Defining the Molecular Actions of Dietary Fatty Acids in Breast Cancer: Selective Modulation of Peroxisome Proliferator-Activated Receptor Gamma

DTIC Science & Technology

2005-05-01

Maximum 200 Words) Stark differences in the actions of lenoleic acid (LAA), an omega-6 fatty acid , and eicosapentaenoic acid (EPA), an omega-3 fatty acid ...AD_ Award Number: W81XWH-04-1-0532 TITLE: Defining the Molecular Actions of Dietary Fatty acids in Breast Cancer: Selective Modulation of Peroxisome...TITLE AND SUBTITLE 5. FUNDING NUMBERS Defining the Molecular Actions of Dietary Fatty acids in W81XWH-04-1-0532 Breast Cancer: Selective Modulation of

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.

Design and evaluation of a digital module with guided peer feedback for student learning biotechnology and molecular life sciences, attitudinal change, and satisfaction.

PubMed

Noroozi, Omid; Mulder, Martin

2017-01-02

This study aims to investigate the impacts of a digital learning module with guided peer feedback on students' domain-specific knowledge gain and their attitudinal change in the field of biotechnology and molecular life sciences. The extent to which the use of this module is appreciated by students is studied as well. A pre-test, post-test design was used with 203 students who were randomly assigned to groups of three. They were asked to work on the digital module with the aim of exploring various perspectives, and the "pros and cons" on the topic of "Genetically Modified Organisms (GMOs)." The results suggest that the module can be used to foster students' domain-specific knowledge gain and their attitudinal change. Furthermore, the module was evaluated positively in terms of students' motivation and satisfaction with the learning experiences. © 2016 by The International Union of Biochemistry and Molecular Biology, 45(1):31-39, 2017. © 2016 The International Union of Biochemistry and Molecular Biology.

Heritability and molecular genetic basis of acoustic startle eye blink and affectively modulated startle response: A genome-wide association study

PubMed Central

VAIDYANATHAN, UMA; MALONE, STEPHEN M.; MILLER, MICHAEL B.; McGUE, MATT; IACONO, WILLIAM G.

2014-01-01

Acoustic startle responses have been studied extensively in relation to individual differences and psychopathology. We examined three indices of the blink response in a picture-viewing paradigm—overall startle magnitude across all picture types, and aversive and pleasant modulation scores—in 3,323 twins and parents. Biometric models and molecular genetic analyses showed that half the variance in overall startle was due to additive genetic effects. No single nucleotide polymorphism was genome-wide significant, but GRIK3 did produce a significant effect when examined as part of a candidate gene set. In contrast, emotion modulation scores showed little evidence of heritability in either biometric or molecular genetic analyses. However, in a genome-wide scan, PARP14 did produce a significant effect for aversive modulation. We conclude that, although overall startle retains potential as an endophenotype, emotion-modulated startle does not. PMID:25387708

Dialkylthio Substitution: An Effective Method to Modulate the Molecular Energy Levels of 2D-BDT Photovoltaic Polymers.

PubMed

Yao, Huifeng; Zhang, Hao; Ye, Long; Zhao, Wenchao; Zhang, Shaoqing; Hou, Jianhui

2016-02-17

Dialkylthio-substituted thienyl-benzodithiophene (BDT-DST) was designed and synthesized as a building block to modulate the molecular levels of the conjugated polymers, and three copolymers named PDST-BDD, PDST-TT and PDST-DPP were prepared and applied in polymer solar cells (PSCs). Theoretical calculations and electrochemical cyclic voltammetry (CV) measurement suggested that the dialkylthio group could decrease the molecular energy levels of the resulting polymers distinctly. The open-circuit voltage (VOC) of PSC devices based on PDST-BDD, PDST-TT, and PDST-DPP are as high as 1.0, 0.98, and 0.88 V, respectively, which are ∼0.15 V higher than those of the corresponding alky-substituted analogues. Moreover, the influence of the dialkylthio group on the absorption spectra, crystalline properties, hole mobilities, and blend morphologies of the polymers was also investigated. The results indicate that the dialkythio substitution is an effective method to modulate the molecular energy levels and that the BDT-DST unit has potential for constructing high-efficiency photovoltaic polymers.

Polysaccharide of Black cumin (Nigella sativa) modulates molecular signaling cascade of gastric ulcer pathogenesis.

PubMed

Manjegowda, Srikanta Belagihalli; Rajagopal, Harsha Mysore; Dharmesh, Shylaja Mallaiah

2017-08-01

Gastric ulcer is a multi-step disease and healing requires a complex process including repair and re-architecture of gastric mucosa with the involvement of molecular events. Current study was designed to understand the gastric ulcer healing mechanism of rhamnogalacturonan-I type pectic polysaccharide of black cumin (BCPP) utilizing acetic acid induced gastric ulcers in rats. BCPP fed groups at 200mg/kg b.w. for 10days showed up to 85% healing of gastric ulcers with modulation of key molecular events involved in ulcer healing process such as increase in gastric mucin content, cyclooxygenase-2 (Cox-2) and prostaglandin E 2 (PGE 2 ). The increase in extracellular signal-regulated kinase-2 (ERK-2) indicated that, BCPP could induce PGE-2 synthesis by increasing ERK-2 mediated COX-2 activity. Increase in matrix metalloproteinase-2 (MMP-2) and decrease in MMP-9 levels in BCPP treated groups indicated differential regulation of MMP-2 and 9, an essential event required for gastric mucosal re-modulation. BCPP containing bound phenolics (26mg/g) might have also played a role in increasing speed and quality of ulcer healing by inhibiting H + , K + -ATPase and decreasing free radical mediated oxidation and cellular damages. Overall, studies showed that the polysaccharide can mediate ulcer healing by modulating signaling pathways involved in either ulcer aggravation or healing process. Copyright © 2017. Published by Elsevier B.V.

Recent advance in the design of small molecular modulators of estrogen-related receptors.

PubMed

Lu, Xiaoyun; Peng, Lijie; Lv, Man; ding, Ke

2012-01-01

The estrogen-related receptors (ERRs), comprising ERRα, ERRβ and ERRγ, are the members of the nuclear receptor superfamily, which have been functionally implicated in estrogen signal pathway in various patterns. However, no natural ligand of ERRs has been identified to data, so identification of the synthetic modulators (inverse agonist and agonist) of ERRs would be highly effective in the treatment of estrogen-related pathologies, such as diabetes, breast cancer and osteoporosis. This review summarizes the structures and biological functions of ERR subtypes, and the progress in designing the small molecular modulators of ERRs as well as the detailed description of available co-crystal structures of the LBD of ERRs in three distinct states: unligand, inverse agonist bound, and agonist bound.

Improved Student Linkage of Mendelian and Molecular Genetic Concepts through a Yeast-Based Laboratory Module

ERIC Educational Resources Information Center

Wolyniak, Michael J.

2013-01-01

A study of modern genetics requires students to successfully unite the principles of Mendelian genetics with the functions of DNA. Traditional means of teaching genetics are often successful in teaching Mendelian and molecular ideas but not in allowing students to see how the two subjects relate. The laboratory module presented here attempts to…

Localized spatially nonlinear matter waves in atomic-molecular Bose-Einstein condensates with space-modulated nonlinearity

PubMed Central

Yao, Yu-Qin; Li, Ji; Han, Wei; Wang, Deng-Shan; Liu, Wu-Ming

2016-01-01

The intrinsic nonlinearity is the most remarkable characteristic of the Bose-Einstein condensates (BECs) systems. Many studies have been done on atomic BECs with time- and space- modulated nonlinearities, while there is few work considering the atomic-molecular BECs with space-modulated nonlinearities. Here, we obtain two kinds of Jacobi elliptic solutions and a family of rational solutions of the atomic-molecular BECs with trapping potential and space-modulated nonlinearity and consider the effect of three-body interaction on the localized matter wave solutions. The topological properties of the localized nonlinear matter wave for no coupling are analysed: the parity of nonlinear matter wave functions depends only on the principal quantum number n, and the numbers of the density packets for each quantum state depend on both the principal quantum number n and the secondary quantum number l. When the coupling is not zero, the localized nonlinear matter waves given by the rational function, their topological properties are independent of the principal quantum number n, only depend on the secondary quantum number l. The Raman detuning and the chemical potential can change the number and the shape of the density packets. The stability of the Jacobi elliptic solutions depends on the principal quantum number n, while the stability of the rational solutions depends on the chemical potential and Raman detuning. PMID:27403634

Advances in molecular engineering of carbohydrate-binding modules.

PubMed

Armenta, Silvia; Moreno-Mendieta, Silvia; Sánchez-Cuapio, Zaira; Sánchez, Sergio; Rodríguez-Sanoja, Romina

2017-09-01

Carbohydrate-binding modules (CBMs) are non-catalytic domains that are generally appended to carbohydrate-active enzymes. CBMs have a broadly conserved structure that allows recognition of a notable variety of carbohydrates, in both their soluble and insoluble forms, as well as in their alpha and beta conformations and with different types of bonds or substitutions. This versatility suggests a high functional plasticity that is not yet clearly understood, in spite of the important number of studies relating protein structure and function. Several studies have explored the flexibility of these systems by changing or improving their specificity toward substrates of interest. In this review, we examine the molecular strategies used to identify CBMs with novel or improved characteristics. The impact of the spatial arrangement of the functional amino acids of CBMs is discussed in terms of unexpected new functions that are not related to the original biological roles of the enzymes. Proteins 2017; 85:1602-1617. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Application of mass spectrometry technologies for the discovery of low-molecular weight modulators of enzymes and protein-protein interactions.

PubMed

Zehender, Hartmut; Mayr, Lorenz M

2007-10-01

In recent years, mass spectrometry has gained widespread use as an assay and screening technology in drug discovery because it enables sensitive, label-free detection of low-molecular weight modulators of biomolecules as well as sensitive and accurate detection of high-molecular weight modifications of biomolecules. Electrospray and matrix-assisted laser desorption ionization are the most widely used ionization techniques to identify chemical compounds interfering with enzymatic function, receptor-ligand binding or molecules modulating a protein-protein interaction of interest. Mass spectrometry based techniques are no longer restricted to screening in biochemical assay systems but have now become also applicable to imaging of biomolecules and chemical compounds in cell-based assay systems and even in highly complex tissue sections.

Markov-modulated Markov chains and the covarion process of molecular evolution.

PubMed

Galtier, N; Jean-Marie, A

2004-01-01

The covarion (or site specific rate variation, SSRV) process of biological sequence evolution is a process by which the evolutionary rate of a nucleotide/amino acid/codon position can change in time. In this paper, we introduce time-continuous, space-discrete, Markov-modulated Markov chains as a model for representing SSRV processes, generalizing existing theory to any model of rate change. We propose a fast algorithm for diagonalizing the generator matrix of relevant Markov-modulated Markov processes. This algorithm makes phylogeny likelihood calculation tractable even for a large number of rate classes and a large number of states, so that SSRV models become applicable to amino acid or codon sequence datasets. Using this algorithm, we investigate the accuracy of the discrete approximation to the Gamma distribution of evolutionary rates, widely used in molecular phylogeny. We show that a relatively large number of classes is required to achieve accurate approximation of the exact likelihood when the number of analyzed sequences exceeds 20, both under the SSRV and among site rate variation (ASRV) models.

The Potential Role of Aerobic Exercise to Modulate Cardiotoxicity of Molecularly Targeted Cancer Therapeutics

PubMed Central

Lakoski, Susan; Mackey, John R.; Douglas, Pamela S.; Haykowsky, Mark J.; Jones, Lee W.

2013-01-01

Molecularly targeted therapeutics (MTT) are the future of cancer systemic therapy. They have already moved from palliative therapy for advanced solid malignancies into the setting of curative-intent treatment for early-stage disease. Cardiotoxicity is a frequent and potentially serious adverse complication of some targeted therapies, leading to a broad range of potentially life-threatening complications, therapy discontinuation, and poor quality of life. Low-cost pleiotropic interventions are therefore urgently required to effectively prevent and/or treat MTT-induced cardiotoxicity. Aerobic exercise therapy has the unique capacity to modulate, without toxicity, multiple gene expression pathways in several organ systems, including a plethora of cardiac-specific molecular and cell-signaling pathways implicated in MTT-induced cardiac toxicity. In this review, we examine the molecular signaling of antiangiogenic and HER2-directed therapies that may underpin cardiac toxicity and the hypothesized molecular mechanisms underlying the cardioprotective properties of aerobic exercise. It is hoped that this knowledge can be used to maximize the benefits of small molecule inhibitors, while minimizing cardiac damage in patients with solid malignancies. PMID:23335619

Molecular modeling on structure-function analysis of human progesterone receptor modulators.

PubMed

Pal, Ria; Islam, Md Ataul; Hossain, Tabassum; Saha, Achintya

2011-01-01

Considering the significance of progesterone receptor (PR) modulators, the present study is explored to envisage the biophoric signals for binding to selective PR subtype-A using ligand-based quantitative structure activity relationship (QSAR) and pharmacophore space modeling studies on nonsteroidal substituted quinoline and cyclocymopol monomethyl ether derivatives. Consensus QSAR models (Training set (Tr): n(Tr)=100, R(2) (pred)=0.702; test set (Ts): n(Ts)=30, R(2) (pred)=0.705, R(2) (m)=0.635; validation set (Vs): n(Vs)=40, R(2) (pred)=0.715, R(2) (m)=0.680) suggest that molecular topology, atomic polarizability and electronegativity, atomic mass and van der Waals volume of the ligands have influence on the presence of functional atoms (F, Cl, N and O) and consequently contribute significant relations on ligand binding affinity. Receptor independent space modeling study (Tr: n(Tr)=26, Q(2)=0.927; Ts: n(Ts)=60, R(2) (pred)=0.613, R(2) (m)=0.545; Vs: n(Vs)=84, R(2) (pred)=0.611, R(2) (m)=0.507) indicates the importance of aromatic ring, hydrogen bond donor, molecular hydrophobicity and steric influence for receptor binding. The structure-function characterization is adjudged with the receptor-based docking study, explaining the significance of the mapped molecular attributes for ligand-receptor interaction in the catalytic cleft of PR-A.

Modulation of Molecular Flux Using a Graphene Nanopore Capacitor.

PubMed

Shankla, Manish; Aksimentiev, Aleksei

2017-04-20

Modulation of ionic current flowing through nanoscale pores is one of the fundamental biological processes. Inspired by nature, nanopores in synthetic solid-state membranes are being developed to enable rapid analysis of biological macromolecules and to serve as elements of nanofludic circuits. Here, we theoretically investigate ion and water transport through a graphene-insulator-graphene membrane containing a single, electrolyte-filled nanopore. By means of all-atom molecular dynamics simulations, we show that the charge state of such a graphene nanopore capacitor can regulate both the selectivity and the magnitude of the nanopore ionic current. At a fixed transmembrane bias, the ionic current can be switched from being carried by an equal mixture of cations and anions to being carried almost exclusively by either cationic or anionic species, depending on the sign of the charge assigned to both plates of the capacitor. Assigning the plates of the capacitor opposite sign charges can either increase the nanopore current or reduce it substantially, depending on the polarity of the bias driving the transmembrane current. Facilitated by the changes of the nanopore surface charge, such ionic current modulations are found to occur despite the physical dimensions of the nanopore being an order of magnitude larger than the screening length of the electrolyte. The ionic current rectification is accompanied by a pronounced electro-osmotic effect that can transport neutral molecules such as proteins and drugs across the solid-state membrane and thereby serve as an interface between electronic and chemical signals.

Oligomerization of a molecular chaperone modulates its activity

PubMed Central

Kawagoe, Soichiro; Ishimori, Koichiro

2018-01-01

Molecular chaperones alter the folding properties of cellular proteins via mechanisms that are not well understood. Here, we show that Trigger Factor (TF), an ATP-independent chaperone, exerts strikingly contrasting effects on the folding of non-native proteins as it transitions between a monomeric and a dimeric state. We used NMR spectroscopy to determine the atomic resolution structure of the 100 kDa dimeric TF. The structural data show that some of the substrate-binding sites are buried in the dimeric interface, explaining the lower affinity for protein substrates of the dimeric compared to the monomeric TF. Surprisingly, the dimeric TF associates faster with proteins and it exhibits stronger anti-aggregation and holdase activity than the monomeric TF. The structural data show that the dimer assembles in a way that substrate-binding sites in the two subunits form a large contiguous surface inside a cavity, thus accounting for the observed accelerated association with unfolded proteins. Our results demonstrate how the activity of a chaperone can be modulated to provide distinct functional outcomes in the cell. PMID:29714686

A Module Analysis Approach to Investigate Molecular Mechanism of TCM Formula: A Trial on Shu-feng-jie-du Formula

PubMed Central

Zhang, Fangbo; Tang, Shihuan; Liu, Xi; Gao, Yibo; Wang, Yanping

2013-01-01

At the molecular level, it is acknowledged that a TCM formula is often a complex system, which challenges researchers to fully understand its underlying pharmacological action. However, module detection technique developed from complex network provides new insight into systematic investigation of the mode of action of a TCM formula from the molecule perspective. We here proposed a computational approach integrating the module detection technique into a 2-class heterogeneous network (2-HN) which models the complex pharmacological system of a TCM formula. This approach takes three steps: construction of a 2-HN, identification of primary pharmacological units, and pathway analysis. We employed this approach to study Shu-feng-jie-du (SHU) formula, which aimed at discovering its molecular mechanism in defending against influenza infection. Actually, four primary pharmacological units were identified from the 2-HN for SHU formula and further analysis revealed numbers of biological pathways modulated by the four pharmacological units. 24 out of 40 enriched pathways that were ranked in top 10 corresponding to each of the four pharmacological units were found to be involved in the process of influenza infection. Therefore, this approach is capable of uncovering the mode of action underlying a TCM formula via module analysis. PMID:24376467

Molecular Correlates of Cortical Network Modulation by Long-Term Sensory Experience in the Adult Rat Barrel Cortex

ERIC Educational Resources Information Center

Vallès, Astrid; Granic, Ivica; De Weerd, Peter; Martens, Gerard J. M.

2014-01-01

Modulation of cortical network connectivity is crucial for an adaptive response to experience. In the rat barrel cortex, long-term sensory stimulation induces cortical network modifications and neuronal response changes of which the molecular basis is unknown. Here, we show that long-term somatosensory stimulation by enriched environment…

Molecular interference of fibrin’s divalent polymerization mechanism enables modulation of multiscale material properties

PubMed Central

Brown, Ashley C.; Baker, Stephen; Douglas, Alison; Keating, Mark; Alvarez-Elizondo, Martha; Botvinick, Elliot; Guthold, Martin; Barker, Thomas H.

2015-01-01

Protein based polymers provide an exciting and complex landscape for tunable natural biomaterials through modulation of molecular level interactions. Here we demonstrate the ability to modify protein polymer structural and mechanical properties at multiple length scales by molecular ‘interference’ of fibrin’s native polymerization mechanism. We have previously reported that engagement of fibrin’s polymerization ‘hole b’, also known as ‘b-pockets’, through PEGylated complimentary ‘knob B’ mimics can increase fibrin network porosity but also, somewhat paradoxically, increase network stiffness. Here, we explore the possible mechanistic underpinning of this phenomenon through characterization of the effects of knob B-fibrin interaction at multiple length scales from molecular to bulk polymer. Despite its weak monovalent binding affinity for fibrin, addition of both knob B and PEGylated knob B at concentrations near the binding coefficient, Kd, increased fibrin network porosity, consistent with the reported role of knob B-hole b interactions in promoting lateral growth of fibrin fibers. Addition of PEGylated knob B decreases the extensibility of single fibrin fibers at concentrations near its Kd but increases extensibility of fibers at concentrations above its Kd. The data suggest this bimodal behavior is due to the individual contributions knob B, which decreases fiber extensibility, and PEG, which increase fiber extensibility. Taken together with laser trap-based microrheological and bulk rheological analyses of fibrin polymers, our data strongly suggests that hole b engagement increases in single fiber stiffness that translates to higher storage moduli of fibrin polymers despite their increased porosity. These data point to possible strategies for tuning fibrin polymer mechanical properties through modulation of single fiber mechanics. PMID:25725552

Synergistic effect of fluorination on molecular energy level modulation in highly efficient photovoltaic polymers.

PubMed

Zhang, Maojie; Guo, Xia; Zhang, Shaoqing; Hou, Jianhui

2014-02-01

The synergistic effect of fluorination on molecular energy level modulation is realized by introducing fluorine atoms onto both the donor and the acceptor moieties in a D-A polymer, and as a result, the polymer solar cell device based on the trifluorinated polymer, PBT-3F, shows a high efficiency of 8.6%, under illumination of AM 1.5G, 100 mW cm(-) (2) . © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

GABAB Receptor Positive Modulation Decreases Selective Molecular and Behavioral Effects of Cocaine

PubMed Central

Lhuillier, Loic; Mombereau, Cedric; Cryan, John F.; Kaupmann, Klemens

2006-01-01

Exposure to cocaine induces selective behavioral and molecular adaptations. In rodents, acute cocaine induces increased locomotor activity whereas prolonged drug exposure results in behavioral locomotor sensitization, which is thought to be a consequence of drug–induced neuroadaptive changes. Recent attention has been given to compounds activating GABAB receptors as potential anti-addictive therapies. In particular the principle of allosteric positive GABAB receptor modulators is very promising in this respect, as positive modulators lack the sedative and muscle relaxant properties of full GABAB receptor agonists such as baclofen. Here we investigated the effects of systemic application of the GABAB receptor positive modulator GS39783 in animals treated with acute and chronic cocaine administration. Both GS39783 and baclofen dose-dependently attenuated acute cocaine-induced hyperlocomotion. Furthermore, both compounds also efficiently blocked cocaine-induced Fos induction in the striatal complex. In chronic studies GS39783 induced a modest attenuation of cocaine-induced locomotor sensitization. Chronic cocaine induces the accumulation of the transcription factor ΔFosB and up regulates cAMP-response-element-binding-protein (CREB) and dopamine-and-cAMP-regulated-phosphoprotein of 32 kd (DARPP-32). GS39783 blocked the induction/activation of DARPP-32 and CREB in the nucleus accumbens and dorsal striatum and partially inhibited ΔFosB accumulation in the dorsal striatum. In summary our data provide evidence that GS39783 attenuates the acute behavioral effects of cocaine exposure in rodents and in addition prevents the induction of selective long-term adaptive changes in dopaminergic signaling pathways. Further investigation of GABAB receptor positive modulation as a novel therapeutic strategy for the treatment of cocaine dependence and possibly other drugs of abuse is therefore warranted. PMID:16710312

Thermally modulated nano-trampoline material as smart skin for gas molecular mass detection

NASA Astrophysics Data System (ADS)

Xia, Hua

2012-06-01

Conventional multi-component gas analysis is based either on laser spectroscopy, laser and photoacoustic absorption at specific wavelengths, or on gas chromatography by separating the components of a gas mixture primarily due to boiling point (or vapor pressure) differences. This paper will present a new gas molecular mass detection method based on thermally modulated nano-trampoline material as smart skin for gas molecular mass detection by fiber Bragg grating-based gas sensors. Such a nanomaterial and fiber Bragg grating integrated sensing device has been designed to be operated either at high-energy level (highly thermal strained status) or at low-energy level (low thermal strained status). Thermal energy absorption of gas molecular trigs the sensing device transition from high-thermal-energy status to low-thermal- energy status. Experiment has shown that thermal energy variation due to gas molecular thermal energy absorption is dependent upon the gas molecular mass, and can be detected by fiber Bragg resonant wavelength shift with a linear function from 17 kg/kmol to 32 kg/kmol and a sensitivity of 0.025 kg/kmol for a 5 micron-thick nano-trampoline structure and fiber Bragg grating integrated gas sensing device. The laboratory and field validation data have further demonstrated its fast response characteristics and reliability to be online gas analysis instrument for measuring effective gas molecular mass from single-component gas, binary-component gas mixture, and multi-gas mixture. The potential industrial applications include fouling and surge control for gas charge centrifugal compressor ethylene production, gas purity for hydrogen-cooled generator, gasification for syngas production, gasoline/diesel and natural gas fuel quality monitoring for consumer market.

Gene modules associated with breast cancer distant metastasis-free survival in the PAM50 molecular subtypes.

PubMed

Liu, Rong; Zhang, Wei; Liu, Zhao-Qian; Zhou, Hong-Hao

2016-04-19

To identify PAM50 subtype-specific associations between distant metastasis-free survival (DMFS) in breast cancer (BC) patients and gene modules describing potentially targetable oncogenic pathways, a comprehensive analysis evaluating the prognostic efficacy of published gene signatures in 2027 BC patients from 13 studies was conducted. We calculated 21 gene modules and computed hazard ratios (HRs) for DMFS for one-unit increases in module score, with and without adjustment for clinical characteristics. By comparing gene expression to survival outcomes, we derived four subtype-specific prognostic signatures for BC. Univariate and multivariate analyses showed that in the luminal A subgroup, E2F3, PTEN and GGI gene module scores were associated with clinical outcome. In the luminal B tumors, RAS was associated with DMFS and in the basal-like tumors, ER was associated with DMFS. Our defined gene modules predicted high-risk patients in multivariate analyses for the basal-like (HR: 2.19, p=2.5×10-4), luminal A (HR: 3.03, p=7.2×10-5), luminal B (HR: 3.00, p=2.4×10-10) and HER2+ (HR: 5.49, p=9.7×10-10) subgroups. We found that different modules are associated with DMFS in different BC subtypes. The results of this study could help to identify new therapeutic strategies for specific molecular subgroups of BC, and could enhance efforts to improve patient-specific therapy options.

Atmospheric pressure plasma analysis by modulated molecular beam mass spectrometry

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

Aranda Gonzalvo, Y.; Whitmore, T.D.; Rees, J.A.

Fractional number density measurements for a rf plasma 'needle' operating at atmospheric pressure have been obtained using a molecular beam mass spectrometer (MBMS) system designed for diagnostics of atmospheric plasmas. The MBMS system comprises three differentially pumped stages and a mass/energy analyzer and includes an automated beam-to-background measurement facility in the form of a software-controlled chopper mechanism. The automation of the beam modulation allows the neutral components in the plasma to be rapidly and accurately measured using the mass spectrometer by threshold ionization techniques. Data are reported for plasma generated by a needle plasma source operated using a helium/air mixture.more » In particular, data for the conversion of atmospheric oxygen and nitrogen into nitric oxide are discussed with reference to its significance for medical applications such as disinfecting wounds and dental cavities and for microsurgery.« less

Molecular Basis for Modulation of Metabotropic Glutamate Receptors and Their Drug Actions by Extracellular Ca2+

PubMed Central

Zou, Juan; Jiang, Jason Y.; Yang, Jenny J.

2017-01-01

Metabotropic glutamate receptors (mGluRs) associated with the slow phase of the glutamatergic signaling pathway in neurons of the central nervous system have gained importance as drug targets for chronic neurodegenerative diseases. While extracellular Ca2+ was reported to exhibit direct activation and modulation via an allosteric site, the identification of those binding sites was challenged by weak binding. Herein, we review the discovery of extracellular Ca2+ in regulation of mGluRs, summarize the recent developments in probing Ca2+ binding and its co-regulation of the receptor based on structural and biochemical analysis, and discuss the molecular basis for Ca2+ to regulate various classes of drug action as well as its importance as an allosteric modulator in mGluRs. PMID:28335551

Design and Evaluation of a Digital Module with Guided Peer Feedback for Student Learning Biotechnology and Molecular Life Sciences, Attitudinal Change, and Satisfaction

ERIC Educational Resources Information Center

Noroozi, Omid; Mulder, Martin

2017-01-01

This study aims to investigate the impacts of a digital learning module with guided peer feedback on students' domain-specific knowledge gain and their attitudinal change in the field of biotechnology and molecular life sciences. The extent to which the use of this module is appreciated by students is studied as well. A pre-test, post-test design…

Frequency modulation spectroscopy with a THz quantum-cascade laser.

PubMed

Eichholz, R; Richter, H; Wienold, M; Schrottke, L; Hey, R; Grahn, H T; Hübers, H-W

2013-12-30

We report on a terahertz spectrometer for high-resolution molecular spectroscopy based on a quantum-cascade laser. High-frequency modulation (up to 50 MHz) of the laser driving current produces a simultaneous modulation of the frequency and amplitude of the laser output. The modulation generates sidebands, which are symmetrically positioned with respect to the laser carrier frequency. The molecular transition is probed by scanning the sidebands across it. In this way, the absorption and the dispersion caused by the molecular transition are measured. The signals are modeled by taking into account the simultaneous modulation of the frequency and amplitude of the laser emission. This allows for the determination of the strength of the frequency as well as amplitude modulation of the laser and of molecular parameters such as pressure broadening.

Molecular physiology and modulation of somatodendritic A-type potassium channels.

PubMed

Jerng, Henry H; Pfaffinger, Paul J; Covarrubias, Manuel

2004-12-01

The somatodendritic subthreshold A-type K+ current (ISA) in nerve cells is a critical component of the ensemble of voltage-gated ionic currents that determine somatodendritic signal integration. The underlying K+ channel belongs to the Shal subfamily of voltage-gated K+ channels. Most Shal channels across the animal kingdom share a high degree of structural conservation, operate in the subthreshold range of membrane potentials, and exhibit relatively fast inactivation and recovery from inactivation. Mammalian Shal K+ channels (Kv4) undergo preferential closed-state inactivation with features that are generally inconsistent with the classical mechanisms of inactivation typical of Shaker K+ channels. Here, we review (1) the physiological and genetic properties of ISA, 2 the molecular mechanisms of Kv4 inactivation and its remodeling by a family of soluble calcium-binding proteins (KChIPs) and a membrane-bound dipeptidase-like protein (DPPX), and (3) the modulation of Kv4 channels by protein phosphorylation.

Selective Modulators of PPAR-γ Activity: Molecular Aspects Related to Obesity and Side-Effects

PubMed Central

Zhang, Fang; Lavan, Brian E.; Gregoire, Francine M.

2007-01-01

Peroxisome proliferator-activated receptor γ (PPAR-γ) is a key regulator of lipid metabolism and energy balance implicated in the development of insulin resistance and obesity. The identification of putative natural and synthetic ligands and activators of PPAR-γ has helped to unravel the molecular basis of its function, including molecular details regarding ligand binding, conformational changes of the receptor, and cofactor binding, leading to the emergence of the concept of selective PPAR-γ modulators (SPPARγMs). SPPARγMs bind in distinct manners to the ligand-binding pocket of PPAR-γ, leading to alternative receptor conformations, differential cofactor recruitment/displacement, differential gene expression, and ultimately differential biological responses. Based on this concept, new and improved antidiabetic agents for the treatment of diabetes are in development. This review summarizes the current knowledge on the mechanism of action and biological effects of recently characterized SPPARγMs, including metaglidasen/halofenate, PA-082, and the angiotensin receptor antagonists, recently characterized as a new class of SPPARγMs. PMID:17389769

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.

A molecular beam/quadrupole mass spectrometer system with synchronized beam modulation and digital waveform analysis

NASA Technical Reports Server (NTRS)

Pellett, G. L.; Adams, B. R.

1983-01-01

A performance evaluation is conducted for a molecular beam/mass spectrometer (MB/MS) system, as applied to a 1-30 torr microwave-discharge flow reactor (MWFR) used in the formation of the methylperoxy radical and a study of its subsequent destruction in the presence or absence of NO(x). The modulated MB/MS system is four-staged and differentially pumped. The results obtained by the MWFR study is illustrative of overall system performance, including digital waveform analysis; significant improvements over previous designs are noted in attainable S/N ratio, detection limit, and accuracy.

Magnetomotive Molecular Nanoprobes

PubMed Central

John, Renu; Boppart, Stephen A.

2012-01-01

Tremendous developments in the field of biomedical imaging in the past two decades have resulted in the transformation of anatomical imaging to molecular-specific imaging. The main approaches towards imaging at a molecular level are the development of high resolution imaging modalities with high penetration depths and increased sensitivity, and the development of molecular probes with high specificity. The development of novel molecular contrast agents and their success in molecular optical imaging modalities have lead to the emergence of molecular optical imaging as a more versatile and capable technique for providing morphological, spatial, and functional information at the molecular level with high sensitivity and precision, compared to other imaging modalities. In this review, we discuss a new class of dynamic contrast agents called magnetomotive molecular nanoprobes for molecular-specific imaging. Magnetomotive agents are superparamagnetic nanoparticles, typically iron-oxide, that are physically displaced by the application of a small modulating external magnetic field. Dynamic phase-sensitive position measurements are performed using any high resolution imaging modality, including optical coherence tomography (OCT), ultrasonography, or magnetic resonance imaging (MRI). The dynamics of the magnetomotive agents can be used to extract the biomechanical tissue properties in which the nanoparticles are bound, and the agents can be used to deliver therapy via magnetomotive displacements to modulate or disrupt cell function, or hyperthermia to kill cells. These agents can be targeted via conjugation to antibodies, and in vivo targeted imaging has been shown in a carcinogen-induced rat mammary tumor model. The iron-oxide nanoparticles also exhibit negative T2 contrast in MRI, and modulations can produce ultrasound imaging contrast for multimodal imaging applications. PMID:21517766

Molecular Dynamics Simulations of Voltage-Gated Cation Channels: Insights on Voltage-Sensor Domain Function and Modulation

PubMed Central

Delemotte, Lucie; Klein, Michael L.; Tarek, Mounir

2012-01-01

Since their discovery in the 1950s, the structure and function of voltage-gated cation channels (VGCC) has been largely understood thanks to results stemming from electrophysiology, pharmacology, spectroscopy, and structural biology. Over the past decade, computational methods such as molecular dynamics (MD) simulations have also contributed, providing molecular level information that can be tested against experimental results, thereby allowing the validation of the models and protocols. Importantly, MD can shed light on elements of VGCC function that cannot be easily accessed through “classical” experiments. Here, we review the results of recent MD simulations addressing key questions that pertain to the function and modulation of the VGCC’s voltage-sensor domain (VSD) highlighting: (1) the movement of the S4-helix basic residues during channel activation, articulating how the electrical driving force acts upon them; (2) the nature of the VSD intermediate states on transitioning between open and closed states of the VGCC; and (3) the molecular level effects on the VSD arising from mutations of specific S4 positively charged residues involved in certain genetic diseases. PMID:22654756

A high pressure modulated molecular beam mass spectrometric sampling system

NASA Technical Reports Server (NTRS)

Stearns, C. A.; Kohl, F. J.; Fryburg, G. C.; Miller, R. A.

1977-01-01

The current state of understanding of free-jet high pressure sampling is critically reviewed and modifications of certain theoretical and empirical considerations are presented. A high pressure, free-jet expansion, modulated molecular beam, mass spectrometric sampling apparatus was constructed and this apparatus is described in detail. Experimental studies have demonstrated that the apparatus can be used to sample high temperature systems at pressures up to one atmosphere. Condensible high temperature gaseous species have been routinely sampled and the mass spectrometric detector has provided direct identification of sampled species. System sensitivity is better than one tenth of a part per million. Experimental results obtained with argon and nitrogen beams are presented and compared to theoretical predictions. These results and the respective comparison are taken to indicate acceptable performance of the sampling apparatus. Results are also given for two groups of experiments related to hot corrosion studies. The formation of gaseous sodium sulfate in doped methane-oxygen flames was characterized and the oxidative vaporization of metals was studied in an atmospheric pressure flowing gas system to which gaseous salt partial pressures were added.

Understanding allosteric interactions in G protein-coupled receptors using Supervised Molecular Dynamics: A prototype study analysing the human A3 adenosine receptor positive allosteric modulator LUF6000.

PubMed

Deganutti, Giuseppe; Cuzzolin, Alberto; Ciancetta, Antonella; Moro, Stefano

2015-07-15

The search for G protein-coupled receptors (GPCRs) allosteric modulators represents an active research field in medicinal chemistry. Allosteric modulators usually exert their activity only in the presence of the orthosteric ligand by binding to protein sites topographically different from the orthosteric cleft. They therefore offer potentially therapeutic advantages by selectively influencing tissue responses only when the endogenous agonist is present. The prediction of putative allosteric site location, however, is a challenging task. In facts, they are usually located in regions showing more structural variation among the family members. In the present work, we applied the recently developed Supervised Molecular Dynamics (SuMD) methodology to interpret at the molecular level the positive allosteric modulation mediated by LUF6000 toward the human adenosine A3 receptor (hA3 AR). Our data suggest at least two possible mechanisms to explain the experimental data available. This study represent, to the best of our knowledge, the first case reported of an allosteric recognition mechanism depicted by means of molecular dynamics simulations. Copyright © 2015 Elsevier Ltd. All rights reserved.

Serum-free culture success of glial tumors is related to specific molecular profiles and expression of extracellular matrix–associated gene modules

PubMed Central

Balvers, Rutger K.; Kleijn, Anne; Kloezeman, Jenneke J.; French, Pim J.; Kremer, Andreas; van den Bent, Martin J.; Dirven, Clemens M. F.; Leenstra, Sieger; Lamfers, Martine L. M.

2013-01-01

Background Recent molecular characterization studies have identified clinically relevant molecular subtypes to coexist within the same histological entities of glioma. Comparative studies between serum-supplemented and serum-free (SF) culture conditions have demonstrated that SF conditions select for glioma stem-like cells, which superiorly conserve genomic alterations. However, neither the representation of molecular subtypes within SF culture assays nor the molecular distinctions between successful and nonsuccessful attempts have been elucidated. Methods A cohort of 261 glioma samples from varying histological grades was documented for SF culture success and clinical outcome. Gene expression and single nucleotide polymorphism arrays were interrogated on a panel of tumors for comparative analysis of SF+ (successful cultures) and SF− (unsuccessful cultures). Results SF culture outcome was correlated with tumor grade, while no relation was found between SF+ and patient overall survival. Copy number–based hierarchical clustering revealed an absolute separation between SF+ and SF− parental tumors. All SF+ cultures are derived from tumors that are isocitrate dehydrogenase 1 (IDH1) wild type, chromosome 7 amplified, and chromosome 10q deleted. SF− cultures derived from IDH1 mutant tumors demonstrated a fade-out of mutated cells during the first passages. SF+ tumors were enriched for The Cancer Genome Atlas Classical subtype and intrinsic glioma subtype-18. Comparative gene ontology analysis between SF+ and SF− tumors demonstrated enrichment for modules associated with extracellular matrix composition, Hox-gene signaling, and inflammation. Conclusion SF cultures are derived from a subset of parental tumors with a shared molecular background including enrichment for extracellular matrix–associated gene modules. These results provide leads to develop enhanced culture protocols for glioma samples not propagatable under current SF conditions. PMID:24046260

Metabotropic glutamate receptor subtype 5: molecular pharmacology, allosteric modulation and stimulus bias

PubMed Central

Sengmany, K

2015-01-01

The metabotropic glutamate receptor subtype 5 (mGlu5) is a family C GPCR that has been implicated in various neuronal processes and, consequently, in several CNS disorders. Over the past few decades, GPCR‐based drug discovery, including that for mGlu5 receptors, has turned considerable attention to targeting allosteric binding sites. Modulation of endogenous agonists by allosteric ligands offers the advantages of spatial and temporal fine‐tuning of receptor activity, increased selectivity and reduced adverse effects with the potential to elicit improved clinical outcomes. Further, with greater appreciation of the multifaceted nature of the transduction of mGlu5 receptor signalling, it is increasingly apparent that drug discovery must take into consideration unique receptor conformations and the potential for stimulus‐bias. This novel paradigm proposes that different ligands may differentially modulate distinct signalling pathways arising from the same receptor. We review our current understanding of the complexities of mGlu5 receptor signalling and regulation, and how these relate to allosteric ligands. Ultimately, a deeper appreciation of these relationships will provide the foundation for targeted drug design of compounds with increased selectivity, not only for the desired receptor but also for the desired signalling outcome from the receptor. Linked Articles This article is part of a themed section on Molecular Pharmacology of G Protein‐Coupled Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v173.20/issuetoc PMID:26276909

Motifs, modules and games in bacteria.

PubMed

Wolf, Denise M; Arkin, Adam P

2003-04-01

Global explorations of regulatory network dynamics, organization and evolution have become tractable thanks to high-throughput sequencing and molecular measurement of bacterial physiology. From these, a nascent conceptual framework is developing, that views the principles of regulation in term of motifs, modules and games. Motifs are small, repeated, and conserved biological units ranging from molecular domains to small reaction networks. They are arranged into functional modules, genetically dissectible cellular functions such as the cell cycle, or different stress responses. The dynamical functioning of modules defines the organism's strategy to survive in a game, pitting cell against cell, and cell against environment. Placing pathway structure and dynamics into an evolutionary context begins to allow discrimination between those physical and molecular features that particularize a species to its surroundings, and those that provide core physiological function. This approach promises to generate a higher level understanding of cellular design, pathway evolution and cellular bioengineering.

Molecular Mechanism of Action for Allosteric Modulators and Agonists in CC-chemokine Receptor 5 (CCR5).

PubMed

Karlshøj, Stefanie; Amarandi, Roxana Maria; Larsen, Olav; Daugvilaite, Viktorija; Steen, Anne; Brvar, Matjaž; Pui, Aurel; Frimurer, Thomas Michael; Ulven, Trond; Rosenkilde, Mette Marie

2016-12-23

The small molecule metal ion chelators bipyridine and terpyridine complexed with Zn 2+ (ZnBip and ZnTerp) act as CCR5 agonists and strong positive allosteric modulators of CCL3 binding to CCR5, weak modulators of CCL4 binding, and competitors for CCL5 binding. Here we describe their binding site using computational modeling, binding, and functional studies on WT and mutated CCR5. The metal ion Zn 2+ is anchored to the chemokine receptor-conserved Glu-283 VII:06/7.39 Both chelators interact with aromatic residues in the transmembrane receptor domain. The additional pyridine ring of ZnTerp binds deeply in the major binding pocket and, in contrast to ZnBip, interacts directly with the Trp-248 VI:13/6.48 microswitch, contributing to its 8-fold higher potency. The impact of Trp-248 was further confirmed by ZnClTerp, a chloro-substituted version of ZnTerp that showed no inherent agonism but maintained positive allosteric modulation of CCL3 binding. Despite a similar overall binding mode of all three metal ion chelator complexes, the pyridine ring of ZnClTerp blocks the conformational switch of Trp-248 required for receptor activation, thereby explaining its lack of activity. Importantly, ZnClTerp becomes agonist to the same extent as ZnTerp upon Ala mutation of Ile-116 III:16/3.40 , a residue that constrains the Trp-248 microswitch in its inactive conformation. Binding studies with 125 I-CCL3 revealed an allosteric interface between the chemokine and the small molecule binding site, including residues Tyr-37 I:07/1.39 , Trp-86 II:20/2.60 , and Phe-109 III:09/3.33 The small molecules and CCL3 approach this interface from opposite directions, with some residues being mutually exploited. This study provides new insight into the molecular mechanism of CCR5 activation and paves the way for future allosteric drugs for chemokine receptors. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

The Application of Ligand-Mapping Molecular Dynamics Simulations to the Rational Design of Peptidic Modulators of Protein-Protein Interactions.

PubMed

Tan, Yaw Sing; Spring, David R; Abell, Chris; Verma, Chandra S

2015-07-14

A computational ligand-mapping approach to detect protein surface pockets that interact with hydrophobic moieties is presented. In this method, we incorporated benzene molecules into explicit solvent molecular dynamics simulations of various protein targets. The benzene molecules successfully identified the binding locations of hydrophobic hot-spot residues and all-hydrocarbon cross-links from known peptidic ligands. They also unveiled cryptic binding sites that are occluded by side chains and the protein backbone. Our results demonstrate that ligand-mapping molecular dynamics simulations hold immense promise to guide the rational design of peptidic modulators of protein-protein interactions, including that of stapled peptides, which show promise as an exciting new class of cell-penetrating therapeutic molecules.

Translational PK-PD modelling of molecular target modulation for the AMPA receptor positive allosteric modulator Org 26576.

PubMed

Bursi, Roberta; Erdemli, Gul; Campbell, Robert; Hutmacher, Matthew M; Kerbusch, Thomas; Spanswick, David; Jeggo, Ross; Nations, Kari R; Dogterom, Peter; Schipper, Jacques; Shahid, Mohammed

2011-12-01

The α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor potentiator Org 26576 represents an interesting pharmacological tool to evaluate the utility of glutamatergic enhancement towards the treatment of psychiatric disorders. In this study, a rat-human translational pharmacokinetic-pharmacodynamic (PK-PD) model of AMPA receptor modulation was used to predict human target engagement and inform dose selection in efficacy clinical trials. Modelling and simulation was applied to rat plasma and cerebrospinal fluid (CSF) pharmacokinetic and pharmacodynamic measurements to identify a target concentration (EC(80)) for AMPA receptor modulation. Human plasma pharmacokinetics was determined from 33 healthy volunteers and eight major depressive disorder patients. From four out of these eight patients, CSF PK was also determined. Simulations of human CSF levels were performed for several doses of Org 26576. Org 26576 (0.1-10 mg/kg, i.v.) potentiated rat hippocampal AMPA receptor responses in an exposure-dependant manner. The rat plasma and CSF PK data were fitted by one-compartment model each. The rat CSF PK-PD model yielded an EC(80) value of 593 ng/ml (90% confidence interval 406.8, 1,264.1). The human plasma and CSF PK data were simultaneously well described by a two-compartment model. Simulations showed that in humans at 100 mg QD, CSF levels of Org 26576 would exceed the EC(80) target concentration for about 2 h and that 400 mg BID would engage AMPA receptors for 24 h. The modelling approach provided useful insight on the likely human dose-molecular target engagement relationship for Org 26576. Based on the current analysis, 100 and 400 mg BID would be suitable to provide 'phasic' and 'continuous' AMPA receptor engagement, respectively.

