophage-related organs such as thymus, spleen, lung, intestine and adipose. Consistently, a comprehensive assessment of changes in expression of the 58 members of the mouse CCCH family during macrophage activation also revealed that these CCCH zinc finger genes were associated with the activation of bone marrow-derived macrophages by lipopolysaccharide. Taken together, this study not only identified a functional module of CCCH zinc finger genes in the regulation of macrophage activation but also provided the framework for future studies to dissect the function of this emerging gene family. PMID:18682727

A characterization of low luminance static and dynamic modulation transfer function curves for P-1, P-43, and P-53 phosphorus

NASA Astrophysics Data System (ADS)

Beasley, Howard H.; Martin, John S.; Klymenko, Victor; Harding, Thomas H.; Verona, Robert W.; Rash, Clarence E.

1995-07-01

A counterphase modulation technique is used to measure the static and dynamic modulation transfer functions for three phosphorus of current interest to U.S. Army aviation helmet-mounted displays (P-1, P-43, and P-53). A family of modulation transfer curves, one for each temporal frequency, is presented for each phosphorus. The measured MFT curves generally support the supposition that phosphorus persistence is a critical parameter in the ability of a CRT display to accurately reproduce contrast modulation transfer in dynamic environments.

Photovoltaic module encapsulation design and materials selection, volume 1

NASA Technical Reports Server (NTRS)

Cuddihy, E.; Carroll, W.; Coulbert, C.; Gupta, A.; Liang, R. H.

1982-01-01

Encapsulation material system requirements, material selection criteria, and the status and properties of encapsulation materials and processes available are presented. Technical and economic goals established for photovoltaic modules and encapsulation systems and their status are described. Available encapsulation technology and data are presented to facilitate design and material selection for silicon flat plate photovoltaic modules, using the best materials available and processes optimized for specific power applications and geographic sites. The operational and environmental loads that encapsulation system functional requirements and candidate design concepts and materials that are identified to have the best potential to meet the cost and performance goals for the flat plate solar array project are described. Available data on encapsulant material properties, fabrication processing, and module life and durability characteristics are presented.

Integrating Module - NEMS Documentation

EIA Publications

2014-01-01

Provides an overview of the complete National Energy Modeling System (NEMS) model, and includes brief descriptions of the modules with which the Integrating Module interacts. The emphasis and focus, however, is on the structure and function of the Integrating Module of NEMS.

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

NASA Astrophysics Data System (ADS)

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

2013-02-01

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

Levodopa modulates small-world architecture of functional brain networks in Parkinson's disease.

PubMed

Berman, Brian D; Smucny, Jason; Wylie, Korey P; Shelton, Erika; Kronberg, Eugene; Leehey, Maureen; Tregellas, Jason R

2016-11-01

PD is associated with disrupted connectivity to a large number of distributed brain regions. How the disease alters the functional topological organization of the brain, however, remains poorly understood. Furthermore, how levodopa modulates network topology in PD is largely unknown. The objective of this study was to use resting-state functional MRI and graph theory to determine how small-world architecture is altered in PD and affected by levodopa administration. Twenty-one PD patients and 20 controls underwent functional MRI scanning. PD patients were scanned off medication and 1 hour after 200 mg levodopa. Imaging data were analyzed using 226 nodes comprising 10 intrinsic brain networks. Correlation matrices were generated for each subject and converted into cost-thresholded, binarized adjacency matrices. Cost-integrated whole-brain global and local efficiencies were compared across groups and tested for relationships with disease duration and severity. Data from 2 patients and 4 controls were excluded because of excess motion. Patients off medication showed no significant changes in global efficiency and overall local efficiency, but in a subnetwork analysis did show increased local efficiency in executive (P = 0.006) and salience (P = 0.018) networks. Levodopa significantly decreased local efficiency (P = 0.039) in patients except within the subcortical network, in which it significantly increased local efficiency (P = 0.007). Levodopa modulates global and local efficiency measures of small-world topology in PD, suggesting that degeneration of nigrostriatal neurons in PD may be associated with a large-scale network reorganization and that levodopa tends to normalize the disrupted network topology in PD. © 2016 International Parkinson and Movement Disorder Society. © 2016 International Parkinson and Movement Disorder Society.

Screening for autism identifies behavioral disorders in children functional defecation disorders.

PubMed

Kuizenga-Wessel, Sophie; Di Lorenzo, Carlo; Nicholson, Lisa M; Butter, Eric M; Ratliff-Schaub, Karen L; Benninga, Marc A; Williams, Kent C

2016-10-01

This study prospectively assessed whether positive screening surveys for autism spectrum disorders (ASDs) in children with functional defecation disorders (FDDs) accurately identify ASD. Parents of children (4-12 years) who met Rome III criteria for functional constipation (FC), FC with fecal incontinence (FI) and functional nonretentive FI (FNRFI) completed two ASD screening surveys. Children with positive screens were referred for psychological evaluation, and a year later, follow-up surveys were conducted. Of the 97 study participants, 30.9 % were diagnosed with FC, 62.9 % with FC with FI, and 6.2 % with FNRFI. ASD surveys were positive for 27 children (27.8 %). New DSM diagnoses were made in 10 out of the 15 children that completed further evaluation. Two (2.1 %) met criteria for ASD, and 12 (12.4 %) met criteria for other behavioral disorders. Average SRS and SCQ-L scores were higher in subjects with FC with FI as compared to FC alone and in those who reported no improvement versus those who reported improvement 1 year later. While positive ASD screening surveys did not correctly identify ASD in the majority, it did help to identify other unrecognized behavioral disorders in children with FDD. High screening scores were more common in children with FC with FI and in children with poorer responses to current medical treatments. •A prior study found that 29 % of children with FDD scored positive on ASD screening questionnaires. •Whether positive screens correctly identify ASD in children with FDD is unknown. What is New: •This study shows that positive ASD screens do not correctly identify ASD in children with FDD. However, the use of ASD screening questionnaires can identify previously unrecognized and untreated behavioral/developmental disorders in children with FDD. •High screening scores are more common in children with FC with FI and in children with poorer responses to current medical treatments.

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

Identifying Support Functions in Developmental Relationships: A Self-Determination Perspective

ERIC Educational Resources Information Center

Janssen, Suzanne; van Vuuren, Mark; de Jong, Menno D. T.

2013-01-01

This study examines the content of developmental networks from the perspective of self-determination theory. We qualitatively examine 18 proteges' constellations of developmental relationships to identify specific types of developmental support functions. Our study shows that the adoption of self-determination theory leads to a theory-based…

Fluorescence Polarization Screening Assays for Small Molecule Allosteric Modulators of ABL Kinase Function

PubMed Central

Grover, Prerna; Shi, Haibin; Baumgartner, Matthew; Camacho, Carlos J.; Smithgall, Thomas E.

2015-01-01

The ABL protein-tyrosine kinase regulates intracellular signaling pathways controlling diverse cellular processes and contributes to several forms of cancer. The kinase activity of ABL is repressed by intramolecular interactions involving its regulatory Ncap, SH3 and SH2 domains. Small molecules that allosterically regulate ABL kinase activity through its non-catalytic domains may represent selective probes of ABL function. Here we report a screening assay for chemical modulators of ABL kinase activity that target the regulatory interaction of the SH3 domain with the SH2-kinase linker. This fluorescence polarization (FP) assay is based on a purified recombinant ABL protein consisting of the N-cap, SH3 and SH2 domains plus the SH2-kinase linker (N32L protein) and a short fluorescein-labeled probe peptide that binds to the SH3 domain. In assay development experiments, we found that the probe peptide binds to the recombinant ABL N32L protein in vitro, producing a robust FP signal that can be competed with an excess of unlabeled peptide. The FP signal is not observed with control N32L proteins bearing either an inactivating mutation in the SH3 domain or enhanced SH3:linker interaction. A pilot screen of 1200 FDA-approved drugs identified four compounds that specifically reduced the FP signal by at least three standard deviations from the untreated controls. Secondary assays showed that one of these hit compounds, the antithrombotic drug dipyridamole, enhances ABL kinase activity in vitro to a greater extent than the previously described ABL agonist, DPH. Docking studies predicted that this compound binds to a pocket formed at the interface of the SH3 domain and the linker, suggesting that it activates ABL by disrupting this regulatory interaction. These results show that screening assays based on the non-catalytic domains of ABL can identify allosteric small molecule regulators of kinase function, providing a new approach to selective drug discovery for this important

Fluorescence Polarization Screening Assays for Small Molecule Allosteric Modulators of ABL Kinase Function.

PubMed

Grover, Prerna; Shi, Haibin; Baumgartner, Matthew; Camacho, Carlos J; Smithgall, Thomas E

2015-01-01

The ABL protein-tyrosine kinase regulates intracellular signaling pathways controlling diverse cellular processes and contributes to several forms of cancer. The kinase activity of ABL is repressed by intramolecular interactions involving its regulatory Ncap, SH3 and SH2 domains. Small molecules that allosterically regulate ABL kinase activity through its non-catalytic domains may represent selective probes of ABL function. Here we report a screening assay for chemical modulators of ABL kinase activity that target the regulatory interaction of the SH3 domain with the SH2-kinase linker. This fluorescence polarization (FP) assay is based on a purified recombinant ABL protein consisting of the N-cap, SH3 and SH2 domains plus the SH2-kinase linker (N32L protein) and a short fluorescein-labeled probe peptide that binds to the SH3 domain. In assay development experiments, we found that the probe peptide binds to the recombinant ABL N32L protein in vitro, producing a robust FP signal that can be competed with an excess of unlabeled peptide. The FP signal is not observed with control N32L proteins bearing either an inactivating mutation in the SH3 domain or enhanced SH3:linker interaction. A pilot screen of 1200 FDA-approved drugs identified four compounds that specifically reduced the FP signal by at least three standard deviations from the untreated controls. Secondary assays showed that one of these hit compounds, the antithrombotic drug dipyridamole, enhances ABL kinase activity in vitro to a greater extent than the previously described ABL agonist, DPH. Docking studies predicted that this compound binds to a pocket formed at the interface of the SH3 domain and the linker, suggesting that it activates ABL by disrupting this regulatory interaction. These results show that screening assays based on the non-catalytic domains of ABL can identify allosteric small molecule regulators of kinase function, providing a new approach to selective drug discovery for this important

Connexin channels and phospholipids: association and modulation

PubMed Central

Locke, Darren; Harris, Andrew L

2009-01-01

Background For membrane proteins, lipids provide a structural framework and means to modulate function. Paired connexin hemichannels form the intercellular channels that compose gap junction plaques while unpaired hemichannels have regulated functions in non-junctional plasma membrane. The importance of interactions between connexin channels and phospholipids is poorly understood. Results Endogenous phospholipids most tightly associated with purified connexin26 or connexin32 hemichannels or with junctional plaques in cell membranes, those likely to have structural and/or modulatory effects, were identified by tandem electrospray ionization-mass spectrometry using class-specific interpretative methods. Phospholipids were characterized by headgroup class, charge, glycerol-alkyl chain linkage and by acyl chain length and saturation. The results indicate that specific endogenous phospholipids are uniquely associated with either connexin26 or connexin32 channels, and some phospholipids are associated with both. Functional effects of the major phospholipid classes on connexin channel activity were assessed by molecular permeability of hemichannels reconstituted into liposomes. Changes to phospholipid composition(s) of the liposome membrane altered the activity of connexin channels in a manner reflecting changes to the surface charge/potential of the membrane and, secondarily, to cholesterol content. Together, the data show that connexin26 and connexin32 channels have a preference for tight association with unique anionic phospholipids, and that these, independent of headgroup, have a positive effect on the activity of both connexin26 and connexin32 channels. Additionally, the data suggest that the likely in vivo phospholipid modulators of connexin channel structure-function that are connexin isoform-specific are found in the cytoplasmic leaflet. A modulatory role for phospholipids that promote negative curvature is also inferred. Conclusion This study is the first to

Unbiased screen identifies aripiprazole as a modulator of abundance of the polyglutamine disease protein, ataxin-3

PubMed Central

Costa, Maria do Carmo; Ashraf, Naila S.; Fischer, Svetlana; Yang, Yemen; Schapka, Emily; Joshi, Gnanada; McQuade, Thomas J.; Dharia, Rahil M.; Dulchavsky, Mark; Ouyang, Michelle; Cook, David; Sun, Duxin; Larsen, Martha J.; Gestwicki, Jason E.; Todi, Sokol V.; Ivanova, Magdalena I.; Paulson, Henry L.

2016-01-01

No disease-modifying treatment exists for the fatal neurodegenerative polyglutamine disease known both as Machado-Joseph disease and spinocerebellar ataxia type 3. As a potential route to therapy, we identified small molecules that reduce levels of the mutant disease protein, ATXN3. Screens of a small molecule collection, including 1250 Food and Drug Administration-approved drugs, in a novel cell-based assay, followed by secondary screens in brain slice cultures from transgenic mice expressing the human disease gene, identified the atypical antipsychotic aripiprazole as one of the hits. Aripiprazole increased longevity in a Drosophila model of Machado-Joseph disease and effectively reduced aggregated ATXN3 species in flies and in brains of transgenic mice treated for 10 days. The aripiprazole-mediated decrease in ATXN3 abundance may reflect a complex response culminating in the modulation of specific components of cellular protein homeostasis. Aripiprazole represents a potentially promising therapeutic drug for Machado-Joseph disease and possibly other neurological proteinopathies. PMID:27645800

Determination of modulation transfer function of a printer by measuring the autocorrelation of the transmission function of a printed Ronchi grating

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

Madanipour, Khosro; Tavassoly, Mohammad T

2009-02-01

We show theoretically and verify experimentally that the modulation transfer function (MTF) of a printing system can be determined by measuring the autocorrelation of a printed Ronchi grating. In practice, two similar Ronchi gratings are printed on two transparencies and the transparencies are superimposed with parallel grating lines. Then, the gratings are uniformly illuminated and the transmitted light from a large section is measured versus the displacement of one grating with respect to the other in a grating pitch interval. This measurement provides the required autocorrelation function for determination of the MTF.

Dose-dependent modulation of CD8 and functional avidity as a result of peptide encounter

PubMed Central

Kroger, Charles J; Alexander-Miller, Martha A

2007-01-01

The generation of an optimal CD8+ cytotoxic T lymphocyte (CTL) response is critical for the clearance of many intracellular pathogens. Previous studies suggest that one contributor to an optimal immune response is the presence of CD8+ cells exhibiting high functional avidity. In this regard, CD8 expression has been shown to contribute to peptide sensitivity. Here, we investigated the ability of naive splenocytes to modulate CD8 expression according to the concentration of stimulatory peptide antigen. Our results showed that the level of CD8 expressed was inversely correlated with the amount of peptide used for the primary stimulation, with higher concentrations of antigen resulting in lower expression of both CD8α and CD8β. Importantly the ensuing CD8low and CD8high CTL populations were not the result of the selective outgrowth of naive CD8+ T-cell subpopulations expressing distinct levels of CD8. Subsequent encounter with peptide antigen resulted in continued modulation of both the absolute level and the isoform of CD8 expressed and in the functional avidity of the responding cells. We propose that CD8 cell surface expression is not a static property, but can be modulated to ‘fine tune’ the sensitivity of responding CTL to a defined concentration of antigen. PMID:17484768

Systematic analysis of microarray datasets to identify Parkinson's disease‑associated pathways and genes.

PubMed

Feng, Yinling; Wang, Xuefeng

2017-03-01

In order to investigate commonly disturbed genes and pathways in various brain regions of patients with Parkinson's disease (PD), microarray datasets from previous studies were collected and systematically analyzed. Different normalization methods were applied to microarray datasets from different platforms. A strategy combining gene co‑expression networks and clinical information was adopted, using weighted gene co‑expression network analysis (WGCNA) to screen for commonly disturbed genes in different brain regions of patients with PD. Functional enrichment analysis of commonly disturbed genes was performed using the Database for Annotation, Visualization, and Integrated Discovery (DAVID). Co‑pathway relationships were identified with Pearson's correlation coefficient tests and a hypergeometric distribution‑based test. Common genes in pathway pairs were selected out and regarded as risk genes. A total of 17 microarray datasets from 7 platforms were retained for further analysis. Five gene coexpression modules were identified, containing 9,745, 736, 233, 101 and 93 genes, respectively. One module was significantly correlated with PD samples and thus the 736 genes it contained were considered to be candidate PD‑associated genes. Functional enrichment analysis demonstrated that these genes were implicated in oxidative phosphorylation and PD. A total of 44 pathway pairs and 52 risk genes were revealed, and a risk gene pathway relationship network was constructed. Eight modules were identified and were revealed to be associated with PD, cancers and metabolism. A number of disturbed pathways and risk genes were unveiled in PD, and these findings may help advance understanding of PD pathogenesis.

Modulation Transfer Function Analysis of Kelvin Wakes and Ambient Wave Images

DTIC Science & Technology

1991-09-01

O n s ŕ-6 1 ed.’.. to a vvff" I Pý,o r . ~, -t~m t . t," for ,. ,eo~rV (I0, msv os . fl *vo ~tn flq **ta ~ cfK tat W~.4 ~ n ?’Ct of -t¶~ .19 t.#aw...TYPE AND DATES COVERED September 1991 Technical 10/J/90 - 9/30/91 4. TITLE AND SUBTITLE S. FUNDIN i NUMBERS Modulation Transfer Function Analysis of ...ADDRESSUES) 1. PERFORMING ORGANIZATION REPORT NUMBER Environmental Research Institute of Michigan (ERIM) P.O. Box 134001 207500-7-T Ann Arbor, MI 48113-4001 9

Hazardous drinking and military community functioning: identifying mediating risk factors.