Motifs, modules and games in bacteria

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

Wolf, Denise M.; Arkin, Adam P.

2003-04-01

Global explorations of regulatory network dynamics, organization and evolution have become tractable thanks to high-throughput sequencing and molecular measurement of bacterial physiology. From these, a nascent conceptual framework is developing, that views the principles of regulation in term of motifs, modules and games. Motifs are small, repeated, and conserved biological units ranging from molecular domains to small reaction networks. They are arranged into functional modules, genetically dissectible cellular functions such as the cell cycle, or different stress responses. The dynamical functioning of modules defines the organism's strategy to survive in a game, pitting cell against cell, and cell against environment.more » Placing pathway structure and dynamics into an evolutionary context begins to allow discrimination between those physical and molecular features that particularize a species to its surroundings, and those that provide core physiological function. This approach promises to generate a higher level understanding of cellular design, pathway evolution and cellular bioengineering.« less

Macrophage Integrins Modulate Response to Ultra-High Molecular Weight Polyethylene Particles and Direct Particle-Induced Osteolysis

PubMed Central

Zaveri, Toral D.; Dolgova, Natalia V.; Lewis, Jamal S.; Hamaker, Kiri; Clare-Salzler, Michael J.; Keselowsky, Benjamin G.

2016-01-01

Aseptic loosening due to peri-prosthetic osteolysis is one of the primary causes for failure of artificial joint replacements. Implant-derived wear particles, often ultra-high molecular weight polyethylene (UHMWPE) microparticles, initiate an inflammatory cascade upon phagocytosis by macrophages, which leads to osteoclast recruitment and activation, ultimately resulting in osteolysis. Investigation into integrin receptors, involved in cellular interactions with biomaterial-adsorbed adhesive proteins, is of interest to understand and modulate inflammatory processes. In this work, we investigate the role of macrophage integrins Mac-1 and RGD-binding integrins in response to UHMWPE wear particles. Using integrin knockout mice as well as integrin blocking techniques, reduction in macrophage phagocytosis and inflammatory cytokine secretion is demonstrated when these receptors are either absent or blocked. Along this line, various opsonizing proteins are shown to differentially modulate microparticle uptake and macrophage secretion of inflammatory cytokines. Furthermore, using a calvarial osteolysis model it is demonstrated that both Mac-1 integrin and RGD-binding integrins modulate the particle induced osteolysis response to UHMWPE microparticles, with a 40% decrease in the area of osteolysis by the absence or blocking of these integrins, in vivo. Altogether, these findings indicate Mac-1 and RGD-binding integrins are involved in macrophage-directed inflammatory responses to UHMWPE and may serve as therapeutic targets to mitigate wear particle induced peri-prosthetic osteolysis for improved performance of implanted joints. PMID:27889664

Virtual Screening and Molecular Dynamics Study of Potential Negative Allosteric Modulators of mGluR1 from Chinese Herbs.

PubMed

Jiang, Ludi; Zhang, Xianbao; Chen, Xi; He, Yusu; Qiao, Liansheng; Zhang, Yanling; Li, Gongyu; Xiang, Yuhong

2015-07-15

The metabotropic glutamate subtype 1 (mGluR1), a member of the metabotropic glutamate receptors, is a therapeutic target for neurological disorders. However, due to the lower subtype selectivity of mGluR1 orthosteric compounds, a new targeted strategy, known as allosteric modulators research, is needed for the treatment of mGluR1-related diseases. Recently, the structure of the seven-transmembrane domain (7TMD) of mGluR1 has been solved, which reveals the binding site of allosteric modulators and provides an opportunity for future subtype-selectivity drug design. In this study, a series of computer-aided drug design methods were utilized to discover potential mGluR1 negative allosteric modulators (NAMs). Pharmacophore models were constructed based on three different structure types of mGluR1 NAMs. After validation using the built-in parameters and test set, the optimal pharmacophore model of each structure type was selected and utilized as a query to screen the Traditional Chinese Medicine Database (TCMD). Then, three different hit lists of compounds were obtained. Molecular docking was used based on the latest crystal structure of mGluR1-7TMD to further filter these hits. As a compound with high QFIT and LibDock Score was preferred, a total of 30 compounds were retained. MD simulation was utilized to confirm the stability of potential compounds binding. From the computational results, thesinine-4'-O-β-d-glucoside, nigrolineaxanthone-P and nodakenin might exhibit negative allosteric moderating effects on mGluR1. This paper indicates the applicability of molecular simulation technologies for discovering potential natural mGluR1 NAMs from Chinese herbs.

Design and evaluation of basic standard encryption algorithm modules using nanosized complementary metal oxide semiconductor molecular circuits

NASA Astrophysics Data System (ADS)

Masoumi, Massoud; Raissi, Farshid; Ahmadian, Mahmoud; Keshavarzi, Parviz

2006-01-01

We are proposing that the recently proposed semiconductor-nanowire-molecular architecture (CMOL) is an optimum platform to realize encryption algorithms. The basic modules for the advanced encryption standard algorithm (Rijndael) have been designed using CMOL architecture. The performance of this design has been evaluated with respect to chip area and speed. It is observed that CMOL provides considerable improvement over implementation with regular CMOS architecture even with a 20% defect rate. Pseudo-optimum gate placement and routing are provided for Rijndael building blocks and the possibility of designing high speed, attack tolerant and long key encryptions are discussed.

Temperature modulates the cell wall mechanical properties of rice coleoptiles by altering the molecular mass of hemicellulosic polysaccharides

NASA Technical Reports Server (NTRS)

Nakamura, Yukiko; Wakabayashi, Kazuyuki; Hoson, Takayuki

2003-01-01

The present study was conducted to investigate the mechanism inducing the difference in the cell wall extensibility of rice (Oryza sativa L. cv. Koshihikari) coleoptiles grown under various temperature (10-50 degrees C) conditions. The growth rate and the cell wall extensibility of rice coleoptiles exhibited the maximum value at 30-40 degrees C, and became smaller as the growth temperature rose or dropped from this temperature range. The amounts of cell wall polysaccharides per unit length of coleoptile increased in coleoptiles grown at 40 degrees C, but not at other temperature conditions. On the other hand, the molecular size of hemicellulosic polysaccharides was small at temperatures where the cell wall extensibility was high (30-40 degrees C). The autolytic activities of cell walls obtained from coleoptiles grown at 30 and 40 degrees C were substantially higher than those grown at 10, 20 and 50 degrees C. Furthermore, the activities of (1-->3),(1-->4)-beta-glucanases extracted from coleoptile cell walls showed a similar tendency. When oat (1-->3),(1-->4)-beta-glucans with high molecular mass were incubated with the cell wall enzyme preparations from coleoptiles grown at various temperature conditions, the extensive molecular mass downshifts were brought about only by the cell wall enzymes obtained from coleoptiles grown at 30-40 degrees C. There were close correlations between the cell wall extensibility and the molecular mass of hemicellulosic polysaccharides or the activity of beta -glucanases. These results suggest that the environmental temperature regulates the cell wall extensibility of rice coleoptiles by modifying mainly the molecular mass of hemicellulosic polysaccharides. Modulation of the activity of beta-glucanases under various temperature conditions may be involved in the alteration of the molecular size of hemicellulosic polysaccharides.

Physical Exercise Modulates L-DOPA-Regulated Molecular Pathways in the MPTP Mouse Model of Parkinson's Disease.

PubMed

Klemann, Cornelius J H M; Xicoy, Helena; Poelmans, Geert; Bloem, Bas R; Martens, Gerard J M; Visser, Jasper E

2018-07-01

Parkinson's disease (PD) is characterized by the degeneration of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc), resulting in motor and non-motor dysfunction. Physical exercise improves these symptoms in PD patients. To explore the molecular mechanisms underlying the beneficial effects of physical exercise, we exposed 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrimidine (MPTP)-treated mice to a four-week physical exercise regimen, and subsequently explored their motor performance and the transcriptome of multiple PD-linked brain areas. MPTP reduced the number of DA neurons in the SNpc, whereas physical exercise improved beam walking, rotarod performance, and motor behavior in the open field. Further, enrichment analyses of the RNA-sequencing data revealed that in the MPTP-treated mice physical exercise predominantly modulated signaling cascades that are regulated by the top upstream regulators L-DOPA, RICTOR, CREB1, or bicuculline/dalfampridine, associated with movement disorders, mitochondrial dysfunction, and epilepsy-related processes. To elucidate the molecular pathways underlying these cascades, we integrated the proteins encoded by the exercise-induced differentially expressed mRNAs for each of the upstream regulators into a molecular landscape, for multiple key brain areas. Most notable was the opposite effect of physical exercise compared to previously reported effects of L-DOPA on the expression of mRNAs in the SN and the ventromedial striatum that are involved in-among other processes-circadian rhythm and signaling involving DA, neuropeptides, and endocannabinoids. Altogether, our findings suggest that physical exercise can improve motor function in PD and may, at the same time, counteract L-DOPA-mediated molecular mechanisms. Further, we hypothesize that physical exercise has the potential to improve non-motor symptoms of PD, some of which may be the result of (chronic) L-DOPA use.

A Modularity-Based Method Reveals Mixed Modules from Chemical-Gene Heterogeneous Network

PubMed Central

Song, Jianglong; Tang, Shihuan; Liu, Xi; Gao, Yibo; Yang, Hongjun; Lu, Peng

2015-01-01

For a multicomponent therapy, molecular network is essential to uncover its specific mode of action from a holistic perspective. The molecular system of a Traditional Chinese Medicine (TCM) formula can be represented by a 2-class heterogeneous network (2-HN), which typically includes chemical similarities, chemical-target interactions and gene interactions. An important premise of uncovering the molecular mechanism is to identify mixed modules from complex chemical-gene heterogeneous network of a TCM formula. We thus proposed a novel method (MixMod) based on mixed modularity to detect accurate mixed modules from 2-HNs. At first, we compared MixMod with Clauset-Newman-Moore algorithm (CNM), Markov Cluster algorithm (MCL), Infomap and Louvain on benchmark 2-HNs with known module structure. Results showed that MixMod was superior to other methods when 2-HNs had promiscuous module structure. Then these methods were tested on a real drug-target network, in which 88 disease clusters were regarded as real modules. MixMod could identify the most accurate mixed modules from the drug-target 2-HN (normalized mutual information 0.62 and classification accuracy 0.4524). In the end, MixMod was applied to the 2-HN of Buchang naoxintong capsule (BNC) and detected 49 mixed modules. By using enrichment analysis, we investigated five mixed modules that contained primary constituents of BNC intestinal absorption liquid. As a matter of fact, the findings of in vitro experiments using BNC intestinal absorption liquid were found to highly accord with previous analysis. Therefore, MixMod is an effective method to detect accurate mixed modules from chemical-gene heterogeneous networks and further uncover the molecular mechanism of multicomponent therapies, especially TCM formulae. PMID:25927435

Molecular mechanics and dynamics characterization of an in silico mutated protein: a stand-alone lab module or support activity for in vivo and in vitro analyses of targeted proteins.

PubMed

Chiang, Harry; Robinson, Lucy C; Brame, Cynthia J; Messina, Troy C

2013-01-01

Over the past 20 years, the biological sciences have increasingly incorporated chemistry, physics, computer science, and mathematics to aid in the development and use of mathematical models. Such combined approaches have been used to address problems from protein structure-function relationships to the workings of complex biological systems. Computer simulations of molecular events can now be accomplished quickly and with standard computer technology. Also, simulation software is freely available for most computing platforms, and online support for the novice user is ample. We have therefore created a molecular dynamics laboratory module to enhance undergraduate student understanding of molecular events underlying organismal phenotype. This module builds on a previously described project in which students use site-directed mutagenesis to investigate functions of conserved sequence features in members of a eukaryotic protein kinase family. In this report, we detail the laboratory activities of a MD module that provide a complement to phenotypic outcomes by providing a hypothesis-driven and quantifiable measure of predicted structural changes caused by targeted mutations. We also present examples of analyses students may perform. These laboratory activities can be integrated with genetics or biochemistry experiments as described, but could also be used independently in any course that would benefit from a quantitative approach to protein structure-function relationships. Copyright © 2013 Wiley Periodicals, Inc.

Sub-molecular modulation of a 4f driven Kondo resonance by surface-induced asymmetry

NASA Astrophysics Data System (ADS)

Warner, Ben; El Hallak, Fadi; Atodiresei, Nicolae; Seibt, Philipp; Prüser, Henning; Caciuc, Vasile; Waters, Michael; Fisher, Andrew J.; Blügel, Stefan; van Slageren, Joris; Hirjibehedin, Cyrus F.

2016-09-01

Coupling between a magnetic impurity and an external bath can give rise to many-body quantum phenomena, including Kondo and Hund's impurity states in metals, and Yu-Shiba-Rusinov states in superconductors. While advances have been made in probing the magnetic properties of d-shell impurities on surfaces, the confinement of f orbitals makes them difficult to access directly. Here we show that a 4f driven Kondo resonance can be modulated spatially by asymmetric coupling between a metallic surface and a molecule containing a 4f-like moment. Strong hybridization of dysprosium double-decker phthalocyanine with Cu(001) induces Kondo screening of the central magnetic moment. Misalignment between the symmetry axes of the molecule and the surface induces asymmetry in the molecule's electronic structure, spatially mediating electronic access to the magnetic moment through the Kondo resonance. This work demonstrates the important role that molecular ligands have in mediating electronic and magnetic coupling and in accessing many-body quantum states.

Identification of common coexpression modules based on quantitative network comparison.

PubMed

Jo, Yousang; Kim, Sanghyeon; Lee, Doheon

2018-06-13

Finding common molecular interactions from different samples is essential work to understanding diseases and other biological processes. Coexpression networks and their modules directly reflect sample-specific interactions among genes. Therefore, identification of common coexpression network or modules may reveal the molecular mechanism of complex disease or the relationship between biological processes. However, there has been no quantitative network comparison method for coexpression networks and we examined previous methods for other networks that cannot be applied to coexpression network. Therefore, we aimed to propose quantitative comparison methods for coexpression networks and to find common biological mechanisms between Huntington's disease and brain aging by the new method. We proposed two similarity measures for quantitative comparison of coexpression networks. Then, we performed experiments using known coexpression networks. We showed the validity of two measures and evaluated threshold values for similar coexpression network pairs from experiments. Using these similarity measures and thresholds, we quantitatively measured the similarity between disease-specific and aging-related coexpression modules and found similar Huntington's disease-aging coexpression module pairs. We identified similar Huntington's disease-aging coexpression module pairs and found that these modules are related to brain development, cell death, and immune response. It suggests that up-regulated cell signalling related cell death and immune/ inflammation response may be the common molecular mechanisms in the pathophysiology of HD and normal brain aging in the frontal cortex.

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.

Exploring the relative reactivities of the hydroxyl groups of monosaccharides by molecular modeling and molecular mechanics

NASA Astrophysics Data System (ADS)

Box, V. G. S.; Evans-Lora, T.

2000-01-01

The molecular modeling program STR3DI.EXE, and its molecular mechanics module, QVBMM, were used to simulate, and evaluate, the stereo-electronic effects in the mono-alkoxides of the 4,6- O-ethylideneglycopyranosides of allose, mannose, galactose and glucose. This study has confirmed the ability of these molecular modeling tools to predict the regiochemistry and reactivity of these sugar derivatives, and holds considerable implications for unraveling the chemistry of the rare monosaccharides.

Gadolinium-modulated 19F signals from Perfluorocarbon Nanoparticles as a New Strategy for Molecular Imaging

PubMed Central

Neubauer, Anne M.; Myerson, Jacob; Caruthers, Shelton D.; Hockett, Franklin D.; Winter, Patrick M.; Chen, Junjie; Gaffney, Patrick J.; Robertson, J. David; Lanza, Gregory M.; Wickline, Samuel A.

2008-01-01

Recent advances in the design of fluorinated nanoparticles for magnetic resonance molecular imaging have enabled specific detection of 19F nuclei, providing unique and quantifiable spectral signatures. However, a pressing need for signal enhancement exists because the total 19F in imaging voxels is often limited. By directly incorporating a relaxation agent (gadolinium) into the lipid monolayer that surrounds the perfluorocarbon, a marked augmentation of the 19F signal from 200nm nanoparticles was achieved. This design increases the magnetic relaxation rate of the 19F nuclei 4-fold at 1.5 T and effects a 125% increase in signal, an effect which is maintained when they are targeted to human plasma clots. By varying the surface concentration of gadolinium, the relaxation effect can be quantitatively modulated to tailor particle properties. This novel strategy dramatically improves the sensitivity and range of 19F MRI/MRS and forms the basis for designing contrast agents capable of sensing their surface chemistry. PMID:18956457

Adsorption of GA module onto graphene and graphene oxide: A molecular dynamics simulation study

NASA Astrophysics Data System (ADS)

Chen, Junlang; Wang, Xiaogang; Dai, Chaoqing; Chen, Shude; Tu, Yusong

2014-08-01

Using all-atom molecular dynamics (MD) simulation, we have investigated the adsorption of protein GA module (GA53) onto graphene oxide (GO), compared with similar adsorption onto pristine graphene (PG). We find that: (1) the protein GA53 can be easily and firmly adsorbed onto the surface of GO and PG, but the binding sites are not specific; the main difference is that the secondary structure of GA53 can be well preserved in protein-GO system, while GA53 will partially lose its secondary structure after adsorbed on PG. (2) in protein-GO system, hydroxyl and epoxy groups increase the distance between protein and GO, which weaken their vdW interactions, meanwhile, hydrogen bonds and electrostatic interactions enhance their binding affinity. In protein-PG system, strong vdW interactions between residues of GA53 and PG have destroyed its secondary structure. (3) π-π stacking interactions still exist between aromatic residues and both the basal plane of GO and PG. In comparison with PG, our results suggest that GO presents better biocompatibility to preserve protein secondary structure when simultaneously absorbing protein.

Versatile derivatives of carbohydrate-binding modules for imaging of complex carbohydrates approaching the molecular level of resolution.

PubMed

Ding, Shi-You; Xu, Qi; Ali, Mursheda K; Baker, John O; Bayer, Edward A; Barak, Yoav; Lamed, Raphael; Sugiyama, Junji; Rumbles, Garry; Himmel, Michael E

2006-10-01

The innate binding specificity of different carbohydrate-binding modules (CBMs) offers a versatile approach for mapping the chemistry and structure of surfaces that contain complex carbohydrates. We have employed the distinct recognition properties of a double His-tagged recombinant CBM tagged with semiconductor quantum dots for direct imaging of crystalline cellulose at the molecular level of resolution, using transmission and scanning transmission electron microscopy. In addition, three different types of CBMs from families 3, 6, and 20 that exhibit different carbohydrate specificities were each fused with either green fluorescent protein (GFP) or red fluorescent protein (RFP) and employed for double-labeling fluorescence microscopy studies of primary cell walls and various mixtures of complex carbohydrate target molecules. CBM probes can be used for characterizing both native complex carbohydrates and engineered biomaterials.

DiME: A Scalable Disease Module Identification Algorithm with Application to Glioma Progression

PubMed Central

Liu, Yunpeng; Tennant, Daniel A.; Zhu, Zexuan; Heath, John K.; Yao, Xin; He, Shan

2014-01-01

Disease module is a group of molecular components that interact intensively in the disease specific biological network. Since the connectivity and activity of disease modules may shed light on the molecular mechanisms of pathogenesis and disease progression, their identification becomes one of the most important challenges in network medicine, an emerging paradigm to study complex human disease. This paper proposes a novel algorithm, DiME (Disease Module Extraction), to identify putative disease modules from biological networks. We have developed novel heuristics to optimise Community Extraction, a module criterion originally proposed for social network analysis, to extract topological core modules from biological networks as putative disease modules. In addition, we have incorporated a statistical significance measure, B-score, to evaluate the quality of extracted modules. As an application to complex diseases, we have employed DiME to investigate the molecular mechanisms that underpin the progression of glioma, the most common type of brain tumour. We have built low (grade II) - and high (GBM) - grade glioma co-expression networks from three independent datasets and then applied DiME to extract potential disease modules from both networks for comparison. Examination of the interconnectivity of the identified modules have revealed changes in topology and module activity (expression) between low- and high- grade tumours, which are characteristic of the major shifts in the constitution and physiology of tumour cells during glioma progression. Our results suggest that transcription factors E2F4, AR and ETS1 are potential key regulators in tumour progression. Our DiME compiled software, R/C++ source code, sample data and a tutorial are available at http://www.cs.bham.ac.uk/~szh/DiME. PMID:24523864

Basic characteristics of high-frequency Stark-effect modulation of CO2 lasers.

NASA Technical Reports Server (NTRS)

Claspy, P. C.; Pao, Y. H.

1971-01-01

The molecular Stark effect and its application to the modulation of infrared laser radiation have been investigated both theoretically and experimentally. Using a density matrix approach, a quantum mechanical description of the effect of a time-varying electric field on the absorption coefficient and refractive index of a molecular gas near an absorption line has been formulated. For modulation applications a quantity known as the ?modulation depth' is of prime importance. Theoretical expressions for the frequency dependence of the modulation depth show that the response to the frequency of a time-varying Stark field is separated into a nondispersive and a dispersive region, depending on whether the modulating frequency is less than or greater than the homogeneous absorption linewidth. Experimental results showing nondispersive modulation at frequencies to 30 MHz are presented. In addition it is shown that the response of modulation depth to Stark field amplitude is separated into linear and nonlinear regions, the field at which nonlinearities begin being determined by the absorption spectrum of the molecule being used.

[The molecular mechanisms and morphological manifestations of leiomyoma reduction induced by selective progesterone receptor modulators].

PubMed

Demura, T A; Revazova, Z V; Kogan, E A; Adamyan, L V

to investigate the molecular mechanisms and morphological substrate of reduced uterine leiomyoma in patients receiving the selective progesterone receptor modulator (SPRM) ulipristal acetate for 3 months, by estimating the immunohistochemical expression of the markers steroid receptor coactivator 1 (SRC-1), nuclear receptor corepressor 1 (NCoR-1), ER, PgR, Ki-67, p16, TGF-β, and VEGF in tumor tissue. The investigation enrolled 75 women with uterine leiomyoma, menorrhagias, and anemia. Group 1 included 40 patients who were treated with ulipristal for 3 months, followed by laparoscopic myomectomy. Group 2 consisted of 35 patients who underwent surgery without previous preparation. The intra- and postoperative parameters and molecular and morphological changes in the myomatous nodules were comparatively analyzed in both groups. After 3 months of therapy initiation, menorrhagia completely ceased, myomatous nodules decreased in size (p<0.05), hemoglobin levels were elevated (p<0.01), and total intraoperative blood loss and operative time decreased in all the patients in Group 1. The morphological substrate of partial leiomyoma reduction was leiomyocyte apoptosis and dystrophy, tumor stroma sclerosis and hyalinosis with diminished Ki-67 expression and elevated p16 in the smooth muscle cells, trophic nodular tissue disorders exhibited by vascular wall sclerosis and lower VEGF and TGF-β expression, and leiomyocyte hormonal reception dysregulation that made itself evident through the reduced expression of SRC-1 with the unchanged expression of PR and ER and the maintained level of NCoR-1. The molecular mechanisms of tumor reduction involved the reduced Ki-67 expression and elevated p16, lower VEGF and TGF-β, diminished SRC-1 expression with the maintained level of PR, ER, and NCoR-1. Overall, this is suggestive of enhanced apoptosis and reduced leiomyoma proliferation and angiogenesis induced by SPRM and indicative of the expediency of using ulipristal acetate as a

Molecular oxygen detection using frequency modulation diode laser spectroscopy

NASA Technical Reports Server (NTRS)

Wang, Liang-Guo; Sachse, Glen

1990-01-01

A high-sensitivity spectroscopic measurement of O2 using two-tone frequency modulation spectroscopy with a GaAlAs diode laser is presented. An oxygen sensor based on this technique would be non-intrusive, compact and possess high sensitivity and fast time response.

Orion Aerodynamics for Hypersonic Free Molecular to Continuum Conditions

NASA Technical Reports Server (NTRS)

Moss, James N.; Greene, Francis A.; Boyles, Katie A.

2006-01-01

Numerical simulations are performed for the Orion Crew Module, previously known as the Crew Exploration Vehicle (CEV) Command Module, to characterize its aerodynamics during the high altitude portion of its reentry into the Earth's atmosphere, that is, from free molecular to continuum hypersonic conditions. The focus is on flow conditions similar to those that the Orion Crew Module would experience during a return from the International Space Station. The bulk of the calculations are performed with two direct simulation Monte Carlo (DSMC) codes, and these data are anchored with results from both free molecular and Navier-Stokes calculations. Results for aerodynamic forces and moments are presented that demonstrate their sensitivity to rarefaction, that is, for free molecular to continuum conditions (Knudsen numbers of 111 to 0.0003). Also included are aerodynamic data as a function of angle of attack for different levels of rarefaction and results that demonstrate the aerodynamic sensitivity of the Orion CM to a range of reentry velocities (7.6 to 15 km/s).

Engineered Aptamers to Probe Molecular Interactions on the Cell Surface

PubMed Central

Batool, Sana; Bhandari, Sanam; George, Shanell; Okeoma, Precious; Van, Nabeela; Zümrüt, Hazan E.; Mallikaratchy, Prabodhika

2017-01-01

Significant progress has been made in understanding the nature of molecular interactions on the cell membrane. To decipher such interactions, molecular scaffolds can be engineered as a tool to modulate these events as they occur on the cell membrane. To guarantee reliability, scaffolds that function as modulators of cell membrane events must be coupled to a targeting moiety with superior chemical versatility. In this regard, nucleic acid aptamers are a suitable class of targeting moieties. Aptamers are inherently chemical in nature, allowing extensive site-specific chemical modification to engineer sensing molecules. Aptamers can be easily selected using a simple laboratory-based in vitro evolution method enabling the design and development of aptamer-based functional molecular scaffolds against wide range of cell surface molecules. This article reviews the application of aptamers as monitors and modulators of molecular interactions on the mammalian cell surface with the aim of increasing our understanding of cell-surface receptor response to external stimuli. The information gained from these types of studies could eventually prove useful in engineering improved medical diagnostics and therapeutics. PMID:28850067

Spray-dried powders enhance vaginal siRNA delivery by potentially modulating the mucus molecular sieve structure.

PubMed

Wu, Na; Zhang, Xinxin; Li, Feifei; Zhang, Tao; Gan, Yong; Li, Juan

2015-01-01

Vaginal small interfering RNA (siRNA) delivery provides a promising strategy for the prevention and treatment of vaginal diseases. However, the densely cross-linked mucus layer on the vaginal wall severely restricts nanoparticle-mediated siRNA delivery to the vaginal epithelium. In order to overcome this barrier and enhance vaginal mucus penetration, we prepared spray-dried powders containing siRNA-loaded nanoparticles. Powders with Pluronic F127 (F127), hydroxypropyl methyl cellulose (HPMC), and mannitol as carriers were obtained using an ultrasound-assisted spray-drying technique. Highly dispersed dry powders with diameters of 5-15 μm were produced. These powders showed effective siRNA protection and sustained release. The mucus-penetrating properties of the powders differed depending on their compositions. They exhibited different potential of opening mesh size of molecular sieve in simulated vaginal mucus system. A powder formulation with 0.6% F127 and 0.1% HPMC produced the maximum increase in the pore size of the model gel used to simulate vaginal mucus by rapidly extracting water from the gel and interacting with the gel; the resulting modulation of the molecular sieve effect achieved a 17.8-fold improvement of siRNA delivery in vaginal tract and effective siRNA delivery to the epithelium. This study suggests that powder formulations with optimized compositions have the potential to alter the steric barrier posed by mucus and hold promise for effective vaginal siRNA delivery.

Realization of Molecular-Based Transistors.

PubMed

Richter, Shachar; Mentovich, Elad; Elnathan, Roey

2018-06-06

Molecular-based devices are widely considered as significant candidates to play a role in the next generation of "post-complementary metal-oxide-semiconductor" devices. In this context, molecular-based transistors: molecular junctions that can be electrically gated-are of particular interest as they allow new modes of operation. The properties of molecular transistors composed of a single- or multimolecule assemblies, focusing on their practicality as real-world devices, concerning industry demands and its roadmap are compared. Also, the capability of the gate electrode to modulate the molecular transistor characteristics efficiently is addressed, showing that electrical gating can be easily facilitated in single molecular transistors and that gating of transistor composed of molecular assemblies is possible if the device is formed vertically. It is concluded that while the single-molecular transistor exhibits better performance on the lab-scale, its realization faces signifacant challenges when compared to those faced by transistors composed of a multimolecule assembly. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Computer-aided design of negative allosteric modulators of metabotropic glutamate receptor 5 (mGluR5): Comparative molecular field analysis of aryl ether derivatives.

PubMed

Selvam, Chelliah; Thilagavathi, Ramasamy; Narasimhan, Balasubramanian; Kumar, Pradeep; Jordan, Brian C; Ranganna, Kasturi

2016-02-15

The metabotropic glutamate receptors (mGlu receptors) have emerged as attractive targets for number of neurological and psychiatric disorders. Recently, mGluR5 negative allosteric modulators (NAMs) have gained considerable attention in pharmacological research. Comparative molecular field analysis (CoMFA) was performed on 73 analogs of aryl ether which were reported as mGluR5 NAMs. The study produced a statistically significant model with high correlation coefficient and good predictive abilities. Published by Elsevier Ltd.

Molecular deconstruction, detection, and computational prediction of microenvironment-modulated cellular responses to cancer therapeutics

PubMed Central

LaBarge, Mark A; Parvin, Bahram; Lorens, James B

2014-01-01

The field of bioengineering has pioneered the application of new precision fabrication technologies to model the different geometric, physical or molecular components of tissue microenvironments on solid-state substrata. Tissue engineering approaches building on these advances are used to assemble multicellular mimetic-tissues where cells reside within defined spatial contexts. The functional responses of cells in fabricated microenvironments has revealed a rich interplay between the genome and extracellular effectors in determining cellular phenotypes, and in a number of cases has revealed the dominance of microenvironment over genotype. Precision bioengineered substrata are limited to a few aspects, whereas cell/tissue-derived microenvironments have many undefined components. Thus introducing a computational module may serve to integrate these types of platforms to create reasonable models of drug responses in human tissues. This review discusses how combinatorial microenvironment microarrays and other biomimetic microenvironments have revealed emergent properties of cells in particular microenvironmental contexts, the platforms that can measure phenotypic changes within those contexts, and the computational tools that can unify the microenvironment-imposed functional phenotypes with underlying constellations of proteins and genes. Ultimately we propose that a merger of these technologies will enable more accurate pre-clinical drug discovery. PMID:24582543

LRRK2 kinase activity regulates synaptic vesicle trafficking and neurotransmitter release through modulation of LRRK2 macro-molecular complex

PubMed Central

Cirnaru, Maria D.; Marte, Antonella; Belluzzi, Elisa; Russo, Isabella; Gabrielli, Martina; Longo, Francesco; Arcuri, Ludovico; Murru, Luca; Bubacco, Luigi; Matteoli, Michela; Fedele, Ernesto; Sala, Carlo; Passafaro, Maria; Morari, Michele; Greggio, Elisa; Onofri, Franco; Piccoli, Giovanni

2014-01-01

Mutations in Leucine-rich repeat kinase 2 gene (LRRK2) are associated with familial and sporadic Parkinson's disease (PD). LRRK2 is a complex protein that consists of multiple domains executing several functions, including GTP hydrolysis, kinase activity, and protein binding. Robust evidence suggests that LRRK2 acts at the synaptic site as a molecular hub connecting synaptic vesicles to cytoskeletal elements via a complex panel of protein-protein interactions. Here we investigated the impact of pharmacological inhibition of LRRK2 kinase activity on synaptic function. Acute treatment with LRRK2 inhibitors reduced the frequency of spontaneous currents, the rate of synaptic vesicle trafficking and the release of neurotransmitter from isolated synaptosomes. The investigation of complementary models lacking LRRK2 expression allowed us to exclude potential off-side effects of kinase inhibitors on synaptic functions. Next we studied whether kinase inhibition affects LRRK2 heterologous interactions. We found that the binding among LRRK2, presynaptic proteins and synaptic vesicles is affected by kinase inhibition. Our results suggest that LRRK2 kinase activity influences synaptic vesicle release via modulation of LRRK2 macro-molecular complex. PMID:24904275

An easy and effective method to modulate molecular energy level of the polymer based on benzodithiophene for the application in polymer solar cells.

PubMed

Zhang, Maojie; Guo, Xia; Ma, Wei; Zhang, Shaoqing; Huo, Lijun; Ade, Harald; Hou, Jianhui

2014-04-02

Attaching meta-alkoxy-phenyl groups as conjugated side chains is an easy and effective way to modulate the molecular energy level of D-A polymer for photovoltaic application, and the polymer solar cells based on the polymer consisting meta-alkoxy-phenyl groups as conjugated side chain, PBT-OP, shows an enhanced open circuit voltage and thus higher efficiency of 7.50%, under the illumination of AM 1.5G, 100 mW/cm(2) . © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Effects of HCM cTnI Mutation R145G on Troponin Structure and Modulation by PKA Phosphorylation Elucidated by Molecular Dynamics Simulations

PubMed Central

Lindert, Steffen; Cheng, Yuanhua; Kekenes-Huskey, Peter; Regnier, Michael; McCammon, J. Andrew

2015-01-01

Cardiac troponin (cTn) is a key molecule in the regulation of human cardiac muscle contraction. The N-terminal cardiac-specific peptide of the inhibitory subunit of troponin, cTnI (cTnI1-39), is a target for phosphorylation by protein kinase A (PKA) during β-adrenergic stimulation. We recently presented evidence indicating that this peptide interacts with the inhibitory peptide (cTnl137–147) when S23 and S24 are phosphorylated. The inhibitory peptide is also the target of the point mutation cTnI-R145G, which is associated with hypertrophic cardiomyopathy (HCM), a disease associated with sudden death in apparently healthy young adults. It has been shown that both phosphorylation and this mutation alter the cTnC-cTnI (C-I) interaction, which plays a crucial role in modulating contractile activation. However, little is known about the molecular-level events underlying this modulation. Here, we computationally investigated the effects of the cTnI-R145G mutation on the dynamics of cTn, cTnC Ca2+ handling, and the C-I interaction. Comparisons were made with the cTnI-R145G/S23D/S24D phosphomimic mutation, which has been used both experimentally and computationally to study the cTnI N-terminal specific effects of PKA phosphorylation. Additional comparisons between the phosphomimic mutations and the real phosphorylations were made. For this purpose, we ran triplicate 150 ns molecular dynamics simulations of cTnI-R145G Ca2+-bound cTnC1-161-cTnI1-172-cTnT236-285, cTnI-R145G/S23D/S24D Ca2+-bound cTnC1-161-cTnI1-172-cTnT236-285, and cTnI-R145G/PS23/PS24 Ca2+-bound cTnC1-161-cTnI1-172-cTnT236-285, respectively. We found that the cTnI-R145G mutation did not impact the overall dynamics of cTn, but stabilized crucial Ca2+-coordinating interactions. However, the phosphomimic mutations increased overall cTn fluctuations and destabilized Ca2+ coordination. Interestingly, cTnI-R145G blunted the intrasubunit interactions between the cTnI N-terminal extension and the cTnI inhibitory

Effects of HCM cTnI mutation R145G on troponin structure and modulation by PKA phosphorylation elucidated by molecular dynamics simulations.

PubMed

Lindert, Steffen; Cheng, Yuanhua; Kekenes-Huskey, Peter; Regnier, Michael; McCammon, J Andrew

2015-01-20

Cardiac troponin (cTn) is a key molecule in the regulation of human cardiac muscle contraction. The N-terminal cardiac-specific peptide of the inhibitory subunit of troponin, cTnI (cTnI(1-39)), is a target for phosphorylation by protein kinase A (PKA) during β-adrenergic stimulation. We recently presented evidence indicating that this peptide interacts with the inhibitory peptide (cTnl(137-147)) when S23 and S24 are phosphorylated. The inhibitory peptide is also the target of the point mutation cTnI-R145G, which is associated with hypertrophic cardiomyopathy (HCM), a disease associated with sudden death in apparently healthy young adults. It has been shown that both phosphorylation and this mutation alter the cTnC-cTnI (C-I) interaction, which plays a crucial role in modulating contractile activation. However, little is known about the molecular-level events underlying this modulation. Here, we computationally investigated the effects of the cTnI-R145G mutation on the dynamics of cTn, cTnC Ca(2+) handling, and the C-I interaction. Comparisons were made with the cTnI-R145G/S23D/S24D phosphomimic mutation, which has been used both experimentally and computationally to study the cTnI N-terminal specific effects of PKA phosphorylation. Additional comparisons between the phosphomimic mutations and the real phosphorylations were made. For this purpose, we ran triplicate 150 ns molecular dynamics simulations of cTnI-R145G Ca(2+)-bound cTnC(1-161)-cTnI(1-172)-cTnT(236-285), cTnI-R145G/S23D/S24D Ca(2+)-bound cTnC(1-161)-cTnI(1-172)-cTnT(236-285), and cTnI-R145G/PS23/PS24 Ca(2+)-bound cTnC(1-161)-cTnI(1-172)-cTnT(236-285), respectively. We found that the cTnI-R145G mutation did not impact the overall dynamics of cTn, but stabilized crucial Ca(2+)-coordinating interactions. However, the phosphomimic mutations increased overall cTn fluctuations and destabilized Ca(2+) coordination. Interestingly, cTnI-R145G blunted the intrasubunit interactions between the cTnI N

How Dynamic Visualization Technology Can Support Molecular Reasoning

ERIC Educational Resources Information Center

Levy, Dalit

2013-01-01

This paper reports the results of a study aimed at exploring the advantages of dynamic visualization for the development of better understanding of molecular processes. We designed a technology-enhanced curriculum module in which high school chemistry students conduct virtual experiments with dynamic molecular visualizations of solid, liquid, and…

Molecular mechanisms of curcumin action: gene expression.

PubMed

Shishodia, Shishir

2013-01-01

Curcumin derived from the tropical plant Curcuma longa has a long history of use as a dietary agent, food preservative, and in traditional Asian medicine. It has been used for centuries to treat biliary disorders, anorexia, cough, diabetic wounds, hepatic disorders, rheumatism, and sinusitis. The preventive and therapeutic properties of curcumin are associated with its antioxidant, anti-inflammatory, and anticancer properties. Extensive research over several decades has attempted to identify the molecular mechanisms of curcumin action. Curcumin modulates numerous molecular targets by altering their gene expression, signaling pathways, or through direct interaction. Curcumin regulates the expression of inflammatory cytokines (e.g., TNF, IL-1), growth factors (e.g., VEGF, EGF, FGF), growth factor receptors (e.g., EGFR, HER-2, AR), enzymes (e.g., COX-2, LOX, MMP9, MAPK, mTOR, Akt), adhesion molecules (e.g., ELAM-1, ICAM-1, VCAM-1), apoptosis related proteins (e.g., Bcl-2, caspases, DR, Fas), and cell cycle proteins (e.g., cyclin D1). Curcumin modulates the activity of several transcription factors (e.g., NF-κB, AP-1, STAT) and their signaling pathways. Based on its ability to affect multiple targets, curcumin has the potential for the prevention and treatment of various diseases including cancers, arthritis, allergies, atherosclerosis, aging, neurodegenerative disease, hepatic disorders, obesity, diabetes, psoriasis, and autoimmune diseases. This review summarizes the molecular mechanisms of modulation of gene expression by curcumin. Copyright © 2012 International Union of Biochemistry and Molecular Biology, Inc.

O-GlcNAcylation is a key modulator of skeletal muscle sarcomeric morphometry associated to modulation of protein-protein interactions.

PubMed

Lambert, Matthias; Richard, Elodie; Duban-Deweer, Sophie; Krzewinski, Frederic; Deracinois, Barbara; Dupont, Erwan; Bastide, Bruno; Cieniewski-Bernard, Caroline

2016-09-01

The sarcomere structure of skeletal muscle is determined through multiple protein-protein interactions within an intricate sarcomeric cytoskeleton network. The molecular mechanisms involved in the regulation of this sarcomeric organization, essential to muscle function, remain unclear. O-GlcNAcylation, a post-translational modification modifying several key structural proteins and previously described as a modulator of the contractile activity, was never considered to date in the sarcomeric organization. C2C12 skeletal myotubes were treated with Thiamet-G (OGA inhibitor) in order to increase the global O-GlcNAcylation level. Our data clearly showed a modulation of the O-GlcNAc level more sensitive and dynamic in the myofilament-enriched fraction than total proteome. This fine O-GlcNAc level modulation was closely related to changes of the sarcomeric morphometry. Indeed, the dark-band and M-line widths increased, while the I-band width and the sarcomere length decreased according to the myofilament O-GlcNAc level. Some structural proteins of the sarcomere such as desmin, αB-crystallin, α-actinin, moesin and filamin-C have been identified within modulated protein complexes through O-GlcNAc level variations. Their interactions seemed to be changed, especially for desmin and αB-crystallin. For the first time, our findings clearly demonstrate that O-GlcNAcylation, through dynamic regulations of the structural interactome, could be an important modulator of the sarcomeric structure and may provide new insights in the understanding of molecular mechanisms of neuromuscular diseases characterized by a disorganization of the sarcomeric structure. In the present study, we demonstrated a role of O-GlcNAcylation in the sarcomeric structure modulation. Copyright © 2016 Elsevier B.V. All rights reserved.

Incommensurate Chirality Density Wave Transition in a Hybrid Molecular Framework.

PubMed

Hill, Joshua A; Christensen, Kirsten E; Goodwin, Andrew L

2017-09-15

Using single-crystal x-ray diffraction we characterize the 235 K incommensurate phase transition in the hybrid molecular framework tetraethylammonium silver(I) dicyanoargentate, [NEt_{4}]Ag_{3}(CN)_{4}. We demonstrate the transition to involve spontaneous resolution of chiral [NEt_{4}]^{+} conformations, giving rise to a state in which molecular chirality is incommensurately modulated throughout the crystal lattice. We refer to this state as an incommensurate chirality density wave (XDW) phase, which represents a fundamentally new type of chiral symmetry breaking in the solid state. Drawing on parallels to the incommensurate ferroelectric transition of NaNO_{2}, we suggest the XDW state arises through coupling between acoustic (shear) and molecular rotoinversion modes. Such coupling is symmetry forbidden at the Brillouin zone center but symmetry allowed for small but finite modulation vectors q=[0,0,q_{z}]^{*}. The importance of long-wavelength chirality modulations in the physics of this hybrid framework may have implications for the generation of mesoscale chiral textures, as required for advanced photonic materials.

Incommensurate Chirality Density Wave Transition in a Hybrid Molecular Framework

NASA Astrophysics Data System (ADS)

Hill, Joshua A.; Christensen, Kirsten E.; Goodwin, Andrew L.

2017-09-01

Using single-crystal x-ray diffraction we characterize the 235 K incommensurate phase transition in the hybrid molecular framework tetraethylammonium silver(I) dicyanoargentate, [NEt4]Ag3(CN )4 . We demonstrate the transition to involve spontaneous resolution of chiral [NEt4]+ conformations, giving rise to a state in which molecular chirality is incommensurately modulated throughout the crystal lattice. We refer to this state as an incommensurate chirality density wave (XDW) phase, which represents a fundamentally new type of chiral symmetry breaking in the solid state. Drawing on parallels to the incommensurate ferroelectric transition of NaNO2 , we suggest the XDW state arises through coupling between acoustic (shear) and molecular rotoinversion modes. Such coupling is symmetry forbidden at the Brillouin zone center but symmetry allowed for small but finite modulation vectors q =[0 ,0 ,qz]* . The importance of long-wavelength chirality modulations in the physics of this hybrid framework may have implications for the generation of mesoscale chiral textures, as required for advanced photonic materials.

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

A Cobalt Supramolecular Triple-Stranded Helicate-based Discrete Molecular Cage

PubMed Central

Mai, Hien Duy; Kang, Philjae; Kim, Jin Kyung; Yoo, Hyojong

2017-01-01

We report a strategy to achieve a discrete cage molecule featuring a high level of structural hierarchy through a multiple-assembly process. A cobalt (Co) supramolecular triple-stranded helicate (Co-TSH)-based discrete molecular cage (1) is successfully synthesized and fully characterized. The solid-state structure of 1 shows that it is composed of six triple-stranded helicates interconnected by four linking cobalt species. This is an unusual example of a highly symmetric cage architecture resulting from the coordination-driven assembly of metallosupramolecular modules. The molecular cage 1 shows much higher CO2 uptake properties and selectivity compared with the separate supramolecular modules (Co-TSH, complex 2) and other molecular platforms. PMID:28262690

Kinetic control over pathway complexity in supramolecular polymerization through modulating the energy landscape by rational molecular design.

PubMed

Ogi, Soichiro; Fukui, Tomoya; Jue, Melinda L; Takeuchi, Masayuki; Sugiyasu, Kazunori

2014-12-22

Far-from-equilibrium thermodynamic systems that are established as a consequence of coupled equilibria are the origin of the complex behavior of biological systems. Therefore, research in supramolecular chemistry has recently been shifting emphasis from a thermodynamic standpoint to a kinetic one; however, control over the complex kinetic processes is still in its infancy. Herein, we report our attempt to control the time evolution of supramolecular assembly in a process in which the supramolecular assembly transforms from a J-aggregate to an H-aggregate over time. The transformation proceeds through a delicate interplay of these two aggregation pathways. We have succeeded in modulating the energy landscape of the respective aggregates by a rational molecular design. On the basis of this understanding of the energy landscape, programming of the time evolution was achieved through adjusting the balance between the coupled equilibria. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Optical/MRI Multimodality Molecular Imaging

NASA Astrophysics Data System (ADS)

Ma, Lixin; Smith, Charles; Yu, Ping

2007-03-01

Multimodality molecular imaging that combines anatomical and functional information has shown promise in development of tumor-targeted pharmaceuticals for cancer detection or therapy. We present a new multimodality imaging technique that combines fluorescence molecular tomography (FMT) and magnetic resonance imaging (MRI) for in vivo molecular imaging of preclinical tumor models. Unlike other optical/MRI systems, the new molecular imaging system uses parallel phase acquisition based on heterodyne principle. The system has a higher accuracy of phase measurements, reduced noise bandwidth, and an efficient modulation of the fluorescence diffuse density waves. Fluorescent Bombesin probes were developed for targeting breast cancer cells and prostate cancer cells. Tissue phantom and small animal experiments were performed for calibration of the imaging system and validation of the targeting probes.

Mode-selective vibrational modulation of charge transport in organic electronic devices

PubMed Central

Bakulin, Artem A.; Lovrincic, Robert; Yu, Xi; Selig, Oleg; Bakker, Huib J.; Rezus, Yves L. A.; Nayak, Pabitra K.; Fonari, Alexandr; Coropceanu, Veaceslav; Brédas, Jean-Luc; Cahen, David

2015-01-01

The soft character of organic materials leads to strong coupling between molecular, nuclear and electronic dynamics. This coupling opens the way to influence charge transport in organic electronic devices by exciting molecular vibrational motions. However, despite encouraging theoretical predictions, experimental realization of such approach has remained elusive. Here we demonstrate experimentally that photoconductivity in a model organic optoelectronic device can be modulated by the selective excitation of molecular vibrations. Using an ultrafast infrared laser source to create a coherent superposition of vibrational motions in a pentacene/C60 photoresistor, we observe that excitation of certain modes in the 1,500–1,700 cm−1 region leads to photocurrent enhancement. Excited vibrations affect predominantly trapped carriers. The effect depends on the nature of the vibration and its mode-specific character can be well described by the vibrational modulation of intermolecular electronic couplings. This presents a new tool for studying electron–phonon coupling and charge dynamics in (bio)molecular materials. PMID:26246039

Mode-selective vibrational modulation of charge transport in organic electronic devices

NASA Astrophysics Data System (ADS)

Bakulin, Artem A.; Lovrincic, Robert; Yu, Xi; Selig, Oleg; Bakker, Huib J.; Rezus, Yves L. A.; Nayak, Pabitra K.; Fonari, Alexandr; Coropceanu, Veaceslav; Brédas, Jean-Luc; Cahen, David

2015-08-01

The soft character of organic materials leads to strong coupling between molecular, nuclear and electronic dynamics. This coupling opens the way to influence charge transport in organic electronic devices by exciting molecular vibrational motions. However, despite encouraging theoretical predictions, experimental realization of such approach has remained elusive. Here we demonstrate experimentally that photoconductivity in a model organic optoelectronic device can be modulated by the selective excitation of molecular vibrations. Using an ultrafast infrared laser source to create a coherent superposition of vibrational motions in a pentacene/C60 photoresistor, we observe that excitation of certain modes in the 1,500-1,700 cm-1 region leads to photocurrent enhancement. Excited vibrations affect predominantly trapped carriers. The effect depends on the nature of the vibration and its mode-specific character can be well described by the vibrational modulation of intermolecular electronic couplings. This presents a new tool for studying electron-phonon coupling and charge dynamics in (bio)molecular materials.

Modulating protein behaviors on responsive surface by external electric fields: A molecular dynamics study

NASA Astrophysics Data System (ADS)

Xie, Yun; Pan, Yufang; Zhang, Rong; Liang, Ying; Li, Zhanchao

2015-01-01

Molecular dynamics simulations were employed to investigate the modulation of protein behaviors on the electrically responsive zwitterionic phosphorylcholine self-assembled monolayers (PC-SAMs). Results show that PC-SAMs could sensitively respond to the applied electric fields and exhibit three states with different charge distributions, namely both the negatively charged phosphate groups and the positively charged choline groups are exposed to the solution in the absence of electric fields (state 1), phosphate groups exposed in the presence of positive electric fields (state 2), and choline groups exposed in the presence of negative electric fields (state 3). Under state 1, the adsorption of Cyt c on the PC-SAM is reversible and the orientations of Cyt c are randomly distributed. Under state 2, the adsorption of Cyt c is enhanced due to the electrostatic attractions between the exposed phosphate groups and the positively charged protein; when adsorbed on the PC-SAMs, Cyt c tends to adopt the orientation with the heme plane perpendicular to the surface plane, and the percentage of this orientation increases as the field strength rises up. Under state 3, the adsorption of Cyt c is retarded because of the electrostatic repulsions between the exposed choline groups and the protein; however, if the gaps between PC chains are large enough, Cyt c could insert into the PC-SAM and access the phosphate groups after overcoming a slight energy barrier. Under three states, the basic backbone structures of Cyt c are well kept within the simulation time since the conformation of Cyt c is mainly affected by the surface-generated electric fields, whose strengths are modulated by the external electric fields and are not strong enough to deform protein. The results indicate the possibility of regulating protein behaviors, including promoting or retarding protein adsorption and regulating protein orientations, on responsive surfaces by applying electric fields on the surfaces without

Photostability Can Be Significantly Modulated by Molecular Packing in Glasses

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

Qiu, Yue; Antony, Lucas W.; de Pablo, Juan J.

2016-08-12

While previous work has demonstrated that molecular packing in organic crystals can strongly influence photochemical stability, efforts to tune photostability in amorphous materials have shown much smaller effects. Here we show that physical vapor deposition can substantially improve the photostability of organic glasses. Disperse Orange 37 (DO37), an azobenzene derivative, is studied as a model system. Photostability is assessed through changes in the density and molecular orientation of glassy thin films during light irradiation. By optimizing the substrate temperature used for deposition, we can increase photostability by a factor of 50 relative to the liquid-cooled glass. Photostability correlates with glassmore » density, with density increases of up to 1.3%. Coarse-grained molecular simulations, which mimic glass preparation and the photoisomerization reaction, also indicate that glasses with higher density have substantially increased photostability. These results provide insights that may assist in the design of organic photovoltaics and light emission devices with longer lifetimes.« less

Photostability can be significantly modulated by molecular packing in glasses

DOE Data Explorer

Ediger, Mark [University of Wisconsin-Madison; de Pablo, Juan [University of Chicago; Anthony, Lucas [University of Chicago; Qiu, Yue [University of Chicago

2016-04-10

While previous work has demonstrated that molecular packing in organic crystals can strongly influence photochemical stability, efforts to tune photostability in amorphous materials have shown much smaller effects. Here we show that physical vapor deposition can substantially improve the photostability of organic glasses. Disperse Orange 37 (DO37), an azobenzene derivative, is studied as a model system. Photostability is assessed through changes in the density and molecular orientation of glassy thin films during light irradiation. By optimizing the substrate temperature used for deposition, we can increase photostability by a factor of 50 relative to the liquid-cooled glass. Photostability correlates with glass density, with density increases of up to 1.3%. Coarse-grained molecular simulations, which mimic glass preparation and the photoisomerization reaction, also indicate that glasses with higher density have substantially increased photostability. These results provide insights that may assist in the design of organic photovoltaics and light emission devices with longer lifetimes.

Extension of wavelength-modulation spectroscopy to large modulation depth for diode laser absorption measurements in high-pressure gases

NASA Astrophysics Data System (ADS)

Li, Hejie; Rieker, Gregory B.; Liu, Xiang; Jeffries, Jay B.; Hanson, Ronald K.

2006-02-01

Tunable diode laser absorption measurements at high pressures by use of wavelength-modulation spectroscopy (WMS) require large modulation depths for optimum detection of molecular absorption spectra blended by collisional broadening or dense spacing of the rovibrational transitions. Diode lasers have a large and nonlinear intensity modulation when the wavelength is modulated over a large range by injection-current tuning. In addition to this intensity modulation, other laser performance parameters are measured, including the phase shift between the frequency modulation and the intensity modulation. Following published theory, these parameters are incorporated into an improved model of the WMS signal. The influence of these nonideal laser effects is investigated by means of wavelength-scanned WMS measurements as a function of bath gas pressure on rovibrational transitions of water vapor near 1388 nm. Lock-in detection of the magnitude of the 2f signal is performed to remove the dependence on detection phase. We find good agreement between measurements and the improved model developed for the 2f component of the WMS signal. The effects of the nonideal performance parameters of commercial diode lasers are especially important away from the line center of discrete spectra, and these contributions become more pronounced for 2f signals with the large modulation depths needed for WMS at elevated pressures.

Modulation by metformin of molecular and histopathological alterations in the lung of cigarette smoke-exposed mice

PubMed Central

Izzotti, Alberto; Balansky, Roumen; D'Agostini, Francesco; Longobardi, Mariagrazia; Cartiglia, Cristina; Micale, Rosanna T; La Maestra, Sebastiano; Camoirano, Anna; Ganchev, Gancho; Iltcheva, Marietta; Steele, Vernon E; De Flora, Silvio

2014-01-01

The anti-diabetic drug metformin is endowed with anti-cancer properties. Epidemiological and experimental studies, however, did not provide univocal results regarding its role in pulmonary carcinogenesis. We used Swiss H mice of both genders in order to detect early molecular alterations and tumors induced by mainstream cigarette smoke. Based on a subchronic toxicity study, oral metformin was used at a dose of 800 mg/kg diet, which is 3.2 times higher than the therapeutic dose in humans. Exposure of mice to smoke for 4 months, starting at birth, induced a systemic clastogenic damage, formation of DNA adducts, oxidative DNA damage, and extensive downregulation of microRNAs in lung after 10 weeks. Preneoplastic lesions were detectable after 7.5 months in both lung and urinary tract along with lung tumors, both benign and malignant. Modulation by metformin of 42 of 1281 pulmonary microRNAs in smoke-free mice highlighted a variety of mechanisms, including modulation of AMPK, stress response, inflammation, NFκB, Tlr9, Tgf, p53, cell cycle, apoptosis, antioxidant pathways, Ras, Myc, Dicer, angiogenesis, stem cell recruitment, and angiogenesis. In smoke-exposed mice, metformin considerably decreased DNA adduct levels and oxidative DNA damage, and normalized the expression of several microRNAs. It did not prevent smoke-induced lung tumors but inhibited preneoplastic lesions in both lung and kidney. In conclusion, metformin was able to protect the mouse lung from smoke-induced DNA and microRNA alterations and to inhibit preneoplastic lesions in lung and kidney but failed to prevent lung adenomas and malignant tumors induced by this complex mixture. PMID:24683044

Molecular mechanism of the sweet taste enhancers.

PubMed

Zhang, Feng; Klebansky, Boris; Fine, Richard M; Liu, Haitian; Xu, Hong; Servant, Guy; Zoller, Mark; Tachdjian, Catherine; Li, Xiaodong

2010-03-09

Positive allosteric modulators of the human sweet taste receptor have been developed as a new way of reducing dietary sugar intake. Besides their potential health benefit, the sweet taste enhancers are also valuable tool molecules to study the general mechanism of positive allosteric modulations of T1R taste receptors. Using chimeric receptors, mutagenesis, and molecular modeling, we reveal how these sweet enhancers work at the molecular level. Our data argue that the sweet enhancers follow a similar mechanism as the natural umami taste enhancer molecules. Whereas the sweeteners bind to the hinge region and induce the closure of the Venus flytrap domain of T1R2, the enhancers bind close to the opening and further stabilize the closed and active conformation of the receptor.

Molecular deconstruction, detection, and computational prediction of microenvironment-modulated cellular responses to cancer therapeutics.

PubMed

Labarge, Mark A; Parvin, Bahram; Lorens, James B

2014-04-01

The field of bioengineering has pioneered the application of new precision fabrication technologies to model the different geometric, physical or molecular components of tissue microenvironments on solid-state substrata. Tissue engineering approaches building on these advances are used to assemble multicellular mimetic-tissues where cells reside within defined spatial contexts. The functional responses of cells in fabricated microenvironments have revealed a rich interplay between the genome and extracellular effectors in determining cellular phenotypes and in a number of cases have revealed the dominance of microenvironment over genotype. Precision bioengineered substrata are limited to a few aspects, whereas cell/tissue-derived microenvironments have many undefined components. Thus, introducing a computational module may serve to integrate these types of platforms to create reasonable models of drug responses in human tissues. This review discusses how combinatorial microenvironment microarrays and other biomimetic microenvironments have revealed emergent properties of cells in particular microenvironmental contexts, the platforms that can measure phenotypic changes within those contexts, and the computational tools that can unify the microenvironment-imposed functional phenotypes with underlying constellations of proteins and genes. Ultimately we propose that a merger of these technologies will enable more accurate pre-clinical drug discovery. Copyright © 2014 Elsevier B.V. All rights reserved.

Damage-associated molecular pattern activated Toll-like receptor 4 signalling modulates blood pressure in L-NAME-induced hypertension.

PubMed

Sollinger, Daniel; Eißler, Ruth; Lorenz, Steffen; Strand, Susanne; Chmielewski, Stefan; Aoqui, Cristiane; Schmaderer, Christoph; Bluyssen, Hans; Zicha, Josef; Witzke, Oliver; Scherer, Elias; Lutz, Jens; Heemann, Uwe; Baumann, Marcus

2014-03-01

Recent publications have shed new light on the role of the adaptive and innate immune system in the pathogenesis of hypertension. However, there are limited data whether receptors of the innate immune system may influence blood pressure. Toll-like receptor 4 (TLR4), a pattern recognition receptor, is a key component of the innate immune system, which is activated by exogenous and endogenous ligands. Hypertension is associated with end-organ damage and thus might lead to the release of damage-associated molecular patterns (DAMPs), which are endogenous activators of TLR4 receptors. The present study aimed to elucidate whether TLR4 signalling is able to modulate vascular contractility in an experimental model of hypertension thus contributing to blood pressure regulation. NG-nitro-l-arginine methyl ester (l-NAME)-induced hypertension was blunted in TLR4(-/-) when compared with wild-type mice. Treatment with l-NAME was associated with a release of DAMPs, leading to reactive oxygen species production of smooth muscle cells in a TLR4-dependent manner. As oxidative stress leads to an impaired function of the NO-sGC-cyclic GMP (cGMP) pathway, we were able to demonstrate that TLR4(-/-) was protected from sGC inactivation. Consequently, arterial contractility was reduced in TLR4(-/-). Cell damage-associated TLR4 signalling might act as a direct mediator of vascular contractility providing a molecular link between inflammation and hypertension.

Drosophila Nanos acts as a molecular clamp that modulates the RNA-binding and repression activities of Pumilio

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

Weidmann, Chase A.; Qiu, Chen; Arvola, René M.

Collaboration among the multitude of RNA-binding proteins (RBPs) is ubiquitous, yet our understanding of these key regulatory complexes has been limited to single RBPs. We investigated combinatorial translational regulation by Drosophila Pumilio (Pum) and Nanos (Nos), which control development, fertility, and neuronal functions. Our results show how the specificity of one RBP (Pum) is modulated by cooperative RNA recognition with a second RBP (Nos) to synergistically repress mRNAs. Crystal structures of Nos-Pum-RNA complexes reveal that Nos embraces Pum and RNA, contributes sequence-specific contacts, and increases Pum RNA-binding affinity. Nos shifts the recognition sequence and promotes repression complex formation on mRNAsmore » that are not stably bound by Pum alone, explaining the preponderance of sub-optimal Pum sites regulated in vivo. Our results illuminate the molecular mechanism of a regulatory switch controlling crucial gene expression programs, and provide a framework for understanding how the partnering of RBPs evokes changes in binding specificity that underlie regulatory network dynamics.« less

Drosophila Nanos acts as a molecular clamp that modulates the RNA-binding and repression activities of Pumilio

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

Weidmann, Chase A.; Qiu, Chen; Arvola, René M.

Collaboration among the multitude of RNA-binding proteins (RBPs) is ubiquitous, yet our understanding of these key regulatory complexes has been limited to single RBPs. We investigated combinatorial translational regulation byDrosophilaPumilio (Pum) and Nanos (Nos), which control development, fertility, and neuronal functions. Our results show how the specificity of one RBP (Pum) is modulated by cooperative RNA recognition with a second RBP (Nos) to synergistically repress mRNAs. Crystal structures of Nos-Pum-RNA complexes reveal that Nos embraces Pum and RNA, contributes sequence-specific contacts, and increases Pum RNA-binding affinity. Nos shifts the recognition sequence and promotes repression complex formation on mRNAs that aremore » not stably bound by Pum alone, explaining the preponderance of sub-optimal Pum sites regulatedin vivo. Our results illuminate the molecular mechanism of a regulatory switch controlling crucial gene expression programs, and provide a framework for understanding how the partnering of RBPs evokes changes in binding specificity that underlie regulatory network dynamics.« less

Structure and mechanism of a molecular rheostat, an RNA thermometer that modulates immune evasion by Neisseria meningitidis

PubMed Central

Barnwal, Ravi Pratap; Loh, Edmund; Godin, Katherine S.; Yip, Jordan; Lavender, Hayley; Tang, Christoph M.; Varani, Gabriele

2016-01-01

Neisseria meningitidis causes bacterial meningitis and septicemia. It evades the host complement system by upregulating expression of immune evasion factors in response to changes in temperature. RNA thermometers within mRNAs control expression of bacterial immune evasion factors, including CssA, in the 5′-untranslated region of the operon for capsule biosynthesis. We dissect the molecular mechanisms of thermoregulation and report the structure of the CssA thermometer. We show that the RNA thermometer acts as a rheostat, whose stability is optimized to respond in a small temperature range around 37°C as occur within the upper airways during infection. Small increases in temperature gradually open up the structure to allow progressively increased access to the ribosome binding site. Even small changes in stability induced by mutations of imperfect base pairs, as in naturally occurring polymorphisms, shift the thermometer response outside of the desired temperature range, suggesting that its activity could be modulated by pharmacological intervention. PMID:27369378

Drosophila Nanos acts as a molecular clamp that modulates the RNA-binding and repression activities of Pumilio

DOE PAGES

Weidmann, Chase A.; Qiu, Chen; Arvola, René M.; ...

2016-08-02

Collaboration among the multitude of RNA-binding proteins (RBPs) is ubiquitous, yet our understanding of these key regulatory complexes has been limited to single RBPs. We investigated combinatorial translational regulation by Drosophila Pumilio (Pum) and Nanos (Nos), which control development, fertility, and neuronal functions. Our results show how the specificity of one RBP (Pum) is modulated by cooperative RNA recognition with a second RBP (Nos) to synergistically repress mRNAs. Crystal structures of Nos-Pum-RNA complexes reveal that Nos embraces Pum and RNA, contributes sequence-specific contacts, and increases Pum RNA-binding affinity. Nos shifts the recognition sequence and promotes repression complex formation on mRNAsmore » that are not stably bound by Pum alone, explaining the preponderance of sub-optimal Pum sites regulated in vivo. Our results illuminate the molecular mechanism of a regulatory switch controlling crucial gene expression programs, and provide a framework for understanding how the partnering of RBPs evokes changes in binding specificity that underlie regulatory network dynamics.« less

Drosophila Nanos acts as a molecular clamp that modulates the RNA-binding and repression activities of Pumilio.

PubMed

Weidmann, Chase A; Qiu, Chen; Arvola, René M; Lou, Tzu-Fang; Killingsworth, Jordan; Campbell, Zachary T; Tanaka Hall, Traci M; Goldstrohm, Aaron C

2016-08-02

Collaboration among the multitude of RNA-binding proteins (RBPs) is ubiquitous, yet our understanding of these key regulatory complexes has been limited to single RBPs. We investigated combinatorial translational regulation by Drosophila Pumilio (Pum) and Nanos (Nos), which control development, fertility, and neuronal functions. Our results show how the specificity of one RBP (Pum) is modulated by cooperative RNA recognition with a second RBP (Nos) to synergistically repress mRNAs. Crystal structures of Nos-Pum-RNA complexes reveal that Nos embraces Pum and RNA, contributes sequence-specific contacts, and increases Pum RNA-binding affinity. Nos shifts the recognition sequence and promotes repression complex formation on mRNAs that are not stably bound by Pum alone, explaining the preponderance of sub-optimal Pum sites regulated in vivo. Our results illuminate the molecular mechanism of a regulatory switch controlling crucial gene expression programs, and provide a framework for understanding how the partnering of RBPs evokes changes in binding specificity that underlie regulatory network dynamics.

FUS Phase Separation Is Modulated by a Molecular Chaperone and Methylation of Arginine Cation-π Interactions.

PubMed

Qamar, Seema; Wang, GuoZhen; Randle, Suzanne J; Ruggeri, Francesco Simone; Varela, Juan A; Lin, Julie Qiaojin; Phillips, Emma C; Miyashita, Akinori; Williams, Declan; Ströhl, Florian; Meadows, William; Ferry, Rodylyn; Dardov, Victoria J; Tartaglia, Gian G; Farrer, Lindsay A; Kaminski Schierle, Gabriele S; Kaminski, Clemens F; Holt, Christine E; Fraser, Paul E; Schmitt-Ulms, Gerold; Klenerman, David; Knowles, Tuomas; Vendruscolo, Michele; St George-Hyslop, Peter

2018-04-19

Reversible phase separation underpins the role of FUS in ribonucleoprotein granules and other membrane-free organelles and is, in part, driven by the intrinsically disordered low-complexity (LC) domain of FUS. Here, we report that cooperative cation-π interactions between tyrosines in the LC domain and arginines in structured C-terminal domains also contribute to phase separation. These interactions are modulated by post-translational arginine methylation, wherein arginine hypomethylation strongly promotes phase separation and gelation. Indeed, significant hypomethylation, which occurs in FUS-associated frontotemporal lobar degeneration (FTLD), induces FUS condensation into stable intermolecular β-sheet-rich hydrogels that disrupt RNP granule function and impair new protein synthesis in neuron terminals. We show that transportin acts as a physiological molecular chaperone of FUS in neuron terminals, reducing phase separation and gelation of methylated and hypomethylated FUS and rescuing protein synthesis. These results demonstrate how FUS condensation is physiologically regulated and how perturbations in these mechanisms can lead to disease. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Frequency Domain Fluorescent Molecular Tomography and Molecular Probes for Small Animal Imaging

NASA Astrophysics Data System (ADS)

Kujala, Naresh Gandhi

Fluorescent molecular tomography (FMT) is a noninvasive biomedical optical imaging that enables 3-dimensional quantitative determination of fluorochromes distributed in biological tissues. There are three methods for imaging large volume tissues based on different light sources: (a) using a light source of constant intensity, through a continuous or constant wave, (b) using a light source that is intensity modulated with a radio frequency (RF), and (c) using ultrafast pulses in the femtosecond range. In this study, we have developed a frequency domain fluorescent molecular tomographic system based on the heterodyne technique, using a single source and detector pair that can be used for small animal imaging. In our system, the intensity of the laser source is modulated with a RF frequency to produce a diffuse photon density wave in the tissue. The phase of the diffuse photon density wave is measured by comparing the reference signal with the signal from the tissue using a phasemeter. The data acquisition was performed by using a Labview program. The results suggest that we can measure the phase change from the heterogeneous inside tissue. Combined with fiber optics and filter sets, the system can be used to sensitively image the targeted fluorescent molecular probes, allowing the detection of cancer at an early stage. We used the system to detect the tumor-targeting molecular probe Alexa Fluor 680 and Alexa Fluor 750 bombesin peptide conjugates in phantoms as well as mouse tissues. We also developed and evaluated fluorescent Bombesin (BBN) probes to target gastrin-releasing peptide (GRP) receptors for optical molecular imaging. GRP receptors are over-expressed in several types of human cancer cells, including breast, prostate, small cell lung, and pancreatic cancers. BBN is a 14 amino acid peptide that is an analogue to human gastrin-releasing peptide that binds specifically to GRPr receptors. BBN conjugates are significant in cancer detection and therapy. The

An autonomous molecular computer for logical control of gene expression.

PubMed

Benenson, Yaakov; Gil, Binyamin; Ben-Dor, Uri; Adar, Rivka; Shapiro, Ehud

2004-05-27

Early biomolecular computer research focused on laboratory-scale, human-operated computers for complex computational problems. Recently, simple molecular-scale autonomous programmable computers were demonstrated allowing both input and output information to be in molecular form. Such computers, using biological molecules as input data and biologically active molecules as outputs, could produce a system for 'logical' control of biological processes. Here we describe an autonomous biomolecular computer that, at least in vitro, logically analyses the levels of messenger RNA species, and in response produces a molecule capable of affecting levels of gene expression. The computer operates at a concentration of close to a trillion computers per microlitre and consists of three programmable modules: a computation module, that is, a stochastic molecular automaton; an input module, by which specific mRNA levels or point mutations regulate software molecule concentrations, and hence automaton transition probabilities; and an output module, capable of controlled release of a short single-stranded DNA molecule. This approach might be applied in vivo to biochemical sensing, genetic engineering and even medical diagnosis and treatment. As a proof of principle we programmed the computer to identify and analyse mRNA of disease-related genes associated with models of small-cell lung cancer and prostate cancer, and to produce a single-stranded DNA molecule modelled after an anticancer drug.

Accelerating the use of molecular modeling in the high school classroom with VMD Lite.

PubMed

Lundquist, Karl; Herndon, Conner; Harty, Tyson H; Gumbart, James C

2016-01-01

It is often difficult for students to develop an intuition about molecular processes, which occur in a realm far different from day-to-day life. For example, thermal fluctuations take on hurricane-like proportions at the molecular scale. Students need a way to visualize realistic depictions of molecular processes to appreciate them. To this end, we have developed a simplified graphical interface to the widely used molecular visualization and analysis tool Visual Molecular Dynamics (VMD) called VMD lite. We demonstrate the use of VMD lite through a module on diffusion and the hydrophobic effect as they relate to membrane formation. Trajectories from molecular dynamics simulations, which students can interact with freely, illustrate the dynamical behavior of lipid molecules and water. VMD lite was tested by ∼70 students with overall positive reception. Remaining deficiencies in conceptual understanding were noted, however, and the module has been revised in response. © 2016 The International Union of Biochemistry and Molecular Biology.

Demonstration of 40 MHz thin-film electro-optic modulator using an organic molecular salt

NASA Astrophysics Data System (ADS)

Bhowmik, Achintya; Ahyi, Ayayi; Tan, Shida; Mishra, Alpana; Thakur, Mrinal

2000-03-01

Recently we reported the first demonstration of a single-pass thin-film electro-optic modulator based on a DAST single-crystal film.(M. Thakur, J. Xu, A. Bhowmik, and L. Zhou, Appl. Phys. Lett. 74, 635-637 (1999).) In this work, we report a larger modulation depth ( ~80%) and higher speed of operation. Excellent optical quality single-crystal films were prepared by a modified shear method.(M. Thakur and S. Meyler, Macromolecules 18, 2341 (1985); M. Thakur, Y. Shani, G. C. Chi, and K. O'Brien, Synth. Met. 28, D595 (1989).) Thin-film modulator was constructed by depositing electrodes across the polar axis. The beam from a Ti-Sapphire laser, tunable over 720-850 nm, was propagated perpendicular to the film surface. The modulated signal was detected using a fast photodetector, and displayed on a high bandwidth oscilloscope and a spectrum analyzer. The response was independent of the frequency of applied field over the measurement range (2 kHz - 40 MHz). A much higher speed (>100 GHz) of operation should be possible using these films. These modulators involve negligible losses compared to the waveguide structures, and have significant potential for a broad range of applications in high speed optical signal processing.

The effect of molecular shape on oligomerization of hydrophobic drugs: Molecular simulations of ciprofloxacin and nutlin

NASA Astrophysics Data System (ADS)

Li, Jianguo; Beuerman, Roger; Verma, Chandra

2018-03-01

Molecular aggregation plays a significant role in modulating the solubility, permeability, and bioactivity of drugs. The propensity to aggregate depends on hydrophobicity and on molecular shape. Molecular dynamics simulations coupled with enhanced sampling methods are used to explore the early stages of oligomerization of two drug molecules which have a strong aggregation propensity, but with contrasting molecule shapes: the antibiotic ciprofloxacin and the anticancer drug Nutlin-3A. The planar shape of ciprofloxacin induces the formation of stable oligomers at all cluster sizes. The aggregation of ciprofloxacin is driven by two-body interactions, and transferring one ciprofloxacin molecule to an existing cluster involves the desolvation of two faces and the concomitant hydrophobic interactions between the two faces; thus, the corresponding free energy of oligomerization weakly depends on the oligomer size. By contrast, Nutlin-3A has a star-shape and hence can only form stable oligomers when the cluster size is greater than 8. Free energy simulations further confirmed that the free energy of oligomer formation for Nutlin-3A becomes more favorable as the oligomer becomes larger. The aggregation of star-shaped Nutlin-3A results from many-body interactions and hence the free energy of cluster formation is strongly dependent on the size. The findings of this study provide atomistic insights into how molecular shape modulates the aggregation behavior of molecules and may be factored into the design of drugs or nano-particles.

Drosophila Nanos acts as a molecular clamp that modulates the RNA-binding and repression activities of Pumilio

PubMed Central

Weidmann, Chase A; Qiu, Chen; Arvola, René M; Lou, Tzu-Fang; Killingsworth, Jordan; Campbell, Zachary T; Tanaka Hall, Traci M; Goldstrohm, Aaron C

2016-01-01

Collaboration among the multitude of RNA-binding proteins (RBPs) is ubiquitous, yet our understanding of these key regulatory complexes has been limited to single RBPs. We investigated combinatorial translational regulation by Drosophila Pumilio (Pum) and Nanos (Nos), which control development, fertility, and neuronal functions. Our results show how the specificity of one RBP (Pum) is modulated by cooperative RNA recognition with a second RBP (Nos) to synergistically repress mRNAs. Crystal structures of Nos-Pum-RNA complexes reveal that Nos embraces Pum and RNA, contributes sequence-specific contacts, and increases Pum RNA-binding affinity. Nos shifts the recognition sequence and promotes repression complex formation on mRNAs that are not stably bound by Pum alone, explaining the preponderance of sub-optimal Pum sites regulated in vivo. Our results illuminate the molecular mechanism of a regulatory switch controlling crucial gene expression programs, and provide a framework for understanding how the partnering of RBPs evokes changes in binding specificity that underlie regulatory network dynamics. DOI: http://dx.doi.org/10.7554/eLife.17096.001 PMID:27482653

Investigation of allosteric modulation mechanism of metabotropic glutamate receptor 1 by molecular dynamics simulations, free energy and weak interaction analysis

NASA Astrophysics Data System (ADS)

Bai, Qifeng; Yao, Xiaojun

2016-02-01

Metabotropic glutamate receptor 1 (mGlu1), which belongs to class C G protein-coupled receptors (GPCRs), can be coupled with G protein to transfer extracellular signal by dimerization and allosteric regulation. Unraveling the dimer packing and allosteric mechanism can be of great help for understanding specific regulatory mechanism and designing more potential negative allosteric modulator (NAM). Here, we report molecular dynamics simulation studies of the modulation mechanism of FITM on the wild type, T815M and Y805A mutants of mGlu1 through weak interaction analysis and free energy calculation. The weak interaction analysis demonstrates that van der Waals (vdW) and hydrogen bonding play an important role on the dimer packing between six cholesterol molecules and mGlu1 as well as the interaction between allosteric sites T815, Y805 and FITM in wild type, T815M and Y805A mutants of mGlu1. Besides, the results of free energy calculations indicate that secondary binding pocket is mainly formed by the residues Thr748, Cys746, Lys811 and Ser735 except for FITM-bound pocket in crystal structure. Our results can not only reveal the dimer packing and allosteric regulation mechanism, but also can supply useful information for the design of potential NAM of mGlu1.

Nucleocytoplasmic Transport: A Paradigm for Molecular Logistics in Artificial Systems.

PubMed

Vujica, Suncica; Zelmer, Christina; Panatala, Radhakrishnan; Lim, Roderick Y H

2016-01-01

Artificial organelles, molecular factories and nanoreactors are membrane-bound systems envisaged to exhibit cell-like functionality. These constitute liposomes, polymersomes or hybrid lipo-polymersomes that display different membrane-spanning channels and/or enclose molecular modules. To achieve more complex functionality, an artificial organelle should ideally sustain a continuous influx of essential macromolecular modules (i.e. cargoes) and metabolites against an outflow of reaction products. This would benefit from the incorporation of selective nanopores as well as specific trafficking factors that facilitate cargo selectivity, translocation efficiency, and directionality. Towards this goal, we describe how proteinaceous cargoes are transported between the nucleus and cytoplasm by nuclear pore complexes and the biological trafficking machinery in living cells (i.e. nucleocytoplasmic transport). On this basis, we discuss how biomimetic control may be implemented to selectively import, compartmentalize and accumulate diverse macromolecular modules against concentration gradients in artificial organelles.

Interaction of charge carriers with lattice and molecular phonons in crystalline pentacene

NASA Astrophysics Data System (ADS)

Girlando, Alberto; Grisanti, Luca; Masino, Matteo; Brillante, Aldo; Della Valle, Raffaele G.; Venuti, Elisabetta

2011-08-01

The computational protocol we have developed for the calculation of local (Holstein) and non-local (Peierls) carrier-phonon coupling in molecular organic semiconductors is applied to both the low temperature and high temperature bulk crystalline phases of pentacene. The electronic structure is calculated by the semimpirical INDO/S (Intermediate Neglect of Differential Overlap with Spectroscopic parametrization) method. In the phonon description, the rigid molecule approximation is removed, allowing mixing of low-frequency intra-molecular modes with inter-molecular (lattice) phonons. A clear distinction remains between the low-frequency phonons, which essentially modulate the transfer integral from a molecule to another (Peierls coupling), and the high-frequency intra-molecular phonons, which modulate the on-site energy (Holstein coupling). The results of calculation agree well with the values extracted from experiment. The comparison with similar calculations made for rubrene allows us to discuss the implications for the current models of mobility.

Modulation of transcription factors by curcumin.

PubMed

Shishodia, Shishir; Singh, Tulika; Chaturvedi, Madan M

2007-01-01

Curcumin is the active ingredient of turmeric that has been consumed as a dietary spice for ages. Turmeric is widely used in traditional Indian medicine to cure biliary disorders, anorexia, cough, diabetic wounds, hepatic disorders, rheumatism, and sinusitis. Extensive investigation over the last five decades has indicated that curcumin reduces blood cholesterol, prevents low-density lipoprotein oxidation, inhibits platelet aggregation, suppresses thrombosis and myocardial infarction, suppresses symptoms associated with type II diabetes, rheumatoid arthritis, multiple sclerosis, and Alzheimer's disease, inhibits HIV replication, enhances wound healing, protects from liver injury, increases bile secretion, protects from cataract formation, and protects from pulmonary toxicity and fibrosis. Evidence indicates that the divergent effects of curcumin are dependent on its pleiotropic molecular effects. These include the regulation of signal transduction pathways and direct modulation of several enzymatic activities. Most of these signaling cascades lead to the activation of transcription factors. Curcumin has been found to modulate the activity of several key transcription factors and, in turn, the cellular expression profiles. Curcumin has been shown to elicit vital cellular responses such as cell cycle arrest, apoptosis, and differentiation by activating a cascade of molecular events. In this chapter, we briefly review the effects of curcumin on transcription factors NF-KB, AP-1, Egr-1, STATs, PPAR-gamma, beta-catenin, nrf2, EpRE, p53, CBP, and androgen receptor (AR) and AR-related cofactors giving major emphasis to the molecular mechanisms of its action.

An autonomous molecular computer for logical control of gene expression

PubMed Central

Benenson, Yaakov; Gil, Binyamin; Ben-Dor, Uri; Adar, Rivka; Shapiro, Ehud

2013-01-01

Early biomolecular computer research focused on laboratory-scale, human-operated computers for complex computational problems1–7. Recently, simple molecular-scale autonomous programmable computers were demonstrated8–15 allowing both input and output information to be in molecular form. Such computers, using biological molecules as input data and biologically active molecules as outputs, could produce a system for ‘logical’ control of biological processes. Here we describe an autonomous biomolecular computer that, at least in vitro, logically analyses the levels of messenger RNA species, and in response produces a molecule capable of affecting levels of gene expression. The computer operates at a concentration of close to a trillion computers per microlitre and consists of three programmable modules: a computation module, that is, a stochastic molecular automaton12–17; an input module, by which specific mRNA levels or point mutations regulate software molecule concentrations, and hence automaton transition probabilities; and an output module, capable of controlled release of a short single-stranded DNA molecule. This approach might be applied in vivo to biochemical sensing, genetic engineering and even medical diagnosis and treatment. As a proof of principle we programmed the computer to identify and analyse mRNA of disease-related genes18–22 associated with models of small-cell lung cancer and prostate cancer, and to produce a single-stranded DNA molecule modelled after an anticancer drug. PMID:15116117

Method of assembly of molecular-sized nets and scaffolding

DOEpatents

Michl, Josef; Magnera, Thomas F.; David, Donald E.; Harrison, Robin M.

1999-01-01

The present invention relates to methods and starting materials for forming molecular-sized grids or nets, or other structures based on such grids and nets, by creating molecular links between elementary molecular modules constrained to move in only two directions on an interface or surface by adhesion or bonding to that interface or surface. In the methods of this invention, monomers are employed as the building blocks of grids and more complex structures. Monomers are introduced onto and allowed to adhere or bond to an interface. The connector groups of adjacent adhered monomers are then polymerized with each other to form a regular grid in two dimensions above the interface. Modules that are not bound or adhered to the interface are removed prior to reaction of the connector groups to avoid undesired three-dimensional cross-linking and the formation of non-grid structures. Grids formed by the methods of this invention are useful in a variety of applications, including among others, for separations technology, as masks for forming regular surface structures (i.e., metal deposition) and as templates for three-dimensional molecular-sized structures.

Method of assembly of molecular-sized nets and scaffolding

DOEpatents

Michl, J.; Magnera, T.F.; David, D.E.; Harrison, R.M.

1999-03-02

The present invention relates to methods and starting materials for forming molecular-sized grids or nets, or other structures based on such grids and nets, by creating molecular links between elementary molecular modules constrained to move in only two directions on an interface or surface by adhesion or bonding to that interface or surface. In the methods of this invention, monomers are employed as the building blocks of grids and more complex structures. Monomers are introduced onto and allowed to adhere or bond to an interface. The connector groups of adjacent adhered monomers are then polymerized with each other to form a regular grid in two dimensions above the interface. Modules that are not bound or adhered to the interface are removed prior to reaction of the connector groups to avoid undesired three-dimensional cross-linking and the formation of non-grid structures. Grids formed by the methods of this invention are useful in a variety of applications, including among others, for separations technology, as masks for forming regular surface structures (i.e., metal deposition) and as templates for three-dimensional molecular-sized structures. 9 figs.

Single molecular force across single integrins dictates cell spreading.

PubMed

Chowdhury, Farhan; Li, Isaac T S; Leslie, Benjamin J; Doğanay, Sultan; Singh, Rishi; Wang, Xuefeng; Seong, Jihye; Lee, Sang-Hak; Park, Seongjin; Wang, Ning; Ha, Taekjip

2015-10-01

Cells' ability to sense and interpret mechanical signals from the extracellular milieu modulates the degree of cell spreading. Yet how cells detect such signals and activate downstream signaling at the molecular level remain elusive. Herein, we utilize tension gauge tether (TGT) platform to investigate the underlying molecular mechanism of cell spreading. Our data from both differentiated cells of cancerous and non-cancerous origin show that for the same stiff underlying glass substrates and for same ligand density it is the molecular forces across single integrins that ultimately determine cell spreading responses. Furthermore, by decoupling molecular stiffness and molecular tension we demonstrate that molecular stiffness has little influence on cell spreading. Our data provide strong evidence that links molecular forces at the cell-substrate interface to the degree of cell spreading.

Biphasic patterns of diversification and the emergence of modules

PubMed Central

Mittenthal, Jay; Caetano-Anollés, Derek; Caetano-Anollés, Gustavo

2012-01-01

The intricate molecular and cellular structure of organisms converts energy to work, which builds and maintains structure. Evolving structure implements modules, in which parts are tightly linked. Each module performs characteristic functions. In this work we propose that a module can emerge through two phases of diversification of parts. Early in the first phase of this biphasic pattern, the parts have weak linkage—they interact weakly and associate variously. The parts diversify and compete. Under selection for performance, interactions among the parts increasingly constrain their structure and associations. As many variants are eliminated, parts self-organize into modules with tight linkage. Linkage may increase in response to exogenous stresses as well as endogenous processes. In the second phase of diversification, variants of the module and its functions evolve and become new parts for a new cycle of generation of higher-level modules. This linkage hypothesis can interpret biphasic patterns in the diversification of protein domain structure, RNA and protein shapes, and networks in metabolism, codes, and embryos, and can explain hierarchical levels of structural organization that are widespread in biology. PMID:22891076

Long noncoding RNA GAPLINC promotes gastric cancer cell proliferation by acting as a molecular sponge of miR-378 to modulate MAPK1 expression.

PubMed

Diao, Lingyun; Wang, Shengying; Sun, Zhiguang

2018-01-01

Dysregulated long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) play key roles in the development of human cancers. LncRNA GAPLINC has been reported to be increased in gastric cancer (GC) tissues. Real-time PCR assays were used to measure expressions of GAPLINC, miR-378, and MAPK1 mRNA. Western blot assays were employed to examine MAPK1 protein expression. Cell proliferation and cell cycle were measured by CCK-8 and propidium iodide-detection assays, respectively. The interaction between GAPLINC and miR-378 was confirmed by site-directed mutagenesis and luciferase assays. Luciferase assays were also used to study whether GAPLINC was able to act as a molecular sponge of miR-378 to modulate MAPK1 expression. The lncRNA GAPLINC expression was upregulated and positively correlated with MAPK1 expression in gastric cancer tissues and cells. Additionally, lncRNA GAPLINC promoted the expression of MAPK1 and the enhancement of GC cell proliferation and cell cycle progression by LncRNA GAPLINC was dependent on MAPK1 in vitro and in vivo. Consequently, we found that miR-378 expression was inversely correlated with GAPLINC expression in GC tissues and cells. miR-378 could directly bind to GAPLINC and decreased GAPLINC expression, thus reducing MAPK1 expression. Furthermore, overexpression of miR-378 inhibited MAPK1 expression, cell proliferation, and cell cycle progression of gastric cancer cells, while these effects were abrogated by upregulating lncRNA GAPLINC expression. Taken together, lncRNA GAPLINC promotes gastric cancer cell proliferation by acting as a molecular sponge of miR-378 to modulate MAPK1 expression.

Exploration of cell cycle regulation and modulation of the DNA methylation mechanism of pelargonidin: Insights from the molecular modeling approach.