PubMed

Foran, Heather M; Heyman, Richard E; Slep, Amy M Smith

2011-08-01

Hazardous drinking is a serious societal concern in military populations. Efforts to reduce hazardous drinking among military personnel have been limited in effectiveness. There is a need for a deeper understanding of how community-based prevention models apply to hazardous drinking in the military. Community-wide prevention efforts may be most effective in targeting community functioning (e.g., support from formal agencies, community cohesion) that impacts hazardous drinking via other proximal risk factors. The goal of the current study is to inform community-wide prevention efforts by testing a model of community functioning and mediating risk factors of hazardous drinking among active duty U.S. Air Force personnel. A large, representative survey sample of U.S. Air Force active duty members (N = 52,780) was collected at 82 bases worldwide. Hazardous drinking was assessed with the widely used Alcohol Use Disorders Identification Test (Saunders, Aasland, Babor, de la Fuente, & Grant, 1993). A variety of individual, family, and community measures were also assessed. Structural equation modeling was used to test a hypothesized model of community functioning, mediating risk factors and hazardous drinking. Depressive symptoms, perceived financial stress, and satisfaction with the U.S. Air Force were identified as significant mediators of the link between community functioning and hazardous drinking for men and women. Relationship satisfaction was also identified as a mediator for men. These results provide a framework for further community prevention research and suggest that prevention efforts geared at increasing aspects of community functioning (e.g., the U.S. Air Force Community Capacity model) may indirectly lead to reductions in hazardous drinking through other proximal risk factors.

Modulation transfer function of partial gating detector by liquid crystal auto-controlling light intensity

NASA Astrophysics Data System (ADS)

Yang, Xusan; Tang, Yuanhe; Liu, Kai; Liu, Hanchen; Gao, Haiyang; Li, Qing; Zhang, Ruixia; Ye, Na; Liang, Yuan; Zhao, Gaoxiang

2008-12-01

Based on the electro-optical properties of liquid crystal, we have designed a novel partial gating detector. Liquid crystal can be taken to change its own transmission according to the light intensity outside. Every single pixel of the image is real-time modulated by liquid crystal, thus the strong light is weakened and low light goes through the detector normally .The purpose of partial-gating strong light (>105lx) can be achieved by this detector. The modulation transfer function (MTF) equations of the main optical sub-systems are calculated in this paper, they are liquid crystal panels, linear fiber panel and CCD array detector. According to the relevant size, the MTF value of this system is fitted out. The result is MTF= 0.518 at Nyquist frequency.

Drosophila Cancer Models Identify Functional Differences between Ret Fusions.

PubMed

Levinson, Sarah; Cagan, Ross L

2016-09-13

We generated and compared Drosophila models of RET fusions CCDC6-RET and NCOA4-RET. Both RET fusions directed cells to migrate, delaminate, and undergo EMT, and both resulted in lethality when broadly expressed. In all phenotypes examined, NCOA4-RET was more severe than CCDC6-RET, mirroring their effects on patients. A functional screen against the Drosophila kinome and a library of cancer drugs found that CCDC6-RET and NCOA4-RET acted through different signaling networks and displayed distinct drug sensitivities. Combining data from the kinome and drug screens identified the WEE1 inhibitor AZD1775 plus the multi-kinase inhibitor sorafenib as a synergistic drug combination that is specific for NCOA4-RET. Our work emphasizes the importance of identifying and tailoring a patient's treatment to their specific RET fusion isoform and identifies a multi-targeted therapy that may prove effective against tumors containing the NCOA4-RET fusion. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Prostaglandin E2 modulates dendritic cell function via EP2 and EP4 receptor subtypes.

PubMed

Harizi, Hedi; Grosset, Christophe; Gualde, Norbert

2003-06-01

We have reported previously that PGE(2) inhibits dendritic cells (DC) functions. Because E prostanoid receptor (EPR) subtypes involved in this action are unknown, expression and functions of these receptors were examined in DC. Western blot and flow cytometry analyses showed that all EPRs were coexpressed in DC. In a dose-dependent manner, lipopolysaccharide (LPS) enhanced EP(2)R/EP(4)R but not EP(1)R/EP(3)R expressions. NS-398, a cyclooxygenase (COX)-2-selective inhibitor, suppressed LPS-enhanced EP(2)R/EP(4)R expression, suggesting that COX-2-issued prostaglandin E(2) (PGE(2)) modulates DC function through stimulation of specific EPR subtypes. Using selective agonists, we found that butaprost, an EP(2)R agonist, and PGE(1) alcohol, an EP(2)R and EP(2)R/EP(4)R agonist, inhibited major histocompatibility complex class II expression and enhanced interleukin-10 production from DC. However, no effect was observed with sulprostone and 17-phenyl-omega-trinor-PGE(2), selective agonists for EP(1)R and EP(1)R/EP(3)R, respectively. Treatment of DC with dibutyryl cyclic adenosine monophosphate (cAMP), an analog of cAMP, mimics PGE(2)-induced, inhibitory effects. Taken together, our data demonstrate that EP(2)R/EP(4)R are efficient for mediating PGE(2)-induced modulation of DC functions.

Emotional Availability Modulates Electrophysiological Correlates of Executive Functions in Preschool Children

PubMed Central

Schneider-Hassloff, Henriette; Zwönitzer, Annabel; Künster, Anne K.; Mayer, Carmen; Ziegenhain, Ute; Kiefer, Markus

2016-01-01

Executive functions (EFs) – a set of cognitive control abilities – mediate resilience to stress and are associated with academic achievement and health throughout life. They are crucially linked to prefrontal cortex function as well as to other cortical and subcortical brain functions, which are maturing throughout childhood at different rates. Recent behavioral research suggested that children’s EFs were related to parenting quality and child attachment security, but the neural correlates of these associations are unknown. With this study we tested in 4- to 6-year-old healthy children (N = 27) how emotional availability (EA) of the mother-child-interaction was associated with behavioral and electrophysiological correlates of response inhibition (a core EF) in a Go/Nogo task, using event-related potential recordings (ERPs), and with behavioral performance in a Delay of Gratification (DoG) and a Head-Toes-Knees-Shoulders task (HTKS). Our data showed that the Go/Nogo task modulated children’s ERP components resembling adult electrophysiological indices of response inhibition - the N2 and P3/LPC ERPs-, but the children’s N2 and P3/LPC ERPs showed longer latencies. Higher maternal autonomy-fostering behavior and greater child responsiveness were significantly associated with smaller children’s N2 Go/Nogo effects at fronto-central and parietal sites and with greater Go/Nogo effects in the N2 time window at occipital sites, over and above children’s age and intelligence. Additionally, greater maternal sensitivity and a higher dyadic EA quality of the mother-child-interaction went along with greater occipital Go/Nogo effects in the N2 time window, but this effect clearly diminished when we controlled for children’s age and intelligence. Higher maternal autonomy-support was also positively associated with better HTKS performance, and higher dyadic EA quality went along with higher HTKS and DoG scores. However, no significant associations were found between

Emotional Availability Modulates Electrophysiological Correlates of Executive Functions in Preschool Children.

PubMed

Schneider-Hassloff, Henriette; Zwönitzer, Annabel; Künster, Anne K; Mayer, Carmen; Ziegenhain, Ute; Kiefer, Markus

2016-01-01

Executive functions (EFs) - a set of cognitive control abilities - mediate resilience to stress and are associated with academic achievement and health throughout life. They are crucially linked to prefrontal cortex function as well as to other cortical and subcortical brain functions, which are maturing throughout childhood at different rates. Recent behavioral research suggested that children's EFs were related to parenting quality and child attachment security, but the neural correlates of these associations are unknown. With this study we tested in 4- to 6-year-old healthy children (N = 27) how emotional availability (EA) of the mother-child-interaction was associated with behavioral and electrophysiological correlates of response inhibition (a core EF) in a Go/Nogo task, using event-related potential recordings (ERPs), and with behavioral performance in a Delay of Gratification (DoG) and a Head-Toes-Knees-Shoulders task (HTKS). Our data showed that the Go/Nogo task modulated children's ERP components resembling adult electrophysiological indices of response inhibition - the N2 and P3/LPC ERPs-, but the children's N2 and P3/LPC ERPs showed longer latencies. Higher maternal autonomy-fostering behavior and greater child responsiveness were significantly associated with smaller children's N2 Go/Nogo effects at fronto-central and parietal sites and with greater Go/Nogo effects in the N2 time window at occipital sites, over and above children's age and intelligence. Additionally, greater maternal sensitivity and a higher dyadic EA quality of the mother-child-interaction went along with greater occipital Go/Nogo effects in the N2 time window, but this effect clearly diminished when we controlled for children's age and intelligence. Higher maternal autonomy-support was also positively associated with better HTKS performance, and higher dyadic EA quality went along with higher HTKS and DoG scores. However, no significant associations were found between EA variables and

Delta-9-Tetrahydrocannabinol Potentiates Fear Memory Salience Through Functional Modulation of Mesolimbic Dopaminergic Activity States.

PubMed

Fitoussi, Aurelie; Zunder, Jordan; Tan, Huibing; Laviolette, Steven R

2018-05-18

Chronic or acute exposure to delta-9-tetrahydrocannabinol (THC), the main psychoactive compound in cannabis, has been associated with numerous neuropsychiatric side-effects, including dysregulation of emotional processing and associative memory formation. Clinical and pre-clinical evidence suggests that the effects of THC are due to the ability to modulate mesolimbic dopamine (DA) activity states in the nucleus accumbens (NAc) and ventral tegmental area (VTA). Nevertheless, the mechanisms by which THC modulates mesolimbic DA function and emotional processing are not well understood. Using an olfactory associative fear memory procedure combined with in vivo neuronal electrophysiology, we examined the effects of direct THC microinfusions targeting the shell region of the NAc (NASh) and examined how THC may modulate the processing of fear-related emotional memory and concomitant activity states of the mesolimbic DA system. We report that intra-NASh THC dose-dependently potentiates the emotional salience of normally sub-threshold fear-conditioning cues. These effects were dependent upon intra-VTA transmission through GABAergic receptor mechanisms and intra-NASh DAergic transmission. Furthermore, doses of intra-NASh THC that potentiated fear memory salience were found to modulate intra-VTA neuronal network activity by increasing the spontaneous firing and bursting frequency of DAergic neurons whilst decreasing the activity levels of a subpopulation of putative GABAergic VTA neurons. These findings demonstrate that THC can act directly in the NASh to modulate mesolimbic activity states and induce disturbances in emotional salience and memory formation through modulation of VTA DAergic transmission. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Fragrant Dioxane Derivatives Identify β1-Subunit-containing GABAA Receptors*

PubMed Central

Sergeeva, Olga A.; Kletke, Olaf; Kragler, Andrea; Poppek, Anja; Fleischer, Wiebke; Schubring, Stephan R.; Görg, Boris; Haas, Helmut L.; Zhu, Xin-Ran; Lübbert, Hermann; Gisselmann, Günter; Hatt, Hanns

2010-01-01

Nineteen GABAA receptor (GABAAR) subunits are known in mammals with only a restricted number of functionally identified native combinations. The physiological role of β1-subunit-containing GABAARs is unknown. Here we report the discovery of a new structural class of GABAAR positive modulators with unique β1-subunit selectivity: fragrant dioxane derivatives (FDD). At heterologously expressed α1βxγ2L (x-for 1,2,3) GABAAR FDD were 6 times more potent at β1- versus β2- and β3-containing receptors. Serine at position 265 was essential for the high sensitivity of the β1-subunit to FDD and the β1N286W mutation nearly abolished modulation; vice versa the mutation β3N265S shifted FDD sensitivity toward the β1-type. In posterior hypothalamic neurons controlling wakefulness GABA-mediated whole-cell responses and GABAergic synaptic currents were highly sensitive to FDD, in contrast to β1-negative cerebellar Purkinje neurons. Immunostaining for the β1-subunit and the potency of FDD to modulate GABA responses in cultured hypothalamic neurons was drastically diminished by β1-siRNA treatment. In conclusion, with the help of FDDs we reveal a functional expression of β1-containing GABAARs in the hypothalamus, offering a new tool for studies on the functional diversity of native GABAARs. PMID:20511229

Engineering micropatterned surfaces to modulate the function of vascular stem cells

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

Li, Jennifer; Wu, Michelle; Chu, Julia

2014-02-21

Highlights: • We examine vascular stem cell function on microgrooved and micropost patterned polymer substrates. • 10 μm microgrooved surfaces significantly lower VSC proliferation but do not modulate calcified matrix deposition. • Micropost surfaces significantly lower VSC proliferation and decrease calcified matrix deposition. - Abstract: Multipotent vascular stem cells have been implicated in vascular disease and in tissue remodeling post therapeutic intervention. Hyper-proliferation and calcified extracellular matrix deposition of VSC cause blood vessel narrowing and plaque hardening thereby increasing the risk of myocardial infarct. In this study, to optimize the surface design of vascular implants, we determined whether micropatterned polymermore » surfaces can modulate VSC differentiation and calcified matrix deposition. Undifferentiated rat VSC were cultured on microgrooved surfaces of varied groove widths, and on micropost surfaces. 10 μm microgrooved surfaces elongated VSC and decreased cell proliferation. However, microgrooved surfaces did not attenuate calcified extracellular matrix deposition by VSC cultured in osteogenic media conditions. In contrast, VSC cultured on micropost surfaces assumed a dendritic morphology, were significantly less proliferative, and deposited minimal calcified extracellular matrix. These results have significant implications for optimizing the design of cardiovascular implant surfaces.« less

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

PubMed Central

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

2013-01-01

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

Prospects for detection of target-dependent annual modulation in direct dark matter searches

DOE PAGES

Nobile, Eugenio Del; Gelmini, Graciela B.; Witte, Samuel J.

2016-02-03

Earth's rotation about the Sun produces an annual modulation in the expected scattering rate at direct dark matter detection experiments. The annual modulation as a function of the recoil energy E R imparted by the dark matter particle to a target nucleus is expected to vary depending on the detector material. However, for most interactions a change of variables from E R to v min, the minimum speed a dark matter particle must have to impart a fixed E R to a target nucleus, produces an annual modulation independent of the target element. We recently showed that if the darkmore » matter-nucleus cross section contains a non-factorizable target and dark matter velocity dependence, the annual modulation as a function of v min can be target dependent. Here we examine more extensively the necessary conditions for target-dependent modulation, its observability in present-day experiments, and the extent to which putative signals could identify a dark matter-nucleus differential cross section with a non-factorizable dependence on the dark matter velocity.« less

Systems view of adipogenesis via novel omics-driven and tissue-specific activity scoring of network functional modules

NASA Astrophysics Data System (ADS)

Nassiri, Isar; Lombardo, Rosario; Lauria, Mario; Morine, Melissa J.; Moyseos, Petros; Varma, Vijayalakshmi; Nolen, Greg T.; Knox, Bridgett; Sloper, Daniel; Kaput, Jim; Priami, Corrado

2016-07-01

The investigation of the complex processes involved in cellular differentiation must be based on unbiased, high throughput data processing methods to identify relevant biological pathways. A number of bioinformatics tools are available that can generate lists of pathways ranked by statistical significance (i.e. by p-value), while ideally it would be desirable to functionally score the pathways relative to each other or to other interacting parts of the system or process. We describe a new computational method (Network Activity Score Finder - NASFinder) to identify tissue-specific, omics-determined sub-networks and the connections with their upstream regulator receptors to obtain a systems view of the differentiation of human adipocytes. Adipogenesis of human SBGS pre-adipocyte cells in vitro was monitored with a transcriptomic data set comprising six time points (0, 6, 48, 96, 192, 384 hours). To elucidate the mechanisms of adipogenesis, NASFinder was used to perform time-point analysis by comparing each time point against the control (0 h) and time-lapse analysis by comparing each time point with the previous one. NASFinder identified the coordinated activity of seemingly unrelated processes between each comparison, providing the first systems view of adipogenesis in culture. NASFinder has been implemented into a web-based, freely available resource associated with novel, easy to read visualization of omics data sets and network modules.

Spatial and spectral imaging of point-spread functions using a spatial light modulator

NASA Astrophysics Data System (ADS)

Munagavalasa, Sravan; Schroeder, Bryce; Hua, Xuanwen; Jia, Shu

2017-12-01

We develop a point-spread function (PSF) engineering approach to imaging the spatial and spectral information of molecular emissions using a spatial light modulator (SLM). We show that a dispersive grating pattern imposed upon the emission reveals spectral information. We also propose a deconvolution model that allows the decoupling of the spectral and 3D spatial information in engineered PSFs. The work is readily applicable to single-molecule measurements and fluorescent microscopy.

Cortical organization of inhibition-related functions and modulation by psychopathology

PubMed Central

Warren, Stacie L.; Crocker, Laura D.; Spielberg, Jeffery M.; Engels, Anna S.; Banich, Marie T.; Sutton, Bradley P.; Miller, Gregory A.; Heller, Wendy

2013-01-01

Individual differences in inhibition-related functions have been implicated as risk factors for a broad range of psychopathology, including anxiety and depression. Delineating neural mechanisms of distinct inhibition-related functions may clarify their role in the development and maintenance of psychopathology. The present study tested the hypothesis that activity in common and distinct brain regions would be associated with an ecologically sensitive, self-report measure of inhibition and a laboratory performance measure of prepotent response inhibition. Results indicated that sub-regions of DLPFC distinguished measures of inhibition, whereas left inferior frontal gyrus and bilateral inferior parietal cortex were associated with both types of inhibition. Additionally, co-occurring anxiety and depression modulated neural activity in select brain regions associated with response inhibition. Results imply that specific combinations of anxiety and depression dimensions are associated with failure to implement top-down attentional control as reflected in inefficient recruitment of posterior DLPFC and increased activation in regions associated with threat (MTG) and worry (BA10). Present findings elucidate possible neural mechanisms of interference that could help explain executive control deficits in psychopathology. PMID:23781192

Cortical organization of inhibition-related functions and modulation by psychopathology.