PubMed

Karthi, Natesan; Karthiga, Arumugasamy; Kalaiyarasu, Thangaraj; Stalin, Antony; Manju, Vaiyapuri; Singh, Sanjeev Kumar; Cyril, Ravi; Lee, Sang-Myeong

2017-10-01

Pelargonidin is an anthocyanidin isolated from plant resources. It shows strong cytotoxicity toward various cancer cell lines, even though the carcinogenesis-modulating pathway of pelargonidin is not yet known. One of our previous reports showed that pelargonidin arrests the cell cycle and induces apoptosis in HT29 cells. Flowcytometry and immunoblot analysis confirmed that pelargonidin specifically inhibits the activation of CDK1 and blocks the G2-M transition of the cell cycle. In addition, DNA fragmentation was observed along with induction of cytochrome c release-mediated apoptosis. Hence, the aim of the present study was to investigate the molecular mechanism of pelargonidin's action on cell cycle regulators CDK1, CDK4, and CDK6 as well as the substrate-binding domain of DNMT1 and DNMT3A, which regulate the epigenetic signals related to DNA methylation. The results of docking analysis, binding free energy calculation, and molecular dynamics simulation correlated with the experimental results, and pelargonidin showed a specific interaction with CDK1. In this context, pelargonidin may also inhibit the recognition of DNA and catalytic binding by DNMT1 and DNMT3A. The HOMO-LUMO analysis mapped the functional groups of pelargonidin. Prediction of pharmacological descriptors suggested that pelargonidin can serve as a multitarget inhibitor for cancer treatment. Copyright © 2017 Elsevier Ltd. All rights reserved.

Solvent fluctuations and nuclear quantum effects modulate the molecular hyperpolarizability of water

NASA Astrophysics Data System (ADS)

Liang, Chungwen; Tocci, Gabriele; Wilkins, David M.; Grisafi, Andrea; Roke, Sylvie; Ceriotti, Michele

2017-07-01

Second-harmonic scattering (SHS) experiments provide a unique approach to probe noncentrosymmetric environments in aqueous media, from bulk solutions to interfaces, living cells, and tissue. A central assumption made in analyzing SHS experiments is that each molecule scatters light according to a constant molecular hyperpolarizability tensor β(2 ). Here, we investigate the dependence of the molecular hyperpolarizability of water on its environment and internal geometric distortions, in order to test the hypothesis of constant β(2 ). We use quantum chemistry calculations of the hyperpolarizability of a molecule embedded in point-charge environments obtained from simulations of bulk water. We demonstrate that both the heterogeneity of the solvent configurations and the quantum mechanical fluctuations of the molecular geometry introduce large variations in the nonlinear optical response of water. This finding has the potential to change the way SHS experiments are interpreted: In particular, isotopic differences between H2O and D2O could explain recent SHS observations. Finally, we show that a machine-learning framework can predict accurately the fluctuations of the molecular hyperpolarizability. This model accounts for the microscopic inhomogeneity of the solvent and represents a step towards quantitative modeling of SHS experiments.

Rapid effects of estrogens on behavior: environmental modulation and molecular mechanisms.

PubMed

Laredo, Sarah A; Villalon Landeros, Rosalina; Trainor, Brian C

2014-10-01

Estradiol can modulate neural activity and behavior via both genomic and nongenomic mechanisms. Environmental cues have a major impact on the relative importance of these signaling pathways with significant consequences for behavior. First we consider how photoperiod modulates nongenomic estrogen signaling on behavior. Intriguingly, short days permit rapid effects of estrogens on aggression in both rodents and song sparrows. This highlights the importance of considering photoperiod as a variable in laboratory research. Next we review evidence for rapid effects of estradiol on ecologically-relevant behaviors including aggression, copulation, communication, and learning. We also address the impact of endocrine disruptors on estrogen signaling, such as those found in corncob bedding used in rodent research. Finally, we examine the biochemical mechanisms that may mediate rapid estrogen action on behavior in males and females. A common theme across these topics is that the effects of estrogens on social behaviors vary across different environmental conditions. Copyright © 2014 Elsevier Inc. All rights reserved.

Molecular Dynamics Simulations Reveal the Mechanisms of Allosteric Activation of Hsp90 by Designed Ligands

NASA Astrophysics Data System (ADS)

Vettoretti, Gerolamo; Moroni, Elisabetta; Sattin, Sara; Tao, Jiahui; Agard, David A.; Bernardi, Anna; Colombo, Giorgio

2016-04-01

Controlling biochemical pathways through chemically designed modulators may provide novel opportunities to develop therapeutic drugs and chemical tools. The underlying challenge is to design new molecular entities able to act as allosteric chemical switches that selectively turn on/off functions by modulating the conformational dynamics of their target protein. We examine the origins of the stimulation of ATPase and closure kinetics in the molecular chaperone Hsp90 by allosteric modulators through atomistic molecular dynamics (MD) simulations and analysis of protein-ligand interactions. In particular, we focus on the cross-talk between allosteric ligands and protein conformations and its effect on the dynamic properties of the chaperone’s active state. We examine the impact of different allosteric modulators on the stability, structural and internal dynamics properties of Hsp90 closed state. A critical aspect of this study is the development of a quantitative model that correlates Hsp90 activation to the presence of a certain compound, making use of information on the dynamic adaptation of protein conformations to the presence of the ligand, which allows to capture conformational states relevant in the activation process. We discuss the implications of considering the conformational dialogue between allosteric ligands and protein conformations for the design of new functional modulators.

Angular and Intensity Dependent Spectral Modulations in High Harmonics from N2

NASA Astrophysics Data System (ADS)

McFarland, Brian; Farrell, Joseph; Bucksbaum, Philip; Guehr, Markus

2009-05-01

The spectral amplitude and phase modulation of high harmonics (HHG) in molecules provides important clues to molecular structure and dynamics in strong laser fields. We have studied these effects in aligned N2. Earlier results of HHG experiments claimed that the spectral amplitude modulation was predominantly due to geometrical interference between the recombining electron and the highest occupied molecular orbital (HOMO) [1]. We report evidence that contradicts this simple view. We observe a phase jump accompanied by a spectral minimum for HHG in aligned N2. The minimum shifts to lower harmonics as the angle between the molecular axis and harmonic generation polarization increases, and shifts to higher harmonics with increasing harmonic generation intensity. The features observed cannot be fully explained by a geometrical model. We discuss alternative explanations involving multi orbital effects [2]. [0pt] [1] Lein et al., Phys. Rev. A, 66, 023805 (2002) [2] B. K. McFarland, J. P. Farrell, P. H. Bucksbaum and M. Gühr, Science 322, 1232 (2008)

Molecular transistors based on BDT-type molecular bridges.

PubMed

Wheeler, W D; Dahnovsky, Yu

2008-10-21

In this work we study the effect of electron correlations in molecular transistors with molecular bridges based on 1,4-benzene-dithiol (BDT) and 2-nitro-1,4-benzene-dithiol (nitro-BDT) by using ab initio electron propagator calculations. We find that there is no gate field effect for the BDT based transistor in accordance with the experimental data. After verifying the computational method on the BDT molecule, we consider a transistor with a nitro-BDT molecular bridge. From the electron propagator calculations, we predict strong negative differential resistance at small positive and negative values of source-drain voltages. The explanation of the peak and the minimum in the current is given in terms of the molecular orbital picture and switch-on (-off) properties due to the voltage dependencies of the Dyson poles (ionization potentials). When the current is off, the electronic states on both electrodes are populated resulting in the vanishing tunneling probability due to the Pauli principle. Besides the minimum and the maximum in the I-V characteristics, we find a strong gate field effect in the conductance where the peak at V(sd) = 0.15 eV and E(g) = 4x10(-3) a.u. switches to the minimum at E(g) = -4x10(-3) a.u. A similar behavior is discovered at the negative V(sd). Such a feature can be used for fast current modulation by changing the polarity of a gate field.

Molecular Mechanisms of Neuroplasticity: An Expanding Universe.

PubMed

Gulyaeva, N V

2017-03-01

Biochemical processes in synapses and other neuronal compartments underlie neuroplasticity (functional and structural alterations in the brain enabling adaptation to the environment, learning, memory, as well as rehabilitation after brain injury). This basic molecular level of brain plasticity covers numerous specific proteins (enzymes, receptors, structural proteins, etc.) participating in many coordinated and interacting signal and metabolic processes, their modulation forming a molecular basis for brain plasticity. The articles in this issue are focused on different "hot points" in the research area of biochemical mechanisms supporting neuroplasticity.

GHz Modulation of GaAs-Based Bipolar Cascade VCSELs (Preprint)

DTIC Science & Technology

2006-11-01

VCSELs were grown on n+ GaAs substrates by molecular beam epitaxy . The laser cavities consist of 1-, 2-, or 3-stage 52λ microcavi- ties, each containing...AFRL-SN-WP-TP-2006-128 GHz MODULATION OF GaAs-BASED BIPOLAR CASCADE VCSELs (PREPRINT) W.J. Siskaninetz, R.G. Bedford, T.R. Nelson, Jr., J.E...TITLE AND SUBTITLE GHz MODULATION OF GaAs-BASED BIPOLAR CASCADE VCSELs (PREPRINT) 5c. PROGRAM ELEMENT NUMBER 69199F 5d. PROJECT NUMBER 2002 5e

CURVATURE-DRIVEN MOLECULAR FLOW ON MEMBRANE SURFACE*

PubMed Central

MIKUCKI, MICHAEL; ZHOU, Y. C.

2017-01-01

This work presents a mathematical model for the localization of multiple species of diffusion molecules on membrane surfaces. Morphological change of bilayer membrane in vivo is generally modulated by proteins. Most of these modulations are associated with the localization of related proteins in the crowded lipid environments. We start with the energetic description of the distributions of molecules on curved membrane surface, and define the spontaneous curvature of bilayer membrane as a function of the molecule concentrations on membrane surfaces. A drift-diffusion equation governs the gradient flow of the surface molecule concentrations. We recast the energetic formulation and the related governing equations by using an Eulerian phase field description to define membrane morphology. Computational simulations with the proposed mathematical model and related numerical techniques predict (i) the molecular localization on static membrane surfaces at locations with preferred mean curvatures, and (ii) the generation of preferred mean curvature which in turn drives the molecular localization. PMID:29056778

Modulation of DNA binding by gene-specific transcription factors.

PubMed

Schleif, Robert F

2013-10-01

The transcription of many genes, particularly in prokaryotes, is controlled by transcription factors whose activity can be modulated by controlling their DNA binding affinity. Understanding the molecular mechanisms by which DNA binding affinity is regulated is important, but because forming definitive conclusions usually requires detailed structural information in combination with data from extensive biophysical, biochemical, and sometimes genetic experiments, little is truly understood about this topic. This review describes the biological requirements placed upon DNA binding transcription factors and their consequent properties, particularly the ways that DNA binding affinity can be modulated and methods for its study. What is known and not known about the mechanisms modulating the DNA binding affinity of a number of prokaryotic transcription factors, including CAP and lac repressor, is provided.

Enhancing molecular logic through modulation of temporal and spatial constraints with quantum dot-based systems that use fluorescent (Förster) resonance energy transfer

NASA Astrophysics Data System (ADS)

Claussen, Jonathan C.; Algar, W. Russ; Hildebrandt, Niko; Susumu, Kimihiro; Ancona, Mario G.; Medintz, Igor L.

2013-10-01

Luminescent semiconductor nanocrystals or quantum dots (QDs) contain favorable photonic properties (e.g., resistance to photobleaching, size-tunable PL, and large effective Stokes shifts) that make them well-suited for fluorescence (Förster) resonance energy transfer (FRET) based applications including monitoring proteolytic activity, elucidating the effects of nanoparticles-mediated drug delivery, and analyzing the spatial and temporal dynamics of cellular biochemical processes. Herein, we demonstrate how unique considerations of temporal and spatial constraints can be used in conjunction with QD-FRET systems to open up new avenues of scientific discovery in information processing and molecular logic circuitry. For example, by conjugating both long lifetime luminescent terbium(III) complexes (Tb) and fluorescent dyes (A647) to a single QD, we can create multiple FRET lanes that change temporally as the QD acts as both an acceptor and donor at distinct time intervals. Such temporal FRET modulation creates multi-step FRET cascades that produce a wealth of unique photoluminescence (PL) spectra that are well-suited for the construction of a photonic alphabet and photonic logic circuits. These research advances in bio-based molecular logic open the door to future applications including multiplexed biosensing and drug delivery for disease diagnostics and treatment.

bc-GenExMiner 3.0: new mining module computes breast cancer gene expression correlation analyses.

PubMed

Jézéquel, Pascal; Frénel, Jean-Sébastien; Campion, Loïc; Guérin-Charbonnel, Catherine; Gouraud, Wilfried; Ricolleau, Gabriel; Campone, Mario

2013-01-01

We recently developed a user-friendly web-based application called bc-GenExMiner (http://bcgenex.centregauducheau.fr), which offered the possibility to evaluate prognostic informativity of genes in breast cancer by means of a 'prognostic module'. In this study, we develop a new module called 'correlation module', which includes three kinds of gene expression correlation analyses. The first one computes correlation coefficient between 2 or more (up to 10) chosen genes. The second one produces two lists of genes that are most correlated (positively and negatively) to a 'tested' gene. A gene ontology (GO) mining function is also proposed to explore GO 'biological process', 'molecular function' and 'cellular component' terms enrichment for the output lists of most correlated genes. The third one explores gene expression correlation between the 15 telomeric and 15 centromeric genes surrounding a 'tested' gene. These correlation analyses can be performed in different groups of patients: all patients (without any subtyping), in molecular subtypes (basal-like, HER2+, luminal A and luminal B) and according to oestrogen receptor status. Validation tests based on published data showed that these automatized analyses lead to results consistent with studies' conclusions. In brief, this new module has been developed to help basic researchers explore molecular mechanisms of breast cancer. DATABASE URL: http://bcgenex.centregauducheau.fr

Molecular Phenotyping Combines Molecular Information, Biological Relevance, and Patient Data to Improve Productivity of Early Drug Discovery.

PubMed

Drawnel, Faye Marie; Zhang, Jitao David; Küng, Erich; Aoyama, Natsuyo; Benmansour, Fethallah; Araujo Del Rosario, Andrea; Jensen Zoffmann, Sannah; Delobel, Frédéric; Prummer, Michael; Weibel, Franziska; Carlson, Coby; Anson, Blake; Iacone, Roberto; Certa, Ulrich; Singer, Thomas; Ebeling, Martin; Prunotto, Marco

2017-05-18

Today, novel therapeutics are identified in an environment which is intrinsically different from the clinical context in which they are ultimately evaluated. Using molecular phenotyping and an in vitro model of diabetic cardiomyopathy, we show that by quantifying pathway reporter gene expression, molecular phenotyping can cluster compounds based on pathway profiles and dissect associations between pathway activities and disease phenotypes simultaneously. Molecular phenotyping was applicable to compounds with a range of binding specificities and triaged false positives derived from high-content screening assays. The technique identified a class of calcium-signaling modulators that can reverse disease-regulated pathways and phenotypes, which was validated by structurally distinct compounds of relevant classes. Our results advocate for application of molecular phenotyping in early drug discovery, promoting biological relevance as a key selection criterion early in the drug development cascade. Copyright © 2017 Elsevier Ltd. All rights reserved.

Molecular Modulation of Prefrontal Cortex: Rational Development of Treatments for Psychiatric Disorders

PubMed Central

Gamo, Nao J.; Arnsten, Amy F.T.

2011-01-01

Dysfunction of the prefrontal cortex (PFC) is a central feature of many psychiatric disorders, such as attention deficit hyperactivity disorder (ADHD), post-traumatic stress disorder (PTSD), schizophrenia and bipolar disorder. Thus, understanding molecular influences on PFC function through basic research in animals is essential to rational drug development. In this review, we discuss the molecular signaling events initiated by norepinephrine and dopamine that strengthen working memory function mediated by the dorsolateral PFC under optimal conditions, and weaken working memory function during uncontrollable stress. We also discuss how these intracellular mechanisms can be compromised in psychiatric disorders, and how novel treatments based on these findings may restore a molecular environment conducive to PFC regulation of behavior, thought and emotion. Examples of successful translation from animals to humans include guanfacine for the treatment of ADHD and related PFC disorders, and prazosin for the treatment of PTSD. PMID:21480691

Building gene expression signatures indicative of transcription factor activation to predict AOP modulation

EPA Science Inventory

Building gene expression signatures indicative of transcription factor activation to predict AOP modulation Adverse outcome pathways (AOPs) are a framework for predicting quantitative relationships between molecular initiatin...

Nutritional strategies to modulate the adaptive response to endurance training.

PubMed

Hawley, John A

2013-01-01

In recent years, advances in molecular biology have allowed scientists to elucidate how endurance exercise training stimulates skeletal muscle remodeling (i.e. promotes mitochondrial biogenesis). A growing field of interest directly arising from our understanding of the molecular bases of training adaptation is how nutrient availability can alter the regulation of many contraction-induced events in muscle in response to endurance exercise. Acutely manipulating substrate availability can exert profound effects on muscle energy stores and patterns of fuel metabolism during exercise, as well as many processes activating gene expression and cell signaling. Accordingly, such interventions when repeated over weeks and months have the potential to modulate numerous adaptive processes in skeletal muscle that ultimately drive the phenotype-specific characteristics observed in highly trained athletes. In this review, the molecular and cellular events that occur in skeletal muscle during and after endurance exercise are discussed and evidence provided to demonstrate that nutrient availability plays an important role in modulating many of the adaptive responses to training. Emphasis is on human studies that have determined the regulatory role of muscle glycogen availability on cell metabolism, endurance training capacity and performance. Copyright © 2013 Nestec Ltd., Vevey/S. Karger AG, Basel.

Chemical and thermal modulation of molecular motor activities

NASA Astrophysics Data System (ADS)

Hong, Weili

Molecular motors of kinesin and dynein families are responsible for various intracellular activities, from long distance movement of organelles, vesicles, protein complexes, and mRNAs to powering mitotic processes. They can take nanometer steps using chemical energy from the hydrolysis of ATP (adenosine triphosphate), and their dysfunction is involved in many neurodegenerative diseases that require long distance transport of cargos. Here I report on the study of the properties of molecular motors at a single-molecule level using optical trappings. I first studied the inhibition properties of kinesin motors by marine natural compound adociasulfates. I showed that adociasulfates compete with microtubules for binding to kinesins and thus inhibit kinesins' activity. Although adociasulfates are a strong inhibitor for all kinesin members, they show a much higher inhibition effect for conventional kinesins than for mitotic kinesins. Thus adociasulfates can be used to specifically inhibit conventional kinesins. By comparing the inhibition of kinesins by two structurally similar adociasulfates, one can see that the negatively charged sulfate residue of adociasulfates can be replaced by other negative residues and thus make it possible for adociasulfate-derived compounds to be more cell permeable. Kinesins and dyneins move cargos towards opposite directions along a microtubule. Cargos with both kinesins and dyneins attached often move bidirectionally due to undergoing a tug-of-war between the oppositely moving kinesin and dynein motors. Here I studied the effect of temperature on microtubule-based kinesin and dynein motor transport. While kinesins' and dyneins' velocities are closely matched above 15 °C, below this temperature the dyneins' velocity decreases much faster than the kinesins'. The kinesins' and dyneins' forces do not measurably change with temperature. The results suggest that temperature has significant effects on bidirectional transport and can be used to

GLADIATOR: a global approach for elucidating disease modules.

PubMed

Silberberg, Yael; Kupiec, Martin; Sharan, Roded

2017-05-26

Understanding the genetic basis of disease is an important challenge in biology and medicine. The observation that disease-related proteins often interact with one another has motivated numerous network-based approaches for deciphering disease mechanisms. In particular, protein-protein interaction networks were successfully used to illuminate disease modules, i.e., interacting proteins working in concert to drive a disease. The identification of these modules can further our understanding of disease mechanisms. We devised a global method for the prediction of multiple disease modules simultaneously named GLADIATOR (GLobal Approach for DIsease AssociaTed mOdule Reconstruction). GLADIATOR relies on a gold-standard disease phenotypic similarity to obtain a pan-disease view of the underlying modules. To traverse the search space of potential disease modules, we applied a simulated annealing algorithm aimed at maximizing the correlation between module similarity and the gold-standard phenotypic similarity. Importantly, this optimization is employed over hundreds of diseases simultaneously. GLADIATOR's predicted modules highly agree with current knowledge about disease-related proteins. Furthermore, the modules exhibit high coherence with respect to functional annotations and are highly enriched with known curated pathways, outperforming previous methods. Examination of the predicted proteins shared by similar diseases demonstrates the diverse role of these proteins in mediating related processes across similar diseases. Last, we provide a detailed analysis of the suggested molecular mechanism predicted by GLADIATOR for hyperinsulinism, suggesting novel proteins involved in its pathology. GLADIATOR predicts disease modules by integrating knowledge of disease-related proteins and phenotypes across multiple diseases. The predicted modules are functionally coherent and are more in line with current biological knowledge compared to modules obtained using previous disease

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

Single-Molecule Real-Time 3D Imaging of the Transcription Cycle by Modulation Interferometry.

PubMed

Wang, Guanshi; Hauver, Jesse; Thomas, Zachary; Darst, Seth A; Pertsinidis, Alexandros

2016-12-15

Many essential cellular processes, such as gene control, employ elaborate mechanisms involving the coordination of large, multi-component molecular assemblies. Few structural biology tools presently have the combined spatial-temporal resolution and molecular specificity required to capture the movement, conformational changes, and subunit association-dissociation kinetics, three fundamental elements of how such intricate molecular machines work. Here, we report a 3D single-molecule super-resolution imaging study using modulation interferometry and phase-sensitive detection that achieves <2 nm axial localization precision, well below the few-nanometer-sized individual protein components. To illustrate the capability of this technique in probing the dynamics of complex macromolecular machines, we visualize the movement of individual multi-subunit E. coli RNA polymerases through the complete transcription cycle, dissect the kinetics of the initiation-elongation transition, and determine the fate of σ 70 initiation factors during promoter escape. Modulation interferometry sets the stage for single-molecule studies of several hitherto difficult-to-investigate multi-molecular transactions that underlie genome regulation. Copyright © 2016 Elsevier Inc. All rights reserved.

Interactions Between Anandamide and Corticotropin-Releasing Factor Signaling Modulate Human Amygdala Function and Risk for Anxiety Disorders: An Imaging Genetics Strategy for Modeling Molecular Interactions.

PubMed

Demers, Catherine H; Drabant Conley, Emily; Bogdan, Ryan; Hariri, Ahmad R

2016-09-01

Preclinical models reveal that stress-induced amygdala activity and impairment in fear extinction reflect reductions in anandamide driven by corticotropin-releasing factor receptor type 1 (CRF1) potentiation of the anandamide catabolic enzyme fatty acid amide hydrolase. Here, we provide clinical translation for the importance of these molecular interactions using an imaging genetics strategy to examine whether interactions between genetic polymorphisms associated with differential anandamide (FAAH rs324420) and CRF1 (CRHR1 rs110402) signaling modulate amygdala function and anxiety disorder diagnosis. Analyses revealed that individuals with a genetic background predicting relatively high anandamide and CRF1 signaling exhibited blunted basolateral amygdala habituation, which further mediated increased risk for anxiety disorders among these same individuals. The convergence of preclinical and clinical data suggests that interactions between anandamide and CRF1 represent a fundamental molecular mechanism regulating amygdala function and anxiety. Our results further highlight the potential of imaging genetics to powerfully translate complex preclinical findings to clinically meaningful human phenotypes. Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

The Jukes-Cantor Model of Molecular Evolution

ERIC Educational Resources Information Center

Erickson, Keith

2010-01-01

The material in this module introduces students to some of the mathematical tools used to examine molecular evolution. This topic is standard fare in many mathematical biology or bioinformatics classes, but could also be suitable for classes in linear algebra or probability. While coursework in matrix algebra, Markov processes, Monte Carlo…

Exploring protein structure and dynamics through a project-oriented biochemistry laboratory module.

PubMed

Lipchock, James M; Ginther, Patrick S; Douglas, Bonnie B; Bird, Kelly E; Patrick Loria, J

2017-09-01

Here, we present a 10-week project-oriented laboratory module designed to provide a course-based undergraduate research experience in biochemistry that emphasizes the importance of biomolecular structure and dynamics in enzyme function. This module explores the impact of mutagenesis on an important active site loop for a biomedically-relevant human enzyme, protein tyrosine phosphatase 1B (PTP1B). Over the course of the semester students guide their own mutant of PTP1B from conception to characterization in a cost-effective manner and gain exposure to fundamental techniques in biochemistry, including site-directed DNA mutagenesis, bacterial recombinant protein expression, affinity column purification, protein quantitation, SDS-PAGE, and enzyme kinetics. This project-based approach allows an instructor to simulate a research setting and prepare students for productive research beyond the classroom. Potential modifications to expand or contract this module are also provided. © 2017 by The International Union of Biochemistry and Molecular Biology, 45(5):403-410, 2017. © 2017 The International Union of Biochemistry and Molecular Biology.

Peroxisome Proliferators-Activated Receptor (PPAR) Modulators and Metabolic Disorders

PubMed Central

Cho, Min-Chul; Lee, Kyoung; Paik, Sang-Gi; Yoon, Do-Young

2008-01-01

Overweight and obesity lead to an increased risk for metabolic disorders such as impaired glucose regulation/insulin resistance, dyslipidemia, and hypertension. Several molecular drug targets with potential to prevent or treat metabolic disorders have been revealed. Interestingly, the activation of peroxisome proliferator-activated receptor (PPAR), which belongs to the nuclear receptor superfamily, has many beneficial clinical effects. PPAR directly modulates gene expression by binding to a specific ligand. All PPAR subtypes (α, γ, and σ) are involved in glucose metabolism, lipid metabolism, and energy balance. PPAR agonists play an important role in therapeutic aspects of metabolic disorders. However, undesired effects of the existing PPAR agonists have been reported. A great deal of recent research has focused on the discovery of new PPAR modulators with more beneficial effects and more safety without producing undesired side effects. Herein, we briefly review the roles of PPAR in metabolic disorders, the effects of PPAR modulators in metabolic disorders, and the technologies with which to discover new PPAR modulators. PMID:18566691

Scoria: a Python module for manipulating 3D molecular data.

PubMed

Ropp, Patrick; Friedman, Aaron; Durrant, Jacob D

2017-09-18

Third-party packages have transformed the Python programming language into a powerful computational-biology tool. Package installation is easy for experienced users, but novices sometimes struggle with dependencies and compilers. This presents a barrier that can hinder the otherwise broad adoption of new tools. We present Scoria, a Python package for manipulating three-dimensional molecular data. Unlike similar packages, Scoria requires no dependencies, compilation, or system-wide installation. One can incorporate the Scoria source code directly into their own programs. But Scoria is not designed to compete with other similar packages. Rather, it complements them. Our package leverages others (e.g. NumPy, SciPy), if present, to speed and extend its own functionality. To show its utility, we use Scoria to analyze a molecular dynamics trajectory. Our FootPrint script colors the atoms of one chain by the frequency of their contacts with a second chain. We are hopeful that Scoria will be a useful tool for the computational-biology community. A copy is available for download free of charge (Apache License 2.0) at http://durrantlab.com/scoria/ . Graphical abstract .

The microstructure of starchy food modulates its digestibility.

PubMed

Tian, Jinhu; Ogawa, Yukiharu; Shi, John; Chen, Shiguo; Zhang, Huiling; Liu, Donghong; Ye, Xingqian

2018-06-05

Starch is the main carbohydrate in human nutrition and shows a range of desired food properties. It has been demonstrated that fast digestion of starchy food can induce many health issues (e.g., hyperglycaemia, diabetes, etc.); therefore, how to modulate its digestion is an interesting topic. Previous studies have revealed that the microstructure and digestibility of starchy food of different botanical origin or from multiple processes are quite different; modulating starch digestion by retaining or altering its microstructure may be effective. In the present review, the current knowledge of the relationship between microstructural changes to starchy food and its digestibility at molecular, cell and tissue, and food processing levels is summarized. New technologies focused on microstructure studies and ways to manipulate food microstructure to modulate starch digestibility are also reviewed. In particular, some insights focusing on the future study of microstructure and the digestibility of starchy food are also suggested.

Linking Assessment Questions to a Research Article to Stimulate Self-directed Learning and Develop High-order Cognitive Skills in an Undergraduate Module of Molecular Genetics

PubMed Central

2009-01-01

Assessment plays a crucial role in the learning process, but current assessments focus on assessment of learning rather than assessment for learning. In this study, a novel method for open-book continuous assessment (CA) was developed. The aim was to encourage students to learn beyond the textbook by challenging students with questions linked to a research article. Research articles closely related to lecture contents were selected and released to students before the CA for perusal. CA questions were set at three different levels to assess conceptual understanding, application, and synthesis. The CA was administered to first-year undergraduate students majoring in life science as part of Molecular Genetics, a compulsory module. It contributed 10% of the student's grade for the module. Students’ CA scores indicated that the majority could answer correctly all the questions. Students’ feedback on the CA showed that most of them praised the CA model for its novelty, motivation, and application. Only a few criticized it due to its poor coverage of lecture contents. Overall, this CA went beyond the traditional role of assessments in the assignment of scores and stimulated curiosity and self-directed learning. PMID:19952097

Semi-Technical Cryogenic Molecular Sieve Bed for the Tritium Extraction System of the Test Blanket Module for ITER

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

Beloglazov, S.; Bekris, N.; Glugla, M.

2005-07-15

The tritium extraction from the ITER Helium Cooled Pebble Bed (HCPB) Test Blanket Module purge gas is proposed to be performed in a two steps process: trapping water in a cryogenic Cold Trap, and adsorption of hydrogen isotopes (H{sub 2}, HT, T{sub 2}) as well as impurities (N{sub 2}, O{sub 2}) in a Cryogenic Molecular Sieve Bed (CMSB) at 77K. A CMSB in a semi-technical scale (one-sixth of the flow rate of the ITER-HCPB) was design and constructed at the Forschungszentrum Karlsruhe. The full capacity of CMSB filled with 20 kg of MS-5A was calculated based on adsorption isotherm datamore » to be 9.4 mol of H{sub 2} at partial pressure 120 Pa. The breakthrough tests at flow rates up to 2 Nm{sup 3}h{sup -1} of He with 110 Pa of H{sub 2} conformed with good agreement the adsorption capacity of the CMSB. The mass-transfer zone was found to be relatively narrow (12.5 % of the MS Bed height) allowing to scale up the CMSB to ITER flow rates.« less

A physico-genetic module for the polarisation of auxin efflux carriers PIN-FORMED (PIN)

NASA Astrophysics Data System (ADS)

Hernández-Hernández, Valeria; Barrio, Rafael A.; Benítez, Mariana; Nakayama, Naomi; Romero-Arias, José Roberto; Villarreal, Carlos

2018-05-01

Intracellular polarisation of auxin efflux carriers is crucial for understanding how auxin gradients form in plants. The polarisation dynamics of auxin efflux carriers PIN-FORMED (PIN) depends on both biomechanical forces as well as chemical, molecular and genetic factors. Biomechanical forces have shown to affect the localisation of PIN transporters to the plasma membrane. We propose a physico-genetic module of PIN polarisation that integrates biomechanical, molecular, and cellular processes as well as their non-linear interactions. The module was implemented as a discrete Boolean model and then approximated to a continuous dynamic system, in order to explore the relative contribution of the factors mediating PIN polarisation at the scale of single cell. Our models recovered qualitative behaviours that have been experimentally observed and enable us to predict that, in the context of PIN polarisation, the effects of the mechanical forces can predominate over the activity of molecular factors such as the GTPase ROP6 and the ROP-INTERACTIVE CRIB MOTIF-CONTAINING PROTEIN RIC1.

Molecular and physiological manifestations and measurement of aging in humans.

PubMed

Khan, Sadiya S; Singer, Benjamin D; Vaughan, Douglas E

2017-08-01

Biological aging is associated with a reduction in the reparative and regenerative potential in tissues and organs. This reduction manifests as a decreased physiological reserve in response to stress (termed homeostenosis) and a time-dependent failure of complex molecular mechanisms that cumulatively create disorder. Aging inevitably occurs with time in all organisms and emerges on a molecular, cellular, organ, and organismal level with genetic, epigenetic, and environmental modulators. Individuals with the same chronological age exhibit differential trajectories of age-related decline, and it follows that we should assess biological age distinctly from chronological age. In this review, we outline mechanisms of aging with attention to well-described molecular and cellular hallmarks and discuss physiological changes of aging at the organ-system level. We suggest methods to measure aging with attention to both molecular biology (e.g., telomere length and epigenetic marks) and physiological function (e.g., lung function and echocardiographic measurements). Finally, we propose a framework to integrate these molecular and physiological data into a composite score that measures biological aging in humans. Understanding the molecular and physiological phenomena that drive the complex and multifactorial processes underlying the variable pace of biological aging in humans will inform how researchers assess and investigate health and disease over the life course. This composite biological age score could be of use to researchers seeking to characterize normal, accelerated, and exceptionally successful aging as well as to assess the effect of interventions aimed at modulating human aging. © 2017 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

Molecularly Imprinted Intelligent Scaffolds for Tissue Engineering Applications.

PubMed

Neves, Mariana I; Wechsler, Marissa E; Gomes, Manuela E; Reis, Rui L; Granja, Pedro L; Peppas, Nicholas A

2017-02-01

The development of molecularly imprinted polymers (MIPs) using biocompatible production methods enables the possibility to further exploit this technology for biomedical applications. Tissue engineering (TE) approaches use the knowledge of the wound healing process to design scaffolds capable of modulating cell behavior and promote tissue regeneration. Biomacromolecules bear great interest for TE, together with the established recognition of the extracellular matrix, as an important source of signals to cells, both promoting cell-cell and cell-matrix interactions during the healing process. This review focuses on exploring the potential of protein molecular imprinting to create bioactive scaffolds with molecular recognition for TE applications based on the most recent approaches in the field of molecular imprinting of macromolecules. Considerations regarding essential components of molecular imprinting technology will be addressed for TE purposes. Molecular imprinting of biocompatible hydrogels, namely based on natural polymers, is also reviewed here. Hydrogel scaffolds with molecular memory show great promise for regenerative therapies. The first molecular imprinting studies analyzing cell adhesion report promising results with potential applications for cell culture systems, or biomaterials for implantation with the capability for cell recruitment by selectively adsorbing desired molecules.

Conservative and dissipative force imaging of switchable rotaxanes with frequency-modulation atomic force microscopy

NASA Astrophysics Data System (ADS)

Farrell, Alan A.; Fukuma, Takeshi; Uchihashi, Takayuki; Kay, Euan R.; Bottari, Giovanni; Leigh, David A.; Yamada, Hirofumi; Jarvis, Suzanne P.

2005-09-01

We compare constant amplitude frequency modulation atomic force microscopy (FM-AFM) in ambient conditions to ultrahigh vacuum (UHV) experiments by analysis of thin films of rotaxane molecules. Working in ambient conditions is important for the development of real-world molecular devices. We show that the FM-AFM technique allows quantitative measurement of conservative and dissipative forces without instabilities caused by any native water layer. Molecular resolution is achieved despite the low Q-factor in the air. Furthermore, contrast in the energy dissipation is observed even at the molecular level. This should allow investigations into stimuli-induced sub-molecular motion of organic films.

Combined-modality treatment of solid tumors using radiotherapy and molecular targeted agents.

PubMed

Ma, Brigette B Y; Bristow, Robert G; Kim, John; Siu, Lillian L

2003-07-15

Molecular targeted agents have been combined with radiotherapy (RT) in recent clinical trials in an effort to optimize the therapeutic index of RT. The appeal of this strategy lies in their potential target specificity and clinically acceptable toxicity. This article integrates the salient, published research findings into the underlying molecular mechanisms, preclinical efficacy, and clinical applicability of combining RT with molecular targeted agents. These agents include inhibitors of intracellular signal transduction molecules, modulators of apoptosis, inhibitors of cell cycle checkpoints control, antiangiogenic agents, and cyclo-oxygenase-2 inhibitors. Molecular targeted agents can have direct effects on the cytoprotective and cytotoxic pathways implicated in the cellular response to ionizing radiation (IR). These pathways involve cellular proliferation, DNA repair, cell cycle progression, nuclear transcription, tumor angiogenesis, and prostanoid-associated inflammation. These pathways can also converge to alter RT-induced apoptosis, terminal growth arrest, and reproductive cell death. Pharmacologic modulation of these pathways may potentially enhance tumor response to RT though inhibition of tumor repopulation, improvement of tumor oxygenation, redistribution during the cell cycle, and alteration of intrinsic tumor radiosensitivity. Combining RT and molecular targeted agents is a rational approach in the treatment of solid tumors. Translation of this approach from promising preclinical data to clinical trials is actively underway.

Mathematical Biology Modules Based on Modern Molecular Biology and Modern Discrete Mathematics

ERIC Educational Resources Information Center

Robeva, Raina; Davies, Robin; Hodge, Terrell; Enyedi, Alexander

2010-01-01

We describe an ongoing collaborative curriculum materials development project between Sweet Briar College and Western Michigan University, with support from the National Science Foundation. We present a collection of modules under development that can be used in existing mathematics and biology courses, and we address a critical national need to…

Gas sensing using wavelength modulation spectroscopy

NASA Astrophysics Data System (ADS)

Viveiros, D.; Ribeiro, J.; Flores, D.; Ferreira, J.; Frazao, O.; Santos, J. L.; Baptista, J. M.

2014-08-01

An experimental setup has been developed for different gas species sensing based on the Wavelength Modulation Spectroscopy (WMS) principle. The target is the measurement of ammonia, carbon dioxide and methane concentrations. The WMS is a rather sensitive technique for detecting atomic/molecular species presenting the advantage that it can be used in the near-infrared region using optical telecommunications technology. In this technique, the laser wavelength and intensity are modulated applying a sine wave signal through the injection current, which allows the shift of the detection bandwidth to higher frequencies where laser intensity noise is reduced. The wavelength modulated laser light is tuned to the absorption line of the target gas and the absorption information can be retrieved by means of synchronous detection using a lock-in amplifier, where the amplitude of the second harmonic of the laser modulation frequency is proportional to the gas concentration. The amplitude of the second harmonic is normalised by the average laser intensity and detector gain through a LabVIEW® application, where the main advantage of normalising is that the effects of laser output power fluctuations and any variations in laser transmission, or optical-electrical detector gain are eliminated. Two types of sensing heads based on free space light propagation with different optical path length were used, permitting redundancy operation and technology validation.

Preparation, Purification, and Secondary Structure Determination of Bacillus Circulans Xylanase. A Molecular Laboratory Incorporating Aspects of Molecular Biology, Biochemistry, and Biophysical Chemistry

ERIC Educational Resources Information Center

Russo, Sal; Gentile, Lisa

2006-01-01

A project module designed for biochemistry or cellular and molecular biology student which involves determining the secondary structure of Bacillus circulans xylanase (BCX) by circular dichroism (CD) spectroscopy under conditions that compromise its stabilizing intramolecular forces is described. The lab model enhanced students knowledge of the…

Modeling Carbon and Hydrocarbon Molecular Structures in EZTB

NASA Technical Reports Server (NTRS)

Lee, Seungwon; vonAllmen, Paul

2007-01-01

A software module that models the electronic and mechanical aspects of hydrocarbon molecules and carbon molecular structures on the basis of first principles has been written for incorporation into, and execution within, the Easy (Modular) Tight-Binding (EZTB) software infrastructure, which is summarized briefly in the immediately preceding article. Of particular interest, this module can model carbon crystals and nanotubes characterized by various coordinates and containing defects, without need to adjust parameters of the physical model. The module has been used to study the changes in electronic properties of carbon nanotubes, caused by bending of the nanotubes, for potential utility as the basis of a nonvolatile, electriccharge- free memory devices. For example, in one application of the module, it was found that an initially 50-nmlong carbon, (10,10)-chirality nanotube, which is a metallic conductor when straight, becomes a semiconductor with an energy gap of .3 meV when bent to a lateral displacement of 4 nm at the middle.

Systems toxicology of chemically induced liver and kidney injuries: histopathology‐associated gene co‐expression modules

PubMed Central

Te, Jerez A.; AbdulHameed, Mohamed Diwan M.

2016-01-01

Abstract Organ injuries caused by environmental chemical exposures or use of pharmaceutical drugs pose a serious health risk that may be difficult to assess because of a lack of non‐invasive diagnostic tests. Mapping chemical injuries to organ‐specific histopathology outcomes via biomarkers will provide a foundation for designing precise and robust diagnostic tests. We identified co‐expressed genes (modules) specific to injury endpoints using the Open Toxicogenomics Project‐Genomics Assisted Toxicity Evaluation System (TG‐GATEs) – a toxicogenomics database containing organ‐specific gene expression data matched to dose‐ and time‐dependent chemical exposures and adverse histopathology assessments in Sprague–Dawley rats. We proposed a protocol for selecting gene modules associated with chemical‐induced injuries that classify 11 liver and eight kidney histopathology endpoints based on dose‐dependent activation of the identified modules. We showed that the activation of the modules for a particular chemical exposure condition, i.e., chemical‐time‐dose combination, correlated with the severity of histopathological damage in a dose‐dependent manner. Furthermore, the modules could distinguish different types of injuries caused by chemical exposures as well as determine whether the injury module activation was specific to the tissue of origin (liver and kidney). The generated modules provide a link between toxic chemical exposures, different molecular initiating events among underlying molecular pathways and resultant organ damage. Published 2016. This article is a U.S. Government work and is in the public domain in the USA. Journal of Applied Toxicology published by John Wiley & Sons, Ltd. PMID:26725466

Biologic Modulators in Allergic and Autoinflammatory Diseases

PubMed Central

Broderick, Lori; Tourangeau, Louanne M.; Kavanaugh, Arthur; Wasserman, Stephen I.

2011-01-01

Purpose of review The advent of molecular techniques has resulted in the ability to tailor medications to specific protein targets. This review will emphasize several biological therapies, specifically directed toward cytokine receptors and inhibitors, and their role in the treatment of atopic and autoinflammatory diseases. Recent findings Translational research and the identification of the molecular pathophysiology of diseases have led to more targeted treatment approaches. The biologic modulators, encompassing monoclonal antibodies as cytokine inhibitors, receptor blocking antibodies and new fusion receptors are now being applied to diseases beyond their original application. Summary The expanded use of biological therapies has experienced success in the treatment of numerous disorders, especially in subsets of patients with disease that has been refractory to conventional therapies. PMID:21659854

How Dynamic Visualization Technology can Support Molecular Reasoning

NASA Astrophysics Data System (ADS)

Levy, Dalit

2013-10-01

This paper reports the results of a study aimed at exploring the advantages of dynamic visualization for the development of better understanding of molecular processes. We designed a technology-enhanced curriculum module in which high school chemistry students conduct virtual experiments with dynamic molecular visualizations of solid, liquid, and gas. They interact with the visualizations and carry out inquiry activities to make and refine connections between observable phenomena and atomic level processes related to phase change. The explanations proposed by 300 pairs of students in response to pre/post-assessment items have been analyzed using a scale for measuring the level of molecular reasoning. Results indicate that from pretest to posttest, students make progress in their level of molecular reasoning and are better able to connect intermolecular forces and phase change in their explanations. The paper presents the results through the lens of improvement patterns and the metaphor of the "ladder of molecular reasoning," and discusses how this adds to our understanding of the benefits of interacting with dynamic molecular visualizations.

Switchable molecular magnets

PubMed Central

SATO, Osamu

2012-01-01

Various molecular magnetic compounds whose magnetic properties can be controlled by external stimuli have been developed, including electrochemically, photochemically, and chemically tunable bulk magnets as well as a phototunable antiferromagnetic phase of single chain magnet. In addition, we present tunable paramagnetic mononuclear complexes ranging from spin crossover complexes and valence tautomeric complexes to Co complexes in which orbital angular momentum can be switched. Furthermore, we recently developed several switchable clusters and one-dimensional coordination polymers. The switching of magnetic properties can be achieved by modulating metals, ligands, and molecules/ions in the second sphere of the complexes. PMID:22728438

Non-invasive optical modulation of local vascular permeability

NASA Astrophysics Data System (ADS)

Choi, Myunghwan; Choi, Chulhee

2011-03-01

For a systemically administered drug to act, it first needs to cross the vascular wall. This step represents a bottleneck for drug development, especially in the brain or retina, where tight junctions between endothelial cells form physiological barriers. Here, we demonstrate that femtosecond pulsed laser irradiation focused on the blood vessel wall induces transient permeabilization of plasma. Nonlinear absorption of the pulsed laser enabled the noninvasive modulation of vascular permeability with high spatial selectivity in three dimensions. By combining this method with systemic injection, we could locally deliver molecular probes in various tissues, such as brain cortex, meninges, ear, striated muscle, and bone. We suggest this method as a novel delivery tool for molecular probes or drugs.

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.

Direct Modulation of Heterotrimeric G Protein-coupled Signaling by a Receptor Kinase Complex.

PubMed

Tunc-Ozdemir, Meral; Urano, Daisuke; Jaiswal, Dinesh Kumar; Clouse, Steven D; Jones, Alan M

2016-07-01

Plants and some protists have heterotrimeric G protein complexes that activate spontaneously without canonical G protein-coupled receptors (GPCRs). In Arabidopsis, the sole 7-transmembrane regulator of G protein signaling 1 (AtRGS1) modulates the G protein complex by keeping it in the resting state (GDP-bound). However, it remains unknown how a myriad of biological responses is achieved with a single G protein modulator. We propose that in complete contrast to G protein activation in animals, plant leucine-rich repeat receptor-like kinases (LRR RLKs), not GPCRs, provide this discrimination through phosphorylation of AtRGS1 in a ligand-dependent manner. G protein signaling is directly activated by the pathogen-associated molecular pattern flagellin peptide 22 through its LRR RLK, FLS2, and co-receptor BAK1. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Azadirachtin(A) distinctively modulates subdomain 2 of actin - novel mechanism to induce depolymerization revealed by molecular dynamics study.

PubMed

Pravin Kumar, R; Roopa, L; Sudheer Mohammed, M M; Kulkarni, Naveen

2016-12-01

Azadirachtin(A) (AZA), a potential insecticide from neem, binds to actin and induces depolymerization in Drosophila. AZA binds to the pocket same as that of Latrunculin A (LAT), but LAT inhibits actin polymerization by stiffening the actin structure and affects the ADP-ATP exchange. The mechanism by which AZA induces actin depolymerization is not clearly understood. Therefore, different computational experiments were conducted to delineate the precise mechanism of AZA-induced actin depolymerization. Molecular dynamics studies showed that AZA strongly interacted with subdomain 2 and destabilized the interactions between subdomain 2 of one actin and subdomains 1 and 4 of the adjacent actin, causing the separation of actin subunits. The separation was observed between subdomain 3 of subunit n and subdomain 4 of subunit n + 2. However, the specific triggering point for the separation of the subunits was the destabilization of direct interactions between subdomain 2 of subunit n (Arg39, Val45, Gly46 and Arg62) and subdomain 4 of subunit n + 2 (Asp286, Ile287, Asp288, Ile289, Asp244 and Lys291). These results reveal a unique mechanism of an actin filament modulator that induces depolymerization. This mechanism of AZA can be used to design similar molecules against mammalian actins for cancer therapy.

Molecular imaging of drug-modulated protein-protein interactions in living subjects.

PubMed

Paulmurugan, Ramasamy; Massoud, Tarik F; Huang, Jing; Gambhir, Sanjiv S

2004-03-15

Networks of protein interactions mediate cellular responses to environmental stimuli and direct the execution of many different cellular functional pathways. Small molecules synthesized within cells or recruited from the external environment mediate many protein interactions. The study of small molecule-mediated interactions of proteins is important to understand abnormal signal transduction pathways in cancer and in drug development and validation. In this study, we used split synthetic renilla luciferase (hRLUC) protein fragment-assisted complementation to evaluate heterodimerization of the human proteins FRB and FKBP12 mediated by the small molecule rapamycin. The concentration of rapamycin required for efficient dimerization and that of its competitive binder ascomycin required for dimerization inhibition were studied in cell lines. The system was dually modulated in cell culture at the transcription level, by controlling nuclear factor kappaB promoter/enhancer elements using tumor necrosis factor alpha, and at the interaction level, by controlling the concentration of the dimerizer rapamycin. The rapamycin-mediated dimerization of FRB and FKBP12 also was studied in living mice by locating, quantifying, and timing the hRLUC complementation-based bioluminescence imaging signal using a cooled charged coupled device camera. This split reporter system can be used to efficiently screen small molecule drugs that modulate protein-protein interactions and also to assess drugs in living animals. Both are essential steps in the preclinical evaluation of candidate pharmaceutical agents targeting protein-protein interactions, including signaling pathways in cancer cells.

Problem-Solving Modules in Large Introductory Biology Lectures Enhance Student Understanding

ERIC Educational Resources Information Center

Cooper, Scott; Hanmer, Deborah; Cerbin, Bill

2006-01-01

We studied the effect of formative assessment and feedback on learning. Students produced phylogenetic trees based upon morphological and molecular data. The trees were projected in class, feedback provided, and the process repeated twice with new data. Assessment revealed that these in-class modules resulted in significant improvement in student…

Modular Chemical Descriptor Language (MCDL): Stereochemical modules

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

Gakh, Andrei A; Burnett, Michael N; Trepalin, Sergei V.

2011-01-01

In our previous papers we introduced the Modular Chemical Descriptor Language (MCDL) for providing a linear representation of chemical information. A subsequent development was the MCDL Java Chemical Structure Editor which is capable of drawing chemical structures from linear representations and generating MCDL descriptors from structures. In this paper we present MCDL modules and accompanying software that incorporate unique representation of molecular stereochemistry based on Cahn-Ingold-Prelog and Fischer ideas in constructing stereoisomer descriptors. The paper also contains additional discussions regarding canonical representation of stereochemical isomers, and brief algorithm descriptions of the open source LINDES, Java applet, and Open Babel MCDLmore » processing module software packages. Testing of the upgraded MCDL Java Chemical Structure Editor on compounds taken from several large and diverse chemical databases demonstrated satisfactory performance for storage and processing of stereochemical information in MCDL format.« less

Non-autonomous matter-wave solitons in hybrid atomic-molecular Bose-Einstein condensates with tunable interactions and harmonic potential

NASA Astrophysics Data System (ADS)

Wang, Deng-Shan; Liu, Jiang; Wang, Lizhen

2018-03-01

In this paper, we investigate matter-wave solitons in hybrid atomic-molecular Bose-Einstein condensates with tunable interactions and external potentials. Three types of time-modulated harmonic potentials are considered and, for each of them, two groups of exact non-autonomous matter-wave soliton solutions of the coupled Gross-Pitaevskii equation are presented. Novel nonlinear structures of these non-autonomous matter-wave solitons are analyzed by displaying their density distributions. It is shown that the time-modulated nonlinearities and external potentials can support exact non-autonomous atomic-molecular matter-wave solitons.

Internal Electric Field Modulation in Molecular Electronic Devices by Atmosphere and Mobile Ions.

PubMed

Chandra Mondal, Prakash; Tefashe, Ushula M; McCreery, Richard L

2018-06-13

The internal potential profile and electric field are major factors controlling the electronic behavior of molecular electronic junctions consisting of ∼1-10 nm thick layers of molecules oriented in parallel between conducting contacts. The potential profile is assumed linear in the simplest cases, but can be affected by internal dipoles, charge polarization, and electronic coupling between the contacts and the molecular layer. Electrochemical processes in solutions or the solid state are entirely dependent on modification of the electric field by electrolyte ions, which screen the electrodes and form the ionic double layers that are fundamental to electrode kinetics and widespread applications. The current report investigates the effects of mobile ions on nominally solid-state molecular junctions containing aromatic molecules covalently bonded between flat, conducting carbon surfaces, focusing on changes in device conductance when ions are introduced into an otherwise conventional junction design. Small changes in conductance were observed when a polar molecule, acetonitrile, was present in the junction, and a large decrease of conductance was observed when both acetonitrile (ACN) and lithium ions (Li + ) were present. Transient experiments revealed that conductance changes occur on a microsecond-millisecond time scale, and are accompanied by significant alteration of device impedance and temperature dependence. A single molecular junction containing lithium benzoate could be reversibly transformed from symmetric current-voltage behavior to a rectifier by repetitive bias scans. The results are consistent with field-induced reorientation of acetonitrile molecules and Li + ion motion, which screen the electrodes and modify the internal potential profile and provide a potentially useful means to dynamically alter junction electronic behavior.

Alternative splicing modulates Kv channel clustering through a molecular ball and chain mechanism

NASA Astrophysics Data System (ADS)

Zandany, Nitzan; Marciano, Shir; Magidovich, Elhanan; Frimerman, Teddy; Yehezkel, Rinat; Shem-Ad, Tzilhav; Lewin, Limor; Abdu, Uri; Orr, Irit; Yifrach, Ofer

2015-03-01

Ion channel clustering at the post-synaptic density serves a fundamental role in action potential generation and transmission. Here, we show that interaction between the Shaker Kv channel and the PSD-95 scaffold protein underlying channel clustering is modulated by the length of the intrinsically disordered C terminal channel tail. We further show that this tail functions as an entropic clock that times PSD-95 binding. We thus propose a ‘ball and chain’ mechanism to explain Kv channel binding to scaffold proteins, analogous to the mechanism describing channel fast inactivation. The physiological relevance of this mechanism is demonstrated in that alternative splicing of the Shaker channel gene to produce variants of distinct tail lengths resulted in differential channel cell surface expression levels and clustering metrics that correlate with differences in affinity of the variants for PSD-95. We suggest that modulating channel clustering by specific spatial-temporal spliced variant targeting serves a fundamental role in nervous system development and tuning.

Structural basis for modulation of a G-protein-coupled receptor by allosteric drugs

NASA Astrophysics Data System (ADS)

Dror, Ron O.; Green, Hillary F.; Valant, Celine; Borhani, David W.; Valcourt, James R.; Pan, Albert C.; Arlow, Daniel H.; Canals, Meritxell; Lane, J. Robert; Rahmani, Raphaël; Baell, Jonathan B.; Sexton, Patrick M.; Christopoulos, Arthur; Shaw, David E.

2013-11-01

The design of G-protein-coupled receptor (GPCR) allosteric modulators, an active area of modern pharmaceutical research, has proved challenging because neither the binding modes nor the molecular mechanisms of such drugs are known. Here we determine binding sites, bound conformations and specific drug-receptor interactions for several allosteric modulators of the M2 muscarinic acetylcholine receptor (M2 receptor), a prototypical family A GPCR, using atomic-level simulations in which the modulators spontaneously associate with the receptor. Despite substantial structural diversity, all modulators form cation-π interactions with clusters of aromatic residues in the receptor extracellular vestibule, approximately 15Å from the classical, `orthosteric' ligand-binding site. We validate the observed modulator binding modes through radioligand binding experiments on receptor mutants designed, on the basis of our simulations, either to increase or to decrease modulator affinity. Simulations also revealed mechanisms that contribute to positive and negative allosteric modulation of classical ligand binding, including coupled conformational changes of the two binding sites and electrostatic interactions between ligands in these sites. These observations enabled the design of chemical modifications that substantially alter a modulator's allosteric effects. Our findings thus provide a structural basis for the rational design of allosteric modulators targeting muscarinic and possibly other GPCRs.

Update 0.2 to "pysimm: A python package for simulation of molecular systems"

NASA Astrophysics Data System (ADS)

Demidov, Alexander G.; Fortunato, Michael E.; Colina, Coray M.

2018-01-01

An update to the pysimm Python molecular simulation API is presented. A major part of the update is the implementation of a new interface with CASSANDRA - a modern, versatile Monte Carlo molecular simulation program. Several significant improvements in the LAMMPS communication module that allow better and more versatile simulation setup are reported as well. An example of an application implementing iterative CASSANDRA-LAMMPS interaction is illustrated.

InGaAs Multiple Quantum Well Modulating Retro-reflector for Free Space Optical Communications

DTIC Science & Technology

2002-01-01

PIN optical modulators grown on GaAs substrates by molecular beam epitaxy ,J. Vac Sci. B 18, 1609-16 13 (2000). Peter G. Goetz, W. S. Rabinovich...reflector is then interrogated by a cw laser beam from a conventional optical communications system and returns a modulated signal beam to the...optical communication systems. By mounting an electro-optic shutter in front of the corner- cube, the retro-reflected beam can be turned on or off (or at

An Introductory Classroom Exercise on Protein Molecular Model Visualization and Detailed Analysis of Protein-Ligand Binding

ERIC Educational Resources Information Center

Poeylaut-Palena, Andres, A.; de los Angeles Laborde, Maria

2013-01-01

A learning module for molecular level analysis of protein structure and ligand/drug interaction through the visualization of X-ray diffraction is presented. Using DeepView as molecular model visualization software, students learn about the general concepts of protein structure. This Biochemistry classroom exercise is designed to be carried out by…

Topology of molecular interaction networks.

PubMed

Winterbach, Wynand; Van Mieghem, Piet; Reinders, Marcel; Wang, Huijuan; de Ridder, Dick

2013-09-16

Molecular interactions are often represented as network models which have become the common language of many areas of biology. Graphs serve as convenient mathematical representations of network models and have themselves become objects of study. Their topology has been intensively researched over the last decade after evidence was found that they share underlying design principles with many other types of networks.Initial studies suggested that molecular interaction network topology is related to biological function and evolution. However, further whole-network analyses did not lead to a unified view on what this relation may look like, with conclusions highly dependent on the type of molecular interactions considered and the metrics used to study them. It is unclear whether global network topology drives function, as suggested by some researchers, or whether it is simply a byproduct of evolution or even an artefact of representing complex molecular interaction networks as graphs.Nevertheless, network biology has progressed significantly over the last years. We review the literature, focusing on two major developments. First, realizing that molecular interaction networks can be naturally decomposed into subsystems (such as modules and pathways), topology is increasingly studied locally rather than globally. Second, there is a move from a descriptive approach to a predictive one: rather than correlating biological network topology to generic properties such as robustness, it is used to predict specific functions or phenotypes.Taken together, this change in focus from globally descriptive to locally predictive points to new avenues of research. In particular, multi-scale approaches are developments promising to drive the study of molecular interaction networks further.

Topology of molecular interaction networks

PubMed Central

2013-01-01

Molecular interactions are often represented as network models which have become the common language of many areas of biology. Graphs serve as convenient mathematical representations of network models and have themselves become objects of study. Their topology has been intensively researched over the last decade after evidence was found that they share underlying design principles with many other types of networks. Initial studies suggested that molecular interaction network topology is related to biological function and evolution. However, further whole-network analyses did not lead to a unified view on what this relation may look like, with conclusions highly dependent on the type of molecular interactions considered and the metrics used to study them. It is unclear whether global network topology drives function, as suggested by some researchers, or whether it is simply a byproduct of evolution or even an artefact of representing complex molecular interaction networks as graphs. Nevertheless, network biology has progressed significantly over the last years. We review the literature, focusing on two major developments. First, realizing that molecular interaction networks can be naturally decomposed into subsystems (such as modules and pathways), topology is increasingly studied locally rather than globally. Second, there is a move from a descriptive approach to a predictive one: rather than correlating biological network topology to generic properties such as robustness, it is used to predict specific functions or phenotypes. Taken together, this change in focus from globally descriptive to locally predictive points to new avenues of research. In particular, multi-scale approaches are developments promising to drive the study of molecular interaction networks further. PMID:24041013

The SDF-1–CXCR4 signaling pathway: a molecular hub modulating neo-angiogenesis

PubMed Central

Petit, Isabelle; Jin, David; Rafii, Shahin

2010-01-01

Pro-angiogenic bone marrow (BM) cells include subsets of hematopoietic cells that provide vascular support and endothelial progenitor cells (EPCs), which under certain permissive conditions could differentiate into functional vascular cells. Recent evidence demonstrates that the chemokine stromal-cell derived factor-1 (SDF-1, also known as CXCL12) has a major role in the recruitment and retention of CXCR4+ BM cells to the neo-angiogenic niches supporting revascularization of ischemic tissue and tumor growth. However, the precise mechanism by which activation of CXCR4 modulates neo-angiogenesis is not clear. SDF-1 not only promotes revascularization by engaging with CXCR4 expressed on the vascular cells but also supports mobilization of pro-angiogenic CXCR4+VEGFR1+ hematopoietic cells, thereby accelerating revascularization of ischemic organs. Here, we attempt to define the multiple functions of the SDF-1–CXCR4 signaling pathway in the regulation of neo-vascularization during acute ischemia and tumor growth. In particular, we introduce the concept that, by modulating plasma SDF-1 levels, the CXCR4 antagonist AMD3100 acutely promotes, while chronic AMD3100 treatment inhibits, mobilization of pro-angiogenic cells. We will also discuss strategies to modulate the mobilization of essential subsets of BM cells that participate in neo-angiogenesis, setting up the stage for enhancing revascularization or targeting tumor vessels by exploiting CXCR4 agonists and antagonists, respectively. PMID:17560169

Fibrin-based biomaterials: Modulation of macroscopic properties through rational design at the molecular level

PubMed Central

Brown, Ashley C.; Barker, Thomas H.

2013-01-01

Fibrinogen is one of the primary components of the coagulation cascade and rapidly forms an insoluble matrix following tissue injury. In addition to its important role in hemostasis, fibrin acts as a scaffold for tissue repair and provides important cues for directing cell phenotype following injury. Because of these properties and the ease of polymerization of the material, fibrin has been widely utilized as a biomaterial for over a century. Modifying the macroscopic properties of fibrin, such as elasticity and porosity, has been somewhat elusive until recently, yet with a molecular-level rational design approach can now be somewhat easily modified through alterations of molecular interactions key to the protein’s polymerization process. This review outlines the biochemistry of fibrin and discusses methods for modification of molecular interactions and their application to fibrin based biomaterials. PMID:24056097

Necroptosis: Modules and molecular switches with therapeutic implications.

PubMed

Arora, Deepika; Sharma, Pradeep Kumar; Siddiqui, Mohammed Haris; Shukla, Yogeshwer

2017-06-01

Among the various programmed cell death (PCD) pathways, "Necroptosis" has gained much importance as a novel paradigm of cell death. This pathway has emerged as a backup mechanism when physiologically conserved PCD (apoptosis) is non-functional either genetically or pathogenically. The expanding spectrum of necroptosis from physiological development to diverse patho-physiological disorders, including xenobiotics-mediated toxicity has now grabbed the attention worldwide. The efficient role of necroptosis regulators in disease development and management are under constant examination. In fact, few regulators (e.g. MLKL) have already paved their way towards clinical trials and others are in queue. In this review, emphasis has been paid to the various contributing factors and molecular switches that can regulate necroptosis. Here we linked the overview of current knowledge of this enigmatic signaling with magnitude of therapeutics that may underpin the opportunities for novel therapeutic approaches to suppress the pathogenesis of necroptosis-driven disorders. Copyright © 2017 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). 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

Evaluating the effectiveness of a practical inquiry-based learning bioinformatics module on undergraduate student engagement and applied skills.

PubMed

Brown, James A L

2016-05-06

A pedagogic intervention, in the form of an inquiry-based peer-assisted learning project (as a practical student-led bioinformatics module), was assessed for its ability to increase students' engagement, practical bioinformatic skills and process-specific knowledge. Elements assessed were process-specific knowledge following module completion, qualitative student-based module evaluation and the novelty, scientific validity and quality of written student reports. Bioinformatics is often the starting point for laboratory-based research projects, therefore high importance was placed on allowing students to individually develop and apply processes and methods of scientific research. Students led a bioinformatic inquiry-based project (within a framework of inquiry), discovering, justifying and exploring individually discovered research targets. Detailed assessable reports were produced, displaying data generated and the resources used. Mimicking research settings, undergraduates were divided into small collaborative groups, with distinctive central themes. The module was evaluated by assessing the quality and originality of the students' targets through reports, reflecting students' use and understanding of concepts and tools required to generate their data. Furthermore, evaluation of the bioinformatic module was assessed semi-quantitatively using pre- and post-module quizzes (a non-assessable activity, not contributing to their grade), which incorporated process- and content-specific questions (indicative of their use of the online tools). Qualitative assessment of the teaching intervention was performed using post-module surveys, exploring student satisfaction and other module specific elements. Overall, a positive experience was found, as was a post module increase in correct process-specific answers. In conclusion, an inquiry-based peer-assisted learning module increased students' engagement, practical bioinformatic skills and process-specific knowledge. © 2016 by

Ballasted photovoltaic module and module arrays

DOEpatents

Botkin, Jonathan [El Cerrito, CA; Graves, Simon [Berkeley, CA; Danning, Matt [Oakland, CA

2011-11-29

A photovoltaic (PV) module assembly including a PV module and a ballast tray. The PV module includes a PV device and a frame. A PV laminate is assembled to the frame, and the frame includes an arm. The ballast tray is adapted for containing ballast and is removably associated with the PV module in a ballasting state where the tray is vertically under the PV laminate and vertically over the arm to impede overt displacement of the PV module. The PV module assembly can be installed to a flat commercial rooftop, with the PV module and the ballast tray both resting upon the rooftop. In some embodiments, the ballasting state includes corresponding surfaces of the arm and the tray being spaced from one another under normal (low or no wind) conditions, such that the frame is not continuously subjected to a weight of the tray.

Genetic, molecular and physiological basis of variation in Drosophila gut immunocompetence.

PubMed

Bou Sleiman, Maroun S; Osman, Dani; Massouras, Andreas; Hoffmann, Ary A; Lemaitre, Bruno; Deplancke, Bart

2015-07-27

Gut immunocompetence involves immune, stress and regenerative processes. To investigate the determinants underlying inter-individual variation in gut immunocompetence, we perform enteric infection of 140 Drosophila lines with the entomopathogenic bacterium Pseudomonas entomophila and observe extensive variation in survival. Using genome-wide association analysis, we identify several novel immune modulators. Transcriptional profiling further shows that the intestinal molecular state differs between resistant and susceptible lines, already before infection, with one transcriptional module involving genes linked to reactive oxygen species (ROS) metabolism contributing to this difference. This genetic and molecular variation is physiologically manifested in lower ROS activity, lower susceptibility to ROS-inducing agent, faster pathogen clearance and higher stem cell activity in resistant versus susceptible lines. This study provides novel insights into the determinants underlying population-level variability in gut immunocompetence, revealing how relatively minor, but systematic genetic and transcriptional variation can mediate overt physiological differences that determine enteric infection susceptibility.

Large Modulation of Charge Carrier Mobility in Doped Nanoporous Organic Transistors.

PubMed

Zhang, Fengjiao; Dai, Xiaojuan; Zhu, Weikun; Chung, Hyunjoong; Diao, Ying

2017-07-01

Molecular doping of organic electronics has shown promise to sensitively modulate important device metrics. One critical challenge is the disruption of structure order upon doping of highly crystalline organic semiconductors, which significantly reduces the charge carrier mobility. This paper demonstrates a new method to achieve large modulation of charge carrier mobility via channel doping without disrupting the molecular ordering. Central to the method is the introduction of nanopores into the organic semiconductor thin films via a simple and robust templated meniscus-guided coating method. Using this method, the charge carrier mobility of C 8 -benzothieno[3,2-b]benzothiophene transistors is boosted by almost sevenfold. This paper further demonstrates enhanced electron transport by close to an order of magnitude in a diketopyrrolopyrrole-based donor-acceptor polymer. Combining spectroscopic measurements, density functional theory calculations, and electrical characterizations, the doping mechanism is identified as partial-charge-transfer induced trap filling. The nanopores serve to enhance the dopant/organic semiconductor charge transfer reaction by exposing the π-electrons to the pore wall. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Large Modulation of Charge Carrier Mobility in Doped Nanoporous Organic Transistors

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

Zhang, Fengjiao; Dai, Xiaojuan; Zhu, Weikun

Molecular doping of organic electronics has shown promise to sensitively modulate important device metrics. One critical challenge is the disruption of structure order upon doping of highly crystalline organic semiconductors, which significantly reduces the charge carrier mobility. This paper demonstrates a new method to achieve large modulation of charge carrier mobility via channel doping without disrupting the molecular ordering. Central to the method is the introduction of nanopores into the organic semiconductor thin films via a simple and robust templated meniscus-guided coating method. Using this method, the charge carrier mobility of C8-benzothieno[3,2-b]benzothiophene transistors is boosted by almost sevenfold. This papermore » further demonstrates enhanced electron transport by close to an order of magnitude in a diketopyrrolopyrrole-based donor–acceptor polymer. Combining spectroscopic measurements, density functional theory calculations, and electrical characterizations, the doping mechanism is identified as partial-charge-transfer induced trap filling. The nanopores serve to enhance the dopant/organic semiconductor charge transfer reaction by exposing the π-electrons to the pore wall.« less

Convergent modulation of singlet and triplet excited states of phosphine-oxide hosts through the management of molecular structure and functional-group linkages for low-voltage-driven electrophosphorescence.

PubMed

Han, Chunmiao; Zhang, Zhensong; Xu, Hui; Xie, Guohua; Li, Jing; Zhao, Yi; Deng, Zhaopeng; Liu, Shiyong; Yan, Pengfei

2013-01-02

The controllable tuning of the excited states in a series of phosphine-oxide hosts (DPExPOCzn) was realized through introducing carbazolyl and diphenylphosphine-oxide (DPPO) moieties to adjust the frontier molecular orbitals, molecular rigidity, and the location of the triplet excited states by suppressing the intramolecular interplay of the combined multi-insulating and meso linkage. On increasing the number of substituents, simultaneous lowering of the first singlet energy levels (S(1)) and raising of the first triplet energy levels (T(1), about 3.0 eV) were achieved. The former change was mainly due to the contribution of the carbazolyl group to the HOMOs and the extended conjugation. The latter change was due to an enhanced molecular rigidity and the shift of the T(1) states from the diphenylether group to the carbazolyl moieties. This kind of convergent modulation of excited states not only facilitates the exothermic energy transfer to the dopants in phosphorescent organic light-emitting diodes (PHOLEDs), but also realizes the fine-tuning of electrical properties to achieve the balanced carrier injection and transportation in the emitting layers. As the result, the favorable performance of blue-light-emitting PHOLEDs was demonstrated, including much-lower driving voltages of 2.6 V for onset and 3.0 V at 100 cd m(-2), as well as a remarkably improved E.Q.E. of 12.6%. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Photovoltaic module and interlocked stack of photovoltaic modules

DOEpatents

Wares, Brian S.

2014-09-02

One embodiment relates to an arrangement of photovoltaic modules configured for transportation. The arrangement includes a plurality of photovoltaic modules, each photovoltaic module including a frame. A plurality of individual male alignment features and a plurality of individual female alignment features are included on each frame. Adjacent photovoltaic modules are interlocked by multiple individual male alignment features on a first module of the adjacent photovoltaic modules fitting into and being surrounded by corresponding individual female alignment features on a second module of the adjacent photovoltaic modules. Other embodiments, features and aspects are also disclosed.

Small Molecule Modulators of Pre-mRNA Splicing in Cancer Therapy.

PubMed

Salton, Maayan; Misteli, Tom

2016-01-01

Pre-mRNA splicing is a fundamental process in mammalian gene expression and alternative RNA splicing plays a considerable role in generating protein diversity. RNA splicing events are also key to the pathology of numerous diseases, particularly cancers. Some tumors are molecularly addicted to specific RNA splicing isoforms making interference with pre-mRNA processing a viable therapeutic strategy. Several RNA splicing modulators have recently been characterized, some showing promise in preclinical studies. While the targets of most splicing modulators are constitutive RNA processing components, possibly leading to undesirable side effects, selectivity for individual splicing events has been observed. Given the high prevalence of splicing defects in cancer, small molecule modulators of RNA processing represent a potentially promising novel therapeutic strategy in cancer treatment. Here, we review their reported effects, mechanisms, and limitations. Published by Elsevier Ltd.

Modulation of Phytoalexin Biosynthesis in Engineered Plants for Disease Resistance

PubMed Central

Jeandet, Philippe; Clément, Christophe; Courot, Eric; Cordelier, Sylvain

2013-01-01

Phytoalexins are antimicrobial substances of low molecular weight produced by plants in response to infection or stress, which form part of their active defense mechanisms. Starting in the 1950’s, research on phytoalexins has begun with biochemistry and bio-organic chemistry, resulting in the determination of their structure, their biological activity as well as mechanisms of their synthesis and their catabolism by microorganisms. Elucidation of the biosynthesis of numerous phytoalexins has permitted the use of molecular biology tools for the exploration of the genes encoding enzymes of their synthesis pathways and their regulators. Genetic manipulation of phytoalexins has been investigated to increase the disease resistance of plants. The first example of a disease resistance resulting from foreign phytoalexin expression in a novel plant has concerned a phytoalexin from grapevine which was transferred to tobacco. Transformations were then operated to investigate the potential of other phytoalexin biosynthetic genes to confer resistance to pathogens. Unexpectedly, engineering phytoalexins for disease resistance in plants seem to have been limited to exploiting only a few phytoalexin biosynthetic genes, especially those encoding stilbenes and some isoflavonoids. Research has rather focused on indirect approaches which allow modulation of the accumulation of phytoalexin employing transcriptional regulators or components of upstream regulatory pathways. Genetic approaches using gain- or less-of functions in phytoalexin engineering together with modulation of phytoalexin accumulation through molecular engineering of plant hormones and defense-related marker and elicitor genes have been reviewed. PMID:23880860

CFTR Modulators: Shedding Light on Precision Medicine for Cystic Fibrosis

PubMed Central

Lopes-Pacheco, Miquéias

2016-01-01

Cystic fibrosis (CF) is the most common life-threatening monogenic disease afflicting Caucasian people. It affects the respiratory, gastrointestinal, glandular and reproductive systems. The major cause of morbidity and mortality in CF is the respiratory disorder caused by a vicious cycle of obstruction of the airways, inflammation and infection that leads to epithelial damage, tissue remodeling and end-stage lung disease. Over the past decades, life expectancy of CF patients has increased due to early diagnosis and improved treatments; however, these patients still present limited quality of life. Many attempts have been made to rescue CF transmembrane conductance regulator (CFTR) expression, function and stability, thereby overcoming the molecular basis of CF. Gene and protein variances caused by CFTR mutants lead to different CF phenotypes, which then require different treatments to quell the patients’ debilitating symptoms. In order to seek better approaches to treat CF patients and maximize therapeutic effects, CFTR mutants have been stratified into six groups (although several of these mutations present pleiotropic defects). The research with CFTR modulators (read-through agents, correctors, potentiators, stabilizers and amplifiers) has achieved remarkable progress, and these drugs are translating into pharmaceuticals and personalized treatments for CF patients. This review summarizes the main molecular and clinical features of CF, emphasizes the latest clinical trials using CFTR modulators, sheds light on the molecular mechanisms underlying these new and emerging treatments, and discusses the major breakthroughs and challenges to treating all CF patients. PMID:27656143

Molecular mechanisms of fluoride toxicity.

PubMed

Barbier, Olivier; Arreola-Mendoza, Laura; Del Razo, Luz María

2010-11-05

Halfway through the twentieth century, fluoride piqued the interest of toxicologists due to its deleterious effects at high concentrations in human populations suffering from fluorosis and in in vivo experimental models. Until the 1990s, the toxicity of fluoride was largely ignored due to its "good reputation" for preventing caries via topical application and in dental toothpastes. However, in the last decade, interest in its undesirable effects has resurfaced due to the awareness that this element interacts with cellular systems even at low doses. In recent years, several investigations demonstrated that fluoride can induce oxidative stress and modulate intracellular redox homeostasis, lipid peroxidation and protein carbonyl content, as well as alter gene expression and cause apoptosis. Genes modulated by fluoride include those related to the stress response, metabolic enzymes, the cell cycle, cell-cell communications and signal transduction. The primary purpose of this review is to examine recent findings from our group and others that focus on the molecular mechanisms of the action of inorganic fluoride in several cellular processes with respect to potential physiological and toxicological implications. This review presents an overview of the current research on the molecular aspects of fluoride exposure with emphasis on biological targets and their possible mechanisms of involvement in fluoride cytotoxicity. The goal of this review is to enhance understanding of the mechanisms by which fluoride affects cells, with an emphasis on tissue-specific events in humans. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Natural Modulators of Amyloid-Beta Precursor Protein Processing

PubMed Central

Zhang, Can; Tanzi, Rudolph E.

2013-01-01

Alzheimer’s disease (AD) is a devastating neurodegenerative disease and the primary cause of dementia, with no cure currently available. The pathogenesis of AD is believed to be primarily driven by Aβ, the principal component of senile plaques. Aβ is an ~4 kDa peptide generated from the amyloid-β precursor protein (APP) through proteolytic secretases. Natural products, particularly those utilized in traditional Chinese medicine (TCM), have a long history alleviating common clinical disorders, including dementia. However, the cell/molecular pathways mediated by these natural products are largely unknown until recently when the underlying molecular mechanisms of the disorders begin to be elucidated. Here, the mechanisms with which natural products modulate the pathogenesis of AD are discussed, in particular, by focusing on their roles in the processing of APP. PMID:22998566

Cell Adhesions: Actin-Based Modules that Mediate Cell-Extracellular Matrix and Cell-Cell Interactions

PubMed Central

Bachir, Alexia; Horwitz, Alan Rick; Nelson, W. James; Bianchini, Julie M.

2018-01-01

Cell adhesions link cells to the extracellular matrix (ECM) and to each other, and depend on interactions with the actin cytoskeleton. Both cell-ECM and cell-cell adhesion sites contain discrete, yet overlapping functional modules. These modules establish physical association with the actin cytoskeleton, locally modulate actin organization and dynamics, and trigger intracellular signaling pathways. Interplay between these modules generates distinct actin architectures that underlie different stages, types, and functions of cell-ECM and cell-cell adhesions. Actomyosin contractility is required to generate mature, stable adhesions, as well as sense and translate the mechanical properties of the cellular environment to changes in cell organization and behavior. In this chapter we discuss the organization and function of different adhesion modules and how they interact with the actin cytoskeleton. We highlight the molecular mechanisms of mechanotransduction in adhesions, and how adhesion molecules mediate crosstalk between cell-ECM and cell-cell adhesion sites. PMID:28679638

Actin-Based Adhesion Modules Mediate Cell Interactions with the Extracellular Matrix and Neighboring Cells.

PubMed

Bachir, Alexia I; Horwitz, Alan Rick; Nelson, W James; Bianchini, Julie M

2017-07-05

Cell adhesions link cells to the extracellular matrix (ECM) and to each other and depend on interactions with the actin cytoskeleton. Both cell-ECM and cell-cell adhesion sites contain discrete, yet overlapping, functional modules. These modules establish physical associations with the actin cytoskeleton, locally modulate actin organization and dynamics, and trigger intracellular signaling pathways. Interplay between these modules generates distinct actin architectures that underlie different stages, types, and functions of cell-ECM and cell-cell adhesions. Actomyosin contractility is required to generate mature, stable adhesions, as well as to sense and translate the mechanical properties of the cellular environment into changes in cell organization and behavior. Here, we review the organization and function of different adhesion modules and how they interact with the actin cytoskeleton. We highlight the molecular mechanisms of mechanotransduction in adhesions and how adhesion molecules mediate cross talk between cell-ECM and cell-cell adhesion sites. Copyright © 2017 Cold Spring Harbor Laboratory Press; all rights reserved.

Tunable molecular plasmons in polycyclic aromatic hydrocarbons.

PubMed

Manjavacas, Alejandro; Marchesin, Federico; Thongrattanasiri, Sukosin; Koval, Peter; Nordlander, Peter; Sánchez-Portal, Daniel; García de Abajo, F Javier

2013-04-23

We show that chemically synthesized polycyclic aromatic hydrocarbons (PAHs) exhibit molecular plasmon resonances that are remarkably sensitive to the net charge state of the molecule and the atomic structure of the edges. These molecules can be regarded as nanometer-sized forms of graphene, from which they inherit their high electrical tunability. Specifically, the addition or removal of a single electron switches on/off these molecular plasmons. Our first-principles time-dependent density-functional theory (TDDFT) calculations are in good agreement with a simpler tight-binding approach that can be easily extended to much larger systems. These fundamental insights enable the development of novel plasmonic devices based upon chemically available molecules, which, unlike colloidal or lithographic nanostructures, are free from structural imperfections. We further show a strong interaction between plasmons in neighboring molecules, quantified in significant energy shifts and field enhancement, and enabling molecular-based plasmonic designs. Our findings suggest new paradigms for electro-optical modulation and switching, single-electron detection, and sensing using individual molecules.

Random amplified polymorphic DNA PCR in the teaching of molecular epidemiology.

PubMed

Reinoso, Elina B; Bettera, Susana G

2016-07-08

In this article, we describe a basic practical laboratory designed for fifth-year undergraduate students of Microbiology as part of the Epidemiology course. This practice provides the students with the tools for molecular epidemiological analysis of pathogenic microorganisms using a rapid and simple PCR technique. The aim of this work was to assay RAPD-PCR technique in order to infer possible epidemiological relationships. The activity gives students an appreciation of the value of applying a simple molecular biological method as RAPD-PCR to a discipline-specific question. It comprises a three-session laboratory module to genetically assay DNAs from strains isolated from a food outbreak. © 2016 by The International Union of Biochemistry and Molecular Biology, 44(4):391-396, 2016. © 2016 The International Union of Biochemistry and Molecular Biology.

Lactobacillus rhamnosus ATCC 7469 exopolysaccharides synergizes with low level ionizing radiation to modulate signaling molecular targets in colorectal carcinogenesis in rats.

PubMed

Zahran, Walid E; Elsonbaty, Sawsan M; Moawed, Fatma S M

2017-08-01

Combination therapy that targets cellular signaling pathway represents an alternative therapy for the treatment of colon cancer (CRC). The present study was therefore aimed to investigate the probable interaction of Lactobacillus rhamnosus ATCC 7469 exopolysaccharides (EPS) with low level ionizing γ radiation (γ-R) exposure against dimethylhydrazine (DMH)- induced colorectal carcinogenesis in rats. Colon cancer was induced with 20mg DMH/kg BW. Rats received daily by gastric gavage 100mg EPS/Kg BW concomitant with 1Gy γ-R over two months. Colonic oxidative and inflammatory stresses were assessed. The change in the expression of p-p38 MAPK, p-STAT3, β-catenin, NF-kB, COX-2 and iNOS was evaluated by western blotting and q-PCR. It was found that DMH treatment significantly induced colon oxidative injury accompanied by inflammatory disturbance along with increased protein expression of the targeted signaling factors p-p38 MAPK, p-STAT3 and β-catenin. The mRNA gene expression of NF-kB, COX-2 and iNOS was significantly higher in DMH-treated animals. It's worthy to note that colon tissues with DMH treatment showed significant dysplasia and anaplasia of the glandular mucosal lining epithelium with loses of goblet cells formation, pleomorphism in the cells and hyperchromachia in nuclei. Interestingly, EPS treatment with γ-R exposure showed statistically significant amelioration of the oxidative and inflammatory biomarkers with modulated signaling molecular factors accompanied by improved histological structure against DMH-induced CRC. In conclusion, our findings showed that Lactobacillus rhamnosus ATCC 7469 EPS with low level γ-R in synergistic interaction are efficacious control against CRC progression throughout the modulation of key signaling growth factors associated with inflammation via antioxidant mediated anti-inflammatory and anti-proliferative activities. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Modulation of Potassium Channels Inhibits Bunyavirus Infection.

PubMed

Hover, Samantha; King, Barnabas; Hall, Bradley; Loundras, Eleni-Anna; Taqi, Hussah; Daly, Janet; Dallas, Mark; Peers, Chris; Schnettler, Esther; McKimmie, Clive; Kohl, Alain; Barr, John N; Mankouri, Jamel

2016-02-12

Bunyaviruses are considered to be emerging pathogens facilitated by the segmented nature of their genome that allows reassortment between different species to generate novel viruses with altered pathogenicity. Bunyaviruses are transmitted via a diverse range of arthropod vectors, as well as rodents, and have established a global disease range with massive importance in healthcare, animal welfare, and economics. There are no vaccines or anti-viral therapies available to treat human bunyavirus infections and so development of new anti-viral strategies is urgently required. Bunyamwera virus (BUNV; genus Orthobunyavirus) is the model bunyavirus, sharing aspects of its molecular and cellular biology with all Bunyaviridae family members. Here, we show for the first time that BUNV activates and requires cellular potassium (K(+)) channels to infect cells. Time of addition assays using K(+) channel modulating agents demonstrated that K(+) channel function is critical to events shortly after virus entry but prior to viral RNA synthesis/replication. A similar K(+) channel dependence was identified for other bunyaviruses namely Schmallenberg virus (Orthobunyavirus) as well as the more distantly related Hazara virus (Nairovirus). Using a rational pharmacological screening regimen, two-pore domain K(+) channels (K2P) were identified as the K(+) channel family mediating BUNV K(+) channel dependence. As several K2P channel modulators are currently in clinical use, our work suggests they may represent a new and safe drug class for the treatment of potentially lethal bunyavirus disease. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Multi-Scale Molecular Deconstruction of the Serotonin Neuron System

PubMed Central

Okaty, Benjamin W.; Freret, Morgan E.; Rood, Benjamin D.; Brust, Rachael D.; Hennessy, Morgan L.; deBairos, Danielle; Kim, Jun Chul; Cook, Melloni N.; Dymecki, Susan M.

2016-01-01

Summary Serotonergic (5HT) neurons modulate diverse behaviors and physiology and are implicated in distinct clinical disorders. Corresponding diversity in 5HT neuronal phenotypes is becoming apparent and is likely rooted in molecular differences, yet a comprehensive approach characterizing molecular variation across the 5HT system is lacking, as is concomitant linkage to cellular phenotypes. Here we combine intersectional fate mapping, neuron sorting, and genome-wide RNA-Seq to deconstruct the mouse 5HT system at multiple levels of granularity—from anatomy, to genetic sublineages, to single neurons. Our unbiased analyses reveal: principles underlying system organization, novel 5HT neuron subtypes, constellations of differentially expressed genes distinguishing subtypes, and predictions of subtype-specific functions. Using electrophysiology, subtype-specific neuron silencing, and conditional gene knockout, we show that these molecularly defined 5HT neuron subtypes are functionally distinct. Collectively, this resource classifies molecular diversity across the 5HT system and discovers new subtypes, markers, organizing principles, and subtype-specific functions with potential disease relevance. PMID:26549332

Sphingosine 1-Phosphate Receptor Modulators and Drug Discovery

PubMed Central

Park, Soo-Jin; Im, Dong-Soon

2017-01-01

Initial discovery on sphingosine 1-phosphate (S1P) as an intracellular second messenger was faced unexpectedly with roles of S1P as a first messenger, which subsequently resulted in cloning of its G protein-coupled receptors, S1P1–5. The molecular identification of S1P receptors opened up a new avenue for pathophysiological research on this lipid mediator. Cellular and molecular in vitro studies and in vivo studies on gene deficient mice have elucidated cellular signaling pathways and the pathophysiological meanings of S1P receptors. Another unexpected finding that fingolimod (FTY720) modulates S1P receptors accelerated drug discovery in this field. Fingolimod was approved as a first-in-class, orally active drug for relapsing multiple sclerosis in 2010, and its applications in other disease conditions are currently under clinical trials. In addition, more selective S1P receptor modulators with better pharmacokinetic profiles and fewer side effects are under development. Some of them are being clinically tested in the contexts of multiple sclerosis and other autoimmune and inflammatory disorders, such as, psoriasis, Crohn’s disease, ulcerative colitis, polymyositis, dermatomyositis, liver failure, renal failure, acute stroke, and transplant rejection. In this review, the authors discuss the state of the art regarding the status of drug discovery efforts targeting S1P receptors and place emphasis on potential clinical applications. PMID:28035084

DEFINING THE CELLULAR AND MOLECULAR MECHANISMS OF TOXICANT ACTION IN THE TESTIS

EPA Science Inventory

A symposium was held at the 41st annual meeting of the Society of Toxicology with presentations that emphasized novel molecular and cellular pathways that modulate the response to testicular toxicants. The first two presentations described cellular alterations after exposure to t...

Curcumin mediates anticancer effects by modulating multiple cell signaling pathways.

PubMed

Kunnumakkara, Ajaikumar B; Bordoloi, Devivasha; Harsha, Choudhary; Banik, Kishore; Gupta, Subash C; Aggarwal, Bharat B

2017-08-01

Curcumin, a component of a spice native to India, was first isolated in 1815 by Vogel and Pelletier from the rhizomes of Curcuma longa (turmeric) and, subsequently, the chemical structure of curcumin as diferuloylmethane was reported by Milobedzka et al. [(1910) 43., 2163-2170]. Since then, this polyphenol has been shown to exhibit antioxidant, anti-inflammatory, anticancer, antiviral, antibacterial, and antifungal activities. The current review primarily focuses on the anticancer potential of curcumin through the modulation of multiple cell signaling pathways. Curcumin modulates diverse transcription factors, inflammatory cytokines, enzymes, kinases, growth factors, receptors, and various other proteins with an affinity ranging from the pM to the mM range. Furthermore, curcumin effectively regulates tumor cell growth via modulation of numerous cell signaling pathways and potentiates the effect of chemotherapeutic agents and radiation against cancer. Curcumin can interact with most of the targets that are modulated by FDA-approved drugs for cancer therapy. The focus of this review is to discuss the molecular basis for the anticancer activities of curcumin based on preclinical and clinical findings. © 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

Molecular chaperones antagonize proteotoxicity by differentially modulating protein aggregation pathways

PubMed Central

Douglas, Peter M; Summers, Daniel W

2009-01-01

The self-association of misfolded or damaged proteins into ordered amyloid-like aggregates characterizes numerous neurodegenerative disorders. Insoluble amyloid plaques are diagnostic of many disease states. Yet soluble, oligomeric intermediates in the aggregation pathway appear to represent the toxic culprit. Molecular chaperones regulate the fate of misfolded proteins and thereby influence their aggregation state. Chaperones conventionally antagonize aggregation of misfolded, disease proteins and assist in refolding or degradation pathways. Recent work suggests that chaperones may also suppress neurotoxicity by converting toxic, soluble oligomers into benign aggregates. Chaperones can therefore suppress or promote aggregation of disease proteins to ameliorate the proteotoxic accumulation of soluble, assembly intermediates. PMID:19421006

Engineering controllable bidirectional molecular motors based on myosin

NASA Astrophysics Data System (ADS)

Chen, Lu; Nakamura, Muneaki; Schindler, Tony D.; Parker, David; Bryant, Zev

2012-04-01

Cytoskeletal motors drive the transport of organelles and molecular cargoes within cells and have potential applications in molecular detection and diagnostic devices. Engineering molecular motors with controllable properties will allow selective perturbation of mechanical processes in living cells and provide optimized device components for tasks such as molecular sorting and directed assembly. Biological motors have previously been modified by introducing activation/deactivation switches that respond to metal ions and other signals. Here, we show that myosin motors can be engineered to reversibly change their direction of motion in response to a calcium signal. Building on previous protein engineering studies and guided by a structural model for the redirected power stroke of myosin VI, we have constructed bidirectional myosins through the rigid recombination of structural modules. The performance of the motors was confirmed using gliding filament assays and single fluorophore tracking. Our strategy, in which external signals trigger changes in the geometry and mechanics of myosin lever arms, should make it possible to achieve spatiotemporal control over a range of motor properties including processivity, stride size and branchpoint turning.