PubMed

Warren, Stacie L; Crocker, Laura D; Spielberg, Jeffery M; Engels, Anna S; Banich, Marie T; Sutton, Bradley P; Miller, Gregory A; Heller, Wendy

2013-01-01

Individual differences in inhibition-related functions have been implicated as risk factors for a broad range of psychopathology, including anxiety and depression. Delineating neural mechanisms of distinct inhibition-related functions may clarify their role in the development and maintenance of psychopathology. The present study tested the hypothesis that activity in common and distinct brain regions would be associated with an ecologically sensitive, self-report measure of inhibition and a laboratory performance measure of prepotent response inhibition. Results indicated that sub-regions of DLPFC distinguished measures of inhibition, whereas left inferior frontal gyrus and bilateral inferior parietal cortex were associated with both types of inhibition. Additionally, co-occurring anxiety and depression modulated neural activity in select brain regions associated with response inhibition. Results imply that specific combinations of anxiety and depression dimensions are associated with failure to implement top-down attentional control as reflected in inefficient recruitment of posterior DLPFC and increased activation in regions associated with threat (MTG) and worry (BA10). Present findings elucidate possible neural mechanisms of interference that could help explain executive control deficits in psychopathology.

Lunar-edge based on-orbit modulation transfer function (MTF) measurement

NASA Astrophysics Data System (ADS)

Cheng, Ying; Yi, Hongwei; Liu, Xinlong

2017-10-01

Modulation transfer function (MTF) is an important parameter for image quality evaluation of on-orbit optical image systems. Various methods have been proposed to determine the MTF of an imaging system which are based on images containing point, pulse and edge features. In this paper, the edge of the moon can be used as a high contrast target to measure on-orbit MTF of image systems based on knife-edge methods. The proposed method is an extension of the ISO 12233 Slanted-edge Spatial Frequency Response test, except that the shape of the edge is a circular arc instead of a straight line. In order to get more accurate edge locations and then obtain a more authentic edge spread function (ESF), we choose circular fitting method based on least square to fit lunar edge in sub-pixel edge detection process. At last, simulation results show that the MTF value at Nyquist frequency calculated using our lunar edge method is reliable and accurate with error less than 2% comparing with theoretical MTF value.

Expression of Versican 3′-Untranslated Region Modulates Endogenous MicroRNA Functions

PubMed Central

Lee, Daniel Y.; Jeyapalan, Zina; Fang, Ling; Yang, Jennifer; Zhang, Yaou; Yee, Albert Y.; Li, Minhui; Du, William W.; Shatseva, Tatiana; Yang, Burton B.

2010-01-01

Background Mature microRNAs (miRNAs) are single-stranded RNAs that regulate post-transcriptional gene expression. In our previous study, we have shown that versican 3′UTR, a fragment of non-coding transcript, has the ability to antagonize miR-199a-3p function thereby regulating expression of the matrix proteins versican and fibronectin, and thus resulting in enhanced cell-cell adhesion and organ adhesion. However, the impact of this non-coding fragment on tumorigenesis is yet to be determined. Methods and Findings Using computational prediction confirmed with in vitro and in vivo experiments, we report that the expression of versican 3′UTR not only antagonizes miR-199a-3p but can also lower its steady state expression. We found that expression of versican 3′UTR in a mouse breast carcinoma cell line, 4T1, decreased miR-199a-3p levels. The decrease in miRNA activity consequently translated into differences in tumor growth. Computational analysis indicated that both miR-199a-3p and miR-144 targeted a cell cycle regulator, Rb1. In addition, miR-144 and miR-136, which have also been shown to interact with versican 3′UTR, was found to target PTEN. Expression of Rb1 and PTEN were up-regulated synergistically in vitro and in vivo, suggesting that the 3′UTR binds and modulates miRNA activities, freeing Rb1 and PTEN mRNAs for translation. In tumor formation assays, cells transfected with the 3′UTR formed smaller tumors compared with cells transfected with a control vector. Conclusion Our results demonstrated that a 3′UTR fragment can be used to modulate miRNA functions. Our study also suggests that miRNAs in the cancer cells are more susceptible to degradation, due to its interaction with a non-coding 3′UTR. This non-coding component of mRNA may be used retrospectively to modulate miRNA activities. PMID:21049042

Label-free haemogram using wavelength modulated Raman spectroscopy for identifying immune-cell subset

NASA Astrophysics Data System (ADS)

Ashok, Praveen C.; Praveen, Bavishna B.; Campbell, Elaine C.; Dholakia, Kishan; Powis, Simon J.

2014-03-01

Leucocytes in the blood of mammals form a powerful protective system against a wide range of dangerous pathogens. There are several types of immune cells that has specific role in the whole immune system. The number and type of immune cells alter in the disease state and identifying the type of immune cell provides information about a person's state of health. There are several immune cell subsets that are essentially morphologically identical and require external labeling to enable discrimination. Here we demonstrate the feasibility of using Wavelength Modulated Raman Spectroscopy (WMRS) with suitable machine learning algorithms as a label-free method to distinguish between different closely lying immune cell subset. Principal Component Analysis (PCA) was performed on WMRS data from single cells, obtained using confocal Raman microscopy for feature reduction, followed by Support Vector Machine (SVM) for binary discrimination of various cell subset, which yielded an accuracy >85%. The method was successful in discriminating between untouched and unfixed purified populations of CD4+CD3+ and CD8+CD3+ T lymphocyte subsets, and CD56+CD3- natural killer cells with a high degree of specificity. It was also proved sensitive enough to identify unique Raman signatures that allow clear discrimination between dendritic cell subsets, comprising CD303+CD45+ plasmacytoid and CD1c+CD141+ myeloid dendritic cells. The results of this study clearly show that WMRS is highly sensitive and can distinguish between cell types that are morphologically identical.

The Biological Function of the Prion Protein: A Cell Surface Scaffold of Signaling Modules.

PubMed

Linden, Rafael

2017-01-01

The prion glycoprotein (PrP C ) is mostly located at the cell surface, tethered to the plasma membrane through a glycosyl-phosphatydil inositol (GPI) anchor. Misfolding of PrP C is associated with the transmissible spongiform encephalopathies (TSEs), whereas its normal conformer serves as a receptor for oligomers of the β-amyloid peptide, which play a major role in the pathogenesis of Alzheimer's Disease (AD). PrP C is highly expressed in both the nervous and immune systems, as well as in other organs, but its functions are controversial. Extensive experimental work disclosed multiple physiological roles of PrP C at the molecular, cellular and systemic levels, affecting the homeostasis of copper, neuroprotection, stem cell renewal and memory mechanisms, among others. Often each such process has been heralded as the bona fide function of PrP C , despite restricted attention paid to a selected phenotypic trait, associated with either modulation of gene expression or to the engagement of PrP C with a single ligand. In contrast, the GPI-anchored prion protein was shown to bind several extracellular and transmembrane ligands, which are required to endow that protein with the ability to play various roles in transmembrane signal transduction. In addition, differing sets of those ligands are available in cell type- and context-dependent scenarios. To account for such properties, we proposed that PrP C serves as a dynamic platform for the assembly of signaling modules at the cell surface, with widespread consequences for both physiology and behavior. The current review advances the hypothesis that the biological function of the prion protein is that of a cell surface scaffold protein, based on the striking similarities of its functional properties with those of scaffold proteins involved in the organization of intracellular signal transduction pathways. Those properties are: the ability to recruit spatially restricted sets of binding molecules involved in specific

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

PubMed Central

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

2011-01-01

Protozoan parasites of genus Leishmania are the causative agents of leishmaniasis. These digenetic microorganisms undergo a marked environmental temperature shift (TS) during transmission from the sandfly vector (ambient temperature, 25–26°C) to the mammalian host (37°C). We have observed that this TS induces a rapid and dramatic increase in protein release from Leishmania mexicana (cutaneous leishmaniasis) within 4 h. Proteomic identification of the TS-induced secreted proteins revealed 72 proteins, the majority of which lack a signal peptide and are thus thought to be secreted via nonconventional mechanisms. Interestingly, this protein release is accompanied by alterations in parasite morphology including an augmentation in the budding of exovesicles from its surface. Here we show that the exoproteome of L. mexicana upon TS induces cleavage and activation of the host protein tyrosine phosphatases, specifically SHP-1 and PTP1-B, in a murine bone-marrow-derived macrophage cell line. Furthermore, translocation of prominent inflammatory transcription factors, namely NF-κB and AP-1 is altered. The exoproteome also caused inhibition of nitric oxide production, a crucial leishmanicidal function of the macrophage. Overall, our results provide strong evidence that within early moments of interaction with the mammalian host, L. mexicana rapidly releases proteins and exovesicles that modulate signalling and function of the macrophage. These modulations can result in attenuation of the inflammatory response and deactivation of the macrophage aiding the parasite in the establishment of infection. PMID:21559274

Accessory stimulus modulates executive function during stepping task

PubMed Central

Watanabe, Tatsunori; Koyama, Soichiro; Tanabe, Shigeo

2015-01-01

When multiple sensory modalities are simultaneously presented, reaction time can be reduced while interference enlarges. The purpose of this research was to examine the effects of task-irrelevant acoustic accessory stimuli simultaneously presented with visual imperative stimuli on executive function during stepping. Executive functions were assessed by analyzing temporal events and errors in the initial weight transfer of the postural responses prior to a step (anticipatory postural adjustment errors). Eleven healthy young adults stepped forward in response to a visual stimulus. We applied a choice reaction time task and the Simon task, which consisted of congruent and incongruent conditions. Accessory stimuli were randomly presented with the visual stimuli. Compared with trials without accessory stimuli, the anticipatory postural adjustment error rates were higher in trials with accessory stimuli in the incongruent condition and the reaction times were shorter in trials with accessory stimuli in all the task conditions. Analyses after division of trials according to whether anticipatory postural adjustment error occurred or not revealed that the reaction times of trials with anticipatory postural adjustment errors were reduced more than those of trials without anticipatory postural adjustment errors in the incongruent condition. These results suggest that accessory stimuli modulate the initial motor programming of stepping by lowering decision threshold and exclusively under spatial incompatibility facilitate automatic response activation. The present findings advance the knowledge of intersensory judgment processes during stepping and may aid in the development of intervention and evaluation tools for individuals at risk of falls. PMID:25925321

Microbiome dynamic modulation through functional diets based on pre- and probiotics (mannan-oligosaccharides and Saccharomyces cerevisiae) in juvenile rainbow trout (Oncorhynchus mykiss).

PubMed

Gonçalves, A T; Gallardo-Escárate, C

2017-05-01

This study used high-throughput sequencing to evaluate the intestinal microbiome dynamics in rainbow trout (Oncorhynchus mykiss) fed commercial diets supplemented with either pre- or probiotics (0·6% mannan-oligosaccharides and 0·5% Saccharomyces cerevisiae respectively) or the mixture of both. A total of 57 fish whole intestinal mucosa and contents bacterial communities were characterized by high-throughput sequencing and analysis of the V3-V4 region of the 16S rRNA gene, as well as the relationship between plasma biochemical health indicators and microbiome diversity. This was performed at 7, 14 and 30 days after start feeding functional diets, and microbiome diversity increased when fish fed functional diets after 7 days and it was positively correlated with plasma cholesterol levels. Dominant phyla were, in descending order, Proteobacteria, Firmicutes, Actinobacteria, Acidobacteria, Bacteroidetes and Fusobacteria. However, functional diets reduced the abundance of Gammaproteobacteria to favour abundances of organisms from Firmicutes and Fusobacteria, two phyla with members that confer beneficial effects. A dynamic shift of the microbiome composition was observed with changes after 7 days of feeding and the modulation by functional diets tend to cluster the corresponding groups apart from CTRL group. The core microbiome showed an overall stability with functional diets, except genus such as Escherichia-Shigella that suffered severe reductions on their abundances when feeding any of the functional diets. Functional diets based on pre- or probiotics dynamically modulate intestinal microbiota of juvenile trout engaging taxonomical abundance shifts that might impact fish physiological performance. This study shows for the first time the microbiome modulation dynamics by functional diets based on mannan-oligosaccharides and S. cerevisiae and their synergy using culture independent high-throughput sequencing technology, revealing the complexity behind the dietary

FOXO3a regulates BNIP3 and modulates mitochondrial calcium, dynamics, and function in cardiac stress

PubMed Central

Kohlbrenner, Erik; Gamb, Scott I.; Guenzel, Adam J.; Klaus, Katherine; Fayyaz, Ahmed U.; Nair, K. Sreekumaran; Hajjar, Roger J.

2016-01-01

The forkhead box O3a (FOXO3a) transcription factor has been shown to regulate glucose metabolism, muscle atrophy, and cell death in postmitotic cells. Its role in regulation of mitochondrial and myocardial function is not well studied. Based on previous work, we hypothesized that FOXO3a, through BCL2/adenovirus E1B 19-kDa protein-interacting protein 3 (BNIP3), modulates mitochondrial morphology and function in heart failure (HF). We modulated the FOXO3a-BNIP3 pathway in normal and phenylephrine (PE)-stressed adult cardiomyocytes (ACM) in vitro and developed a cardiotropic adeno-associated virus serotype 9 encoding dominant-negative FOXO3a (AAV9.dn-FX3a) for gene delivery in a rat model of HF with preserved ejection fraction (HFpEF). We found that FOXO3a upregulates BNIP3 expression in normal and PE-stressed ACM, with subsequent increases in mitochondrial Ca2+, leading to decreased mitochondrial membrane potential, mitochondrial fragmentation, and apoptosis. Whereas dn-FX3a attenuated the increase in BNIP3 expression and its consequences in PE-stressed ACM, AAV9.dn-FX3a delivery in an experimental model of HFpEF decreased BNIP3 expression, reversed adverse left ventricular remodeling, and improved left ventricular systolic and, particularly, diastolic function, with improvements in mitochondrial structure and function. Moreover, AAV9.dn-FX3a restored phospholamban phosphorylation at S16 and enhanced dynamin-related protein 1 phosphorylation at S637. Furthermore, FOXO3a upregulates maladaptive genes involved in mitochondrial apoptosis, autophagy, and cardiac atrophy. We conclude that FOXO3a activation in cardiac stress is maladaptive, in that it modulates Ca2+ cycling, Ca2+ homeostasis, and mitochondrial dynamics and function. Our results suggest an important role of FOXO3a in HF, making it an attractive potential therapeutic target. Listen to this article's corresponding podcast at http://ajpheart.podbean.com/e/role-of-foxo3a-in-heart-failure/. PMID:27694219

Critical role of the pore domain in the cold response of TRPM8 channels identified by ortholog functional comparison.

PubMed

Pertusa, María; Rivera, Bastián; González, Alejandro; Ugarte, Gonzalo; Madrid, Rodolfo

2018-06-07

In mammals, the main molecular entity involved in innocuous cold transduction is TRPM8.  This polymodal ion channel is activated by cold, cooling compounds such as menthol and voltage.  Despite its relevance, the molecular determinants involved in its activation by cold remain elusive.  In this study we explored the use of TRPM8 orthologs with different cold responses, as a strategy to identify new molecular determinants related with its thermosensitivity.  We focused on mouse TRPM8 (mTRPM8) and chicken TRPM8 (cTRPM8), which present complementary thermo- and chemo-sensitive phenotypes.  While mTRPM8 displays larger responses to cold than cTRPM8, the avian ortholog shows a higher sensitivity to menthol compared to the mouse channel, in both HEK293 cells and primary somatosensory neurons.  We took advantage of these differences to build multiple functional chimeras between these orthologs, in order to identify the regions that account for these discrepancies.  Using a combination of calcium imaging and patch clamping, we identified a region encompassing positions 526-556 in the N-terminus, whose replacement by the cTRPM8 homolog sequence potentiated its response to agonists.  More importantly, we found that the characteristic cold response of these orthologs is due to non-conserved residues located within the pore loop, suggesting that TRPM8 has evolved by increasing the magnitude of its cold response through changes in this region.  Our results reveal that these structural domains are critically involved in cold-sensitivity and functional modulation of TRPM8, and support the idea that the pore domain is a key molecular determinant in temperature responses of this thermo-TRP channel. Published under license by The American Society for Biochemistry and Molecular Biology, Inc.

An extended set of yeast-based functional assays accurately identifies human disease mutations

PubMed Central

Sun, Song; Yang, Fan; Tan, Guihong; Costanzo, Michael; Oughtred, Rose; Hirschman, Jodi; Theesfeld, Chandra L.; Bansal, Pritpal; Sahni, Nidhi; Yi, Song; Yu, Analyn; Tyagi, Tanya; Tie, Cathy; Hill, David E.; Vidal, Marc; Andrews, Brenda J.; Boone, Charles; Dolinski, Kara; Roth, Frederick P.

2016-01-01

We can now routinely identify coding variants within individual human genomes. A pressing challenge is to determine which variants disrupt the function of disease-associated genes. Both experimental and computational methods exist to predict pathogenicity of human genetic variation. However, a systematic performance comparison between them has been lacking. Therefore, we developed and exploited a panel of 26 yeast-based functional complementation assays to measure the impact of 179 variants (101 disease- and 78 non-disease-associated variants) from 22 human disease genes. Using the resulting reference standard, we show that experimental functional assays in a 1-billion-year diverged model organism can identify pathogenic alleles with significantly higher precision and specificity than current computational methods. PMID:26975778

An iterative network partition algorithm for accurate identification of dense network modules

PubMed Central

Sun, Siqi; Dong, Xinran; Fu, Yao; Tian, Weidong

2012-01-01

A key step in network analysis is to partition a complex network into dense modules. Currently, modularity is one of the most popular benefit functions used to partition network modules. However, recent studies suggested that it has an inherent limitation in detecting dense network modules. In this study, we observed that despite the limitation, modularity has the advantage of preserving the primary network structure of the undetected modules. Thus, we have developed a simple iterative Network Partition (iNP) algorithm to partition a network. The iNP algorithm provides a general framework in which any modularity-based algorithm can be implemented in the network partition step. Here, we tested iNP with three modularity-based algorithms: multi-step greedy (MSG), spectral clustering and Qcut. Compared with the original three methods, iNP achieved a significant improvement in the quality of network partition in a benchmark study with simulated networks, identified more modules with significantly better enrichment of functionally related genes in both yeast protein complex network and breast cancer gene co-expression network, and discovered more cancer-specific modules in the cancer gene co-expression network. As such, iNP should have a broad application as a general method to assist in the analysis of biological networks. PMID:22121225

Functional connectome fingerprinting: identifying individuals using patterns of brain connectivity.

PubMed

Finn, Emily S; Shen, Xilin; Scheinost, Dustin; Rosenberg, Monica D; Huang, Jessica; Chun, Marvin M; Papademetris, Xenophon; Constable, R Todd

2015-11-01

Functional magnetic resonance imaging (fMRI) studies typically collapse data from many subjects, but brain functional organization varies between individuals. Here we establish that this individual variability is both robust and reliable, using data from the Human Connectome Project to demonstrate that functional connectivity profiles act as a 'fingerprint' that can accurately identify subjects from a large group. Identification was successful across scan sessions and even between task and rest conditions, indicating that an individual's connectivity profile is intrinsic, and can be used to distinguish that individual regardless of how the brain is engaged during imaging. Characteristic connectivity patterns were distributed throughout the brain, but the frontoparietal network emerged as most distinctive. Furthermore, we show that connectivity profiles predict levels of fluid intelligence: the same networks that were most discriminating of individuals were also most predictive of cognitive behavior. Results indicate the potential to draw inferences about single subjects on the basis of functional connectivity fMRI.

Menthol Suppresses Nicotinic Acetylcholine Receptor Functioning in Sensory Neurons via Allosteric Modulation

PubMed Central

Wilhelm, M.; Swandulla, D.

2012-01-01

In this study, we have investigated how the function of native and recombinant nicotinic acetylcholine receptors (nAChRs) is modulated by the monoterpenoid alcohol from peppermint (−) menthol. In trigeminal neurons (TG), we found that nicotine (75 μM)-activated whole-cell currents through nAChRs were reversibly reduced by menthol in a concentration-dependent manner with an IC50 of 111 μM. To analyze the mechanism underlying menthol's action in more detail, we used single channel and whole-cell recordings from recombinant human α4β2 nAChR expressed in HEK tsA201 cells. Here, we found a shortening of channel open time and a prolongation of channel closed time, and an increase in single channel amplitude leading in summary to a reduction in single channel current. Furthermore, menthol did not affect nicotine's EC50 value for currents through recombinant human α4β2 nAChRs but caused a significant reduction in nicotine's efficacy. Taken together, these findings indicate that menthol is a negative allosteric modulator of nAChRs. PMID:22281529

Modulation Transfer Function of Infrared Focal Plane Arrays

NASA Technical Reports Server (NTRS)

Gunapala, S. D.; Rafol, S. B.; Ting, D. Z.; Soibel, A.; Hill, C. J.; Khoshakhlagh, A.; Liu, J. K.; Mumolo, J. M.; Hoglund, L.; Luong, E. M.

2015-01-01

Modulation transfer function (MTF) is the ability of an imaging system to faithfully image a given object. The MTF of an imaging system quantifies the ability of the system to resolve or transfer spatial frequencies. In this presentation we will discuss the detail MTF measurements of 1024x1024 pixels mid -wavelength and long- wavelength quantum well infrared photodetector, and 320x256 pixels long- wavelength InAs/GaSb superlattice infrared focal plane arrays (FPAs). Long wavelength Complementary Barrier Infrared Detector (CBIRD) based on InAs/GaSb superlattice material is hybridized to recently designed and fabricated 320x256 pixel format ROIC. The n-type CBIRD was characterized in terms of performance and thermal stability. The experimentally measured NE delta T of the 8.8 micron cutoff n-CBIRD FPA was 18.6 mK with 300 K background and f/2 cold stop at 78K FPA operating temperature. The horizontal and vertical MTFs of this pixel fully delineated CBIRD FPA at Nyquist frequency are 49% and 52%, respectively.

Prospective study of functional bone marrow-sparing intensity modulated radiation therapy with concurrent chemotherapy for pelvic malignancies.

PubMed

Liang, Yun; Bydder, Mark; Yashar, Catheryn M; Rose, Brent S; Cornell, Mariel; Hoh, Carl K; Lawson, Joshua D; Einck, John; Saenz, Cheryl; Fanta, Paul; Mundt, Arno J; Bydder, Graeme M; Mell, Loren K

2013-02-01

To test the hypothesis that intensity modulated radiation therapy (IMRT) can reduce radiation dose to functional bone marrow (BM) in patients with pelvic malignancies (phase IA) and estimate the clinical feasibility and acute toxicity associated with this technique (phase IB). We enrolled 31 subjects (19 with gynecologic cancer and 12 with anal cancer) in an institutional review board-approved prospective trial (6 in the pilot study, 10 in phase IA, and 15 in phase IB). The mean age was 52 years; 8 of 31 patients (26%) were men. Twenty-one subjects completed (18)F-fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) simulation and magnetic resonance imaging by use of quantitative IDEAL (IDEAL IQ; GE Healthcare, Waukesha, WI). The PET/CT and IDEAL IQ were registered, and BM subvolumes were segmented above the mean standardized uptake value and below the mean fat fraction within the pelvis and lumbar spine; their intersection was designated as functional BM for IMRT planning. Functional BM-sparing vs total BM-sparing IMRT plans were compared in 12 subjects; 10 were treated with functional BM-sparing pelvic IMRT per protocol. In gynecologic cancer patients, the mean functional BM V(10) (volume receiving ≥10 Gy) and V(20) (volume receiving ≥20 Gy) were 85% vs 94% (P<.0001) and 70% vs 82% (P<.0001), respectively, for functional BM-sparing IMRT vs total BM-sparing IMRT. In anal cancer patients, the corresponding values were 75% vs 77% (P=.06) and 62% vs 67% (P=.002), respectively. Of 10 subjects treated with functional BM-sparing pelvic IMRT, 3 (30%) had acute grade 3 hematologic toxicity or greater. IMRT can reduce dose to BM subregions identified by (18)F-fluorodeoxyglucose-PET/CT and IDEAL IQ. The efficacy of BM-sparing IMRT is being tested in a phase II trial. Copyright © 2013 Elsevier Inc. All rights reserved.

Using a Functional Architecture to Identify Human-Automation Trust Needs and Design Requirements

DTIC Science & Technology

2016-12-01

FUNCTIONAL ARCHITECTURE TO IDENTIFY HUMAN-AUTOMATION TRUST NEEDS AND DESIGN REQUIREMENTS by Bradley A. Johnson December 2016 Thesis Advisor...maximum 200 words) This thesis develops and analyzes the functional architecture for an “autonomous” unmanned aerial system performing an...INTENTIONALLY LEFT BLANK v ABSTRACT This thesis develops and analyzes the functional architecture for an “autonomous” unmanned aerial system

Integrated Module and Gene-Specific Regulatory Inference Implicates Upstream Signaling Networks

PubMed Central

Roy, Sushmita; Lagree, Stephen; Hou, Zhonggang; Thomson, James A.; Stewart, Ron; Gasch, Audrey P.

2013-01-01

Regulatory networks that control gene expression are important in diverse biological contexts including stress response and development. Each gene's regulatory program is determined by module-level regulation (e.g. co-regulation via the same signaling system), as well as gene-specific determinants that can fine-tune expression. We present a novel approach, Modular regulatory network learning with per gene information (MERLIN), that infers regulatory programs for individual genes while probabilistically constraining these programs to reveal module-level organization of regulatory networks. Using edge-, regulator- and module-based comparisons of simulated networks of known ground truth, we find MERLIN reconstructs regulatory programs of individual genes as well or better than existing approaches of network reconstruction, while additionally identifying modular organization of the regulatory networks. We use MERLIN to dissect global transcriptional behavior in two biological contexts: yeast stress response and human embryonic stem cell differentiation. Regulatory modules inferred by MERLIN capture co-regulatory relationships between signaling proteins and downstream transcription factors thereby revealing the upstream signaling systems controlling transcriptional responses. The inferred networks are enriched for regulators with genetic or physical interactions, supporting the inference, and identify modules of functionally related genes bound by the same transcriptional regulators. Our method combines the strengths of per-gene and per-module methods to reveal new insights into transcriptional regulation in stress and development. PMID:24146602

Modulating Cytotoxic Effector Functions by Fc Engineering to Improve Cancer Therapy.

PubMed

Kellner, Christian; Otte, Anna; Cappuzzello, Elisa; Klausz, Katja; Peipp, Matthias

2017-09-01

In the last two decades, monoclonal antibodies have revolutionized the therapy of cancer patients. Although antibody therapy has continuously been improved, still a significant number of patients do not benefit from antibody therapy. Therefore, rational optimization of the antibody molecule by Fc engineering represents a major area of translational research to further improve this potent therapeutic option. Monoclonal antibodies are able to trigger a variety of effector mechanisms. Especially Fc-mediated effector functions such as antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and complement- dependent cytotoxicity (CDC) are considered important in antibody therapy of cancer. Novel mechanistic insights into the action of monoclonal antibodies allowed the development of various Fc engineering approaches to modulate antibodies' effector functions. Strategies in modifying the Fc glycosylation profile (Fc glyco-engineering) or approaches in engineering the protein backbone (Fc protein engineering) have been intensively evaluated. In the current review, Fc engineering strategies resulting in improved ADCC, ADCP and CDC activity are summarized and discussed.

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

PubMed

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

2002-09-01

Until recently cysteine residues, especially those located extracellularly, were thought to be important for metal coordination, catalysis and protein structure by forming disulfide bonds - but they were not thought to regulate protein function. However, this is not the case. Crucial cysteine residues can be involved in modulation of protein activity and signaling events via other reactions of their thiol (sulfhydryl; -SH) groups. These reactions can take several forms, such as redox events (chemical reduction or oxidation), chelation of transition metals (chiefly Zn(2+), Mn(2+) and Cu(2+)) or S-nitrosylation [the catalyzed transfer of a nitric oxide (NO) group to a thiol group]. In several cases, these disparate reactions can compete with one another for the same thiol group on a single cysteine residue, forming a molecular switch composed of a latticework of possible redox, NO or Zn(2+) modifications to control protein function. Thiol-mediated regulation of protein function can also involve reactions of cysteine residues that affect ligand binding allosterically. This article reviews the basis for these molecular cysteine switches, drawing on the NMDA receptor as an exemplary protein, and proposes a molecular model for the action of S-nitrosylation based on recently derived crystal structures.

A Decentralized Wireless Solution to Monitor and Diagnose PV Solar Module Performance Based on Symmetrized-Shifted Gompertz Functions

PubMed Central

Molina-García, Angel; Campelo, José Carlos; Blanc, Sara; Serrano, Juan José; García-Sánchez, Tania; Bueso, María C.

2015-01-01

This paper proposes and assesses an integrated solution to monitor and diagnose photovoltaic (PV) solar modules based on a decentralized wireless sensor acquisition system. Both DC electrical variables and environmental data are collected at PV module level using low-cost and high-energy efficiency node sensors. Data is real-time processed locally and compared with expected PV module performances obtained by a PV module model based on symmetrized-shifted Gompertz functions (as previously developed and assessed by the authors). Sensor nodes send data to a centralized sink-computing module using a multi-hop wireless sensor network architecture. Such integration thus provides extensive analysis of PV installations, and avoids off-line tests or post-processing processes. In comparison with previous approaches, this solution is enhanced with a low-cost system and non-critical performance constraints, and it is suitable for extensive deployment in PV power plants. Moreover, it is easily implemented in existing PV installations, since no additional wiring is required. The system has been implemented and assessed in a Spanish PV power plant connected to the grid. Results and estimations of PV module performances are also included in the paper. PMID:26230694

A Decentralized Wireless Solution to Monitor and Diagnose PV Solar Module Performance Based on Symmetrized-Shifted Gompertz Functions.

PubMed

Molina-García, Angel; Campelo, José Carlos; Blanc, Sara; Serrano, Juan José; García-Sánchez, Tania; Bueso, María C

2015-07-29

This paper proposes and assesses an integrated solution to monitor and diagnose photovoltaic (PV) solar modules based on a decentralized wireless sensor acquisition system. Both DC electrical variables and environmental data are collected at PV module level using low-cost and high-energy efficiency node sensors. Data is real-time processed locally and compared with expected PV module performances obtained by a PV module model based on symmetrized-shifted Gompertz functions (as previously developed and assessed by the authors). Sensor nodes send data to a centralized sink-computing module using a multi-hop wireless sensor network architecture. Such integration thus provides extensive analysis of PV installations, and avoids off-line tests or post-processing processes. In comparison with previous approaches, this solution is enhanced with a low-cost system and non-critical performance constraints, and it is suitable for extensive deployment in PV power plants. Moreover, it is easily implemented in existing PV installations, since no additional wiring is required. The system has been implemented and assessed in a Spanish PV power plant connected to the grid. Results and estimations of PV module performances are also included in the paper.

Cobra CRISP functions as an inflammatory modulator via a novel Zn2+- and heparan sulfate-dependent transcriptional regulation of endothelial cell adhesion molecules.

PubMed

Wang, Yu-Ling; Kuo, Je-Hung; Lee, Shao-Chen; Liu, Jai-Shin; Hsieh, Yin-Cheng; Shih, Yu-Tsung; Chen, Chun-Jung; Chiu, Jeng-Jiann; Wu, Wen-Guey

2010-11-26

Cysteine-rich secretory proteins (CRISPs) have been identified as a toxin family in most animal venoms with biological functions mainly associated with the ion channel activity of cysteine-rich domain (CRD). CRISPs also bind to Zn(2+) at their N-terminal pathogenesis-related (PR-1) domain, but their function remains unknown. Interestingly, similar the Zn(2+)-binding site exists in all CRISP family, including those identified in a wide range of organisms. Here, we report that the CRISP from Naja atra (natrin) could induce expression of vascular endothelial cell adhesion molecules, i.e. intercellular adhesion molecule-1, vascular adhesion molecule-1, and E-selectin, to promote monocytic cell adhesion in a heparan sulfate (HS)- and Zn(2+)-dependent manner. Using specific inhibitors and small interfering RNAs, the activation mechanisms are shown to involve both mitogen-activated protein kinases and nuclear factor-κB. Biophysical characterization of natrin by using fluorescence, circular dichroism, and x-ray crystallographic methods further reveals the presence of two Zn(2+)-binding sites for natrin. The strong binding site is located near the putative Ser-His-Glu catalytic triad of the N-terminal domain. The weak binding site remains to be characterized, but it may modulate HS binding by enhancing its interaction with long chain HS. Our results strongly suggest that natrin may serve as an inflammatory modulator that could perturb the wound-healing process of the bitten victim by regulating adhesion molecule expression in endothelial cells. Our finding uncovers a new aspect of the biological role of CRISP family in immune response and is expected to facilitate future development of new therapeutic strategy for the envenomed victims.

Complex modulation using tandem polarization modulators

NASA Astrophysics Data System (ADS)

Hasan, Mehedi; Hall, Trevor

2017-11-01

A novel photonic technique for implementing frequency up-conversion or complex modulation is proposed. The proposed circuit consists of a sandwich of a quarter-wave plate between two polarization modulators, driven, respectively, by an in-phase and quadrature-phase signals. The operation of the circuit is modelled using a transmission matrix method. The theoretical prediction is then validated by simulation using an industry-standard software tool. The intrinsic conversion efficiency of the architecture is improved by 6 dB over a functionally equivalent design based on dual parallel Mach-Zehnder modulators. Non-ideal scenarios such as imperfect alignment of the optical components and power imbalances and phase errors in the electric drive signals are also analysed. As light travels, along one physical path, the proposed design can be implemented using discrete components with greater control of relative optical path length differences. The circuit can further be integrated in any material platform that offers electro-optic polarization modulators.

Recursive expectation-maximization clustering: A method for identifying buffering mechanisms composed of phenomic modules

NASA Astrophysics Data System (ADS)

Guo, Jingyu; Tian, Dehua; McKinney, Brett A.; Hartman, John L.

2010-06-01

Interactions between genetic and/or environmental factors are ubiquitous, affecting the phenotypes of organisms in complex ways. Knowledge about such interactions is becoming rate-limiting for our understanding of human disease and other biological phenomena. Phenomics refers to the integrative analysis of how all genes contribute to phenotype variation, entailing genome and organism level information. A systems biology view of gene interactions is critical for phenomics. Unfortunately the problem is intractable in humans; however, it can be addressed in simpler genetic model systems. Our research group has focused on the concept of genetic buffering of phenotypic variation, in studies employing the single-cell eukaryotic organism, S. cerevisiae. We have developed a methodology, quantitative high throughput cellular phenotyping (Q-HTCP), for high-resolution measurements of gene-gene and gene-environment interactions on a genome-wide scale. Q-HTCP is being applied to the complete set of S. cerevisiae gene deletion strains, a unique resource for systematically mapping gene interactions. Genetic buffering is the idea that comprehensive and quantitative knowledge about how genes interact with respect to phenotypes will lead to an appreciation of how genes and pathways are functionally connected at a systems level to maintain homeostasis. However, extracting biologically useful information from Q-HTCP data is challenging, due to the multidimensional and nonlinear nature of gene interactions, together with a relative lack of prior biological information. Here we describe a new approach for mining quantitative genetic interaction data called recursive expectation-maximization clustering (REMc). We developed REMc to help discover phenomic modules, defined as sets of genes with similar patterns of interaction across a series of genetic or environmental perturbations. Such modules are reflective of buffering mechanisms, i.e., genes that play a related role in the maintenance

Self-regulation of primary motor cortex activity with motor imagery induces functional connectivity modulation: A real-time fMRI neurofeedback study.