Prepare, Do, Review: A skills-based approach for laboratory practical classes in biochemistry and molecular biology.

PubMed

Arthur, Peter; Ludwig, Martha; Castelli, Joane; Kirkwood, Paul; Attwood, Paul

2016-05-06

A new laboratory practical system is described which is comprised of a number of laboratory practical modules, each based around a particular technique or set of techniques, related to the theory part of the course but not designed to be dependent on it. Each module comprises an online recorded pre-lab lecture, the laboratory practical itself and a post-lab session in which students make oral presentations on different aspects of the practical. Each part of the module is assessed with the aim of providing rapid feedback to staff and students. Each laboratory practical is the responsibility of a single staff member and through this "ownership," continual review and updating is promoted. Examples of changes made by staff to modules as a result of student feedback are detailed. A survey of students who had experienced both the old-style laboratory course and the new one provided evidence of increased satisfaction with the new program. The assessment of acquired shills in the new program showed that it was much more effective than the old course. © 2016 by The International Union of Biochemistry and Molecular Biology, 44:276-287, 2016. © 2016 The International Union of Biochemistry and Molecular Biology.

Molecular property diagnostic suite (MPDS): Development of disease-specific open source web portals for drug discovery.

PubMed

Nagamani, S; Gaur, A S; Tanneeru, K; Muneeswaran, G; Madugula, S S; Consortium, Mpds; Druzhilovskiy, D; Poroikov, V V; Sastry, G N

2017-11-01

Molecular property diagnostic suite (MPDS) is a Galaxy-based open source drug discovery and development platform. MPDS web portals are designed for several diseases, such as tuberculosis, diabetes mellitus, and other metabolic disorders, specifically aimed to evaluate and estimate the drug-likeness of a given molecule. MPDS consists of three modules, namely data libraries, data processing, and data analysis tools which are configured and interconnected to assist drug discovery for specific diseases. The data library module encompasses vast information on chemical space, wherein the MPDS compound library comprises 110.31 million unique molecules generated from public domain databases. Every molecule is assigned with a unique ID and card, which provides complete information for the molecule. Some of the modules in the MPDS are specific to the diseases, while others are non-specific. Importantly, a suitably altered protocol can be effectively generated for another disease-specific MPDS web portal by modifying some of the modules. Thus, the MPDS suite of web portals shows great promise to emerge as disease-specific portals of great value, integrating chemoinformatics, bioinformatics, molecular modelling, and structure- and analogue-based drug discovery approaches.

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

Integrated systems analysis reveals a molecular network underlying autism spectrum disorders

PubMed Central

Li, Jingjing; Shi, Minyi; Ma, Zhihai; Zhao, Shuchun; Euskirchen, Ghia; Ziskin, Jennifer; Urban, Alexander; Hallmayer, Joachim; Snyder, Michael

2014-01-01

Autism is a complex disease whose etiology remains elusive. We integrated previously and newly generated data and developed a systems framework involving the interactome, gene expression and genome sequencing to identify a protein interaction module with members strongly enriched for autism candidate genes. Sequencing of 25 patients confirmed the involvement of this module in autism, which was subsequently validated using an independent cohort of over 500 patients. Expression of this module was dichotomized with a ubiquitously expressed subcomponent and another subcomponent preferentially expressed in the corpus callosum, which was significantly affected by our identified mutations in the network center. RNA-sequencing of the corpus callosum from patients with autism exhibited extensive gene mis-expression in this module, and our immunochemical analysis showed that the human corpus callosum is predominantly populated by oligodendrocyte cells. Analysis of functional genomic data further revealed a significant involvement of this module in the development of oligodendrocyte cells in mouse brain. Our analysis delineates a natural network involved in autism, helps uncover novel candidate genes for this disease and improves our understanding of its molecular pathology. PMID:25549968

Effect of surfactants on the interaction of phenol with laccase: Molecular docking and molecular dynamics simulation studies.

PubMed

Liu, Yujie; Liu, Zhifeng; Zeng, Guangming; Chen, Ming; Jiang, Yilin; Shao, Binbin; Li, Zhigang; Liu, Yang

2018-05-22

Some surfactants can enhance the removal of phenol by laccase (Lac) in various industrial effluents. Their behavior and function in the biodegradation of phenolic wastewater have been experimentally reported by many researchers, but the underlying molecular mechanism is still unclear. Therefore, the interaction mechanisms of phenol with Lac from Trametes versicolor were investigated in the presence or absence of Triton X-100 (TX100) or rhamnolipid (RL) by molecular docking and molecular dynamics (MD) simulations. The results indicate that phenol contacts with an active site of Lac by hydrogen bonds (HBs) and van der Waals (vdW) interactions in aqueous solution for maintaining its stability. The presence of TX100 or RL results in the significant changes of enzymatic conformations. Meanwhile, the hydrophobic parts of surfactants contact with the outside surface of Lac. These changes lead to the decrease of binding energy between phenol and Lac. The migration behavior of water molecules within hydration shell is also inevitably affected. Therefore, the amphipathic TX100 or RL may influence the phenol degradation ability of Lac by modulating their interactions and water environment. This study offers molecular level of understanding on the function of surfactants in biosystem. Copyright © 2018 Elsevier B.V. All rights reserved.

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

Gamma-irradiated β-glucan modulates signaling molecular targets of hepatocellular carcinoma in rats.

PubMed

Elsonbaty, Sawsan M; Zahran, Walid E; Moawed, Fatma Sm

2017-08-01

β-glucans are one of the most abundant forms of polysaccharides known as biological response modifiers which influence host's biological response and stimulate immune system. Accordingly, this study was initiated to evaluate irradiated β-glucan as a modulator for cellular signaling growth factors involved in the pathogenesis of hepatocellular carcinoma in rats. Hepatocellular carcinoma was induced with 20 mg diethylnitrosamine/kg BW. Rats received daily by gastric gavage 65 mg irradiated β-glucan/kg BW. It was found that treatment of rats with diethylnitrosamine induced hepatic injury and caused significant increase in liver injury markers with a concomitant significant increase in both hepatic oxidative and inflammatory indices: alpha-fetoprotein, interferon gamma, and interleukin 6 in comparison with normal and irradiated β-glucan-treated groups. Western immunoblotting showed a significant increase in the signaling growth factors: extracellular signal-regulated kinase 1 and phosphoinositide 3-kinase proteins in a diethylnitrosamine-treated group while both preventive and therapeutic irradiated β-glucan treatments recorded significant improvement versus diethylnitrosamine group via the modulation of growth factors that encounters hepatic toxicity. The transcript levels of vascular endothelial growth factor A and inducible nitric oxide synthase genes were significantly higher in the diethylnitrosamine-treated group in comparison with controls. Preventive and therapeutic treatments with irradiated β-glucan demonstrated that the transcript level of these genes was significantly decreased which demonstrates the protective effect of β-glucan. Histological investigations revealed that diethylnitrosamine treatment affects the hepatic architecture throughout the significant severe appearance of inflammatory cell infiltration in the portal area and congestion in the portal vein in association with severe degeneration and dysplasia in hepatocytes all over hepatic

Secured Optical Communications Using Quantum Entangled Two-Photon Transparency Modulation

NASA Technical Reports Server (NTRS)

Nguyen, Quang-Viet (Inventor); Kojima, Jun (Inventor); Lekki, John (Inventor)

2015-01-01

A system and method is disclosed wherein optical signals are coded in a transmitter by tuning or modulating the interbeam delay time (which modulates the fourth-order coherence) between pairs of entangled photons. The photon pairs are either absorbed or not absorbed (transparent) by an atomic or molecular fluorescer in a receiver, depending on the inter-beam delay that is introduced in the entangled photon pairs. Upon the absorption, corresponding fluorescent optical emissions follow at a certain wavelength, which are then detected by a photon detector. The advantage of the disclosed system is that it eliminates a need of a coincidence counter to realize the entanglement-based secure optical communications because the absorber acts as a coincidence counter for entangled photon pairs.

Optically modulated fluorescence bioimaging: visualizing obscured fluorophores in high background.

PubMed

Hsiang, Jung-Cheng; Jablonski, Amy E; Dickson, Robert M

2014-05-20

Fluorescence microscopy and detection have become indispensible for understanding organization and dynamics in biological systems. Novel fluorophores with improved brightness, photostability, and biocompatibility continue to fuel further advances but often rely on having minimal background. The visualization of interactions in very high biological background, especially for proteins or bound complexes at very low copy numbers, remains a primary challenge. Instead of focusing on molecular brightness of fluorophores, we have adapted the principles of high-sensitivity absorption spectroscopy to improve the sensitivity and signal discrimination in fluorescence bioimaging. Utilizing very long wavelength transient absorptions of kinetically trapped dark states, we employ molecular modulation schemes that do not simultaneously modulate the background fluorescence. This improves the sensitivity and ease of implementation over high-energy photoswitch-based recovery schemes, as no internal dye reference or nanoparticle-based fluorophores are needed to separate the desired signals from background. In this Account, we describe the selection process for and identification of fluorophores that enable optically modulated fluorescence to decrease obscuring background. Differing from thermally stable photoswitches using higher-energy secondary lasers, coillumination at very low energies depopulates transient dark states, dynamically altering the fluorescence and giving characteristic modulation time scales for each modulatable emitter. This process is termed synchronously amplified fluorescence image recovery (SAFIRe) microscopy. By understanding and optically controlling the dye photophysics, we selectively modulate desired fluorophore signals independent of all autofluorescent background. This shifts the fluorescence of interest to unique detection frequencies with nearly shot-noise-limited detection, as no background signals are collected. Although the fluorescence brightness is

Computational Re-design of Synthetic Genetic Oscillators for Independent Amplitude and Frequency Modulation.

PubMed

Tomazou, Marios; Barahona, Mauricio; Polizzi, Karen M; Stan, Guy-Bart

2018-04-25

To perform well in biotechnology applications, synthetic genetic oscillators must be engineered to allow independent modulation of amplitude and period. This need is currently unmet. Here, we demonstrate computationally how two classic genetic oscillators, the dual-feedback oscillator and the repressilator, can be re-designed to provide independent control of amplitude and period and improve tunability-that is, a broad dynamic range of periods and amplitudes accessible through the input "dials." Our approach decouples frequency and amplitude modulation by incorporating an orthogonal "sink module" where the key molecular species are channeled for enzymatic degradation. This sink module maintains fast oscillation cycles while alleviating the translational coupling between the oscillator's transcription factors and output. We characterize the behavior of our re-designed oscillators over a broad range of physiologically reasonable parameters, explain why this facilitates broader function and control, and provide general design principles for building synthetic genetic oscillators that are more precisely controllable. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

P/Q-type calcium channel modulators

PubMed Central

Nimmrich, V; Gross, G

2012-01-01

P/Q-type calcium channels are high-voltage-gated calcium channels contributing to vesicle release at synaptic terminals. A number of neurological diseases have been attributed to malfunctioning of P/Q channels, including ataxia, migraine and Alzheimer's disease. To date, only two specific P/Q-type blockers are known: both are peptides deriving from the spider venom of Agelenopsis aperta, ω-agatoxins. Other peptidic calcium channel blockers with activity at P/Q channels are available, albeit with less selectivity. A number of low molecular weight compounds modulate P/Q-type currents with different characteristics, and some exhibit a peculiar bidirectional pattern of modulation. Interestingly, there are a number of therapeutics in clinical use, which also show P/Q channel activity. Because selectivity as well as the exact mode of action is different between all P/Q-type channel modulators, the interpretation of clinical and experimental data is complicated and needs a comprehensive understanding of their target profile. The situation is further complicated by the fact that information on potency varies vastly in the literature, which may be the result of different experimental systems, conditions or the splice variants of the P/Q channel. This review attempts to provide a comprehensive overview of the compounds available that affect the P/Q-type channel and should help with the interpretation of results of in vitro experiments and animal models. It also aims to explain some clinical observations by implementing current knowledge about P/Q channel modulation of therapeutically used non-selective drugs. Chances and challenges of the development of P/Q channel-selective molecules are discussed. PMID:22670568

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.

Modulation limit of semiconductor lasers by some parametric modulation schemes

NASA Astrophysics Data System (ADS)

Iga, K.

1985-07-01

Using the simple rate equations and small signal analysis, the modulation speed limit of semiconductor lasers with modulation schemes such as gain switching, modulation of nonradiative recombination lifetime of minority carriers, and cavity Q modulation, is calculated and compared with the injection modulation scheme of Ikegami and Suematsu (1968). It is found that the maximum modulation frequency for the gain and Q modulation can exceed the resonance-like frequency by a factor equal to the coefficient of the time derivative of the modulation parameter, though the nonradiative lifetime modulation is not shown to be different from the injection modulation. A solution for the carrier lifetime modulation of LED is obtained, and the possibility of wideband modulation in this scheme is demonstrated.

Ganoderma lucidum reduces obesity in mice by modulating the composition of the gut microbiota.

PubMed

Chang, Chih-Jung; Lin, Chuan-Sheng; Lu, Chia-Chen; Martel, Jan; Ko, Yun-Fei; Ojcius, David M; Tseng, Shun-Fu; Wu, Tsung-Ru; Chen, Yi-Yuan Margaret; Young, John D; Lai, Hsin-Chih

2015-06-23

Obesity is associated with low-grade chronic inflammation and intestinal dysbiosis. Ganoderma lucidum is a medicinal mushroom used in traditional Chinese medicine with putative anti-diabetic effects. Here, we show that a water extract of Ganoderma lucidum mycelium (WEGL) reduces body weight, inflammation and insulin resistance in mice fed a high-fat diet (HFD). Our data indicate that WEGL not only reverses HFD-induced gut dysbiosis-as indicated by the decreased Firmicutes-to-Bacteroidetes ratios and endotoxin-bearing Proteobacteria levels-but also maintains intestinal barrier integrity and reduces metabolic endotoxemia. The anti-obesity and microbiota-modulating effects are transmissible via horizontal faeces transfer from WEGL-treated mice to HFD-fed mice. We further show that high molecular weight polysaccharides (>300 kDa) isolated from the WEGL extract produce similar anti-obesity and microbiota-modulating effects. Our results indicate that G. lucidum and its high molecular weight polysaccharides may be used as prebiotic agents to prevent gut dysbiosis and obesity-related metabolic disorders in obese individuals.

Design Principles of Regulatory Networks: Searching for the Molecular Algorithms of the Cell

PubMed Central

Lim, Wendell A.; Lee, Connie M.; Tang, Chao

2013-01-01

A challenge in biology is to understand how complex molecular networks in the cell execute sophisticated regulatory functions. Here we explore the idea that there are common and general principles that link network structures to biological functions, principles that constrain the design solutions that evolution can converge upon for accomplishing a given cellular task. We describe approaches for classifying networks based on abstract architectures and functions, rather than on the specific molecular components of the networks. For any common regulatory task, can we define the space of all possible molecular solutions? Such inverse approaches might ultimately allow the assembly of a design table of core molecular algorithms that could serve as a guide for building synthetic networks and modulating disease networks. PMID:23352241

Social molecular pathways and the evolution of bee societies

PubMed Central

Bloch, Guy; Grozinger, Christina M.

2011-01-01

Bees provide an excellent model with which to study the neuronal and molecular modifications associated with the evolution of sociality because relatively closely related species differ profoundly in social behaviour, from solitary to highly social. The recent development of powerful genomic tools and resources has set the stage for studying the social behaviour of bees in molecular terms. We review ‘ground plan’ and ‘genetic toolkit’ models which hypothesize that discrete pathways or sets of genes that regulate fundamental behavioural and physiological processes in solitary species have been co-opted to regulate complex social behaviours in social species. We further develop these models and propose that these conserved pathways and genes may be incorporated into ‘social pathways’, which consist of relatively independent modules involved in social signal detection, integration and processing within the nervous and endocrine systems, and subsequent behavioural outputs. Modifications within modules or in their connections result in the evolution of novel behavioural patterns. We describe how the evolution of pheromonal regulation of social pathways may lead to the expression of behaviour under new social contexts, and review plasticity in circadian rhythms as an example for a social pathway with a modular structure. PMID:21690132

The GenTechnique Project: Developing an Open Environment for Learning Molecular Genetics.

ERIC Educational Resources Information Center

Calza, R. E.; Meade, J. T.

1998-01-01

The GenTechnique project at Washington State University uses a networked learning environment for molecular genetics learning. The project is developing courseware featuring animation, hyper-link controls, and interactive self-assessment exercises focusing on fundamental concepts. The first pilot course featured a Web-based module on DNA…

Studying Human Disease Genes in "Caenorhabditis Elegans": A Molecular Genetics Laboratory Project

ERIC Educational Resources Information Center

Cox-Paulson, Elisabeth A.; Grana, Theresa M.; Harris, Michelle A.; Batzli, Janet M.

2012-01-01

Scientists routinely integrate information from various channels to explore topics under study. We designed a 4-wk undergraduate laboratory module that used a multifaceted approach to study a question in molecular genetics. Specifically, students investigated whether "Caenorhabditis elegans" can be a useful model system for studying genes…

Modulation of lateral and longitudinal interdimeric interactions in microtubule models by Laulimalide and Peloruside A association: A molecular modeling approach on the mechanism of microtubule stabilizing agents.

PubMed

Zúñiga, Matías A; Alderete, Joel B; Jaña, Gonzalo A; Fernandez, Pedro A; Ramos, Maria J; Jiménez, Verónica A

2018-05-01

Laulimalide (LAU) and Peloruside A (PLA) are non-taxane microtubule stabilizing agents with promising antimitotic properties. These ligands promote the assembly of microtubules (MTs) by targeting a unique binding site on β-tubulin. The X-ray structure for LAU/PLA-tubulin association was recently elucidated, but little information is available regarding the role of these ligands as modulators of interdimeric interactions across MTs. Herein, we report the use of molecular dynamics (MD), principal component analysis (PCA), MM/GBSA-binding free energy calculations, and computational alanine scanning mutagenesis (ASM) to examine effect of LAU/PLA association on lateral and longitudinal contacts between tubulin dimers in reduced MT models. MD and PCA results revealed that LAU/PLA exerts a strong restriction of lateral and longitudinal interdimeric motions, thus enabling the stabilization of the MT lattice. Besides structural effects, LAU/PLA induces a substantial strengthening of longitudinal interdimeric interactions, whereas lateral contacts are less affected by these ligands, as revealed by MM/GBSA and ASM calculations. These results are valuable to increase understanding about the molecular features involved in MT stabilization by LAU/PLA, and to design novel compounds capable of emulating the mode of action of these ligands. © 2018 John Wiley & Sons A/S.

Phase behavior of Langmuir monolayers with ionic molecular heads: Molecular simulations

NASA Astrophysics Data System (ADS)

González-Castro, Carlos A.; Ramírez-Santiago, Guillermo

2015-03-01

We carried out Monte Carlo simulations in the N ,Π,T ensemble of a Langmuir monolayer coarse-grained molecular model. Considering that the hydrophilic groups can be ionized by modulating acid-base interactions, here we study the phase behavior of a model that incorporates the short-range steric and long-range ionic interactions. The simulations were carried out in the reduced temperature range 0.1 ≤T*<4.0 , where there is a competition of these interactions. Different order parameters were calculated and analyzed for several values of the reduced surface pressure in the interval, 1 ≤Π*≤40. For most of the surface pressures two directions of molecular tilt were found: (i) towards the nearest neighbor (NN) at low temperatures, T*<0.7, and most of the values of Π* and (ii) towards next-nearest neighbors (NNN) in the temperature interval 0.7 ≤T*<1.1 for Π*<25. We also found the coexistence of the NN and NNN at intermediate temperatures and Π*>25 . A low-temperature reentrant disorder-order-disorder transition in the positions of the molecular heads and in the collective tilt of the tails was found for all the surface pressure values. It was also found that the molecular tails arranged forming "rotating patterns" in the temperature interval, 0.5 molecular heads carry an ion in qualitative agreement with experimental observations of fatty acid monolayers with ionic head groups. Two surface pressure versus area per molecule isotherms were also calculated. At low temperatures near the LC-NN ↔ LC-NNN transitions and at higher temperatures close to the LE ↔ LC transitions. From these isotherms the monolayer's area compression modulus was obtained and its variation ranges in the LE and LC phases were

Engineering vaccines and niches for immune modulation.

PubMed

Purwada, Alberto; Roy, Krishnendu; Singh, Ankur

2014-04-01

Controlled modulation of immune response, especially the balance between immunostimulatory and immunosuppressive responses, is critical for a variety of clinical applications, including immunotherapies against cancer and infectious diseases, treatment of autoimmune disorders, transplant surgeries, regenerative medicine, prosthetic implants, etc. Our ability to precisely modify both innate and adaptive immune responses could provide new therapeutic directions in a variety of diseases. In the context of vaccines and immunotherapies, the interplay between antigen-presenting cells (e.g. dendritic cells and macrophages), B cells, T helper and killer subtypes, and regulatory T- and B-cell responses is critical for generating effective immunity against cancer, infectious diseases and autoimmune diseases. In recent years, immunoengineering has emerged as a new field that uses quantitative engineering tools to understand molecular-, cellular- and system-level interactions of the immune system and to develop design-driven approaches to control and modulate immune responses. Biomaterials are an integral part of this engineering toolbox and can exploit the intrinsic biological and mechanical cues of the immune system to directly modulate and train immune cells and direct their response to a particular phenotype. A large body of literature exists on strategies to evade or suppress the immune response in implants, transplantation and regenerative medicine. This review specifically focuses on the use of biomaterials for immunostimulation and controlled modulation, especially in the context of vaccines and immunotherapies against cancer, infectious diseases and autoimmune disorders. Bioengineering smart systems that can simultaneously deliver multiple bioactive agents in a controlled manner or can work as a niche for in situ priming and modulation of the immune system could significantly enhance the efficacy of next-generation immunotherapeutics. In this review, we describe our

Specific polyunsaturated fatty acids modulate lipid delivery and oocyte development in C. elegans revealed by molecular-selective label-free imaging

NASA Astrophysics Data System (ADS)

Chen, Wei-Wen; Yi, Yung-Hsiang; Chien, Cheng-Hao; Hsiung, Kuei-Ching; Ma, Tian-Hsiang; Lin, Yi-Chun; Lo, Szecheng J.; Chang, Ta-Chau

2016-08-01

Polyunsaturated fatty acids (PUFAs) exhibit critical functions in biological systems and their importance during animal oocyte maturation has been increasingly recognized. However, the detailed mechanism of lipid transportation for oocyte development remains largely unknown. In this study, the transportation of yolk lipoprotein (lipid carrier) and the rate of lipid delivery into oocytes in live C. elegans were examined for the first time by using coherent anti-Stokes Raman scattering (CARS) microscopy. The accumulation of secreted yolk lipoprotein in the pseudocoelom of live C. elegans can be detected by CARS microscopy at both protein (~1665 cm-1) and lipid (~2845 cm-1) Raman bands. In addition, an image analysis protocol was established to quantitatively measure the levels of secreted yolk lipoprotein aberrantly accumulated in PUFA-deficient fat mutants (fat-1, fat-2, fat-3, fat-4) and PUFA-supplemented fat-2 worms (the PUFA add-back experiments). Our results revealed that the omega-6 PUFAs, not omega-3 PUFAs, play a critical role in modulating lipid/yolk level in the oocytes and regulating reproductive efficiency of C. elegans. This work demonstrates the value of using CARS microscopy as a molecular-selective label-free imaging technique for the study of PUFA regulation and oocyte development in C. elegans.

A Rab5 GTPase module is important for autophagosome closure

PubMed Central

Lipatova, Zhanna; Sun, Dan; Zhu, Xiaolong; Li, Rui; Wu, Zulin; You, Weiming; Cong, Xiaoxia; Zhou, Yiting; Gyurkovska, Valeriya; Liu, Yutao; Li, Qunli; Li, Wenjing; Cheng, Jie; Segev, Nava

2017-01-01

In the conserved autophagy pathway, the double-membrane autophagosome (AP) engulfs cellular components to be delivered for degradation in the lysosome. While only sealed AP can productively fuse with the lysosome, the molecular mechanism of AP closure is currently unknown. Rab GTPases, which regulate all intracellular trafficking pathways in eukaryotes, also regulate autophagy. Rabs function in GTPase modules together with their activators and downstream effectors. In yeast, an autophagy-specific Ypt1 GTPase module, together with a set of autophagy-related proteins (Atgs) and a phosphatidylinositol-3-phosphate (PI3P) kinase, regulates AP formation. Fusion of APs and endosomes with the vacuole (the yeast lysosome) requires the Ypt7 GTPase module. We have previously shown that the Rab5-related Vps21, within its endocytic GTPase module, regulates autophagy. However, it was not clear which autophagy step it regulates. Here, we show that this module, which includes the Vps9 activator, the Rab5-related Vps21, the CORVET tethering complex, and the Pep12 SNARE, functions after AP expansion and before AP closure. Whereas APs are not formed in mutant cells depleted for Atgs, sealed APs accumulate in cells depleted for the Ypt7 GTPase module members. Importantly, depletion of individual members of the Vps21 module results in a novel phenotype: accumulation of unsealed APs. In addition, we show that Vps21-regulated AP closure precedes another AP maturation step, the previously reported PI3P phosphatase-dependent Atg dissociation. Our results delineate three successive steps in the autophagy pathway regulated by Rabs, Ypt1, Vps21 and Ypt7, and provide the first insight into the upstream regulation of AP closure. PMID:28934205

Grape seed procyanidin extract modulates proliferation and apoptosis of pancreatic beta-cells.

PubMed

Cedó, Lídia; Castell-Auví, Anna; Pallarès, Victor; Blay, Mayte; Ardévol, Anna; Arola, Lluís; Pinent, Montserrat

2013-05-01

Grape seed procyanidin extract (GSPE) modulates glucose homeostasis and insulinemia in several animal models. Under pathological conditions, insulin levels are dependent on pancreatic beta-cell functionality, as well as on the beta-cell mass expansion or apoptosis in the pancreas. In this study, we analysed the effects of GSPE on modulating apoptosis and proliferation in beta-cells. We tested the effects of GSPE in the INS-1E pancreatic beta-cell line, either under basal or altered conditions with high glucose, insulin or palmitate levels. GSPE enhanced the pro-apoptotic effect of high glucose and showed clear antiproliferative effects under high glucose, insulin and palmitate conditions. These antiproliferative effects are likely due to high molecular weight compounds contained in the extract. GSPE also modulated pro- and anti-apoptotic markers in the pancreas of rats fed a cafeteria diet, with the effect depending on the dose of GSPE and duration of treatment. Thus, GSPE is able to modulate apoptosis and proliferation of beta-cells under altered, but not basal, conditions. Copyright © 2012 Elsevier Ltd. All rights reserved.

Coco is a dual activity modulator of TGFβ signaling

PubMed Central

Deglincerti, Alessia; Haremaki, Tomomi; Warmflash, Aryeh; Sorre, Benoit; Brivanlou, Ali H.

2015-01-01

The TGFβ signaling pathway is a crucial regulator of developmental processes and disease. The activity of TGFβ ligands is modulated by various families of soluble inhibitors that interfere with the interactions between ligands and receptors. In an unbiased, genome-wide RNAi screen to identify genes involved in ligand-dependent signaling, we unexpectedly identified the BMP/Activin/Nodal inhibitor Coco as an enhancer of TGFβ1 signaling. Coco synergizes with TGFβ1 in both cell culture and Xenopus explants. Molecularly, Coco binds to TGFβ1 and enhances TGFβ1 binding to its receptor Alk5. Thus, Coco acts as both an inhibitor and an enhancer of signaling depending on the ligand it binds. This finding raises the need for a global reconsideration of the molecular mechanisms regulating TGFβ signaling. PMID:26116664

Bond order potential module for LAMMPS

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

2012-09-11

pair_bop is a module for performing energy calculations using the Bond Order Potential (BOP) for use in the parallel molecular dynamics code LAMMPS. The bop pair style computes BOP based upon quantum mechanical incorporating both sigma and pi bondings. By analytically deriving the BOP pair bop from quantum mechanical theory its transferability to different phases can approach that of quantum mechanical methods. This potential is extremely effective at modeling 111-V and II-VI compounds such as GaAs and CdTe. This potential is similar to the original BOP developed by Pettifor and later updated by Murdock et al. and Ward et al.

Photovoltaic module and interlocked stack of photovoltaic modules

DOEpatents

Wares, Brian S.

2012-09-04

One embodiment relates to an arrangement of photovoltaic modules configured for transportation. The arrangement includes a plurality of photovoltaic modules, each photovoltaic module including a frame having at least a top member and a bottom member. A plurality of alignment features are included on the top member of each frame, and a plurality of alignment features are included on the bottom member of each frame. Adjacent photovoltaic modules are interlocked by the alignment features on the top member of a lower module fitting together with the alignment features on the bottom member of an upper module. Other embodiments, features and aspects are also disclosed.

Molecular design for nonpolar chiral-axial quadratic nonlinear optics

NASA Astrophysics Data System (ADS)

Wiggers, Gregory A.

In this thesis the hyperpolarizability of various multi-dimensional molecules is studied theoretically/computationally, with particular focus on the second-rank Kleinman-disallowed (KD) component of the hyperpolarizability. This component, which transforms as a second-rank traceless symmetric tensor, could be utilized in certain chiral-axial molecular alignment schemes to produce a bulk response. Nonpolar chiral-axial systems have been proposed in contrast to polar media, which utilize the vector component of the molecular hyperpolarizability and require parallel alignment of the molecular dipoles. Such parallel alignment of dipoles must be "frozen in" in order to overcome the natural tendency for dipoles to align anti-parallel. This limits the density of chromophores that can be loaded into a polar material. Nonpolar materials do not have such limits in theory. The two geometric classes of molecules that can most easily be incorporated into nonpolar chiral-uniaxial materials are propeller-shaped (C3 or D3 symmetry) and Λ-shaped (C2v symmetry). This work describes efforts to design molecules within these classes that would be suitable for bulk NLO materials. The sum-over-states (SOS) expression is used to model the molecular hyperpolarizability, and quantum chemical calculations, along with linear absorption data (when available) provide the necessary parameters to evaluate truncated forms of the SOS expression. A host of chemical and geometric modifications will be considered in order to elucidate important structure/function relationships. Also, the SOS model will be tested in some cases when experimental measurements (via Kleinman-disallowed hyper-Rayleigh scattering) are available. While a majority of this work focuses on multi-dimensional molecules, a small section deals with the question of optimizing the hyperpolarizability of a one-dimensional system. It is suggested that the recently-proposed idea of "modulated conjugation" as a means for improving

Anticancer Natural Compounds as Epigenetic Modulators of Gene Expression

PubMed Central

Ratovitski, Edward A.

2017-01-01

Abstract: Accumulating evidence shows that hallmarks of cancer include: “genetic and epigenetic alterations leading to inactivation of cancer suppressors, overexpression of oncogenes, deregulation of intracellular signaling cascades, alterations of cancer cell metabolism, failure to undergo cancer cell death, induction of epithelial to mesenchymal transition, invasiveness, metastasis, deregulation of immune response and changes in cancer microenvironment, which underpin cancer development”. Natural compounds as bioactive ingredients isolated from natural sources (plants, fungi, marine life forms) have revolutionized the field of anticancer therapeutics and rapid developments in preclinical studies are encouraging. Natural compounds could affect the epigenetic molecular mechanisms that modulate gene expression, as well as DNA damage and repair mechanisms. The current review will describe the latest achievements in using naturally produced compounds targeting epigenetic regulators and modulators of gene transcription in vitro and in vivo to generate novel anticancer therapeutics. PMID:28367075

Experiment module concepts study. Volume 3: Module and subsystem design

NASA Technical Reports Server (NTRS)

Hunter, J. R.; Chiarappa, D. J.

1970-01-01

The final common module set exhibiting wide commonality is described. The set consists of three types of modules: one free flying module and two modules that operate attached to the space station. The common module designs provide for the experiment program as defined. The feasibility, economy, and practicality of these modules hinges on factors that do not affect the approach or results of the commonality process, but are important to the validity of the common module concepts. Implementation of the total experiment program requires thirteen common modules: five CM-1, five CM-3, and three CM-4 modules.

Role of density modulation in the spatially resolved dynamics of strongly confined liquids

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

Saw, Shibu, E-mail: shibu.saw@sydney.edu.au; Dasgupta, Chandan, E-mail: cdgupta@physics.iisc.ernet.in

Confinement by walls usually produces a strong modulation in the density of dense liquids near the walls. Using molecular dynamics simulations, we examine the effects of the density modulation on the spatially resolved dynamics of a liquid confined between two parallel walls, using a resolution of a fraction of the interparticle distance in the liquid. The local dynamics is quantified by the relaxation time associated with the temporal autocorrelation function of the local density. We find that this local relaxation time varies in phase with the density modulation. The amplitude of the spatial modulation of the relaxation time can bemore » quite large, depending on the characteristics of the wall and thermodynamic parameters of the liquid. To disentangle the effects of confinement and density modulation on the spatially resolved dynamics, we compare the dynamics of a confined liquid with that of an unconfined one in which a similar density modulation is induced by an external potential. We find several differences indicating that density modulation alone cannot account for all the features seen in the spatially resolved dynamics of confined liquids. We also examine how the dynamics near a wall depends on the separation between the two walls and show that the features seen in our simulations persist in the limit of large wall separation.« less

From molecular to macroscopic engineering: shaping hydrogen-bonded organic nanomaterials.

PubMed

Yoosaf, K; Llanes-Pallas, Anna; Marangoni, Tomas; Belbakra, Abdelhalim; Marega, Riccardo; Botek, Edith; Champagne, Benoît; Bonifazi, Davide; Armaroli, Nicola

2011-03-07

The self-assembly and self-organization behavior of chromophoric acetylenic scaffolds bearing 2,6-bis(acetylamino)pyridine (1, 2) or uracyl-type (3-9) terminal groups has been investigated by photophysical and microscopic methods. Systematic absorption and luminescence studies show that 1 and 2, thanks to a combination of solvophilic/solvophobic forces and π-π stacking interactions, undergo self-organization in apolar solvents (i.e., cyclohexane) and form spherical nanoparticles, as evidenced by wide-field optical microscopy, TEM, and AFM analysis. For the longer molecular module, 2, a more uniform size distribution is found (80-200 nm) compared to 1 (20-1000 nm). Temperature scans in the range 283-353 K show that the self-organized nanoparticles are reversibly formed and destroyed, being stable at lower temperatures. Molecular modules 1 and 2 were then thoroughly mixed with the complementary triply hydrogen-bonding units 3-9. Depending on the specific geometrical structure of 3-9, different nanostructures are evidenced by microscopic investigations. Combination of modules 1 or 2 with 3, which bears only one terminal uracyl unit, leads to the formation of vesicular structures; instead, when 1 is combined with bis-uracyl derivative 4 or 5, a structural evolution from nanoparticles to nanowires is observed. The length of the wires obtained by mixing 1 and 4 or 1 and 5 can be controlled by addition of 3, which prompts transformation of the wires into shorter rods. The replacement of linear system 5 with the related angular modules 6 and 7 enables formation of helical nanostructures, unambiguously evidenced by AFM. Finally, thermally induced self-assembly was studied in parallel with modules 8 and 9, in which the uracyl recognition sites are protected with tert-butyloxycarbonyl (BOC) groups. This strategy allows further control of the self-assembly/self-organization process by temperature, since the BOC group is completely removed on heating. Microscopy studies

ANTIGENIC MODULATION

PubMed Central

Old, Lloyd J.; Stockert, Elisabeth; Boyse, Edward A.; Kim, Jae Ho

1968-01-01

Antigenic modulation (the loss of TL antigens from TL+ cells exposed to TL antibody in the absence of lytic complement) has been demonstrated in vitro. An ascites leukemia, phenotype TL.1,2,3, which modulates rapidly and completely when incubated with TL antiserum in vitro, was selected for further study of the phenomenon. Over a wide range of TL antibody concentrations modulation at 37°C was detectable within 10 min and was complete within approximately 1 hr. The cells were initially sensitized to C' by their contact with antibody, thereafter losing this sensitivity to C' lysis together with their sensitivity to TL antibody and C' in the cytotoxic test. The capacity of the cells to undergo modulation was abolished by actinomycin D and by iodoacetamide, and by reducing the temperature of incubation to 0°C. Thus modulation apparently is an active cellular process. Antigens TL. 1,2, and 3 are all modulated by anti-TL.1,3 serum and by anti-TL.3 serum. This modulation affects all three TL components together, even when antibody to one or two of them is lacking. aAnti-TL.2 serum does not induce modulation and in fact impairs modulation by the other TL antibodies. The influence of the TL phenotype of cells upon the demonstrable content of H-2 (D region) isoantigen, first shown in cells modulated in vivo, has been observed with cells modulated in vitro. Cells undergoing modulation show a progressive increase in H-2 (D region) antigen over a period of 4 hr, with no change in H-2 antigens of the K region. Restoration of the TL+ phenotype of modulated cells after removal of antibody is less rapid than TL+ → TL- modulation and may require several cell divisions. PMID:5636556

Circadian molecular clock in lung pathophysiology

PubMed Central

Sundar, Isaac K.; Yao, Hongwei; Sellix, Michael T.

2015-01-01

Disrupted daily or circadian rhythms of lung function and inflammatory responses are common features of chronic airway diseases. At the molecular level these circadian rhythms depend on the activity of an autoregulatory feedback loop oscillator of clock gene transcription factors, including the BMAL1:CLOCK activator complex and the repressors PERIOD and CRYPTOCHROME. The key nuclear receptors and transcription factors REV-ERBα and RORα regulate Bmal1 expression and provide stability to the oscillator. Circadian clock dysfunction is implicated in both immune and inflammatory responses to environmental, inflammatory, and infectious agents. Molecular clock function is altered by exposomes, tobacco smoke, lipopolysaccharide, hyperoxia, allergens, bleomycin, as well as bacterial and viral infections. The deacetylase Sirtuin 1 (SIRT1) regulates the timing of the clock through acetylation of BMAL1 and PER2 and controls the clock-dependent functions, which can also be affected by environmental stressors. Environmental agents and redox modulation may alter the levels of REV-ERBα and RORα in lung tissue in association with a heightened DNA damage response, cellular senescence, and inflammation. A reciprocal relationship exists between the molecular clock and immune/inflammatory responses in the lungs. Molecular clock function in lung cells may be used as a biomarker of disease severity and exacerbations or for assessing the efficacy of chronotherapy for disease management. Here, we provide a comprehensive overview of clock-controlled cellular and molecular functions in the lungs and highlight the repercussions of clock disruption on the pathophysiology of chronic airway diseases and their exacerbations. Furthermore, we highlight the potential for the molecular clock as a novel chronopharmacological target for the management of lung pathophysiology. PMID:26361874

Chiral expression from molecular to macroscopic level via pH modulation in terbium coordination polymers.

PubMed

Huang, Jian; Ding, Hong-Ming; Xu, Yan; Zeng, Dai; Zhu, Hui; Zang, Dong-Mian; Bao, Song-Song; Ma, Yu-Qiang; Zheng, Li-Min

2017-12-14

Chiral expression from the molecular to macroscopic level is common in biological systems, but is difficult to realise for coordination polymers (CPs). The assembly of homochiral CPs in both crystalline and helical forms can provide a bridge for understanding the relationship between the molecular and macroscopic scales of chirality. Herein, we report homochiral helices of [Tb(R- or S-pempH) 3 ]∙2H 2 O (R - or S -1) (pempH 2  = (1-phenylethylamino)methylphosphonic acid) and their crystalline counterparts (R - or S -3), which are formed at different pH of the reaction mixtures under hydrothermal conditions. By combining the experiments and molecular simulations, we propose that the formation of helices of R -1 or S -1 occurs via a hierarchical self-assembly route, which involves twisted packing due to the geometric incompatibility of the different types of chains. The observed chiral transcription from molecules to morphologies is significant for understanding bio-related self-assembly processes on the nano- to macro-scale.

A Molecular Description of Cellulose Biosynthesis

PubMed Central

McNamara, Joshua T.; Morgan, Jacob L.W.; Zimmer, Jochen

2016-01-01

Cellulose is the most abundant biopolymer on Earth, and certain organisms from bacteria to plants and animals synthesize cellulose as an extracellular polymer for various biological functions. Humans have used cellulose for millennia as a material and an energy source, and the advent of a lignocellulosic fuel industry will elevate it to the primary carbon source for the burgeoning renewable energy sector. Despite the biological and societal importance of cellulose, the molecular mechanism by which it is synthesized is now only beginning to emerge. On the basis of recent advances in structural and molecular biology on bacterial cellulose synthases, we review emerging concepts of how the enzymes polymerize glucose molecules, how the nascent polymer is transported across the plasma membrane, and how bacterial cellulose biosynthesis is regulated during biofilm formation. Additionally, we review evolutionary commonalities and differences between cellulose synthases that modulate the nature of the cellulose product formed. PMID:26034894

Controlled Folding, Motional, and Constitutional Dynamic Processes of Polyheterocyclic Molecular Strands.

PubMed

Barboiu, Mihail; Stadler, Adrian-Mihail; Lehn, Jean-Marie

2016-03-18

General design principles have been developed for the control of the structural features of polyheterocyclic strands and their effector-modulated shape changes. Induced defined molecular motions permit designed enforcement of helical as well as linear molecular shapes. The ability of such molecular strands to bind metal cations allows the generation of coiling/uncoiling processes between helically folded and extended linear states. Large molecular motions are produced on coordination of metal ions, which may be made reversible by competition with an ancillary complexing agent and fueled by sequential acid/base neutralization energy. The introduction of hydrazone units into the strands confers upon them constitutional dynamics, whereby interconversion between different strand compositions is achieved through component exchange. These features have relevance for nanomechanical devices. We present a morphological and functional analysis of such systems developed in our laboratories. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Modulation of Caenorhabditis elegans immune response and modification of Shigella endotoxin upon interaction.

PubMed

Kesika, Periyanaina; Prasanth, Mani Iyer; Balamurugan, Krishnaswamy

2015-04-01

To analyze the pathogenesis at both physiological and molecular level using the model organism, Caenorhabditis elegans at different developmental stages in response to Shigella spp. and its pathogen associated molecular patterns such as lipopolysaccharide. The solid plate and liquid culture-based infection assays revealed that Shigella spp. infects C. elegans and had an impact on the brood size and pharyngeal pumping rate. LPS of Shigella spp. was toxic to C. elegans. qPCR analysis revealed that host innate immune genes have been modulated upon Shigella spp. infections and its LPS challenges. Non-destructive analysis was performed to kinetically assess the alterations in LPS during interaction of Shigella spp. with C. elegans. The modulation of innate immune genes attributed the surrendering of host immune system to Shigella spp. by favoring the infection. LPS appeared to have a major role in Shigella-mediated pathogenesis and Shigella employs a tactic behavior of modifying its LPS content to escape from the recognition of host immune system. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Module Configuration

DOEpatents

Oweis, Salah; D'Ussel, Louis; Chagnon, Guy; Zuhowski, Michael; Sack, Tim; Laucournet, Gaullume; Jackson, Edward J.

2002-06-04

A stand alone battery module including: (a) a mechanical configuration; (b) a thermal management configuration; (c) an electrical connection configuration; and (d) an electronics configuration. Such a module is fully interchangeable in a battery pack assembly, mechanically, from the thermal management point of view, and electrically. With the same hardware, the module can accommodate different cell sizes and, therefore, can easily have different capacities. The module structure is designed to accommodate the electronics monitoring, protection, and printed wiring assembly boards (PWAs), as well as to allow airflow through the module. A plurality of modules may easily be connected together to form a battery pack. The parts of the module are designed to facilitate their manufacture and assembly.