PubMed

Makary, Meena M; Seulgi, Eun; Kyungmo Park

2017-07-01

Recent developments in data acquisition of functional magnetic resonance imaging (fMRI) have led to rapid preprocessing and analysis of brain activity in a quasireal-time basis, what so called real-time fMRI neurofeedback (rtfMRI-NFB). This information is fed back to subjects allowing them to gain a voluntary control over their own region-specific brain activity. Forty-one healthy participants were randomized into an experimental (NFB) group, who received a feedback directly proportional to their brain activity from the primary motor cortex (M1), and a control (CTRL) group who received a sham feedback. The M1 ROI was functionally localized during motor execution and imagery tasks. A resting-state functional run was performed before and after the neurofeedback training to investigate the default mode network (DMN) modulation after training. The NFB group revealed increased DMN functional connectivity after training to the cortical and subcortical sensory/motor areas (M1/S1 and caudate nucleus, respectively), which may be associated with sensorimotor processing of learning in the resting state. These results show that motor imagery training through rtfMRI-NFB could modulate the DMN functional connectivity to motor-related areas, suggesting that this modulation potentially subserved the establishment of motor learning in the NFB group.

Space-time-modulated stochastic processes

NASA Astrophysics Data System (ADS)

Giona, Massimiliano

2017-10-01

Starting from the physical problem associated with the Lorentzian transformation of a Poisson-Kac process in inertial frames, the concept of space-time-modulated stochastic processes is introduced for processes possessing finite propagation velocity. This class of stochastic processes provides a two-way coupling between the stochastic perturbation acting on a physical observable and the evolution of the physical observable itself, which in turn influences the statistical properties of the stochastic perturbation during its evolution. The definition of space-time-modulated processes requires the introduction of two functions: a nonlinear amplitude modulation, controlling the intensity of the stochastic perturbation, and a time-horizon function, which modulates its statistical properties, providing irreducible feedback between the stochastic perturbation and the physical observable influenced by it. The latter property is the peculiar fingerprint of this class of models that makes them suitable for extension to generic curved-space times. Considering Poisson-Kac processes as prototypical examples of stochastic processes possessing finite propagation velocity, the balance equations for the probability density functions associated with their space-time modulations are derived. Several examples highlighting the peculiarities of space-time-modulated processes are thoroughly analyzed.

Curcumin improves intestinal barrier function: modulation of intracellular signaling, and organization of tight junctions.

PubMed

Wang, Jing; Ghosh, Siddhartha S; Ghosh, Shobha

2017-04-01

Association between circulating lipopolysaccharide (LPS) and metabolic diseases (such as type 2 diabetes and atherosclerosis) has shifted the focus from high-fat high-cholesterol containing Western-type diet (WD)-induced changes in gut microbiota per se to release of gut bacteria-derived products (e.g., LPS) into circulation due to intestinal barrier dysfunction as the possible mechanism for the chronic inflammatory state underlying the development of these diseases. We demonstrated earlier that oral supplementation with curcumin attenuates WD-induced development of type 2 diabetes and atherosclerosis. Poor bioavailability of curcumin has precluded the establishment of a causal relationship between oral supplementation and it is in vivo effects. We hypothesized that curcumin attenuates WD-induced chronic inflammation and associated metabolic diseases by modulating the function of intestinal epithelial cells (IECs) and the intestinal barrier function. The objective of the present study was to delineate the underlying mechanisms. The human IEC lines Caco-2 and HT-29 were used for these studies and modulation of direct as well as indirect effects of LPS on intracellular signaling as well as tight junctions were examined. Pretreatment with curcumin significantly attenuated LPS-induced secretion of master cytokine IL-1β from IECs and macrophages. Furthermore, curcumin also reduced IL-1β-induced activation of p38 MAPK in IECs and subsequent increase in expression of myosin light chain kinase involved in the phosphorylation of tight junction proteins and ensuing disruption of their normal arrangement. The major site of action of curcumin is, therefore, likely the IECs and the intestinal barrier, and by reducing intestinal barrier dysfunction, curcumin modulates chronic inflammatory diseases despite poor bioavailability. Copyright © 2017 the American Physiological Society.

Using molecular functional networks to manifest connections between obesity and obesity-related diseases

PubMed Central

Yang, Jialiang; Qiu, Jing; Wang, Kejing; Zhu, Lijuan; Fan, Jingjing; Zheng, Deyin; Meng, Xiaodi; Yang, Jiasheng; Peng, Lihong; Fu, Yu; Zhang, Dahan; Peng, Shouneng; Huang, Haiyun; Zhang, Yi

2017-01-01

Obesity is a primary risk factor for many diseases such as certain cancers. In this study, we have developed three algorithms including a random-walk based method OBNet, a shortest-path based method OBsp and a direct-overlap method OBoverlap, to reveal obesity-disease connections at protein-interaction subnetworks corresponding to thousands of biological functions and pathways. Through literature mining, we also curated an obesity-associated disease list, by which we compared the methods. As a result, OBNet outperforms other two methods. OBNet can predict whether a disease is obesity-related based on its associated genes. Meanwhile, OBNet identifies extensive connections between obesity genes and genes associated with a few diseases at various functional modules and pathways. Using breast cancer and Type 2 diabetes as two examples, OBNet identifies meaningful genes that may play key roles in connecting obesity and the two diseases. For example, TGFB1 and VEGFA are inferred to be the top two key genes mediating obesity-breast cancer connection in modules associated with brain development. Finally, the top modules identified by OBNet in breast cancer significantly overlap with modules identified from TCGA breast cancer gene expression study, revealing the power of OBNet in identifying biological processes involved in the disease. PMID:29156709

Selective modulation of the androgen receptor AF2 domain rescues degeneration in spinal bulbar muscular atrophy.

PubMed

Badders, Nisha M; Korff, Ane; Miranda, Helen C; Vuppala, Pradeep K; Smith, Rebecca B; Winborn, Brett J; Quemin, Emmanuelle R; Sopher, Bryce L; Dearman, Jennifer; Messing, James; Kim, Nam Chul; Moore, Jennifer; Freibaum, Brian D; Kanagaraj, Anderson P; Fan, Baochang; Tillman, Heather; Chen, Ping-Chung; Wang, Yingzhe; Freeman, Burgess B; Li, Yimei; Kim, Hong Joo; La Spada, Albert R; Taylor, J Paul

2018-05-01

Spinal bulbar muscular atrophy (SBMA) is a motor neuron disease caused by toxic gain of function of the androgen receptor (AR). Previously, we found that co-regulator binding through the activation function-2 (AF2) domain of AR is essential for pathogenesis, suggesting that AF2 may be a potential drug target for selective modulation of toxic AR activity. We screened previously identified AF2 modulators for their ability to rescue toxicity in a Drosophila model of SBMA. We identified two compounds, tolfenamic acid (TA) and 1-[2-(4-methylphenoxy)ethyl]-2-[(2-phenoxyethyl)sulfanyl]-1H-benzimidazole (MEPB), as top candidates for rescuing lethality, locomotor function and neuromuscular junction defects in SBMA flies. Pharmacokinetic analyses in mice revealed a more favorable bioavailability and tissue retention of MEPB compared with TA in muscle, brain and spinal cord. In a preclinical trial in a new mouse model of SBMA, MEPB treatment yielded a dose-dependent rescue from loss of body weight, rotarod activity and grip strength. In addition, MEPB ameliorated neuronal loss, neurogenic atrophy and testicular atrophy, validating AF2 modulation as a potent androgen-sparing strategy for SBMA therapy.

A Loss-of-Function Screen for Phosphatases that Regulate Neurite Outgrowth Identifies PTPN12 as a Negative Regulator of TrkB Tyrosine Phosphorylation

PubMed Central

Ambjørn, Malene; Dubreuil, Véronique; Miozzo, Federico; Nigon, Fabienne; Møller, Bente; Issazadeh-Navikas, Shohreh; Berg, Jacob; Lees, Michael; Sap, Jan

2013-01-01

Alterations in function of the neurotrophin BDNF are associated with neurodegeneration, cognitive decline, and psychiatric disorders. BDNF promotes axonal outgrowth and branching, regulates dendritic tree morphology and is important for axonal regeneration after injury, responses that largely result from activation of its tyrosine kinase receptor TrkB. Although intracellular neurotrophin (NT) signaling presumably reflects the combined action of kinases and phosphatases, little is known about the contributions of the latter to TrkB regulation. The issue is complicated by the fact that phosphatases belong to multiple independently evolved families, which are rarely studied together. We undertook a loss-of-function RNA-interference-based screen of virtually all known (254) human phosphatases to understand their function in BDNF/TrkB-mediated neurite outgrowth in differentiated SH-SY5Y cells. This approach identified phosphatases from diverse families, which either positively or negatively modulate BDNF-TrkB-mediated neurite outgrowth, and most of which have little or no previously established function related to NT signaling. “Classical” protein tyrosine phosphatases (PTPs) accounted for 13% of the candidate regulatory phosphatases. The top classical PTP identified as a negative regulator of BDNF-TrkB-mediated neurite outgrowth was PTPN12 (also called PTP-PEST). Validation and follow-up studies showed that endogenous PTPN12 antagonizes tyrosine phosphorylation of TrkB itself, and the downstream activation of ERK1/2. We also found PTPN12 to negatively regulate phosphorylation of p130cas and FAK, proteins with previously described functions related to cell motility and growth cone behavior. Our data provide the first comprehensive survey of phosphatase function in NT signaling and neurite outgrowth. They reveal the complexity of phosphatase control, with several evolutionarily unrelated phosphatase families cooperating to affect this biological response, and hence

The Composite 259-kb Plasmid of Martelella mediterranea DSM 17316T–A Natural Replicon with Functional RepABC Modules from Rhodobacteraceae and Rhizobiaceae

PubMed Central

Bartling, Pascal; Brinkmann, Henner; Bunk, Boyke; Overmann, Jörg; Göker, Markus; Petersen, Jörn

2017-01-01

A multipartite genome organization with a chromosome and many extrachromosomal replicons (ECRs) is characteristic for Alphaproteobacteria. The best investigated ECRs of terrestrial rhizobia are the symbiotic plasmids for legume root nodulation and the tumor-inducing (Ti) plasmid of Agrobacterium tumefaciens. RepABC plasmids represent the most abundant alphaproteobacterial replicon type. The currently known homologous replication modules of rhizobia and Rhodobacteraceae are phylogenetically distinct. In this study, we surveyed type-strain genomes from the One Thousand Microbial Genomes (KMG-I) project and identified a roseobacter-specific RepABC-type operon in the draft genome of the marine rhizobium Martelella mediterranea DSM 17316T. PacBio genome sequencing demonstrated the presence of three circular ECRs with sizes of 593, 259, and 170-kb. The rhodobacteral RepABC module is located together with a rhizobial equivalent on the intermediate sized plasmid pMM259, which likely originated in the fusion of a pre-existing rhizobial ECR with a conjugated roseobacter plasmid. Further evidence for horizontal gene transfer (HGT) is given by the presence of a roseobacter-specific type IV secretion system on the 259-kb plasmid and the rhodobacteracean origin of 62% of the genes on this plasmid. Functionality tests documented that the genuine rhizobial RepABC module from the Martelella 259-kb plasmid is only maintained in A. tumefaciens C58 (Rhizobiaceae) but not in Phaeobacter inhibens DSM 17395 (Rhodobacteraceae). Unexpectedly, the roseobacter-like replication system is functional and stably maintained in both host strains, thus providing evidence for a broader host range than previously proposed. In conclusion, pMM259 is the first example of a natural plasmid that likely mediates genetic exchange between roseobacters and rhizobia. PMID:28983283

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

PubMed

Minor, Daniel L; Findeisen, Felix

2010-01-01

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

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

PubMed Central

Findeisen, Felix

2010-01-01

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

Allosteric modulation by benzodiazepines of GABA-gated chloride channels of an identified insect motor neurone.

PubMed

Buckingham, Steven D; Higashino, Yoshiaki; Sattelle, David B

2009-11-01

The actions of benzodiazepines were studied on the responses to GABA of the fast coxal depressor (D(f)) motor neurone of the cockroach, Periplaneta americana. Ro5-4864, diazepam and clonazepam were investigated. Responses to GABA receptors were enhanced by both Ro5-4864 and diazepam, whereas clonazepam, a potent-positive allosteric modulator of human GABA(A) receptors, was ineffective on the native insect GABA receptors of the D(f) motor neurone. Thus, clear pharmacological differences exist between insect and mammalian native GABA-gated chloride channels with respect to the actions of benzodiazepines. The results enhance our understanding of invertebrate GABA-gated chloride channels which have recently proved important in (a) comparative studies aimed at identifying human allosteric drug-binding sites and (b) understanding the actions of compounds used to control ectoparasites and insect crop pests.

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

ERIC Educational Resources Information Center

Jarvis, Bruce; Mazzocchi, Paul; Hearle, Robert

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

Fragrant dioxane derivatives identify beta1-subunit-containing GABAA receptors.

PubMed

Sergeeva, Olga A; Kletke, Olaf; Kragler, Andrea; Poppek, Anja; Fleischer, Wiebke; Schubring, Stephan R; Görg, Boris; Haas, Helmut L; Zhu, Xin-Ran; Lübbert, Hermann; Gisselmann, Günter; Hatt, Hanns

2010-07-30

Nineteen GABA(A) receptor (GABA(A)R) subunits are known in mammals with only a restricted number of functionally identified native combinations. The physiological role of beta1-subunit-containing GABA(A)Rs is unknown. Here we report the discovery of a new structural class of GABA(A)R positive modulators with unique beta1-subunit selectivity: fragrant dioxane derivatives (FDD). At heterologously expressed alpha1betaxgamma2L (x-for 1,2,3) GABA(A)R FDD were 6 times more potent at beta1- versus beta2- and beta3-containing receptors. Serine at position 265 was essential for the high sensitivity of the beta1-subunit to FDD and the beta1N286W mutation nearly abolished modulation; vice versa the mutation beta3N265S shifted FDD sensitivity toward the beta1-type. In posterior hypothalamic neurons controlling wakefulness GABA-mediated whole-cell responses and GABAergic synaptic currents were highly sensitive to FDD, in contrast to beta1-negative cerebellar Purkinje neurons. Immunostaining for the beta1-subunit and the potency of FDD to modulate GABA responses in cultured hypothalamic neurons was drastically diminished by beta1-siRNA treatment. In conclusion, with the help of FDDs we reveal a functional expression of beta1-containing GABA(A)Rs in the hypothalamus, offering a new tool for studies on the functional diversity of native GABA(A)Rs.

Modulating molecular chaperones improves sensory fiber recovery and mitochondrial function in diabetic peripheral neuropathy

PubMed Central

Urban, Michael J.; Pan, Pan; Farmer, Kevin L.; Zhao, Huiping; Blagg, Brian S.J.; Dobrowsky, Rick T.

2012-01-01

Quantification of intra-epidermal nerve fibers (iENFs) is an important approach to stage diabetic peripheral neuropathy (DPN) and is a promising clinical endpoint for identifying beneficial therapeutics. Mechanistically, diabetes decreases neuronal mitochondrial function and enhancing mitochondrial respiratory capacity may aid neuronal recovery from glucotoxic insults. We have proposed that modulating the activity and expression of heat shock proteins (Hsp) may be of benefit in treating DPN. KU-32 is a C-terminal Hsp90 inhibitor that improved thermal hypoalgesia in diabetic C57Bl/6 mice but it was not determined if this was associated with an increase in iENF density and mitochondrial function. After 16 weeks of diabetes, Swiss Webster mice showed decreased electrophysiological and psychosensory responses and a >30% loss of iENFs. Treatment of the mice with ten weekly doses of 20 mg/kg KU-32 significantly reversed pre-existing deficits in nerve conduction velocity and responses to mechanical and thermal stimuli. KU-32 therapy significantly reversed the pre-existing loss of iENFs despite the identification of a sub-group of drug-treated diabetic mice that showed improved thermal sensitivity but no increase in iENF density. To determine if the improved clinical indices correlated with enhanced mitochondrial activity, sensory neurons were isolated and mitochondrial bioenergetics assessed ex vivo using extracellular flux technology. Diabetes decreased maximal respiratory capacity in sensory neurons and this deficit was improved following KU-32 treatment. In conclusion, KU-32 improved physiological and morphologic markers of degenerative neuropathy and drug efficacy may be related to enhanced mitochondrial bioenergetics in sensory neurons. PMID:22465570

Dietary modulation and structure prediction of rat mucosal pentraxin (Mptx) protein and loss of function in humans

PubMed Central

van der Meer-van Kraaij, Cindy; Siezen, Roland; Kramer, Evelien; Reinders, Marjolein; Blokzijl, Hans; van der Meer, Roelof

2007-01-01

Mucosal pentraxin (Mptx), identified in rats, is a short pentraxin of unknown function. Other subfamily members are Serum amyloid P component (SAP), C-reactive protein (CRP) and Jeltraxin. Rat Mptx mRNA is predominantly expressed in colon and in vivo is strongly (30-fold) regulated by dietary heme and calcium, modulators of colon cancer risk. This renders Mptx a potential nutrient sensitive biomarker of gut health. To support a role as biomarker, we examined whether the pentraxin protein structure is conserved, whether Mptx protein is nutrient-sensitively expressed and whether Mptx is expressed in mouse and human. Sequence comparison and 3D modelling showed that rat Mptx is highly homologous to the other pentraxins. The calcium-binding site and subunit interaction sites are highly conserved, while a loop deletion and charged residues contribute to a distinctive “top” face of the pentamer. In accordance with mRNA expression, Mptx protein is strongly down-regulated in rat colon mucosa in response to high dietary heme intake. Mptx mRNA is expressed in rat and mouse colon, but not in human colon. A stop codon at the beginning of human exon two indicates loss of function, which may be related to differences in intestinal cell turnover between man and rodents. PMID:18850182

Role of Dietary Antioxidants in the Preservation of Vascular Function and the Modulation of Health and Disease

PubMed Central

Varadharaj, Saradhadevi; Kelly, Owen J.; Khayat, Rami N.; Kumar, Purnima S.; Ahmed, Naseer; Zweier, Jay L.

2017-01-01

In vascular diseases, including hypertension and atherosclerosis, vascular endothelial dysfunction (VED) occurs secondary to altered function of endothelial nitric oxide synthase (eNOS). A novel redox regulated pathway was identified through which eNOS is uncoupled due to S-glutathionylation of critical cysteine residues, resulting in superoxide free radical formation instead of the vasodilator molecule, nitric oxide. In addition, the redox sensitive cofactor tetrahydrobiopterin, BH4, is also essential for eNOS coupling. Antioxidants, either individually or combined, can modulate eNOS uncoupling by scavenging free radicals or impairing specific radical generating pathways, thus preventing oxidative stress and ameliorating VED. Epidemiological evidence and dietary guidelines suggest that diets high in antioxidants, or antioxidant supplementation, could preserve vascular health and prevent cardiovascular diseases (CVDs). Therefore, the purpose of this review is to highlight the possible role of dietary antioxidants in regulating eNOS function and uncoupling which is critical for maintenance of vascular health with normal blood flow/circulation and prevention of VED. We hypothesize that a conditioned dietary approach with suitable antioxidants may limit systemic oxidation, maintain a beneficial ratio of reduced to oxidized glutathione, and other redox markers, and minimize eNOS uncoupling serving to prevent CVD and possibly other chronic diseases. PMID:29164133

Tripeptidyl Peptidase II Regulates Sperm Function by Modulating Intracellular Ca2+ Stores via the Ryanodine Receptor

PubMed Central

Zhou, Yuchuan; Ru, Yanfei; Wang, Chunmei; Wang, Shoulin; Zhou, Zuomin; Zhang, Yonglian

2013-01-01

Recent studies have identified Ca2+ stores in sperm cells; however, it is not clear whether these Ca2+ stores are functional and how they are mobilized. Here, in vitro and in vivo, we determined that tripeptidyl peptidase II antagonists strongly activated the cAMP/PKA signaling pathway that drives sperm capacitation-associated protein tyrosine phosphorylation. We demonstrated that in the absence of Ca2+, TPIII antagonists elevated the intracellular Ca2+ levels in sperm, resulting in a marked improvement in sperm movement, capacitation, acrosome reaction, and the in vitro fertilizing ability. This antagonist-induced release of intracellular Ca2+ could be blocked by the inhibitors of ryanodine receptors (RyRs) which are the main intracellular Ca2+ channels responsible for releasing stored Ca2+. Consistent with these results, indirect immunofluorescence assay using anti-RyR antibodies further validated the presence of RyR3 in the acrosomal region of mature sperm. Thus, TPPII can regulate sperm maturation by modulating intracellular Ca2+ stores via the type 3 RyR. PMID:23818952

Model Development of Degradation of PV Modules Backsheet with Locating Place of Module

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

Kempe, Michael D; Wang, Yu; Fairbrother, Andrew

Performance of a photovoltaic (PV) module is related to the micro-environment around the module. The position of photovoltaic modules in an array row have a large effect on the yellowing and gloss of PV module backsheet exposed in Dfa climatic zone (Gaithersburg, MD) with a polyethylene naphthalate (PEN) outer layer. Stress/Response models of yellowing and gloss-losing as function of location parameters of module, including the shed, row, measurement position in a same module and the distance of module location to the row center, are under development. The module installation height had the greatest influence on degradation of PEN PV backsheetmore » in the Dfa climatic zone. The module backsheets at the end of an array have higher degradation rate (edge effect). The edge effect decreases with increasing of module installation heights.« less

Mitochondrial Protein Interaction Mapping Identifies Regulators of Respiratory Chain Function.

PubMed

Floyd, Brendan J; Wilkerson, Emily M; Veling, Mike T; Minogue, Catie E; Xia, Chuanwu; Beebe, Emily T; Wrobel, Russell L; Cho, Holly; Kremer, Laura S; Alston, Charlotte L; Gromek, Katarzyna A; Dolan, Brendan K; Ulbrich, Arne; Stefely, Jonathan A; Bohl, Sarah L; Werner, Kelly M; Jochem, Adam; Westphall, Michael S; Rensvold, Jarred W; Taylor, Robert W; Prokisch, Holger; Kim, Jung-Ja P; Coon, Joshua J; Pagliarini, David J

2016-08-18

Mitochondria are essential for numerous cellular processes, yet hundreds of their proteins lack robust functional annotation. To reveal functions for these proteins (termed MXPs), we assessed condition-specific protein-protein interactions for 50 select MXPs using affinity enrichment mass spectrometry. Our data connect MXPs to diverse mitochondrial processes, including multiple aspects of respiratory chain function. Building upon these observations, we validated C17orf89 as a complex I (CI) assembly factor. Disruption of C17orf89 markedly reduced CI activity, and its depletion is found in an unresolved case of CI deficiency. We likewise discovered that LYRM5 interacts with and deflavinates the electron-transferring flavoprotein that shuttles electrons to coenzyme Q (CoQ). Finally, we identified a dynamic human CoQ biosynthetic complex involving multiple MXPs whose topology we map using purified components. Collectively, our data lend mechanistic insight into respiratory chain-related activities and prioritize hundreds of additional interactions for further exploration of mitochondrial protein function. Copyright © 2016 Elsevier Inc. All rights reserved.

Waveguide Modulator for Interference Tolerant Functional Near Infrared Spectrometer (fNIRS)

NASA Technical Reports Server (NTRS)

Walton, Joanne; Tin, Padetha; Mackey, Jeffrey

2017-01-01

Many crew-related errors in aviation and astronautics are caused by hazardous cognitive states including overstress, disengagement, high fatigue and ineffective crew coordination. Safety can be improved by monitoring and predicting these cognitive states in a non-intrusive manner and designing mitigation strategies. Measuring hemoglobin concentration changes in the brain with functional Near Infrared Spectroscopy is a promising technique for monitoring cognitive state and optimizing human performance during both space and aviation operations. A compact, wearable fNIRS system would provide an innovative early warning system during long duration missions to detect and prevent vigilance decrements in pilots and astronauts. This effort focused on developing a waveguide modulator for use in a fNIRS system.

H-Ras Modulates N-Methyl-d-aspartate Receptor Function via Inhibition of Src Tyrosine Kinase Activity*

PubMed Central

Thornton, Claire; Yaka, Rami; Dinh, Son; Ron, Dorit

2005-01-01

Tyrosine phosphorylation of the NR2A and NR2B subunits of the N-methyl-d-aspartate (NMDA) receptor by Src protein-tyrosine kinases modulates receptor channel activity and is necessary for the induction of long term potentiation (LTP). Deletion of H-Ras increases both NR2 tyrosine phosphorylation and NMDA receptor-mediated hippocampal LTP. Here we investigated whether H-Ras regulates phosphorylation and function of the NMDA receptor via Src family protein-tyrosine kinases. We identified Src as a novel H-Ras binding partner. H-Ras bound to Src but not Fyn both in vitro and in brain via the Src kinase domain. Cotransfection of H-Ras and Src inhibited Src activity and decreased NR2A tyrosine phosphorylation. Treatment of rat brain slices with Tat-H-Ras depleted NR2A from the synaptic membrane, decreased endogenous Src activity and NR2A phosphorylation, and decreased the magnitude of hip-pocampal LTP. No change was observed for NR2B. We suggest that H-Ras negatively regulates Src phosphorylation of NR2A and retention of NR2A into the synaptic membrane leading to inhibition of NMDA receptor function. This mechanism is specific for Src and NR2A and has implications for studies in which regulation of NMDA receptor-mediated LTP is important, such as synaptic plasticity, learning, and memory and addiction. PMID:12695509

Modulation of the functional association between the HIV-1 intasome and the nucleosome by histone amino-terminal tails.

PubMed

Benleulmi, Mohamed S; Matysiak, Julien; Robert, Xavier; Miskey, Csaba; Mauro, Eric; Lapaillerie, Delphine; Lesbats, Paul; Chaignepain, Stéphane; Henriquez, Daniel R; Calmels, Christina; Oladosu, Oyindamola; Thierry, Eloïse; Leon, Oscar; Lavigne, Marc; Andreola, Marie-Line; Delelis, Olivier; Ivics, Zoltán; Ruff, Marc; Gouet, Patrice; Parissi, Vincent

2017-11-28

Stable insertion of the retroviral DNA genome into host chromatin requires the functional association between the intasome (integrase·viral DNA complex) and the nucleosome. The data from the literature suggest that direct protein-protein contacts between integrase and histones may be involved in anchoring the intasome to the nucleosome. Since histone tails are candidates for interactions with the incoming intasomes we have investigated whether they could participate in modulating the nucleosomal integration process. We show here that histone tails are required for an optimal association between HIV-1 integrase (IN) and the nucleosome for efficient integration. We also demonstrate direct interactions between IN and the amino-terminal tail of human histone H4 in vitro. Structure/function studies enabled us to identify amino acids in the carboxy-terminal domain of IN that are important for this interaction. Analysis of the nucleosome-binding properties of catalytically active mutated INs confirmed that their ability to engage the nucleosome for integration in vitro was affected. Pseudovirus particles bearing mutations that affect the IN/H4 association also showed impaired replication capacity due to altered integration and re-targeting of their insertion sites toward dynamic regions of the chromatin with lower nucleosome occupancy. Collectively, our data support a functional association between HIV-1 IN and histone tails that promotes anchoring of the intasome to nucleosomes and optimal integration into chromatin.

MicroRNA-155 Modulates Acute Graft-versus-Host Disease by Impacting T Cell Expansion, Migration, and Effector Function.

PubMed

Zitzer, Nina C; Snyder, Katiri; Meng, Xiamoei; Taylor, Patricia A; Efebera, Yvonne A; Devine, Steven M; Blazar, Bruce R; Garzon, Ramiro; Ranganathan, Parvathi

2018-06-15

MicroRNA-155 (miR-155) is a small noncoding RNA critical for the regulation of inflammation as well as innate and adaptive immune responses. MiR-155 has been shown to be dysregulated in both donor and recipient immune cells during acute graft-versus-host disease (aGVHD). We previously reported that miR-155 is upregulated in donor T cells of mice and humans with aGVHD and that mice receiving miR-155-deficient (miR155 -/- ) splenocytes had markedly reduced aGVHD. However, molecular mechanisms by which miR-155 modulates T cell function in aGVHD have not been fully investigated. We identify that miR-155 expression in both donor CD8 + T cells and conventional CD4 + CD25 - T cells is pivotal for aGVHD pathogenesis. Using murine aGVHD transplant experiments, we show that miR-155 strongly impacts alloreactive T cell expansion through multiple distinct mechanisms, modulating proliferation in CD8 + donor T cells and promoting exhaustion in donor CD4 + T cells in both the spleen and colon. Additionally, miR-155 drives a proinflammatory Th1 phenotype in donor T cells in these two sites, and miR-155 -/- donor T cells are polarized toward an IL-4-producing Th2 phenotype. We further demonstrate that miR-155 expression in donor T cells regulates CCR5 and CXCR4 chemokine-dependent migration. Notably, we show that miR-155 expression is crucial for donor T cell infiltration into multiple target organs. These findings provide further understanding of the role of miR-155 in modulating aGVHD through T cell expansion, effector cytokine production, and migration. Copyright © 2018 by The American Association of Immunologists, Inc.

Integrating Genetic and Gene Co-expression Analysis Identifies Gene Networks Involved in Alcohol and Stress Responses

PubMed Central

Luo, Jie; Xu, Pei; Cao, Peijian; Wan, Hongjian; Lv, Xiaonan; Xu, Shengchun; Wang, Gangjun; Cook, Melloni N.; Jones, Byron C.; Lu, Lu; Wang, Xusheng

2018-01-01

Although the link between stress and alcohol is well recognized, the underlying mechanisms of how they interplay at the molecular level remain unclear. The purpose of this study is to identify molecular networks underlying the effects of alcohol and stress responses, as well as their interaction on anxiety behaviors in the hippocampus of mice using a systems genetics approach. Here, we applied a gene co-expression network approach to transcriptomes of 41 BXD mouse strains under four conditions: stress, alcohol, stress-induced alcohol and control. The co-expression analysis identified 14 modules and characterized four expression patterns across the four conditions. The four expression patterns include up-regulation in no restraint stress and given an ethanol injection (NOE) but restoration in restraint stress followed by an ethanol injection (RSE; pattern 1), down-regulation in NOE but rescue in RSE (pattern 2), up-regulation in both restraint stress followed by a saline injection (RSS) and NOE, and further amplification in RSE (pattern 3), and up-regulation in RSS but reduction in both NOE and RSE (pattern 4). We further identified four functional subnetworks by superimposing protein-protein interactions (PPIs) to the 14 co-expression modules, including γ-aminobutyric acid receptor (GABA) signaling, glutamate signaling, neuropeptide signaling, cAMP-dependent signaling. We further performed module specificity analysis to identify modules that are specific to stress, alcohol, or stress-induced alcohol responses. Finally, we conducted causality analysis to link genetic variation to these identified modules, and anxiety behaviors after stress and alcohol treatments. This study underscores the importance of integrative analysis and offers new insights into the molecular networks underlying stress and alcohol responses. PMID:29674951

Resting Functional Connectivity of the Periaqueductal Gray Is Associated With Normal Inhibition and Pathological Facilitation in Conditioned Pain Modulation.

PubMed

Harper, Daniel E; Ichesco, Eric; Schrepf, Andrew; Hampson, Johnson P; Clauw, Daniel J; Schmidt-Wilcke, Tobias; Harris, Richard E; Harte, Steven E

2018-06-01

Conditioned pain modulation (CPM), a psychophysical paradigm that is commonly used to infer the integrity of endogenous pain-altering systems by observation of the effect of one noxious stimulus on another, has previously identified deficient endogenous analgesia in fibromyalgia (FM) and other chronic pain conditions. The mechanisms underlying this deficiency, be they insufficient inhibition and/or active facilitation, are largely unknown. The present cross-sectional study used a combination of behavioral CPM testing, voxel-based morphometry, and resting state functional connectivity to identify neural correlates of CPM in healthy controls (HC; n = 14) and FM patients (n = 15), and to probe for differences that could explain the pain-facilitative CPM that was observed in our patient sample. Voxel-based morphometry identified a cluster encompassing the periaqueductal gray (PAG) that contained significantly less gray matter volume in FM patients. Higher resting connectivity between this cluster and cortical pain processing regions was associated with more efficient inhibitory CPM in both groups, whereas PAG connectivity with the dorsal pons was associated with greater CPM inhibition only in HC. Greater PAG connectivity to the caudal pons/rostral medulla, which was pain-inhibitory in HC, was associated with pain facilitation in FM patients. These findings indicate that variation in the strength of the PAG resting functional connectivity can explain some of the normal variability in CPM. In addition, pain-facilitative CPM observed in FM patients likely involves attenuation of pain inhibitory as well as amplification of pain facilitative processes in the central nervous system. Copyright © 2018 The American Pain Society. Published by Elsevier Inc. All rights reserved.

A mammalian nervous system-specific plasma membrane proteasome complex that modulates neuronal function

PubMed Central

Ramachandran, Kapil V.; Margolis, Seth S.

2017-01-01

In the nervous system, rapidly occurring processes such as neuronal transmission and calcium signaling are affected by short-term inhibition of proteasome function. It remains unclear how proteasomes can acutely regulate such processes, as this is inconsistent with their canonical role in proteostasis. Here, we made the discovery of a mammalian nervous system-specific membrane proteasome complex that directly and rapidly modulates neuronal function by degrading intracellular proteins into extracellular peptides that can stimulate neuronal signaling. This proteasome complex is tightly associated with neuronal plasma membranes, exposed to the extracellular space, and catalytically active. Selective inhibition of this membrane proteasome complex by a cell-impermeable proteasome inhibitor blocked extracellular peptide production and attenuated neuronal activity-induced calcium signaling. Moreover, membrane proteasome-derived peptides are sufficient to induce neuronal calcium signaling. Our discoveries challenge the prevailing notion that proteasomes primarily function to maintain proteostasis, and highlight a form of neuronal communication through a membrane proteasome complex. PMID:28287632

Modulation transfer function estimation of optical lens system by adaptive neuro-fuzzy methodology

NASA Astrophysics Data System (ADS)

Petković, Dalibor; Shamshirband, Shahaboddin; Pavlović, Nenad T.; Anuar, Nor Badrul; Kiah, Miss Laiha Mat

2014-07-01

The quantitative assessment of image quality is an important consideration in any type of imaging system. The modulation transfer function (MTF) is a graphical description of the sharpness and contrast of an imaging system or of its individual components. The MTF is also known and spatial frequency response. The MTF curve has different meanings according to the corresponding frequency. The MTF of an optical system specifies the contrast transmitted by the system as a function of image size, and is determined by the inherent optical properties of the system. In this study, the adaptive neuro-fuzzy (ANFIS) estimator is designed and adapted to estimate MTF value of the actual optical system. Neural network in ANFIS adjusts parameters of membership function in the fuzzy logic of the fuzzy inference system. The back propagation learning algorithm is used for training this network. This intelligent estimator is implemented using Matlab/Simulink and the performances are investigated. The simulation results presented in this paper show the effectiveness of the developed method.