Integrated network analysis reveals potentially novel molecular mechanisms and therapeutic targets of refractory epilepsies

PubMed Central

Liu, Guangming; Wang, Yiwei; Zhao, Pengyao; Zhu, Yizhun; Yang, Xiaohan; Zheng, Tiezheng; Zhou, Xuezhong; Jin, Weilin; Sun, Changkai

2017-01-01

Epilepsy is a complex neurological disorder and a significant health problem. The pathogenesis of epilepsy remains obscure in a significant number of patients and the current treatment options are not adequate in about a third of individuals which were known as refractory epilepsies (RE). Network medicine provides an effective approach for studying the molecular mechanisms underlying complex diseases. Here we integrated 1876 disease-gene associations of RE and located those genes to human protein-protein interaction (PPI) network to obtain 42 significant RE-associated disease modules. The functional analysis of these disease modules showed novel molecular pathological mechanisms of RE, such as the novel enriched pathways (e.g., “presynaptic nicotinic acetylcholine receptors”, “signaling by insulin receptor”). Further analysis on the relationships between current drug targets and the RE-related disease genes showed the rational mechanisms of most antiepileptic drugs. In addition, we detected ten potential novel drug targets (e.g., KCNA1, KCNA4-6, KCNC3, KCND2, KCNMA1, CAMK2G, CACNB4 and GRM1) located in three RE related disease modules, which might provide novel insights into the new drug discovery for RE therapy. PMID:28388656

Multi-Scale Molecular Deconstruction of the Serotonin Neuron System.

PubMed

Okaty, Benjamin W; Freret, Morgan E; Rood, Benjamin D; Brust, Rachael D; Hennessy, Morgan L; deBairos, Danielle; Kim, Jun Chul; Cook, Melloni N; Dymecki, Susan M

2015-11-18

Serotonergic (5HT) neurons modulate diverse behaviors and physiology and are implicated in distinct clinical disorders. Corresponding diversity in 5HT neuronal phenotypes is becoming apparent and is likely rooted in molecular differences, yet a comprehensive approach characterizing molecular variation across the 5HT system is lacking, as is concomitant linkage to cellular phenotypes. Here we combine intersectional fate mapping, neuron sorting, and genome-wide RNA-seq to deconstruct the mouse 5HT system at multiple levels of granularity-from anatomy, to genetic sublineages, to single neurons. Our unbiased analyses reveal principles underlying system organization, 5HT neuron subtypes, constellations of differentially expressed genes distinguishing subtypes, and predictions of subtype-specific functions. Using electrophysiology, subtype-specific neuron silencing, and conditional gene knockout, we show that these molecularly defined 5HT neuron subtypes are functionally distinct. Collectively, this resource classifies molecular diversity across the 5HT system and discovers sertonergic subtypes, markers, organizing principles, and subtype-specific functions with potential disease relevance. Copyright © 2015 Elsevier Inc. All rights reserved.

Thyroid Hormone Differentially Modulates Warburg Phenotype in Breast Cancer Cells

PubMed Central

Suhane, Sonal; Ramanujan, V Krishnan

2011-01-01

Sustenance of cancer cells in vivo critically depends on a variety of genetic and metabolic adaptations. Aerobic glycolysis or Warburg effect has been a defining biochemical hallmark of transformed cells for more than five decades although a clear molecular basis of this observation is emerging only in recent years. In this study, we present our findings that thyroid hormone exerts its non-genomic and genomic actions in two model human breast cancer cell lines differentially. By laying a clear foundation for experimentally monitoring the Warburg phenotype in living cancer cells, we demonstrate that thyroid hormone-induced modulation of bioenergetic profiles in these two model cell lines depends on the degree of Warburg phenotype that they display. Further we also show that thyroid hormone can sensitize mitochondria in aggressive, triple-negative breast cancer cells favorably to increase the chemotherapeutic efficacy in these cells. Even though the role of thyroid hormone in modulating mitochondrial metabolism has been known, the current study accentuates the critical role it plays in modulating Warburg phenotype in breast cancer cells. The clinical significance of this finding is the possibility to devise strategies for metabolically modulating aggressive triple-negative tumors so as to enhance their chemosensitivity in vivo. PMID:21945435

Microscopic origin of electric-field-induced modulation of Curie temperature in cobalt

NASA Astrophysics Data System (ADS)

Ando, Fuyuki; Yamada, Kihiro T.; Koyama, Tomohiro; Ishibashi, Mio; Shiota, Yoichi; Moriyama, Takahiro; Chiba, Daichi; Ono, Teruo

2018-07-01

The Curie temperature T C is one of the most fundamental physical properties of ferromagnetic materials and can be described by the Weiss molecular field theory with the exchange interaction of neighboring atoms. Here, we demonstrate the electrical control of exchange coupling in cobalt films through direct magnetization measurements. We find that the reduction in magnetization with temperature, which is caused by thermal spin wave excitation and scales with Bloch’s law, clearly depends on the applied electric field. Furthermore, we confirm that the correlation between the electric-field-induced modulation of T C and that of exchange coupling follows the Weiss molecular field theory.

Molecular engineering of antibodies for therapeutic and diagnostic purposes

PubMed Central

Ducancel, Frédéric; Muller, Bruno H.

2012-01-01

During the past ten years, monoclonal antibodies (mAbs) have taken center stage in the field of targeted therapy and diagnosis. This increased interest in mAbs is due to their binding accuracy (affinity and specificity) together with the original molecular and structural rules that govern interactions with their cognate antigen. In addition, the effector properties of antibodies constitute a second major advantage associated with their clinical use. The development of molecular and structural engineering and more recently of in vitro evolution of antibodies has opened up new perspectives in the de novo design of antibodies more adapted to clinical and diagnostic use. Thus, efforts are regularly made by researchers to improve or modulate antibody recognition properties, to adapt their pharmacokinetics, engineer their stability, and control their immunogenicity. This review presents the latest molecular engineering results on mAbs with therapeutic and diagnostic applications. PMID:22684311

Atom-based 3D-QSAR, induced fit docking, and molecular dynamics simulations study of thieno[2,3-b]pyridines negative allosteric modulators of mGluR5.

PubMed

Vijaya Prabhu, Sitrarasu; Singh, Sanjeev Kumar

2018-05-28

Atom-based three dimensional-quantitative structure-activity relationship (3D-QSAR) model was developed on the basis of 5-point pharmacophore hypothesis (AARRR) with two hydrogen bond acceptors (A) and three aromatic rings for the derivatives of thieno[2,3-b]pyridine, which modulates the activity to inhibit the mGluR5 receptor. Generation of a highly predictive 3D-QSAR model was performed using the alignment of predicted pharmacophore hypothesis for the training set (R 2  = 0.84, SD = 0.26, F = 45.8, N = 29) and test set (Q 2  = 0.74, RMSE = 0.235, Pearson-R = 0.94, N = 9). The best pharmacophore hypothesis AARRR was selected, and developed three dimensional-quantitative structure activity relationship (3D-QSAR) model also supported the outcome of this study by means of favorable and unfavorable electron withdrawing group and hydrophobic regions of most active compound 42d and least active compound 18b. Following, induced fit docking and binding free energy calculations reveals the reliable binding orientation of the compounds. Finally, molecular dynamics simulations for 100 ns were performed to depict the protein-ligand stability. We anticipate that the resulted outcome could be supportive to discover potent negative allosteric modulators for metabotropic glutamate receptor 5 (mGluR5).

A molecular network of the aging human brain provides insights into the pathology and cognitive decline of Alzheimer's disease.

PubMed

Mostafavi, Sara; Gaiteri, Chris; Sullivan, Sarah E; White, Charles C; Tasaki, Shinya; Xu, Jishu; Taga, Mariko; Klein, Hans-Ulrich; Patrick, Ellis; Komashko, Vitalina; McCabe, Cristin; Smith, Robert; Bradshaw, Elizabeth M; Root, David E; Regev, Aviv; Yu, Lei; Chibnik, Lori B; Schneider, Julie A; Young-Pearse, Tracy L; Bennett, David A; De Jager, Philip L

2018-06-01

There is a need for new therapeutic targets with which to prevent Alzheimer's disease (AD), a major contributor to aging-related cognitive decline. Here we report the construction and validation of a molecular network of the aging human frontal cortex. Using RNA sequence data from 478 individuals, we first build a molecular network using modules of coexpressed genes and then relate these modules to AD and its neuropathologic and cognitive endophenotypes. We confirm these associations in two independent AD datasets. We also illustrate the use of the network in prioritizing amyloid- and cognition-associated genes for in vitro validation in human neurons and astrocytes. These analyses based on unique cohorts enable us to resolve the role of distinct cortical modules that have a direct effect on the accumulation of AD pathology from those that have a direct effect on cognitive decline, exemplifying a network approach to complex diseases.

Combined, solid-state molecular property and gamma spectrometers for CBRNE detection

NASA Astrophysics Data System (ADS)

Rogers, Ben; Grate, Jay; Pearson, Brett; Gallagher, Neal; Wise, Barry; Whitten, Ralph; Adams, Jesse

2013-05-01

Nevada Nanotech Systems, Inc. (Nevada Nano) has developed a multi-sensor solution to Chemical, Biological, Radiological, Nuclear and Explosives (CBRNE) detection that combines the Molecular Property Spectrometer™ (MPS™)—a micro-electro-mechanical chip-based technology capable of measuring a variety of thermodynamic and electrostatic molecular properties of sampled vapors and particles—and a compact, high-resolution, solid-state gamma spectrometer module for identifying radioactive materials, including isotopes used in dirty bombs and nuclear weapons. By conducting multiple measurements, the system can provide a more complete characterization of an unknown sample, leading to a more accurate identification. Positive identifications of threats are communicated using an integrated wireless module. Currently, system development is focused on detection of commercial, military and improvised explosives, radioactive materials, and chemical threats. The system can be configured for a variety of CBRNE applications, including handheld wands and swab-type threat detectors requiring short sample times, and ultra-high sensitivity detectors in which longer sampling times are used. Here we provide an overview of the system design and operation and present results from preliminary testing.

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

Engineering controllable bidirectional molecular motors based on myosin

PubMed Central

Chen, Lu; Nakamura, Muneaki; Schindler, Tony D.; Parker, David; Bryant, Zev

2012-01-01

Cytoskeletal motors drive the transport of organelles and molecular cargoes within cells1, and have potential applications in molecular detection and diagnostic devices2,3. Engineering molecular motors with dynamically controllable properties will allow selective perturbation of mechanical processes in living cells, and yield optimized device components for complex tasks such as molecular sorting and directed assembly3. Biological motors have previously been modified by introducing activation/deactivation switches that respond to metal ions4,5 and other signals6. Here we show that myosin motors can be engineered to reversibly change their direction of motion in response to a calcium signal. Building on previous protein engineering studies7–11 and guided by a structural model12 for the redirected power stroke of myosin VI, we constructed bidirectional myosins through the rigid recombination of structural modules. The performance of the motors was confirmed using gliding filament assays and single fluorophore tracking. Our general strategy, in which external signals trigger changes in the geometry and mechanics of myosin lever arms, should enable spatiotemporal control over a range of motor properties including processivity, stride size13, and branchpoint turning14. PMID:22343382

A Systems Biology Framework Identifies Molecular Underpinnings of Coronary Heart Disease

PubMed Central

Huan, Tianxiao; Zhang, Bin; Wang, Zhi; Joehanes, Roby; Zhu, Jun; Johnson, Andrew D.; Ying, Saixia; Munson, Peter J.; Raghavachari, Nalini; Wang, Richard; Liu, Poching; Courchesne, Paul; Hwang, Shih-Jen; Assimes, Themistocles L.; McPherson, Ruth; Samani, Nilesh J.; Schunkert, Heribert; Meng, Qingying; Suver, Christine; O'Donnell, Christopher J.; Derry, Jonathan; Yang, Xia; Levy, Daniel

2013-01-01

Objective Genetic approaches have identified numerous loci associated with coronary heart disease (CHD). The molecular mechanisms underlying CHD gene-disease associations, however, remain unclear. We hypothesized that genetic variants with both strong and subtle effects drive gene subnetworks that in turn affect CHD. Approach and Results We surveyed CHD-associated molecular interactions by constructing coexpression networks using whole blood gene expression profiles from 188 CHD cases and 188 age- and sex-matched controls. 24 coexpression modules were identified including one case-specific and one control-specific differential module (DM). The DMs were enriched for genes involved in B-cell activation, immune response, and ion transport. By integrating the DMs with altered gene expression associated SNPs (eSNPs) and with results of GWAS of CHD and its risk factors, the control-specific DM was implicated as CHD-causal based on its significant enrichment for both CHD and lipid eSNPs. This causal DM was further integrated with tissue-specific Bayesian networks and protein-protein interaction networks to identify regulatory key driver (KD) genes. Multi-tissue KDs (SPIB and TNFRSF13C) and tissue-specific KDs (e.g. EBF1) were identified. Conclusions Our network-driven integrative analysis not only identified CHD-related genes, but also defined network structure that sheds light on the molecular interactions of genes associated with CHD risk. PMID:23539213

Molecular switch-modulated fluorescent copper nanoclusters for selective and sensitive detection of histidine and cysteine.

PubMed

Gu, Zefeng; Cao, Zhijuan

2018-06-07

A novel assay for histidine and cysteine has been constructed based on modulation of fluorescent copper nanoclusters (CuNCs) by molecular switches. In our previous work, a dumbbell DNA template with a poly-T (thymine) loop has been developed as an excellent template for the formation of strongly fluorescent CuNCs. Herein, for the first time, we established this biosensor for sensing two amino acids by using dumbbell DNA-templated CuNCs as the single probe. Among 20 natural amino acids, only histidine and cysteine can selectively quench fluorescence emission of CuNCs, because of the specific interaction of these compounds with copper ions. Furthermore, by using nickel ions (Ni 2+ ) and N-ethylmaleimide as the masking agents for histidine and cysteine respectively, an integrated logic gate system was designed by coupling with the fluorescent CuNCs and demonstrated selective and sensitive detection of cysteine and histidine. Under optimal conditions, cysteine can be detected in the concentration ranges of 0.01-10.0 μM with the detection limit (DL) of as low as 98 pM, while histidine can be detected in the ranges of 0.05-40.0 μM with DL of 1.6 nM. In addition, histidine and cysteine can be observed with the naked eye under a hand-held UV lamp (DL, 50 nM), which can be easily adapted to automated high-throughput screening. Finally, the strategy has been successfully utilized for biological fluids. The proposed system can be conducted in homogeneous solution, eliminating the need for organic cosolvents, separation processes of nanomaterials, or any chemical modifications. Overall, the assay provides an alternative method for simultaneous detection of cysteine and histidine by taking the advantages of high speed, no label and enzyme requirement, and good sensitivity and specificity, and will satisfy the great demand for determination of amino acids in fields such as food processing, biochemistry, pharmaceuticals, and clinical analysis. Graphical abstract.

Modulation indices for volumetric modulated arc therapy.

PubMed

Park, Jong Min; Park, So-Yeon; Kim, Hyoungnyoun; Kim, Jin Ho; Carlson, Joel; Ye, Sung-Joon

2014-12-07

The aim of this study is to present a modulation index (MI) for volumetric modulated arc therapy (VMAT) based on the speed and acceleration analysis of modulating-parameters such as multi-leaf collimator (MLC) movements, gantry rotation and dose-rate, comprehensively. The performance of the presented MI (MIt) was evaluated with correlation analyses to the pre-treatment quality assurance (QA) results, differences in modulating-parameters between VMAT plans versus dynamic log files, and differences in dose-volumetric parameters between VMAT plans versus reconstructed plans using dynamic log files. For comparison, the same correlation analyses were performed for the previously suggested modulation complexity score (MCS(v)), leaf travel modulation complexity score (LTMCS) and MI by Li and Xing (MI Li&Xing). In the two-tailed unpaired parameter condition, p values were acquired. The Spearman's rho (r(s)) values of MIt, MCSv, LTMCS and MI Li&Xing to the local gamma passing rate with 2%/2 mm criterion were -0.658 (p < 0.001), 0.186 (p = 0.251), 0.312 (p = 0.05) and -0.455 (p = 0.003), respectively. The values of rs to the modulating-parameter (MLC positions) differences were 0.917, -0.635, -0.857 and 0.795, respectively (p < 0.001). For dose-volumetric parameters, MIt showed higher statistically significant correlations than the conventional MIs. The MIt showed good performance for the evaluation of the modulation-degree of VMAT plans.

Structural insight into RNA recognition motifs: versatile molecular Lego building blocks for biological systems.

PubMed

Muto, Yutaka; Yokoyama, Shigeyuki

2012-01-01

'RNA recognition motifs (RRMs)' are common domain-folds composed of 80-90 amino-acid residues in eukaryotes, and have been identified in many cellular proteins. At first they were known as RNA binding domains. Through discoveries over the past 20 years, however, the RRMs have been shown to exhibit versatile molecular recognition activities and to behave as molecular Lego building blocks to construct biological systems. Novel RNA/protein recognition modes by RRMs are being identified, and more information about the molecular recognition by RRMs is becoming available. These RNA/protein recognition modes are strongly correlated with their biological significance. In this review, we would like to survey the recent progress on these versatile molecular recognition modules. Copyright © 2012 John Wiley & Sons, Ltd.

Interaction of antithrombin with sulfated, low molecular weight lignins: opportunities for potent, selective modulation of antithrombin function.

PubMed

Henry, Brian L; Connell, Justin; Liang, Aiye; Krishnasamy, Chandravel; Desai, Umesh R

2009-07-31

Antithrombin, a major regulator of coagulation and angiogenesis, is known to interact with several natural sulfated polysaccharides. Previously, we prepared sulfated low molecular weight variants of natural lignins, called sulfated dehydrogenation polymers (DHPs) (Henry, B. L., Monien, B. H., Bock, P. E., and Desai, U. R. (2007) J. Biol. Chem. 282, 31891-31899), which have now been found to exhibit interesting antithrombin binding properties. Sulfated DHPs represent a library of diverse noncarbohydrate aromatic scaffolds that possess structures completely different from heparin and heparan sulfate. Fluorescence binding studies indicate that sulfated DHPs bind to antithrombin with micromolar affinity under physiological conditions. Salt dependence of binding affinity indicates that the antithrombin-sulfated DHP interaction involves a massive 80-87% non-ionic component to the free energy of binding. Competitive binding studies with heparin pentasaccharide, epicatechin sulfate, and full-length heparin indicate that sulfated DHPs bind to both the pentasaccharide-binding site and extended heparin-binding site of antithrombin. Affinity capillary electrophoresis resolves a limited number of peaks of antithrombin co-complexes suggesting preferential binding of selected DHP structures to the serpin. Computational genetic algorithm-based virtual screening study shows that only one sulfated DHP structure, out of the 11 present in a library of plausible sequences, bound in the heparin-binding site with a high calculated score supporting selectivity of recognition. Enzyme inhibition studies indicate that only one of the three sulfated DHPs studied is a potent inhibitor of free factor VIIa in the presence of antithrombin. Overall, the chemo-enzymatic origin and antithrombin binding properties of sulfated DHPs present novel opportunities for potent and selective modulation of the serpin function, especially for inhibiting the initiation phase of hemostasis.

Osteoblast dysfunctions in bone diseases: from cellular and molecular mechanisms to therapeutic strategies.

PubMed

Marie, Pierre J

2015-04-01

Several metabolic, genetic and oncogenic bone diseases are characterized by defective or excessive bone formation. These abnormalities are caused by dysfunctions in the commitment, differentiation or survival of cells of the osteoblast lineage. During the recent years, significant advances have been made in our understanding of the cellular and molecular mechanisms underlying the osteoblast dysfunctions in osteoporosis, skeletal dysplasias and primary bone tumors. This led to suggest novel therapeutic approaches to correct these abnormalities such as the modulation of WNT signaling, the pharmacological modulation of proteasome-mediated protein degradation, the induction of osteoprogenitor cell differentiation, the repression of cancer cell proliferation and the manipulation of epigenetic mechanisms. This article reviews our current understanding of the major cellular and molecular mechanisms inducing osteoblastic cell abnormalities in age-related bone loss, genetic skeletal dysplasias and primary bone tumors, and discusses emerging therapeutic strategies to counteract the osteoblast abnormalities in these disorders of bone formation.

Thr729 in human topoisomerase I modulates anti-cancer drug resistance by altering protein domain communications as suggested by molecular dynamics simulations.

PubMed

Chillemi, Giovanni; D'Annessa, Ilda; Fiorani, Paola; Losasso, Carmen; Benedetti, Piero; Desideri, Alessandro

2008-10-01

The role of Thr729 in modulating the enzymatic function of human topoisomerase I has been characterized by molecular dynamics (MD) simulation. In detail, the structural-dynamical behaviour of the Thr729Lys and the Thr729Pro mutants have been characterized because of their in vivo and in vitro functional properties evidenced in the accompanying paper. Both mutants can bind to the DNA substrate and are enzymatically active, but while Thr729Lys is resistant even at high concentration of the camptothecin (CPT) anti-cancer drug, Thr729Pro shows only a mild reduction in drug sensitivity and in DNA binding. MD simulations show that the Thr729Lys mutation provokes a structural perturbation of the CPT-binding pocket. On the other hand, the Thr729Pro mutant maintains the wild-type structural scaffold, only increasing its rigidity. The simulations also show the complete abolishment, in the Thr729Lys mutant, of the protein communications between the C-terminal domain (where the active Tyr723 is located) and the linker domain, that plays an essential role in the control of the DNA rotation, thus explaining the distributive mode of action displayed by this mutant.

Thr729 in human topoisomerase I modulates anti-cancer drug resistance by altering protein domain communications as suggested by molecular dynamics simulations

PubMed Central

Chillemi, Giovanni; D’Annessa, Ilda; Fiorani, Paola; Losasso, Carmen; Benedetti, Piero; Desideri, Alessandro

2008-01-01

The role of Thr729 in modulating the enzymatic function of human topoisomerase I has been characterized by molecular dynamics (MD) simulation. In detail, the structural–dynamical behaviour of the Thr729Lys and the Thr729Pro mutants have been characterized because of their in vivo and in vitro functional properties evidenced in the accompanying paper. Both mutants can bind to the DNA substrate and are enzymatically active, but while Thr729Lys is resistant even at high concentration of the camptothecin (CPT) anti-cancer drug, Thr729Pro shows only a mild reduction in drug sensitivity and in DNA binding. MD simulations show that the Thr729Lys mutation provokes a structural perturbation of the CPT-binding pocket. On the other hand, the Thr729Pro mutant maintains the wild-type structural scaffold, only increasing its rigidity. The simulations also show the complete abolishment, in the Thr729Lys mutant, of the protein communications between the C-terminal domain (where the active Tyr723 is located) and the linker domain, that plays an essential role in the control of the DNA rotation, thus explaining the distributive mode of action displayed by this mutant. PMID:18765473

HCN Channels Modulators: The Need for Selectivity

PubMed Central

Romanelli, Maria Novella; Sartiani, Laura; Masi, Alessio; Mannaioni, Guido; Manetti, Dina; Mugelli, Alessandro; Cerbai, Elisabetta

2016-01-01

Hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels, the molecular correlate of the hyperpolarization-activated current (If/Ih), are membrane proteins which play an important role in several physiological processes and various pathological conditions. In the Sino Atrial Node (SAN) HCN4 is the target of ivabradine, a bradycardic agent that is, at the moment, the only drug which specifically blocks If. Nevertheless, several other pharmacological agents have been shown to modulate HCN channels, a property that may contribute to their therapeutic activity and/or to their side effects. HCN channels are considered potential targets for developing drugs to treat several important pathologies, but a major issue in this field is the discovery of isoform-selective compounds, owing to the wide distribution of these proteins into the central and peripheral nervous systems, heart and other peripheral tissues. This survey is focused on the compounds that have been shown, or have been designed, to interact with HCN channels and on their binding sites, with the aim to summarize current knowledge and possibly to unveil useful information to design new potent and selective modulators. PMID:26975509

A LAMMPS implementation of volume-temperature replica exchange molecular dynamics

NASA Astrophysics Data System (ADS)

Liu, Liang-Chun; Kuo, Jer-Lai

2015-04-01

A driver module for executing volume-temperature replica exchange molecular dynamics (VTREMD) was developed for the LAMMPS package. As a patch code, the VTREMD module performs classical molecular dynamics (MD) with Monte Carlo (MC) decisions between MD runs. The goal of inserting the MC step was to increase the breadth of sampled configurational space. In this method, states receive better sampling by making temperature or density swaps with their neighboring states. As an accelerated sampling method, VTREMD is particularly useful to explore states at low temperatures, where systems are easily trapped in local potential wells. As functional examples, TIP4P/Ew and TIP4P/2005 water models were analyzed using VTREMD. The phase diagram in this study covered the deeply supercooled regime, and this test served as a suitable demonstration of the usefulness of VTREMD in overcoming the slow dynamics problem. To facilitate using the current code, attention was also paid on how to optimize the exchange efficiency by using grid allocation. VTREMD was useful for studying systems with rough energy landscapes, such as those with numerous local minima or multiple characteristic time scales.

Implementation of cascade logic gates and majority logic gate on a simple and universal molecular platform.

PubMed

Gao, Jinting; Liu, Yaqing; Lin, Xiaodong; Deng, Jiankang; Yin, Jinjin; Wang, Shuo

2017-10-25

Wiring a series of simple logic gates to process complex data is significantly important and a large challenge for untraditional molecular computing systems. The programmable property of DNA endows its powerful application in molecular computing. In our investigation, it was found that DNA exhibits excellent peroxidase-like activity in a colorimetric system of TMB/H 2 O 2 /Hemin (TMB, 3,3', 5,5'-Tetramethylbenzidine) in the presence of K + and Cu 2+ , which is significantly inhibited by the addition of an antioxidant. According to the modulated catalytic activity of this DNA-based catalyst, three cascade logic gates including AND-OR-INH (INHIBIT), AND-INH and OR-INH were successfully constructed. Interestingly, by only modulating the concentration of Cu 2+ , a majority logic gate with a single-vote veto function was realized following the same threshold value as that of the cascade logic gates. The strategy is quite straightforward and versatile and provides an instructive method for constructing multiple logic gates on a simple platform to implement complex molecular computing.

The Physics and Physical Chemistry of Molecular Machines.

PubMed

Astumian, R Dean; Mukherjee, Shayantani; Warshel, Arieh

2016-06-17

The concept of a "power stroke"-a free-energy releasing conformational change-appears in almost every textbook that deals with the molecular details of muscle, the flagellar rotor, and many other biomolecular machines. Here, it is shown by using the constraints of microscopic reversibility that the power stroke model is incorrect as an explanation of how chemical energy is used by a molecular machine to do mechanical work. Instead, chemically driven molecular machines operating under thermodynamic constraints imposed by the reactant and product concentrations in the bulk function as information ratchets in which the directionality and stopping torque or stopping force are controlled entirely by the gating of the chemical reaction that provides the fuel for the machine. The gating of the chemical free energy occurs through chemical state dependent conformational changes of the molecular machine that, in turn, are capable of generating directional mechanical motions. In strong contrast to this general conclusion for molecular machines driven by catalysis of a chemical reaction, a power stroke may be (and often is) an essential component for a molecular machine driven by external modulation of pH or redox potential or by light. This difference between optical and chemical driving properties arises from the fundamental symmetry difference between the physics of optical processes, governed by the Bose-Einstein relations, and the constraints of microscopic reversibility for thermally activated processes. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Inflammation Modulates Murine Venous Thrombosis Resolution In Vivo: Assessment by Multimodal Fluorescence Molecular Imaging

PubMed Central

Ripplinger, Crystal M.; Kessinger, Chase W.; Li, Chunqiang; Kim, Jin Won; McCarthy, Jason R.; Weissleder, Ralph; Henke, Peter K.; Lin, Charles P.; Jaffer, Farouc A.

2012-01-01

Objective Assessment of thrombus inflammation in vivo could provide new insights into deep vein thrombosis (DVT) resolution. Here we develop and evaluate two integrated fluorescence molecular-structural imaging strategies to quantify DVT-related inflammation and architecture, and to assess the effect of thrombus inflammation on subsequent DVT resolution in vivo. Methods and Results Murine DVT were created with topical 5% FeCl3 application to thigh or jugular veins (n=35). On day 3, mice received macrophage and matrix metalloproteinase (MMP) activity fluorescence imaging agents. On day 4, integrated assessment of DVT inflammation and architecture was performed using confocal fluorescence intravital microscopy (IVM). Day 4 analyses showed robust relationships among in vivo thrombus macrophages, MMP activity, and FITC-dextran deposition (r>0.70, p<0.01). In a serial two-timepoint study, mice with DVT underwent IVM at day 4 and at day 6. Analyses revealed that the intensity of thrombus inflammation at day 4 predicted the magnitude of DVT resolution at day 6 (p<0.05). In a second approach, noninvasive fluorescence molecular tomography-computed tomography (FMT-CT) was employed, and detected macrophages within jugular DVT (p<0.05 vs. sham-controls). Conclusions Integrated fluorescence molecular-structural imaging demonstrates that the DVT-induced inflammatory response can be readily assessed in vivo, and can inform the magnitude of thrombus resolution. PMID:22995524

Cross-Modulation Interference with Lateralization of Mixed-Modulated Waveforms

ERIC Educational Resources Information Center

Hsieh, I-Hui; Petrosyan, Agavni; Goncalves, Oscar F.; Hickok, Gregory; Saberi, Kourosh

2010-01-01

Purpose: This study investigated the ability to use spatial information in mixed-modulated (MM) sounds containing concurrent frequency-modulated (FM) and amplitude-modulated (AM) sounds by exploring patterns of interference when different modulation types originated from different loci as may occur in a multisource acoustic field. Method:…

Damage/Danger Associated Molecular Patterns (DAMPs) Modulate Chlamydia pecorum and C. trachomatis Serovar E Inclusion Development In Vitro.

PubMed

Leonard, Cory Ann; Schoborg, Robert V; Borel, Nicole

2015-01-01

Persistence, more recently termed the chlamydial stress response, is a viable but non-infectious state constituting a divergence from the characteristic chlamydial biphasic developmental cycle. Damage/danger associated molecular patterns (DAMPs) are normal intracellular components or metabolites that, when released from cells, signal cellular damage/lysis. Purine metabolite DAMPs, including extracellular ATP and adenosine, inhibit chlamydial development in a species-specific manner. Viral co-infection has been shown to reversibly abrogate Chlamydia inclusion development, suggesting persistence/chlamydial stress. Because viral infection can cause host cell DAMP release, we hypothesized DAMPs may influence chlamydial development. Therefore, we examined the effect of extracellular ATP, adenosine, and cyclic AMP exposure, at 0 and 14 hours post infection, on C. pecorum and C. trachomatis serovar E development. In the absence of de novo host protein synthesis, exposure to DAMPs immediately post or at 14 hours post infection reduced inclusion size; however, the effect was less robust upon 14 hours post infection exposure. Additionally, upon exposure to DAMPs immediately post infection, bacteria per inclusion and subsequent infectivity were reduced in both Chlamydia species. These effects were reversible, and C. pecorum exhibited more pronounced recovery from DAMP exposure. Aberrant bodies, typical in virus-induced chlamydial persistence, were absent upon DAMP exposure. In the presence of de novo host protein synthesis, exposure to DAMPs immediately post infection reduced inclusion size, but only variably modulated chlamydial infectivity. Because chlamydial infection and other infections may increase local DAMP concentrations, DAMPs may influence Chlamydia infection in vivo, particularly in the context of poly-microbial infections.

Modulation of protein synthesis by polyamines.

PubMed

Igarashi, Kazuei; Kashiwagi, Keiko

2015-03-01

Polyamines are ubiquitous small basic molecules that play important roles in cell growth and viability. Since polyamines mainly exist as a polyamine-RNA complex, we looked for proteins whose synthesis is preferentially stimulated by polyamines at the level of translation, and thus far identified 17 proteins in Escherichia coli and 6 proteins in eukaryotes. The mechanisms of polyamine stimulation of synthesis of these proteins were investigated. In addition, the role of eIF5A, containing hypusine formed from spermidine, on protein synthesis is described. These results clearly indicate that polyamines and eIF5A contribute to cell growth and viability through modulation of protein synthesis. © 2015 International Union of Biochemistry and Molecular Biology.

Investigation of thermal degradation with extrusion-based dispensing modules for 3D bioprinting technology.

PubMed

Lee, Hyungseok; Yoo, James J; Kang, Hyun-Wook; Cho, Dong-Woo

2016-02-04

Recently, numerous three-dimensional (3D) bioprinting systems have been introduced for the artificial regeneration of tissues. Among them, the extrusion-based dispensing module is the most widely used because of the processability it gives various biomaterials. The module uses high forces and temperature to dispense materials through a micro-nozzle. Generally, the harsh conditions induce thermal degradation of the material in the dispensing procedure. The thermal degradation affects the properties of the materials, and the change of the properties should be carefully controlled, because it severely affects the regeneration of tissues. Therefore, in this research, the relationship between the dispensing module and the thermal degradation of material was investigated. Extrusion-based dispensing modules can be divided into the syringe type (ST) and filament type (FT) based on working principles. We prepared a poly lactic-co-glycolic acid (PLGA) scaffold with the two methods at various time points. Then, the characteristics of the printed scaffolds were assessed by measuring molecular weight (M w), glass transition temperature (T g), in vitro degradation, compressive modulus, and cytocompatibility. The results showed that the PLGA scaffold with the FT dispensing module maintained its properties regardless of printing time points. In contrast, severe thermal degradation was observed in the scaffold group prepared by the ST dispensing module. Consequentially, it was obvious that the FT dispensing module was more suitable for producing scaffolds without severe thermal degradation.

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

Modulation of circular current and associated magnetic field in a molecular junction: A new approach

NASA Astrophysics Data System (ADS)

Patra, Moumita; Maiti, Santanu K.

2017-03-01

A new proposal is given to control local magnetic field in a molecular junction. In presence of finite bias a net circular current is established in the molecular ring which induces a magnetic field at its centre. Allowing a direct coupling between two electrodes, due to their close proximity, and changing its strength we can regulate circular current as well as magnetic field for a wide range, without disturbing any other physical parameters. We strongly believe that our proposal is quite robust compared to existing approaches of controlling local magnetic field and can be verified experimentally.

Apollo 9 Command/Service Modules photographed from Lunar Module

NASA Technical Reports Server (NTRS)

1969-01-01

The Apollo 9 Command/Service Modules photographed from the Lunar Module, 'Spider', on the fifth day of the Apollo 9 earth-orbital mission. Docking mechanism is visible in nose of the Command Module, 'Gumdrop'. Object jutting out from the Service Module aft bulkhead is the high-gain S-Band antenna.

Evidence for factors modulating radiation-induced G2-delay: potential application as radioprotectors

NASA Technical Reports Server (NTRS)

Cheong, N.; Zeng, Z. C.; Wang, Y.; Iliakis, G.

2001-01-01

Manipulation of checkpoint response to DNA damage can be developed as a means for protecting astronauts from the adverse effects of unexpected, or background exposures to ionizing radiation. To achieve this goal reagents need to be developed that protect cells from radiation injury by prolonging checkpoint response, thus promoting repair. We present evidence for a low molecular weight substance excreted by cells that dramatically increases the duration of the G2-delay. This compound is termed G2-Arrest Modulating Activity (GAMA). A rat cell line (A1-5) generated by transforming rat embryo fibroblasts with a temperature sensitive form of p53 plus H-ras demonstrates a dramatic increase in radiation resistance after exposure to low LET radiation that is not associated with an increase in the efficiency of rejoining of DNA double strand breaks. Radioresistance in this cell line correlates with a dramatic increase in the duration of the G2 arrest that is modulated by a GAMA produced by actively growing cells. The properties of GAMA suggest that it is a low molecular weight heat-stable peptide. Further characterization of this substance and elucidation of its mechanism of action may allow the development of a biological response modifier with potential applications as a radioprotector. GAMA may be useful for protecting astronauts from radiation injury as preliminary evidence suggests that it is able to modulate the response of cells exposed to heavy ion radiation, similar to that encountered in outer space.

Cryopreservation: Evolution of Molecular Based Strategies.

PubMed

Baust, John M; Corwin, William; Snyder, Kristi K; Van Buskirk, Robert; Baust, John G

2016-01-01

Cryopreservation (CP) is an enabling process providing for on-demand access to biological material (cells and tissues) which serve as a starting, intermediate or even final product. While a critical tool, CP protocols, approaches and technologies have evolved little over the last several decades. A lack of conversion of discoveries from the CP sciences into mainstream utilization has resulted in a bottleneck in technological progression in areas such as stem cell research and cell therapy. While the adoption has been slow, discoveries including molecular control and buffering of cell stress response to CP as well as the development of new devices for improved sample freezing and thawing are providing for improved CP from both the processing and sample quality perspectives. Numerous studies have described the impact, mechanisms and points of control of cryopreservation-induced delayed-onset cell death (CIDOCD). In an effort to limit CIDOCD, efforts have focused on CP agent and freeze media formulation to provide a solution path and have yielded improvements in survival over traditional approaches. Importantly, each of these areas, new technologies and cell stress modulation, both individually and in combination, are now providing a new foundation to accelerate new research, technology and product development for which CP serves as an integral component. This chapter provides an overview of the molecular stress responses of cells to cryopreservation, the impact of the hypothermic and cell death continuums and the targeted modulation of common and/or cell specific responses to CP in providing a path to improving cell quality.

phylo-node: A molecular phylogenetic toolkit using Node.js.

PubMed

O'Halloran, Damien M

2017-01-01

Node.js is an open-source and cross-platform environment that provides a JavaScript codebase for back-end server-side applications. JavaScript has been used to develop very fast and user-friendly front-end tools for bioinformatic and phylogenetic analyses. However, no such toolkits are available using Node.js to conduct comprehensive molecular phylogenetic analysis. To address this problem, I have developed, phylo-node, which was developed using Node.js and provides a stable and scalable toolkit that allows the user to perform diverse molecular and phylogenetic tasks. phylo-node can execute the analysis and process the resulting outputs from a suite of software options that provides tools for read processing and genome alignment, sequence retrieval, multiple sequence alignment, primer design, evolutionary modeling, and phylogeny reconstruction. Furthermore, phylo-node enables the user to deploy server dependent applications, and also provides simple integration and interoperation with other Node modules and languages using Node inheritance patterns, and a customized piping module to support the production of diverse pipelines. phylo-node is open-source and freely available to all users without sign-up or login requirements. All source code and user guidelines are openly available at the GitHub repository: https://github.com/dohalloran/phylo-node.

Characterization of paramagnetic effects of molecular oxygen on blood oxygenation level-dependent-modulated hyperoxic contrast studies of the human brain.

PubMed

Pilkinton, David T; Gaddam, Santosh R; Reddy, Ravinder

2011-09-01

In hyperoxic contrast studies modulated by the blood oxygenation level-dependent effect, it is often assumed that hyperoxia is a purely intravascular, positive contrast agent in T 2*-weighted images, and the effects that are not due to blood oxygenation level-dependent contrast are small enough to be ignored. In this study, this assumption is re-evaluated and non-blood oxygenation level-dependent effects in T 2*-weighted hyperoxic contrast studies of the human brain were characterized. We observed significant negative signal changes in T 2*-weighted images in the frontal lobes; B(0) maps suggest that this effect was primarily due to increased intravoxel dephasing from increased static field inhomogeneity due to susceptibility changes from oxygen in and around the upper airway. These static field effects were shown to scale with magnetic field strength. Signal changes observed around the brain periphery and in the ventricles suggest the effect of image distortions from oxygen-induced bulk B(0) shifts, along with a possible contribution from decreased T 2* due to oxygen dissolved in the cerebrospinal fluid. Reducing the concentration of inhaled oxygen was shown to mitigate negative contrast of molecular oxygen due to these effects, while still maintaining sufficient blood oxygenation level-dependent contrast to produce accurate measurements of cerebral blood volume. Copyright © 2011 Wiley-Liss, Inc.

A Comparative Study on Selective PPAR Modulators through Quantitative Structure-activity Relationship, Pharmacophore and Docking Analyses.

PubMed

Nandy, Ashis; Roy, Kunal; Saha, Achintya

2018-01-01

Metabolic syndrome is a matrix of different metabolic disorders which are the leading cause of death in human beings. Peroxysome proliferated activated receptor (PPAR) is a nuclear receptor involved in metabolism of fats and glucose. In order to explore structural requirements for selective PPAR modulators to control lipid and carbohydrate metabolism, the multi-cheminformatics studies have been performed. In silico modeling studies have been performed on a diverse set of PPAR modulators through quantitative structure-activity relationship (QSAR), pharmacophore mapping and docking studies. It is observed that the presence of an amide fragment (-CONHRPh) has a detrimental effect while an aliphatic ether linkage has a beneficial effect on PPARα modulation. On the other hand, the presence of an amide fragment has a positive effect on PPARδ modulation, but the aliphatic ether linkage and substituted aromatic ring in the molecular scaffold are very much essential for imparting potent and selective PPARγ modulation. Negative ionizable features (i.e. polar fragments) must be present in PPARδ and α modulators, but a hydrophobic feature is the prime requirement for PPARγ modulation. Here, the essential structural features have been explored for selective modulation of each subtype of PPAR in order to design new modulators with improved activity/selectivity. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Light Controlled Modulation of Gene Expression by Chemical Optoepigenetic Probes

PubMed Central

Reis, Surya A.; Ghosh, Balaram; Hendricks, J. Adam; Szantai-Kis, D. Miklos; Törk, Lisa; Ross, Kenneth N.; Lamb, Justin; Read-Button, Willis; Zheng, Baixue; Wang, Hongtao; Salthouse, Christopher; Haggarty, Stephen J.; Mazitschek, Ralph

2016-01-01

Epigenetic gene regulation is a dynamic process orchestrated by chromatin-modifying enzymes. Many of these master regulators exert their function through covalent modification of DNA and histone proteins. Aberrant epigenetic processes have been implicated in the pathophysiology of multiple human diseases. Small-molecule inhibitors have been essential to advancing our understanding of the underlying molecular mechanisms of epigenetic processes. However, the resolution offered by small molecules is often insufficient to manipulate epigenetic processes with high spatio-temporal control. Here, we present a novel and generalizable approach, referred to as ‘Chemo-Optical Modulation of Epigenetically-regulated Transcription’ (COMET), enabling high-resolution, optical control of epigenetic mechanisms based on photochromic inhibitors of human histone deacetylases using visible light. COMET probes may translate into novel therapeutic strategies for diseases where conditional and selective epigenome modulation is required. PMID:26974814

XUV pulse effect on signal modulations of harmonic spectra from H2+ and T2+

NASA Astrophysics Data System (ADS)

Feng, Liqiang; Liu, Hang; Kapteyn, Henry J.; Feng, April Y.

2018-05-01

The effects of signal modulations on the molecular high-order harmonic generations in H2^{+ } and T2+ have been theoretically investigated. It is found that with the introduction of the XUV pulse, due to the absorption of the extra XUV photons in the recombination process, multiplateaus on the harmonic spectra, separated by the XUV photon energy can be found. Moreover, this multiplateau structure is insensitive to the wavelength of the XUV pulse. In shorter pulse duration, the intensities of the multiplateaus from H2+ are higher than those from T2+; while in longer pulse duration, the opposite results can be found. Finally, by changing the delay time of the XUV pulse, the signal modulations (including the amplitude and the frequency modulations) of the multiplateaus can be controlled.

The NF-YC–RGL2 module integrates GA and ABA signalling to regulate seed germination in Arabidopsis

PubMed Central

Liu, Xu; Hu, Pengwei; Huang, Mingkun; Tang, Yang; Li, Yuge; Li, Ling; Hou, Xingliang

2016-01-01

The antagonistic crosstalk between gibberellic acid (GA) and abscisic acid (ABA) plays a pivotal role in the modulation of seed germination. However, the molecular mechanism of such phytohormone interaction remains largely elusive. Here we show that three Arabidopsis NUCLEAR FACTOR-Y C (NF-YC) homologues NF-YC3, NF-YC4 and NF-YC9 redundantly modulate GA- and ABA-mediated seed germination. These NF-YCs interact with the DELLA protein RGL2, a key repressor of GA signalling. The NF-YC–RGL2 module targets ABI5, a gene encoding a core component of ABA signalling, via specific CCAAT elements and collectively regulates a set of GA- and ABA-responsive genes, thus controlling germination. These results suggest that the NF-YC–RGL2–ABI5 module integrates GA and ABA signalling pathways during seed germination. PMID:27624486

Diode Laser Velocity Measurements by Modulated Filtered Rayleigh Scattering

NASA Technical Reports Server (NTRS)

Mach, J. J.; Varghese, P. L.; Jagodzinski, J. J.