Ribosomal protein RPS-14 modulates let-7 microRNA function in Caenorhabditis elegans

PubMed Central

Chan, Shih-Peng; Slack, Frank J.

2009-01-01

The let-7 microRNA (miRNA) regulates developmental timing at the larval-to-adult transition in Caenorhabditis elegans. Dysregulation of let-7 results in irregular hypodermal and vulval development. Disrupted let-7 function is also a feature of human lung cancer. However, little is known about the mechanism and co-factors of let-7. Here we demonstrate that ribosomal protein RPS-14 is able to modulate let-7 function in C. elegans. The RPS-14 protein co-immunoprecipitated with the nematode Argonaute homolog, ALG-1. Reduction of rps-14 gene expression by RNAi suppressed the aberrant vulva and hypodermis development phenotypes of let-7(n2853) mutant animals and the mis-regulation of a reporter bearing the lin-41 3′UTR, a well established let-7 target. Our results indicate an interactive relationship between let-7 miRNA function and ribosomal protein RPS-14 in regulation of terminal differentiation that may help in understanding the mechanism of translational control by miRNAs. PMID:19627982

Anti–IL-6 neutralizing antibody modulates blood-brain barrier function in the ovine fetus

PubMed Central

Zhang, Jiyong; Sadowska, Grazyna B.; Chen, Xiaodi; Park, Seon Yeong; Kim, Jeong-Eun; Bodge, Courtney A.; Cummings, Erin; Lim, Yow-Pin; Makeyev, Oleksandr; Besio, Walter G.; Gaitanis, John; Banks, William A.; Stonestreet, Barbara S.

2015-01-01

Impaired blood-brain barrier function represents an important component of hypoxic-ischemic brain injury in the perinatal period. Proinflammatory cytokines could contribute to ischemia-related blood-brain barrier dysfunction. IL-6 increases vascular endothelial cell monolayer permeability in vitro. However, contributions of IL-6 to blood-brain barrier abnormalities have not been examined in the immature brain in vivo. We generated pharmacologic quantities of ovine-specific neutralizing anti-IL-6 mAbs and systemically infused mAbs into fetal sheep at 126 days of gestation after exposure to brain ischemia. Anti–IL-6 mAbs were measured by ELISA in fetal plasma, cerebral cortex, and cerebrospinal fluid, blood-brain barrier permeability was quantified using the blood-to-brain transfer constant in brain regions, and IL-6, tight junction proteins, and plasmalemma vesicle protein (PLVAP) were detected by Western immunoblot. Anti–IL-6 mAb infusions resulted in increases in mAb (P < 0.05) in plasma, brain parenchyma, and cerebrospinal fluid and decreases in brain IL-6 protein. Twenty-four hours after ischemia, anti–IL-6 mAb infusions attenuated ischemia-related increases in blood-brain barrier permeability and modulated tight junction and PLVAP protein expression in fetal brain. We conclude that inhibiting the effects of IL-6 protein with systemic infusions of neutralizing antibodies attenuates ischemia-related increases in blood-brain barrier permeability by inhibiting IL-6 and modulates tight junction proteins after ischemia.—Zhang, J., Sadowska, G. B., Chen, X., Park, S. Y., Kim, J.-E., Bodge, C. A., Cummings, E., Lim, Y.-P., Makeyev, O., Besio, W. G., Gaitanis, J., Banks, W. A., Stonestreet, B. S. Anti–IL-6 neutralizing antibody modulates blood-brain barrier function in the ovine fetus. PMID:25609424

Regulation and Modulation of Human DNA Polymerase δ Activity and Function

PubMed Central

Wang, Xiaoxiao; Zhang, Sufang; Zhang, Zhongtao; Lee, Ernest Y. C.

2017-01-01

This review focuses on the regulation and modulation of human DNA polymerase δ (Pol δ). The emphasis is on the mechanisms that regulate the activity and properties of Pol δ in DNA repair and replication. The areas covered are the degradation of the p12 subunit of Pol δ, which converts it from a heterotetramer (Pol δ4) to a heterotrimer (Pol δ3), in response to DNA damage and also during the cell cycle. The biochemical mechanisms that lead to degradation of p12 are reviewed, as well as the properties of Pol δ4 and Pol δ3 that provide insights into their functions in DNA replication and repair. The second focus of the review involves the functions of two Pol δ binding proteins, polymerase delta interaction protein 46 (PDIP46) and polymerase delta interaction protein 38 (PDIP38), both of which are multi-functional proteins. PDIP46 is a novel activator of Pol δ4, and the impact of this function is discussed in relation to its potential roles in DNA replication. Several new models for the roles of Pol δ3 and Pol δ4 in leading and lagging strand DNA synthesis that integrate a role for PDIP46 are presented. PDIP38 has multiple cellular localizations including the mitochondria, the spliceosomes and the nucleus. It has been implicated in a number of cellular functions, including the regulation of specialized DNA polymerases, mitosis, the DNA damage response, mouse double minute 2 homolog (Mdm2) alternative splicing and the regulation of the NADPH oxidase 4 (Nox4). PMID:28737709

Cholinergic modulation of mesolimbic dopamine function and reward.

PubMed

Mark, Gregory P; Shabani, Shkelzen; Dobbs, Lauren K; Hansen, Stephen T

2011-07-25

The substantial health risk posed by obesity and compulsive drug use has compelled a serious research effort to identify the neurobiological substrates that underlie the development these pathological conditions. Despite substantial progress, an understanding of the neurochemical systems that mediate the motivational aspects of drug-seeking and craving remains incomplete. Important work from the laboratory of Bart Hoebel has provided key information on neurochemical systems that interact with dopamine (DA) as potentially important components in both the development of addiction and the expression of compulsive behaviors such as binge eating. One such modulatory system appears to be cholinergic pathways that interact with DA systems at all levels of the reward circuit. Cholinergic cells in the pons project to DA-rich cell body regions in the ventral tegmental area (VTA) and substantial nigra (SN) where they modulate the activity of dopaminergic neurons and reward processing. The DA terminal region of the nucleus accumbens (NAc) contains a small but particularly important group of cholinergic interneurons, which have extensive dendritic arbors that make synapses with a vast majority of NAc neurons and afferents. Together with acetylcholine (ACh) input onto DA cell bodies, cholinergic systems could serve a vital role in gating information flow concerning the motivational value of stimuli through the mesolimbic system. In this report we highlight evidence that CNS cholinergic systems play a pivotal role in behaviors that are motivated by both natural and drug rewards. We argue that the search for underlying neurochemical substrates of compulsive behaviors, as well as attempts to identify potential pharmacotherapeutic targets to combat them, must include a consideration of central cholinergic systems. Copyright © 2011 Elsevier Inc. All rights reserved.

Suggestion-Induced Modulation of Semantic Priming during Functional Magnetic Resonance Imaging

PubMed Central

Ulrich, Martin; Kiefer, Markus; Bongartz, Walter; Grön, Georg; Hoenig, Klaus

2015-01-01

Using functional magnetic resonance imaging during a primed visual lexical decision task, we investigated the neural and functional mechanisms underlying modulations of semantic word processing through hypnotic suggestions aimed at altering lexical processing of primes. The priming task was to discriminate between target words and pseudowords presented 200 ms after the prime word which was semantically related or unrelated to the target. In a counterbalanced study design, each participant performed the task once at normal wakefulness and once after the administration of hypnotic suggestions to perceive the prime as a meaningless symbol of a foreign language. Neural correlates of priming were defined as significantly lower activations upon semantically related compared to unrelated trials. We found significant suggestive treatment-induced reductions in neural priming, albeit irrespective of the degree of suggestibility. Neural priming was attenuated upon suggestive treatment compared with normal wakefulness in brain regions supporting automatic (fusiform gyrus) and controlled semantic processing (superior and middle temporal gyri, pre- and postcentral gyri, and supplementary motor area). Hence, suggestions reduced semantic word processing by conjointly dampening both automatic and strategic semantic processes. PMID:25923740

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

NASA Astrophysics Data System (ADS)

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

2010-11-01

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

Altered brain network modules induce helplessness in major depressive disorder.

PubMed

Peng, Daihui; Shi, Feng; Shen, Ting; Peng, Ziwen; Zhang, Chen; Liu, Xiaohua; Qiu, Meihui; Liu, Jun; Jiang, Kaida; Fang, Yiru; Shen, Dinggang

2014-10-01

The abnormal brain functional connectivity (FC) has been assumed to be a pathophysiological aspect of major depressive disorder (MDD). However, it is poorly understood, regarding the underlying patterns of global FC network and their relationships with the clinical characteristics of MDD. Resting-state functional magnetic resonance imaging data were acquired from 16 first episode, medication-naïve MDD patients and 16 healthy control subjects. The global FC network was constructed using 90 brain regions. The global topological patterns, e.g., small-worldness and modularity, and their relationships with depressive characteristics were investigated. Furthermore, the participant coefficient and module degree of MDD patients were measured to reflect the regional roles in module network, and the impairment of FC was examined by network based statistic. Small-world property was not altered in MDD. However, MDD patients exhibited 5 atypically reorganized modules compared to the controls. A positive relationship was also found among MDD patients between the intra-module I and helplessness factor evaluated via the Hamilton Depression Scale. Specifically, eight regions exhibited the abnormal participant coefficient or module degree, e.g., left superior orbital frontal cortex and right amygdala. The decreased FC was identified among the sub-network of 24 brain regions, e.g., frontal cortex, supplementary motor area, amygdala, thalamus, and hippocampus. The limited size of MDD samples precluded meaningful study of distinct clinical characteristics in relation to aberrant FC. The results revealed altered patterns of brain module network at the global level in MDD patients, which might contribute to the feelings of helplessness. Copyright © 2014 Elsevier B.V. All rights reserved.

Altered brain network modules induce helplessness in major depressive disorder

PubMed Central

Peng, Daihui; Shi, Feng; Shen, Ting; Peng, Ziwen; Zhang, Chen; Liu, Xiaohua; Qiu, Meihui; Liu, Jun; Jiang, Kaida; Shen, Dinggang

2017-01-01

Objective The abnormal brain functional connectivity (FC) has been assumed to be a pathophysiological aspect of major depressive disorder (MDD). However, it is poorly understood, regarding the underlying patterns of global FC network and their relationships with the clinical characteristics of MDD. Methods Resting-state functional magnetic resonance imaging data were acquired from 16 first episode, medication-naïve MDD patients and 16 healthy control subjects. The global FC network was constructed using 90 brain regions. The global topological patterns, e.g., small-worldness and modularity, and their relationships with depressive characteristics were investigated. Furthermore, the participant coefficient and module degree of MDD patients were measured to reflect the regional roles in module network, and the impairment of FC was examined by network based statistic. Results Small-world property was not altered in MDD. However, MDD patients exhibited 5 atypically reorganized modules compared to the controls. A positive relationship was also found among MDD patients between the intra-module I and helplessness factor evaluated via the Hamilton Depression Scale. Specifically, eight regions exhibited the abnormal participant coefficient or module degree, e.g., left superior orbital frontal cortex and right amygdala. The decreased FC was identified among the sub-network of 24 brain regions, e.g., frontal cortex, supplementary motor area, amygdala, thalamus, and hippocampus. Limitation The limited size of MDD samples precluded meaningful study of distinct clinical characteristics in relation to aberrant FC. Conclusions The results revealed altered patterns of brain module network at the global level in MDD patients, which might contribute to the feelings of helplessness. PMID:25033474

Dissecting protein function: an efficient protocol for identifying separation-of-function mutations that encode structurally stable proteins.

PubMed

Lubin, Johnathan W; Rao, Timsi; Mandell, Edward K; Wuttke, Deborah S; Lundblad, Victoria

2013-03-01

Mutations that confer the loss of a single biochemical property (separation-of-function mutations) can often uncover a previously unknown role for a protein in a particular biological process. However, most mutations are identified based on loss-of-function phenotypes, which cannot differentiate between separation-of-function alleles vs. mutations that encode unstable/unfolded proteins. An alternative approach is to use overexpression dominant-negative (ODN) phenotypes to identify mutant proteins that disrupt function in an otherwise wild-type strain when overexpressed. This is based on the assumption that such mutant proteins retain an overall structure that is comparable to that of the wild-type protein and are able to compete with the endogenous protein (Herskowitz 1987). To test this, the in vivo phenotypes of mutations in the Est3 telomerase subunit from Saccharomyces cerevisiae were compared with the in vitro secondary structure of these mutant proteins as analyzed by circular-dichroism spectroscopy, which demonstrates that ODN is a more sensitive assessment of protein stability than the commonly used method of monitoring protein levels from extracts. Reverse mutagenesis of EST3, which targeted different categories of amino acids, also showed that mutating highly conserved charged residues to the oppositely charged amino acid had an increased likelihood of generating a severely defective est3(-) mutation, which nevertheless encoded a structurally stable protein. These results suggest that charge-swap mutagenesis directed at a limited subset of highly conserved charged residues, combined with ODN screening to eliminate partially unfolded proteins, may provide a widely applicable and efficient strategy for generating separation-of-function mutations.

Functional Brain Activation Differences in Stuttering Identified with a Rapid fMRI Sequence

ERIC Educational Resources Information Center

Loucks, Torrey; Kraft, Shelly Jo; Choo, Ai Leen; Sharma, Harish; Ambrose, Nicoline G.

2011-01-01

The purpose of this study was to investigate whether brain activity related to the presence of stuttering can be identified with rapid functional MRI (fMRI) sequences that involved overt and covert speech processing tasks. The long-term goal is to develop sensitive fMRI approaches with developmentally appropriate tasks to identify deviant speech…

Identifying key genes associated with acute myocardial infarction.

PubMed

Cheng, Ming; An, Shoukuan; Li, Junquan

2017-10-01

This study aimed to identify key genes associated with acute myocardial infarction (AMI) by reanalyzing microarray data. Three gene expression profile datasets GSE66360, GSE34198, and GSE48060 were downloaded from GEO database. After data preprocessing, genes without heterogeneity across different platforms were subjected to differential expression analysis between the AMI group and the control group using metaDE package. P < .05 was used as the cutoff for a differentially expressed gene (DEG). The expression data matrices of DEGs were imported in ReactomeFIViz to construct a gene functional interaction (FI) network. Then, DEGs in each module were subjected to pathway enrichment analysis using DAVID. MiRNAs and transcription factors predicted to regulate target DEGs were identified. Quantitative real-time polymerase chain reaction (RT-PCR) was applied to verify the expression of genes. A total of 913 upregulated genes and 1060 downregulated genes were identified in the AMI group. A FI network consists of 21 modules and DEGs in 12 modules were significantly enriched in pathways. The transcription factor-miRNA-gene network contains 2 transcription factors FOXO3 and MYBL2, and 2 miRNAs hsa-miR-21-5p and hsa-miR-30c-5p. RT-PCR validations showed that expression levels of FOXO3 and MYBL2 were significantly increased in AMI, and expression levels of hsa-miR-21-5p and hsa-miR-30c-5p were obviously decreased in AMI. A total of 41 DEGs, such as SOCS3, VAPA, and COL5A2, are speculated to have roles in the pathogenesis of AMI; 2 transcription factors FOXO3 and MYBL2, and 2 miRNAs hsa-miR-21-5p and hsa-miR-30c-5p may be involved in the regulation of the expression of these DEGs.

A systematic analysis of the PARP protein family identifies new functions critical for cell physiology

PubMed Central

Vyas, Sejal; Chesarone-Cataldo, Melissa; Todorova, Tanya; Huang, Yun-Han; Chang, Paul

2013-01-01

The poly(ADP-ribose) polymerase (PARP) family of proteins use NAD+ as their substrate to modify acceptor proteins with adenosine diphosphate-ribose (ADPr) modifications. The function of most PARPs under physiological conditions is unknown. Here, to better understand this protein family, we systematically analyze the cell cycle localization of each PARP and of poly(ADP-ribose), a product of PARP activity, then identify the knock-down phenotype of each protein and perform secondary assays to elucidate function. We show that most PARPs are cytoplasmic, identify cell cycle differences in the ratio of nuclear to cytoplasmic poly(ADP-ribose), and identify four phenotypic classes of PARP function. These include the regulation of membrane structures, cell viability, cell division, and the actin cytoskeleton. Further analysis of PARP14 shows that it is a component of focal adhesion complexes required for proper cell motility and focal adhesion function. In total, we show that PARP proteins are critical regulators of eukaryotic physiology. PMID:23917125

A Functional Genomics Approach to Identify Novel Breast Cancer Gene Targets in Yeast

DTIC Science & Technology

2004-05-01

AD Award Number: DAMD17-03-1-0232 TITLE: A Functional Genomics Approach to Identify Novel Breast Cancer Gene Targets in Yeast PRINCIPAL INVESTIGATOR...Approach to Identify Novel Breast DAMD17-03-1-0232 Cancer Gene Targets in Yeast 6. A UTHOR(S) Craig Bennett, Ph.D. 7. PERFORMING ORGANIZA TION NAME(S...Unlimited 13. ABSTRACT (Maximum 200 Words) We are using the yeast Saccharomyces cerevisiae to identify new cancer gene targets that interact with the

Quantitative Analysis of Localized Sources Identified by Focal Impulse and Rotor Modulation Mapping in Atrial Fibrillation

PubMed Central

Benharash, Peyman; Buch, Eric; Frank, Paul; Share, Michael; Tung, Roderick; Shivkumar, Kalyanam; Mandapati, Ravi

2015-01-01

Background New approaches to ablation of atrial fibrillation (AF) include focal impulse and rotor modulation (FIRM) mapping, and initial results reported with this technique have been favorable. We sought to independently evaluate the approach by analyzing quantitative characteristics of atrial electrograms used to identify rotors and describe acute procedural outcomes of FIRM-guided ablation. Methods and Results All FIRM-guided ablation procedures (n=24; 50% paroxysmal) at University of California, Los Angeles Medical Center were included for analysis. During AF, unipolar atrial electrograms collected from a 64-pole basket catheter were used to construct phase maps and identify putative AF sources. These sites were targeted for ablation, in conjunction with pulmonary vein isolation in most patients (n=19; 79%). All patients had rotors identified (mean, 2.3±0.9 per patient; 72% in left atrium). Prespecified acute procedural end point was achieved in 12 of 24 (50%) patients: AF termination (n=1), organization (n=3), or >10% slowing of AF cycle length (n=8). Basket electrodes were within 1 cm of 54% of left atrial surface area, and a mean of 31 electrodes per patient showed interpretable atrial electrograms. Offline analysis revealed no differences between rotor and distant sites in dominant frequency or Shannon entropy. Electroanatomic mapping showed no rotational activation at FIRM-identified rotor sites in 23 of 24 patients (96%). Conclusions FIRM-identified rotor sites did not exhibit quantitative atrial electrogram characteristics expected from rotors and did not differ quantitatively from surrounding tissue. Catheter ablation at these sites, in conjunction with pulmonary vein isolation, resulted in AF termination or organization in a minority of patients (4/24; 17%). Further validation of this approach is necessary. PMID:25873718

Sestrins: novel antioxidant and AMPK-modulating functions regulated by exercise?

PubMed

Sanchis-Gomar, Fabian

2013-08-01

Oxidative stress results from damage to tissues caused by free radicals and is increased by exercise. Peroxiredoxins (PRXs) maintain the cellular reducing environment by scavenging intracellular hydrogen peroxide. It has been recently noted that physical exercise has a positive effect on the PRX system, exerting a protective effect against oxidative stress-induced damage. However, other compounds, such as sestrins (SESNs), a stress-inducible protein family with antioxidant properties, should also be considered in the function of PRXs. SESNs are clearly involved in the regeneration process of PRXs and therefore may also be modulated by physical exercise. In addition, SESNs are clearly involved in TOR, AMPK, p53, FoxO, and PRXs signaling pathways. The aforementioned pathways are implicated in aging processes by inducing an increased resistance to subsequent stress, thus delaying age-related changes, such as sarcopenia and frailty, and consequently promoting longevity. Likewise, exercise also modulates these pathways. In fact, exercise is one of the most important recommended strategies to prevent sarcopenia and frailty, increase longevity, and improve health in the elderly. Loss of SESNs can cause several chronic pathologies, such as fat accumulation, mitochondrial dysfunction, cardiac arrhythmia, and/or muscle degeneration. Accordingly, physical inactivity leads to accumulation of visceral fat and consequently the activation of a network of inflammatory pathways, which promote development of insulin resistance, atherosclerosis, neurodegeneration, and tumor growth. To date, the SESNs-exercise relationship has not been explored. However, this emerging family of stress proteins may be part of the redox-based adaptive response to exercise. Copyright © 2013 Wiley Periodicals, Inc.

Mediator kinase module and human tumorigenesis.

PubMed

Clark, Alison D; Oldenbroek, Marieke; Boyer, Thomas G

2015-01-01

Mediator is a conserved multi-subunit signal processor through which regulatory informatiosn conveyed by gene-specific transcription factors is transduced to RNA Polymerase II (Pol II). In humans, MED13, MED12, CDK8 and Cyclin C (CycC) comprise a four-subunit "kinase" module that exists in variable association with a 26-subunit Mediator core. Genetic and biochemical studies have established the Mediator kinase module as a major ingress of developmental and oncogenic signaling through Mediator, and much of its function in signal-dependent gene regulation derives from its resident CDK8 kinase activity. For example, CDK8-targeted substrate phosphorylation impacts transcription factor half-life, Pol II activity and chromatin chemistry and functional status. Recent structural and biochemical studies have revealed a precise network of physical and functional subunit interactions required for proper kinase module activity. Accordingly, pathologic change in this activity through altered expression or mutation of constituent kinase module subunits can have profound consequences for altered signaling and tumor formation. Herein, we review the structural organization, biological function and oncogenic potential of the Mediator kinase module. We focus principally on tumor-associated alterations in kinase module subunits for which mechanistic relationships as opposed to strictly correlative associations are established. These considerations point to an emerging picture of the Mediator kinase module as an oncogenic unit, one in which pathogenic activation/deactivation through component change drives tumor formation through perturbation of signal-dependent gene regulation. It follows that therapeutic strategies to combat CDK8-driven tumors will involve targeted modulation of CDK8 activity or pharmacologic manipulation of dysregulated CDK8-dependent signaling pathways.

Mediator kinase module and human tumorigenesis

PubMed Central

Clark, Alison D.; Oldenbroek, Marieke; Boyer, Thomas G.

2016-01-01

Mediator is a conserved multi-subunit signal processor through which regulatory informatiosn conveyed by gene-specific transcription factors is transduced to RNA Polymerase II (Pol II). In humans, MED13, MED12, CDK8 and Cyclin C (CycC) comprise a four-subunit “kinase” module that exists in variable association with a 26-subunit Mediator core. Genetic and biochemical studies have established the Mediator kinase module as a major ingress of developmental and oncogenic signaling through Mediator, and much of its function in signal-dependent gene regulation derives from its resident CDK8 kinase activity. For example, CDK8-targeted substrate phosphorylation impacts transcription factor half-life, Pol II activity and chromatin chemistry and functional status. Recent structural and biochemical studies have revealed a precise network of physical and functional subunit interactions required for proper kinase module activity. Accordingly, pathologic change in this activity through altered expression or mutation of constituent kinase module subunits can have profound consequences for altered signaling and tumor formation. Herein, we review the structural organization, biological function and oncogenic potential of the Mediator kinase module. We focus principally on tumor-associated alterations in kinase module subunits for which mechanistic relationships as opposed to strictly correlative associations are established. These considerations point to an emerging picture of the Mediator kinase module as an oncogenic unit, one in which pathogenic activation/deactivation through component change drives tumor formation through perturbation of signal-dependent gene regulation. It follows that therapeutic strategies to combat CDK8-driven tumors will involve targeted modulation of CDK8 activity or pharmacologic manipulation of dysregulated CDK8-dependent signaling pathways. PMID:26182352

Identifying arsenic trioxide (ATO) functions in leukemia cells by using time series gene expression profiles.

PubMed

Yang, Hong; Lin, Shan; Cui, Jingru

2014-02-10

Arsenic trioxide (ATO) is presently the most active single agent in the treatment of acute promyelocytic leukemia (APL). In order to explore the molecular mechanism of ATO in leukemia cells with time series, we adopted bioinformatics strategy to analyze expression changing patterns and changes in transcription regulation modules of time series genes filtered from Gene Expression Omnibus database (GSE24946). We totally screened out 1847 time series genes for subsequent analysis. The KEGG (Kyoto encyclopedia of genes and genomes) pathways enrichment analysis of these genes showed that oxidative phosphorylation and ribosome were the top 2 significantly enriched pathways. STEM software was employed to compare changing patterns of gene expression with assigned 50 expression patterns. We screened out 7 significantly enriched patterns and 4 tendency charts of time series genes. The result of Gene Ontology showed that functions of times series genes mainly distributed in profiles 41, 40, 39 and 38. Seven genes with positive regulation of cell adhesion function were enriched in profile 40, and presented the same first increased model then decreased model as profile 40. The transcription module analysis showed that they mainly involved in oxidative phosphorylation pathway and ribosome pathway. Overall, our data summarized the gene expression changes in ATO treated K562-r cell lines with time and suggested that time series genes mainly regulated cell adhesive. Furthermore, our result may provide theoretical basis of molecular biology in treating acute promyelocytic leukemia. Copyright © 2013 Elsevier B.V. All rights reserved.

Identifying Predictors, Moderators, and Mediators of Antidepressant Response in Major Depressive Disorder: Neuroimaging Approaches

PubMed Central

Phillips, Mary L.; Chase, Henry W.; Sheline, Yvette I.; Etkin, Amit; Almeida, Jorge R.C.; Deckersbach, Thilo; Trivedi, Madhukar H.

2015-01-01

Objective Despite significant advances in neuroscience and treatment development, no widely accepted biomarkers are available to inform diagnostics or identify preferred treatments for individuals with major depressive disorder. Method In this critical review, the authors examine the extent to which multimodal neuroimaging techniques can identify biomarkers reflecting key pathophysiologic processes in depression and whether such biomarkers may act as predictors, moderators, and mediators of treatment response that might facilitate development of personalized treatments based on a better understanding of these processes. Results The authors first highlight the most consistent findings from neuroimaging studies using different techniques in depression, including structural and functional abnormalities in two parallel neural circuits: serotonergically modulated implicit emotion regulation circuitry, centered on the amygdala and different regions in the medial prefrontal cortex; and dopaminergically modulated reward neural circuitry, centered on the ventral striatum and medial prefrontal cortex. They then describe key findings from the relatively small number of studies indicating that specific measures of regional function and, to a lesser extent, structure in these neural circuits predict treatment response in depression. Conclusions Limitations of existing studies include small sample sizes, use of only one neuroimaging modality, and a focus on identifying predictors rather than moderators and mediators of differential treatment response. By addressing these limitations and, most importantly, capitalizing on the benefits of multimodal neuroimaging, future studies can yield moderators and mediators of treatment response in depression to facilitate significant improvements in shorter- and longer-term clinical and functional outcomes. PMID:25640931

On staggered indecomposable Virasoro modules

NASA Astrophysics Data System (ADS)

Kytölä, Kalle; Ridout, David

2009-12-01

In this article, certain indecomposable Virasoro modules are studied. Specifically, the Virasoro mode L0 is assumed to be nondiagonalizable, possessing Jordan blocks of rank 2. Moreover, the module is further assumed to have a highest weight submodule, the "left module," and that the quotient by this submodule yields another highest weight module, the "right module." Such modules, which have been called staggered, have appeared repeatedly in the logarithmic conformal field theory literature, but their theory has not been explored in full generality. Here, such a theory is developed for the Virasoro algebra using rather elementary techniques. The focus centers on two different but related questions typically encountered in practical studies: How can one identify a given staggered module, and how can one demonstrate the existence of a proposed staggered module. Given just the values of the highest weights of the left and right modules, themselves subject to simple necessary conditions, invariants are defined which together with the knowledge of the left and right modules uniquely identify a staggered module. The possible values of these invariants form a vector space of dimension 0, 1, or 2, and the structures of the left and right modules limit the isomorphism classes of the corresponding staggered modules to an affine subspace (possibly empty). The number of invariants and affine restrictions is purely determined by the structures of the left and right modules. Moreover, in order to facilitate applications, the expressions for the invariants and restrictions are given by formulas as explicit as possible (they generally rely on expressions for Virasoro singular vectors). Finally, the text is liberally peppered throughout with examples illustrating the general concepts. These have been carefully chosen for their physical relevance or for the novel features they exhibit.

Transcriptional Profiling Identifies Functional Interactions of TGFβ and PPARβ/δ Signaling

PubMed Central

Kaddatz, Kerstin; Adhikary, Till; Finkernagel, Florian; Meissner, Wolfgang; Müller-Brüsselbach, Sabine; Müller, Rolf

2010-01-01

Peroxisome proliferator-activated receptors (PPARs) not only play a key role in regulating metabolic pathways but also modulate inflammatory processes, pointing to a functional interaction between PPAR and cytokine signaling pathways. In this study, we show by genome-wide transcriptional profiling that PPARβ/δ and transforming growth factor-β (TGFβ) pathways functionally interact in human myofibroblasts and that a subset of these genes is cooperatively activated by TGFβ and PPARβ/δ. Using the angiopoietin-like 4 (ANGPTL4) gene as a model, we demonstrate that two enhancer regions cooperate to mediate the observed synergistic response. A TGFβ-responsive enhancer located ∼8 kb upstream of the transcriptional start site is regulated by a mechanism involving SMAD3, ETS1, RUNX, and AP-1 transcription factors that interact with multiple contiguous binding sites. A second enhancer (PPAR-E) consisting of three juxtaposed PPAR response elements is located in the third intron ∼3.5 kb downstream of the transcriptional start site. The PPAR-E is strongly activated by all three PPAR subtypes, with a novel type of PPAR response element motif playing a central role. Although the PPAR-E is not regulated by TGFβ, it interacts with SMAD3, ETS1, RUNX2, and AP-1 in vivo, providing a possible mechanistic explanation for the observed synergism. PMID:20595396

Identifying interactions between chemical entities in biomedical text.

PubMed

Lamurias, Andre; Ferreira, João D; Couto, Francisco M

2014-10-23

Interactions between chemical compounds described in biomedical text can be of great importance to drug discovery and design, as well as pharmacovigilance. We developed a novel system, \\"Identifying Interactions between Chemical Entities\\" (IICE), to identify chemical interactions described in text. Kernel-based Support Vector Machines first identify the interactions and then an ensemble classifier validates and classifies the type of each interaction. This relation extraction module was evaluated with the corpus released for the DDI Extraction task of SemEval 2013, obtaining results comparable to state-of-the-art methods for this type of task. We integrated this module with our chemical named entity recognition module and made the whole system available as a web tool at www.lasige.di.fc.ul.pt/webtools/iice.

Identifying interactions between chemical entities in biomedical text.

PubMed

Lamurias, Andre; Ferreira, João D; Couto, Francisco M

2014-12-01

Interactions between chemical compounds described in biomedical text can be of great importance to drug discovery and design, as well as pharmacovigilance. We developed a novel system, "Identifying Interactions between Chemical Entities" (IICE), to identify chemical interactions described in text. Kernel-based Support Vector Machines first identify the interactions and then an ensemble classifier validates and classifies the type of each interaction. This relation extraction module was evaluated with the corpus released for the DDI Extraction task of SemEval 2013, obtaining results comparable to stateof- the-art methods for this type of task. We integrated this module with our chemical named entity recognition module and made the whole system available as a web tool at www.lasige.di.fc.ul.pt/webtools/iice.

Tail and Kinase Modules Differently Regulate Core Mediator Recruitment and Function In Vivo.

PubMed

Jeronimo, Célia; Langelier, Marie-France; Bataille, Alain R; Pascal, John M; Pugh, B Franklin; Robert, François

2016-11-03

Mediator is a highly conserved transcriptional coactivator organized into four modules, namely Tail, Middle, Head, and Kinase (CKM). Previous work suggests regulatory roles for Tail and CKM, but an integrated model for these activities is lacking. Here, we analyzed the genome-wide distribution of Mediator subunits in wild-type and mutant yeast cells in which RNA polymerase II promoter escape is blocked, allowing detection of transient Mediator forms. We found that although all modules are recruited to upstream activated regions (UAS), assembly of Mediator within the pre-initiation complex is accompanied by the release of CKM. Interestingly, our data show that CKM regulates Mediator-UAS interaction rather than Mediator-promoter association. In addition, although Tail is required for Mediator recruitment to UAS, Tailless Mediator nevertheless interacts with core promoters. Collectively, our data suggest that the essential function of Mediator is mediated by Head and Middle at core promoters, while Tail and CKM play regulatory roles. Copyright © 2016 Elsevier Inc. All rights reserved.

Mechanistic analysis of the function of agonists and allosteric modulators: reconciling two-state and operational models

PubMed Central

Roche, David; Gil, Debora; Giraldo, Jesús

2013-01-01

Two-state and operational models of both agonism and allosterism are compared to identify and characterize common pharmacological parameters. To account for the receptor-dependent basal response, constitutive receptor activity is considered in the operational models. By arranging two-state models as the fraction of active receptors and operational models as the fractional response relative to the maximum effect of the system, a one-by-one correspondence between parameters is found. The comparative analysis allows a better understanding of complex allosteric interactions. In particular, the inclusion of constitutive receptor activity in the operational model of allosterism allows the characterization of modulators able to lower the basal response of the system; that is, allosteric modulators with negative intrinsic efficacy. Theoretical simulations and overall goodness of fit of the models to simulated data suggest that it is feasible to apply the models to experimental data and constitute one step forward in receptor theory formalism. Linked Articles Another recent review on allosteric modulation can be found at: Kenakin, T (2013). New concepts in pharmacological efficacy at 7TM receptors: IUPHAR Review 2. British Journal of Pharmacology 168: 554–575. doi: 10.1111/j.1476-5381.2012.02223.x And in this issue of BJP there is an article on a new allosteric modulator: Newman AS, Batis N, Grafton G, Caputo F, Brady CA, Lambert J, Peters JA, Gordon J, Brain KL, Powell AD and Barnes NM (2013). 5-Chloroindole: a potent allosteric modulator of the 5-HT3 receptor. British Journal of Pharmacology 169: 1228–1238. doi: 10.1111/bph.12213 PMID:23647200