1999-01-01

The ability of solid-state lasers to be tuned in operating frequency at MHz rates by input current modulation, while maintaining a relatively narrow line-width, has made them useful for spectroscopic measurements. Their other advantages include low cost, reliability, durability, compact size, and modest power requirements, making them a good choice for a laser source in micro-gravity experiments in drop-towers and in flight. For their size, they are also very bright. In a filtered Rayleigh scattering (FRS) experiment, a diode laser can be used to scan across an atomic or molecular absorption line, generating large changes in transmission at the resonances for very small changes in frequency. The hyperfine structure components of atomic lines of alkali metal vapors are closely spaced and very strong, which makes such atomic filters excellent candidates for sensitive Doppler shift detection and therefore for high-resolution velocimetry. In the work we describe here we use a Rubidium vapor filter, and work with the strong D(sub 2) transitions at 780 nm that are conveniently accessed by near infrared diode lasers. The low power output of infrared laser diodes is their primary drawback relative to other laser systems commonly used for velocimetry. However, the capability to modulate the laser frequency rapidly and continuously helps mitigate this. Using modulation spectroscopy and a heterodyne detection scheme with a lock-in amplifier, one can extract sub-microvolt signals occurring at a specific frequency from a background that is orders of magnitude stronger. The diode laser modulation is simply achieved by adding a small current modulation to the laser bias current. It may also be swept repetitively in wavelength using an additional lower frequency current ramp.

Module-based multiscale simulation of angiogenesis in skeletal muscle

PubMed Central

2011-01-01

Background Mathematical modeling of angiogenesis has been gaining momentum as a means to shed new light on the biological complexity underlying blood vessel growth. A variety of computational models have been developed, each focusing on different aspects of the angiogenesis process and occurring at different biological scales, ranging from the molecular to the tissue levels. Integration of models at different scales is a challenging and currently unsolved problem. Results We present an object-oriented module-based computational integration strategy to build a multiscale model of angiogenesis that links currently available models. As an example case, we use this approach to integrate modules representing microvascular blood flow, oxygen transport, vascular endothelial growth factor transport and endothelial cell behavior (sensing, migration and proliferation). Modeling methodologies in these modules include algebraic equations, partial differential equations and agent-based models with complex logical rules. We apply this integrated model to simulate exercise-induced angiogenesis in skeletal muscle. The simulation results compare capillary growth patterns between different exercise conditions for a single bout of exercise. Results demonstrate how the computational infrastructure can effectively integrate multiple modules by coordinating their connectivity and data exchange. Model parameterization offers simulation flexibility and a platform for performing sensitivity analysis. Conclusions This systems biology strategy can be applied to larger scale integration of computational models of angiogenesis in skeletal muscle, or other complex processes in other tissues under physiological and pathological conditions. PMID:21463529

Aloe vera: Potential candidate in health management via modulation of biological activities

PubMed Central

Rahmani, Arshad H.; Aldebasi, Yousef H.; Srikar, Sauda; Khan, Amjad A.; Aly, Salah M.

2015-01-01

Treatment based on natural products is rapidly increasing worldwide due to the affordability and fewer side effects of such treatment. Various plants and the products derived from them are commonly used in primary health treatment, and they play a pivotal role in the treatment of diseases via modulation of biochemical and molecular pathways. Aloe vera, a succulent species, produces gel and latex, plays a therapeutic role in health management through antioxidant, antitumor, and anti-inflammatory activities, and also offers a suitable alternative approach for the treatment of various types of diseases. In this review, we summarize the possible mechanism of action and the therapeutic implications of Aloe vera in health maintenance based on its modulation of various biological activities. PMID:26392709

The molecular mechanism of plant gravitropism.

PubMed

Wu, Di; Huang, Lin-zhou; Gao, Jin; Wang, Yong-hong

2016-07-20

Gravity is an important environmental factor that regulates plant growth and morphogenesis. In response to gravity stimulus, plants can set the optimum angle between the organs and the gravity vector. Plant gravitropism is divided into four sequential steps, including gravity perception, signal transduction, asymmetrical distribution of auxin, and organ curvature. In recent years, large numbers of mutants with defective gravitropism have been identified and genes involved in the regulation of gravitropism have been functionally characterized. In particular, progress has been achieved on elucidating the molecular mechanisms of gravity perception and asymmetrical distribution of auxin. As one of the most important strategies for plant to adapt environmental changes, gravitropism is also involved in the regulation of rice plant architecture and grain yield through modulating rice tiller angle. Therefore, the investigation of plant gravitropism not only contributes to decipher the regulatory mechanisms of plant growth and development, but also helps to guide the genetic improvement of crop architecture. However, the molecular mechanisms and regulatory network of gravitropism remain to be elusive. In this review, we focus on recent progress on elucidating molecular mechanisms underlying gravitropism and its involvement in regulating rice tiller angle, which is an important agronomic trait that determines rice plant architecture and thus grain yields.

Toward tunable band gap and tunable dirac point in bilayer graphene with molecular doping.

PubMed

Yu, Woo Jong; Liao, Lei; Chae, Sang Hoon; Lee, Young Hee; Duan, Xiangfeng

2011-11-09

The bilayer graphene has attracted considerable attention for potential applications in future electronics and optoelectronics because of the feasibility to tune its band gap with a vertical displacement field to break the inversion symmetry. Surface chemical doping in bilayer graphene can induce an additional offset voltage to fundamentally affect the vertical displacement field and the band gap opening in bilayer graphene. In this study, we investigate the effect of chemical molecular doping on band gap opening in bilayer graphene devices with single or dual gate modulation. Chemical doping with benzyl viologen molecules modulates the displacement field to allow the opening of a transport band gap and the increase of the on/off ratio in the bilayer graphene transistors. Additionally, Fermi energy level in the opened gap can be rationally controlled by the amount of molecular doping to obtain bilayer graphene transistors with tunable Dirac points, which can be readily configured into functional devices, such as complementary inverters.

Drug-Like Protein–Protein Interaction Modulators: Challenges and Opportunities for Drug Discovery and Chemical Biology

PubMed Central

Villoutreix, Bruno O; Kuenemann, Melaine A; Poyet, Jean-Luc; Bruzzoni-Giovanelli, Heriberto; Labbé, Céline; Lagorce, David; Sperandio, Olivier; Miteva, Maria A

2014-01-01

Fundamental processes in living cells are largely controlled by macromolecular interactions and among them, protein–protein interactions (PPIs) have a critical role while their dysregulations can contribute to the pathogenesis of numerous diseases. Although PPIs were considered as attractive pharmaceutical targets already some years ago, they have been thus far largely unexploited for therapeutic interventions with low molecular weight compounds. Several limiting factors, from technological hurdles to conceptual barriers, are known, which, taken together, explain why research in this area has been relatively slow. However, this last decade, the scientific community has challenged the dogma and became more enthusiastic about the modulation of PPIs with small drug-like molecules. In fact, several success stories were reported both, at the preclinical and clinical stages. In this review article, written for the 2014 International Summer School in Chemoinformatics (Strasbourg, France), we discuss in silico tools (essentially post 2012) and databases that can assist the design of low molecular weight PPI modulators (these tools can be found at www.vls3d.com). We first introduce the field of protein–protein interaction research, discuss key challenges and comment recently reported in silico packages, protocols and databases dedicated to PPIs. Then, we illustrate how in silico methods can be used and combined with experimental work to identify PPI modulators. PMID:25254076

Molecular adsorbates on HOPG: Toward modulation of graphene density of states

NASA Astrophysics Data System (ADS)

Groce, Michelle; Einstein, Theodore; Cullen, William

2013-03-01

Ordered molecular superlattices, particularly those made of planar aromatics with their attendant pi orbitals, have the potential to break the graphene sublattice degeneracy and create a band gap. Trimesic acid (TMA) is a promising candidate due to its self-assembly into symmetry-breaking superlattices nearly commensurate with that of graphene. We have used the graphite (0001) surface as a model system to explore the impact of TMA thin films on band structure. By examining correlations between STM topography and STS maps of corresponding regions, we are able to investigate the effects of TMA on the local density of states. Work supported by the University of Maryland NSF-MRSEC, DMR 0520471 and Shared Experimental Facilities.

Natural products with anti-aging potential: Affected targets and molecular mechanisms.

PubMed

Cătană, Cristina-Sorina; Atanasov, Atanas G; Berindan-Neagoe, Ioana

2018-03-27

In recent years, there has been a great deal of attention toward the molecular machinery relevant to age-related progression controlled through the external intervention of polyphenols- an epigenetic-modulating diet. Natural products modulate cellular longevity through histone post-translational modification and can also induce the upregulation of autophagy, thus reducing the level of acetyl coenzyme A (AcCoA). In addition, the effect of caloric restriction (CR) on cancer-related chronic inflammation is of great significance in aging. In line with this, SIRT1 protein levels are expanded in response to calorie restriction mimetics (CRM), in this way acting as autophagy inducers relevant to cancer prevention. Copyright © 2018 Elsevier Inc. All rights reserved.

Molecular wires acting as quantum heat ratchets.

PubMed

Zhan, Fei; Li, Nianbei; Kohler, Sigmund; Hänggi, Peter

2009-12-01

We explore heat transfer in molecular junctions between two leads in the absence of a finite net thermal bias. The application of an unbiased time-periodic temperature modulation of the leads entails a dynamical breaking of reflection symmetry, such that a directed heat current may emerge (ratchet effect). In particular, we consider two cases of adiabatically slow driving, namely, (i) periodic temperature modulation of only one lead and (ii) temperature modulation of both leads with an ac driving that contains a second harmonic, thus, generating harmonic mixing. Both scenarios yield sizable directed heat currents, which should be detectable with present techniques. Adding a static thermal bias allows one to compute the heat current-thermal load characteristics, which includes the ratchet effect of negative thermal bias with positive-valued heat flow against the thermal bias, up to the thermal stop load. The ratchet heat flow in turn generates also an electric current. An applied electric stop voltage, yielding effective zero electric current flow, then mimics a solely heat-ratchet-induced thermopower ("ratchet Seebeck effect"), although no net thermal bias is acting. Moreover, we find that the relative phase between the two harmonics in scenario (ii) enables steering the net heat current into a direction of choice.

Carrier Density Modulation in Ge Heterostructure by Ferroelectric Switching

DOE PAGES

Ponath, Patrick; Fredrickson, Kurt; Posadas, Agham B.; ...

2015-01-14

The development of nonvolatile logic through direct coupling of spontaneous ferroelectric polarization with semiconductor charge carriers is nontrivial, with many issues, including epitaxial ferroelectric growth, demonstration of ferroelectric switching, and measurable semiconductor modulation. Here we report a true ferroelectric field effect carrier density modulation in an underlying Ge(001) substrate by switching of the ferroelectric polarization in the epitaxial c-axis-oriented BaTiO3 (BTO) grown by molecular beam epitaxy (MBE) on Ge. Using density functional theory, we demonstrate that switching of BTO polarization results in a large electric potential change in Ge. Aberration-corrected electron microscopy confirms the interface sharpness, and BTO tetragonality. Electron-energy-lossmore » spectroscopy (EELS) indicates the absence of any low permittivity interlayer at the interface with Ge. Using piezoelectric force microscopy (PFM), we confirm the presence of fully switchable, stable ferroelectric polarization in BTO that appears to be single domain. Using microwave impedance microscopy (MIM), we clearly demonstrate a ferroelectric field effect.« less

NMDA Receptor Modulators in the Treatment of Drug Addiction.

PubMed

Tomek, Seven E; Lacrosse, Amber L; Nemirovsky, Natali E; Olive, M Foster

2013-02-06

Glutamate plays a pivotal role in drug addiction, and the N-methyl-D-aspartate (NMDA) glutamate receptor subtype serves as a molecular target for several drugs of abuse. In this review, we will provide an overview of NMDA receptor structure and function, followed by a review of the mechanism of action, clinical efficacy, and side effect profile of NMDA receptor ligands that are currently in use or being explored for the treatment of drug addiction. These ligands include the NMDA receptor modulators memantine and acamprosate, as well as the partial NMDA agonist D-cycloserine. Data collected to date suggest that direct NMDA receptor modulators have relatively limited efficacy in the treatment of drug addiction, and that partial agonism of NMDA receptors may have some efficacy with regards to extinction learning during cue exposure therapy. However, the lack of consistency in results to date clearly indicates that additional studies are needed, as are studies examining novel ligands with indirect mechanisms for altering NMDA receptor function.

Genomic Heterogeneity of Osteosarcoma - Shift from Single Candidates to Functional Modules

PubMed Central

Maugg, Doris; Eckstein, Gertrud; Baumhoer, Daniel; Nathrath, Michaela; Korsching, Eberhard

2015-01-01

Osteosarcoma (OS), a bone tumor, exhibit a complex karyotype. On the genomic level a highly variable degree of alterations in nearly all chromosomal regions and between individual tumors is observable. This hampers the identification of common drivers in OS biology. To identify the common molecular mechanisms involved in the maintenance of OS, we follow the hypothesis that all the copy number-associated differences between the patients are intercepted on the level of the functional modules. The implementation is based on a network approach utilizing copy number associated genes in OS, paired expression data and protein interaction data. The resulting functional modules of tightly connected genes were interpreted regarding their biological functions in OS and their potential prognostic significance. We identified an osteosarcoma network assembling well-known and lesser-known candidates. The derived network shows a significant connectivity and modularity suggesting that the genes affected by the heterogeneous genetic alterations share the same biological context. The network modules participate in several critical aspects of cancer biology like DNA damage response, cell growth, and cell motility which is in line with the hypothesis of specifically deregulated but functional modules in cancer. Further, we could deduce genes with possible prognostic significance in OS for further investigation (e.g. EZR, CDKN2A, MAP3K5). Several of those module genes were located on chromosome 6q. The given systems biological approach provides evidence that heterogeneity on the genomic and expression level is ordered by the biological system on the level of the functional modules. Different genomic aberrations are pointing to the same cellular network vicinity to form vital, but already neoplastically altered, functional modules maintaining OS. This observation, exemplarily now shown for OS, has been under discussion already for a longer time, but often in a hypothetical manner, and

The Prenylflavonoid Xanthohumol Reduces Alzheimer-Like Changes and Modulates Multiple Pathogenic Molecular Pathways in the Neuro2a/APPswe Cell Model of AD.

PubMed

Huang, Xianfeng; Wang, Jing; Chen, Xiao; Liu, Pan; Wang, Shujin; Song, Fangchen; Zhang, Zaijun; Zhu, Feiqi; Huang, Xinfeng; Liu, Jianjun; Song, Guoqiang; Spencer, Peter S; Yang, Xifei

2018-01-01

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that has proved refractory to drug treatment. Given evidence of neuroprotection in animal models of ischemic stroke, we assessed the prenylflavonoid xanthohumol from the Common Hop ( Humulus lupulus L.) for therapeutic potential in murine neuroblastoma N2a cells stably expressing human Swedish mutant amyloid precursor protein (N2a/APP), a well-characterized cellular model of AD. The ELISA and Western-blot analysis revealed that xanthohumol (Xn) inhibited Aβ accumulation and APP processing, and that Xn ameliorated tau hyperphosphorylation via PP2A, GSK3β pathways in N2a/APP cells. The amelioration of tau hyperphosphorylation by Xn was also validated on HEK293/Tau cells, another cell line with tau hyperphosphorylation. Proteomic analysis (2D-DIGE-coupled MS) revealed a total of 30 differentially expressed lysate proteins in N2a/APP vs. wild-type (WT) N2a cells (N2a/WT), and a total of 21 differentially expressed proteins in lysates of N2a/APP cells in the presence or absence of Xn. Generally, these 51 differential proteins could be classified into seven main categories according to their functions, including: endoplasmic reticulum (ER) stress-associated proteins; oxidative stress-associated proteins; proteasome-associated proteins; ATPase and metabolism-associated proteins; cytoskeleton-associated proteins; molecular chaperones-associated proteins, and others. We used Western-blot analysis to validate Xn-associated changes of some key proteins in several biological/pathogenic processes. Taken together, we show that Xn reduces AD-related changes in stably transfected N2a/APP cells. The underlying mechanisms involve modulation of multiple pathogenic pathways, including those involved in ER stress, oxidative stress, proteasome molecular systems, and the neuronal cytoskeleton. These results suggest Xn may have potential for the treatment of AD and/or neuropathologically related neurodegenerative

Studies on the factors modulating indole-3-acetic acid production in endophytic bacterial isolates from Piper nigrum and molecular analysis of ipdc gene.

PubMed

Jasim, B; Jimtha John, C; Shimil, V; Jyothis, M; Radhakrishnan, E K

2014-09-01

The study mainly aimed quantitative analysis of IAA produced by endophytic bacteria under various conditions including the presence of extract from Piper nigrum. Analysis of genetic basis of IAA production was also conducted by studying the presence and diversity of the ipdc gene among the selected isolates. Five endophytic bacteria isolated previously from P. nigrum were used for the study. The effect of temperature, pH, agitation, tryptophan concentration and plant extract on modulating IAA production of selected isolates was analysed by colorimetric method. Comparative and quantitative analysis of IAA production by colorimetric isolates under optimal culture condition was analysed by HPTLC method. Presence of ipdc gene and thereby biosynthetic basis of IAA production among the selected isolates were studied by PCR-based amplification and subsequent insilico analysis of sequence obtained. Among the selected bacterial isolates from P. nigrum, isolate PnB 8 (Klebsiella pneumoniae) was found to have the maximum yield of IAA under various conditions optimized and was confirmed by colorimetric, HPLC and HPTLC analysis. Very interestingly, the study showed stimulating effect of phytochemicals from P. nigrum on IAA production by endophytic bacteria isolated from same plant. This study is unique because of the selection of endophytes from same source for comparative and quantitative analysis of IAA production under various conditions. Study on stimulatory effect of phytochemicals on bacterial IAA production as explained in the study is a novel approach. Studies on molecular basis of IAA production which was confirmed by sequence analysis of ipdc gene make the study scientifically attractive. Even though microbial production of IAA is well known, current report on detailed optimization, effect of plant extract and molecular confirmation of IAA biosynthesis is comparatively novel in its approach. © 2014 The Society for Applied Microbiology.

Molecular chaperones in Parkinson's disease--present and future.

PubMed

Ebrahimi-Fakhari, Darius; Wahlster, Lara; McLean, Pamela J

2011-01-01

Parkinson's disease, like many other neurodegenerative disorders, is characterized by the progressive accumulation of pathogenic protein species and the formation of intracellular inclusion bodies. The cascade by which the small synaptic protein α-synuclein misfolds to form distinctive protein aggregates, termed Lewy bodies and Lewy neurites, has been the subject of intensive research for more than a decade. Genetic and pathological studies in Parkinson's disease patients as well as experimental studies in disease models have clearly established altered protein metabolism as a key element in the pathogenesis of Parkinson's disease. Alterations in protein metabolism include misfolding and aggregation, post-translational modification and dysfunctional degradation of cytotoxic protein species. Protein folding and re-folding are both mediated by a highly conserved network of molecules, called molecular chaperones and co-chaperones. In addition to the regulatory role in protein folding, molecular chaperone function is intimately associated with pathways of protein degradation, such as the ubiquitin-proteasome system and the autophagy-lysosomal pathway, to effectively remove irreversibly misfolded proteins. Because of the central role of molecular chaperones in maintaining protein homeostasis, we herein review our current knowledge on the involvement of molecular chaperones and co-chaperones in Parkinson's disease. We further discuss the capacity of molecular chaperones to prevent or modulate neurodegeneration, an important concept for future neuroprotective strategies and summarize the current progress in preclinical studies in models of Parkinson's disease and other neurodegenerative disorders. Finally we include a discussion on the future potential of using molecular chaperones as a disease modifying therapy.

A field-deployable mobile molecular diagnostic system for malaria at the point of need.

PubMed

Choi, Gihoon; Song, Daniel; Shrestha, Sony; Miao, Jun; Cui, Liwang; Guan, Weihua

2016-11-01

In response to the urgent need of a field-deployable and highly sensitive malaria diagnosis, we developed a standalone, "sample-in-answer-out" molecular diagnostic system (AnyMDx) to enable quantitative molecular analysis of blood-borne malaria in low resource areas. The system consists of a durable battery-powered analyzer and a disposable microfluidic compact disc loaded with reagents ready for use. A low power thermal module and a novel fluorescence-sensing module are integrated into the analyzer for real-time monitoring of loop-mediated isothermal nucleic acid amplification (LAMP) of target parasite DNA. With 10 μL of raw blood sample, the AnyMDx system automates the nucleic acid sample preparation and subsequent LAMP and real-time detection. Under laboratory conditions with whole-blood samples spiked with cultured Plasmodium falciparum, we achieved a detection limit of ∼0.6 parasite per μL, much lower than those for the conventional microscopy and rapid diagnostic tests (∼50-100 parasites per μL). The turnaround time from sample to answer is less than 40 minutes. The AnyMDx is user-friendly requiring minimal technological training. The analyzer and the disposable reagent compact discs are cost-effective, making AnyMDx a potential tool for malaria molecular diagnosis under field settings for malaria elimination.

Charge Transport Processes in Molecular Junctions

NASA Astrophysics Data System (ADS)

Smith, Christopher Eugene

. Using quantum-based calculations, we modeled 'p-type' polaron transport through oligophenylenethiophene (OPTI) wires and assigned transport activation energies to specific modes of nuclear motion. We also show control over 'n-type', LUMO-mediated transport in short ( 2 nm) redox-active perylenediimide (PDI) SAMs bound to contacts through isocyano linkers. By changing the contact work function (φ) and temperature, we were able to verify thermally-assisted LUMO transport. Transition voltage spectroscopy and the single level model was employed to fit the experimental I-V curves and extract the electronic coupling (epsilon) and the EF-LUMO offset (epsilonl). It was found that epsilonl does not change with φ (LUMO pinning), while Gamma changes with both φ and temperature. Further, the PDI SAMs could be reversibly chemically gated to modulate the transport. These results help advance our understanding of transport behavior in semiconducting molecular thin films, and open opportunities to engineer improved electronic functionality into molecular devices.

Electroabsorption optical modulator

DOEpatents

Skogen, Erik J.

2017-11-21

An electroabsorption modulator incorporates waveguiding regions along the length of the modulator that include quantum wells where at least two of the regions have quantum wells with different bandgaps. In one embodiment of the invention, the regions are arranged such that the quantum wells have bandgaps with decreasing bandgap energy along the length of the modulator from the modulator's input to its output. The bandgap energy of the quantum wells may be decreased in discrete steps or continuously. Advantageously, such an arrangement better distributes the optical absorption as well as the carrier density along the length of the modulator. Further advantageously, the modulator may handle increased optical power as compared with prior art modulators of similar dimensions, which allows for improved link gain when the optical modulator is used in an analog optical communication link.

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.

Negative allosteric modulators that target human alpha4beta2 neuronal nicotinic receptors.

PubMed

Henderson, Brandon J; Pavlovicz, Ryan E; Allen, Jerad D; González-Cestari, Tatiana F; Orac, Crina M; Bonnell, Andrew B; Zhu, Michael X; Boyd, R Thomas; Li, Chenglong; Bergmeier, Stephen C; McKay, Dennis B

2010-09-01

Allosteric modulation of neuronal nicotinic acetylcholine receptors (nAChRs) is considered to be one of the most promising approaches for therapeutics. We have previously reported on the pharmacological activity of several compounds that act as negative allosteric modulators (NAMs) of nAChRs. In the following studies, the effects of 30 NAMs from our small chemical library on both human alpha4beta2 (Halpha4beta2) and human alpha3beta4 (Halpha3beta4) nAChRs expressed in human embryonic kidney ts201 cells were investigated. During calcium accumulation assays, these NAMs inhibited nAChR activation with IC(50) values ranging from 2.4 microM to more than 100 microM. Several NAMs showed relative selectivity for Halpha4beta2 nAChRs with IC(50) values in the low micromolar range. A lead molecule, KAB-18, was identified that shows relative selectivity for Halpha4beta2 nAChRs. This molecule contains three phenyl rings, one piperidine ring, and one ester bond linkage. Structure-activity relationship (SAR) analyses of our data revealed three regions of KAB-18 that contribute to its relative selectivity. Predictive three-dimensional quantitative SAR (comparative molecular field analysis and comparative molecular similarity indices analysis) models were generated from these data, and a pharmacophore model was constructed to determine the chemical features that are important for biological activity. Using docking approaches and molecular dynamics on a Halpha4beta2 nAChR homology model, a binding mode for KAB-18 at the alpha/beta subunit interface that corresponds to the predicted pharmacophore is described. This binding mode was supported by mutagenesis studies. In summary, these studies highlight the importance of SAR, computational, and molecular biology approaches for the design and synthesis of potent and selective antagonists targeting specific nAChR subtypes.

Negative Allosteric Modulators That Target Human α4β2 Neuronal Nicotinic Receptors

PubMed Central

Henderson, Brandon J.; Pavlovicz, Ryan E.; Allen, Jerad D.; González-Cestari, Tatiana F.; Orac, Crina M.; Bonnell, Andrew B.; Zhu, Michael X.; Boyd, R. Thomas; Li, Chenglong; Bergmeier, Stephen C.

2010-01-01

Allosteric modulation of neuronal nicotinic acetylcholine receptors (nAChRs) is considered to be one of the most promising approaches for therapeutics. We have previously reported on the pharmacological activity of several compounds that act as negative allosteric modulators (NAMs) of nAChRs. In the following studies, the effects of 30 NAMs from our small chemical library on both human α4β2 (Hα4β2) and human α3β4 (Hα3β4) nAChRs expressed in human embryonic kidney ts201 cells were investigated. During calcium accumulation assays, these NAMs inhibited nAChR activation with IC50 values ranging from 2.4 μM to more than 100 μM. Several NAMs showed relative selectivity for Hα4β2 nAChRs with IC50 values in the low micromolar range. A lead molecule, KAB-18, was identified that shows relative selectivity for Hα4β2 nAChRs. This molecule contains three phenyl rings, one piperidine ring, and one ester bond linkage. Structure–activity relationship (SAR) analyses of our data revealed three regions of KAB-18 that contribute to its relative selectivity. Predictive three-dimensional quantitative SAR (comparative molecular field analysis and comparative molecular similarity indices analysis) models were generated from these data, and a pharmacophore model was constructed to determine the chemical features that are important for biological activity. Using docking approaches and molecular dynamics on a Hα4β2 nAChR homology model, a binding mode for KAB-18 at the α/β subunit interface that corresponds to the predicted pharmacophore is described. This binding mode was supported by mutagenesis studies. In summary, these studies highlight the importance of SAR, computational, and molecular biology approaches for the design and synthesis of potent and selective antagonists targeting specific nAChR subtypes. PMID:20551292

Lubricin: A Principal Modulator of the Psychoneuroendocrine - Osteoimmune Interactome - Implications for Novel Treatments of Osteoarthritic Pathologies.

PubMed

Khakshooy, Allen; Balenton, Nicole; Chiappelli, Francesco

2017-01-01

Lubricin is a synovial glycoprotein that contributes to joint lubrication. We propose the hypothesis that lubricin is a key modulator of the psychoneuroendocrine-osteoimmune interactome, with important clinical relevance for osteoarthritic pathologies. We consider a variety of neuroendocrine-immune factors, including inflammatory cytokines and chemokines that may contribute to the modulation of lubricin in rheumatic complications. Based on our preliminary immunocytochemistry and fractal analysis data, and in the context of translational research of modern healthcare, we propose that molecular lubricin gene expression modification by means of the novel CRISPR/Cas system be considered for osteoarthritic therapies.

Modulation of K(Ca)3.1 channels by eicosanoids, omega-3 fatty acids, and molecular determinants.

PubMed

Kacik, Michael; Oliván-Viguera, Aida; Köhler, Ralf

2014-01-01

Cytochrome P450- and ω-hydrolase products (epoxyeicosatrienoic acids (EETs), hydroxyeicosatetraeonic acid (20-HETE)), natural omega-3 fatty acids (ω3), and pentacyclic triterpenes have been proposed to contribute to a wide range of vaso-protective and anti-fibrotic/anti-cancer signaling pathways including the modulation of membrane ion channels. Here we studied the modulation of intermediate-conductance Ca(2+)/calmodulin-regulated K(+) channels (K(Ca)3.1) by EETs, 20-HETE, ω3, and pentacyclic triterpenes and the structural requirements of these fatty acids to exert channel blockade. We studied modulation of cloned human hK(Ca)3.1 and the mutant hK(Ca)3.1(V275A) in HEK-293 cells, of rK(Ca)3.1 in aortic endothelial cells, and of mK(Ca)3.1 in 3T3-fibroblasts by inside-out and whole-cell patch-clamp experiments, respectively. In inside-out patches, Ca(2+)-activated hK(Ca)3.1 were inhibited by the ω3, DHA and α-LA, and the ω6, AA, in the lower µmolar range and with similar potencies. 5,6-EET, 8,9-EET, 5,6-DiHETE, and saturated arachidic acid, had no appreciable effects. In contrast, 14,15-EET, its stable derivative, 14,15-EEZE, and 20-HETE produced channel inhibition. 11,12-EET displayed less inhibitory activity. The K(Ca)3.1(V275A) mutant channel was insensitive to any of the blocking EETs. Non-blocking 5,6-EET antagonized the inhibition caused by AA and augmented cloned hK(Ca)3.1 and rK(Ca)3.1 whole-cell currents. Pentacyclic triterpenes did not modulate K(Ca)3.1 currents. Inhibition of K(Ca)3.1 by EETs (14,15-EET), 20-HETE, and ω3 critically depended on the presence of electron double bonds and hydrophobicity within the 10 carbons preceding the carboxyl-head of the molecules. From the physiological perspective, metabolism of AA to non-blocking 5,6,- and 8,9-EET may cause AA-de-blockade and contribute to cellular signal transduction processes influenced by these fatty acids.

Supported PV module assembly

DOEpatents

Mascolo, Gianluigi; Taggart, David F.; Botkin, Jonathan D.; Edgett, Christopher S.

2013-10-15

A supported PV assembly may include a PV module comprising a PV panel and PV module supports including module supports having a support surface supporting the module, a module registration member engaging the PV module to properly position the PV module on the module support, and a mounting element. In some embodiments the PV module registration members engage only the external surfaces of the PV modules at the corners. In some embodiments the assembly includes a wind deflector with ballast secured to a least one of the PV module supports and the wind deflector. An array of the assemblies can be secured to one another at their corners to prevent horizontal separation of the adjacent corners while permitting the PV modules to flex relative to one another so to permit the array of PV modules to follow a contour of the support surface.

Essentially semismall Quasi-Dedekind module relative to a module

NASA Astrophysics Data System (ADS)

Hussain, Mukdad Q.

2018-05-01

Let R be associative ring with identity and M be a unitary R-module. In this paper study the direct summand of essentially semismall quasi-Dedekind module and prove that the direct sum of essentially semismall quasi-Dedekind modules need not be essentially semismall quasi-Dedekind and give the definition of essentially semismall quasi-Dedekind relative to a module with some examples, also give some of their basic properties and some examples that illustrate these properties.

Processing module operating methods, processing modules, and communications systems

DOEpatents

McCown, Steven Harvey; Derr, Kurt W.; Moore, Troy

2014-09-09

A processing module operating method includes using a processing module physically connected to a wireless communications device, requesting that the wireless communications device retrieve encrypted code from a web site and receiving the encrypted code from the wireless communications device. The wireless communications device is unable to decrypt the encrypted code. The method further includes using the processing module, decrypting the encrypted code, executing the decrypted code, and preventing the wireless communications device from accessing the decrypted code. Another processing module operating method includes using a processing module physically connected to a host device, executing an application within the processing module, allowing the application to exchange user interaction data communicated using a user interface of the host device with the host device, and allowing the application to use the host device as a communications device for exchanging information with a remote device distinct from the host device.

Differential Potency of 2,6-Dimethylcyclohexanol Isomers for Positive Modulation of GABAA Receptor Currents.

PubMed

Chowdhury, Luvana; Croft, Celine J; Goel, Shikha; Zaman, Naina; Tai, Angela C-S; Walch, Erin M; Smith, Kelly; Page, Alexandra; Shea, Kevin M; Hall, C Dennis; Jishkariani, D; Pillai, Girinath G; Hall, Adam C

2016-06-01

GABAA receptors meet all of the pharmacological requirements necessary to be considered important targets for the action of general anesthetic agents in the mammalian brain. In the following patch-clamp study, the relative modulatory effects of 2,6-dimethylcyclohexanol diastereomers were investigated on human GABAA (α1β3γ2s) receptor currents stably expressed in human embryonic kidney cells. Cis,cis-, trans,trans-, and cis,trans-isomers were isolated from commercially available 2,6-dimethylcyclohexanol and were tested for positive modulation of submaximal GABA responses. For example, the addition of 30 μM cis,cis-isomer resulted in an approximately 2- to 3-fold enhancement of the EC20 GABA current. Coapplications of 30 μM 2,6-dimethylcyclohexanol isomers produced a range of positive enhancements of control GABA responses with a rank order for positive modulation: cis,cis > trans,trans ≥ mixture of isomers > > cis,trans-isomer. In molecular modeling studies, the three cyclohexanol isomers bound with the highest binding energies to a pocket within transmembrane helices M1 and M2 of the β3 subunit through hydrogen-bonding interactions with a glutamine at the 224 position and a tyrosine at the 220 position. The energies for binding to and hydrogen-bond lengths within this pocket corresponded with the relative potencies of the agents for positive modulation of GABAA receptor currents (cis,cis > trans,trans > cis,trans-2,6-dimethylcyclohexanol). In conclusion, the stereochemical configuration within the dimethylcyclohexanols is an important molecular feature in conferring positive modulation of GABAA receptor activity and for binding to the receptor, a consideration that needs to be taken into account when designing novel anesthetics with enhanced therapeutic indices. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

Velocity modulation spectroscopy of molecular ions II: The millimeter/submillimeter-wave spectrum of TiF + ( X3Φr)

NASA Astrophysics Data System (ADS)

Halfen, D. T.; Ziurys, L. M.

2006-11-01

The pure rotational spectrum of the molecular ion TiF + in its 3Φr ground state has been measured in the range 327-542 GHz using millimeter-wave direct absorption techniques combined with velocity modulation spectroscopy. TiF + was made in an AC discharge from a mixture of TiCl 4, F 2 in He, and argon. Ten transitions of this ion were recorded. In every transition, fluorine hyperfine interactions, as well as the fine structure splittings, were resolved. The fine structure pattern was found to be regular with almost equal spacing in frequency between the three spin components, in contrast to TiCl +, which is perturbed in the ground state. The data were fit with a case ( a) Hamiltonian and rotational, fine structure, and hyperfine constants were determined. The bond length established for TiF +, r0 = 1.7775 Å, was found to be shorter than that of TiF, r0 = 1.8342 Å—also established from mm-wave data. The hyperfine parameters determined are consistent with a δ1π1 electron configuration with the electrons primarily located on the titanium nucleus. The nuclear spin-orbit constant a indicates that the unpaired electrons are closer to the fluorine nucleus in TiF + relative to TiF, as expected with the decrease in bond length for the ion. The shorter bond distance is thought to arise from increased charge on the titanium nucleus as a result of a Ti 2+F - configuration. A similar decrease in bond length was found for TiCl + relative to TiCl.

Investigating ego modules and pathways in osteosarcoma by integrating the EgoNet algorithm and pathway analysis.

PubMed

Chen, X Y; Chen, Y H; Zhang, L J; Wang, Y; Tong, Z C

2017-02-16

Osteosarcoma (OS) is the most common primary bone malignancy, but current therapies are far from effective for all patients. A better understanding of the pathological mechanism of OS may help to achieve new treatments for this tumor. Hence, the objective of this study was to investigate ego modules and pathways in OS utilizing EgoNet algorithm and pathway-related analysis, and reveal pathological mechanisms underlying OS. The EgoNet algorithm comprises four steps: constructing background protein-protein interaction (PPI) network (PPIN) based on gene expression data and PPI data; extracting differential expression network (DEN) from the background PPIN; identifying ego genes according to topological features of genes in reweighted DEN; and collecting ego modules using module search by ego gene expansion. Consequently, we obtained 5 ego modules (Modules 2, 3, 4, 5, and 6) in total. After applying the permutation test, all presented statistical significance between OS and normal controls. Finally, pathway enrichment analysis combined with Reactome pathway database was performed to investigate pathways, and Fisher's exact test was conducted to capture ego pathways for OS. The ego pathway for Module 2 was CLEC7A/inflammasome pathway, while for Module 3 a tetrasaccharide linker sequence was required for glycosaminoglycan (GAG) synthesis, and for Module 6 was the Rho GTPase cycle. Interestingly, genes in Modules 4 and 5 were enriched in the same pathway, the 2-LTR circle formation. In conclusion, the ego modules and pathways might be potential biomarkers for OS therapeutic index, and give great insight of the molecular mechanism underlying this tumor.

Investigating ego modules and pathways in osteosarcoma by integrating the EgoNet algorithm and pathway analysis

PubMed Central

Chen, X.Y.; Chen, Y.H.; Zhang, L.J.; Wang, Y.; Tong, Z.C.

2017-01-01

Osteosarcoma (OS) is the most common primary bone malignancy, but current therapies are far from effective for all patients. A better understanding of the pathological mechanism of OS may help to achieve new treatments for this tumor. Hence, the objective of this study was to investigate ego modules and pathways in OS utilizing EgoNet algorithm and pathway-related analysis, and reveal pathological mechanisms underlying OS. The EgoNet algorithm comprises four steps: constructing background protein-protein interaction (PPI) network (PPIN) based on gene expression data and PPI data; extracting differential expression network (DEN) from the background PPIN; identifying ego genes according to topological features of genes in reweighted DEN; and collecting ego modules using module search by ego gene expansion. Consequently, we obtained 5 ego modules (Modules 2, 3, 4, 5, and 6) in total. After applying the permutation test, all presented statistical significance between OS and normal controls. Finally, pathway enrichment analysis combined with Reactome pathway database was performed to investigate pathways, and Fisher's exact test was conducted to capture ego pathways for OS. The ego pathway for Module 2 was CLEC7A/inflammasome pathway, while for Module 3 a tetrasaccharide linker sequence was required for glycosaminoglycan (GAG) synthesis, and for Module 6 was the Rho GTPase cycle. Interestingly, genes in Modules 4 and 5 were enriched in the same pathway, the 2-LTR circle formation. In conclusion, the ego modules and pathways might be potential biomarkers for OS therapeutic index, and give great insight of the molecular mechanism underlying this tumor. PMID:28225867

Structural basis for alcohol modulation of a pentameric ligand-gated ion channel

PubMed Central

Howard, Rebecca J.; Murail, Samuel; Ondricek, Kathryn E.; Corringer, Pierre-Jean; Lindahl, Erik; Trudell, James R.; Harris, R. Adron

2011-01-01

Despite its long history of use and abuse in human culture, the molecular basis for alcohol action in the brain is poorly understood. The recent determination of the atomic-scale structure of GLIC, a prokaryotic member of the pentameric ligand-gated ion channel (pLGIC) family, provides a unique opportunity to characterize the structural basis for modulation of these channels, many of which are alcohol targets in brain. We observed that GLIC recapitulates bimodal modulation by n-alcohols, similar to some eukaryotic pLGICs: methanol and ethanol weakly potentiated proton-activated currents in GLIC, whereas n-alcohols larger than ethanol inhibited them. Mapping of residues important to alcohol modulation of ionotropic receptors for glycine, γ-aminobutyric acid, and acetylcholine onto GLIC revealed their proximity to transmembrane cavities that may accommodate one or more alcohol molecules. Site-directed mutations in the pore-lining M2 helix allowed the identification of four residues that influence alcohol potentiation, with the direction of their effects reflecting α-helical structure. At one of the potentiation-enhancing residues, decreased side chain volume converted GLIC into a highly ethanol-sensitive channel, comparable to its eukaryotic relatives. Covalent labeling of M2 positions with an alcohol analog, a methanethiosulfonate reagent, further implicated residues at the extracellular end of the helix in alcohol binding. Molecular dynamics simulations elucidated the structural consequences of a potentiation-enhancing mutation and suggested a structural mechanism for alcohol potentiation via interaction with a transmembrane cavity previously termed the “linking tunnel.” These results provide a unique structural model for independent potentiating and inhibitory interactions of n-alcohols with a pLGIC family member. PMID:21730162

Molecular Simulations of Carbohydrates with a Fucose-Binding Burkholderia ambifaria Lectin Suggest Modulation by Surface Residues Outside the Fucose-Binding Pocket

PubMed Central

Dingjan, Tamir; Imberty, Anne; Pérez, Serge; Yuriev, Elizabeth; Ramsland, Paul A.

2017-01-01

Burkholderia ambifaria is an opportunistic respiratory pathogen belonging to the Burkholderia cepacia complex, a collection of species responsible for the rapidly fatal cepacia syndrome in cystic fibrosis patients. A fucose-binding lectin identified in the B. ambifaria genome, BambL, is able to adhere to lung tissue, and may play a role in respiratory infection. X-ray crystallography has revealed the bound complex structures for four fucosylated human blood group epitopes (blood group B, H type 1, H type 2, and Lex determinants). The present study employed computational approaches, including docking and molecular dynamics (MD), to extend the structural analysis of BambL-oligosaccharide complexes to include four additional blood group saccharides (A, Lea, Leb, and Ley) and a library of blood-group-related carbohydrates. Carbohydrate recognition is dominated by interactions with fucose via a hydrogen-bonding network involving Arg15, Glu26, Ala38, and Trp79 and a stacking interaction with Trp74. Additional hydrogen bonds to non-fucose residues are formed with Asp30, Tyr35, Thr36, and Trp74. BambL recognition is dominated by interactions with fucose, but also features interactions with other parts of the ligands that may modulate specificity or affinity. The detailed computational characterization of the BambL carbohydrate-binding site provides guidelines for the future design of lectin inhibitors. PMID:28680402

Molecular Basis of Asbestos-Induced Lung Disease

PubMed Central

Liu, Gang; Cheresh, Paul; Kamp, David W.

2013-01-01

Asbestos causes asbestosis and malignancies by molecular mechanisms that are not fully understood. The modes of action underlying asbestosis, lung cancer, and mesothelioma appear to differ depending on the fiber type, lung clearance, and genetics. After reviewing the key pathologic changes following asbestos exposure, we examine recently identified pathogenic pathways, with a focus on oxidative stress. Alveolar epithelial cell apoptosis, which is an important early event in asbestosis, is mediated by mitochondria- and p53-regulated death pathways and may be modulated by the endoplasmic reticulum. We review mitochondrial DNA (mtDNA)-damage and -repair mechanisms, focusing on 8-oxoguanine DNA glycosylase, as well as cross talk between reactive oxygen species production, mtDNA damage, p53, OGG1, and mitochondrial aconitase. These new insights into the molecular basis of asbestos-induced lung diseases may foster the development of novel therapeutic targets for managing degenerative diseases (e.g., asbestosis and idiopathic pulmonary fibrosis), tumors, and aging, for which effective management is lacking. PMID:23347351

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.

Molecular and Cellular Mechanisms of Axonal Regeneration After Spinal Cord Injury.

PubMed

van Niekerk, Erna A; Tuszynski, Mark H; Lu, Paul; Dulin, Jennifer N

2016-02-01

Following axotomy, a complex temporal and spatial coordination of molecular events enables regeneration of the peripheral nerve. In contrast, multiple intrinsic and extrinsic factors contribute to the general failure of axonal regeneration in the central nervous system. In this review, we examine the current understanding of differences in protein expression and post-translational modifications, activation of signaling networks, and environmental cues that may underlie the divergent regenerative capacity of central and peripheral axons. We also highlight key experimental strategies to enhance axonal regeneration via modulation of intraneuronal signaling networks and the extracellular milieu. Finally, we explore potential applications of proteomics to fill gaps in the current understanding of molecular mechanisms underlying regeneration, and to provide insight into the development of more effective approaches to promote axonal regeneration following injury to the nervous system. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Optical effects module and passive sample array

NASA Technical Reports Server (NTRS)

Linton, R. C.

1983-01-01

The Optical Effects Module (OEM) has the objective to monitor the effects of the deposition and adhesion of both molecular species and particles on optical surfaces in the Shuttle cargo bay environment. The OEM performs inflight measurements of the ultraviolet (253.7 nm) transmittance and diffuse reflectance of five optical samples at regular intervals throughout the orbital mission. Most of the obtained results indicates or implies the absence of a significant accumulation of contamination other than particulates on the samples. The contaminant species (or particulates) adhering to the samples of the Passive Sample Array (PSA) were identified by means of Auger and X-ray energy dispersive analyses. The elements silicon, chlorine, and phosphorus were discovered.

Fast, clash-free RNA conformational morphing using molecular junctions

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

Heliou, Amelie; Budday, Dominik; Fonseca, Rasmus

Non-coding ribonucleic acids (ncRNA) are functional RNA molecules that are not translated into protein. They are extremely dynamic, adopting diverse conformational substates, which enables them to modulate their interaction with a large number of other molecules. The flexibility of ncRNA provides a challenge for probing their complex 3D conformational landscape, both experimentally and computationally. As a result, despite their conformational diversity, ncRNAs mostly preserve their secondary structure throughout the dynamic ensemble. Here we present a kinematics-based procedure to morph an RNA molecule between conformational substates, while avoiding inter-atomic clashes. We represent an RNA as a kinematic linkage, with fixed groupsmore » of atoms as rigid bodies and rotatable bonds as degrees of freedom. Our procedure maintains RNA secondary structure by treating hydrogen bonds between base pairs as constraints. The constraints define a lower-dimensional, secondary-structure constraint manifold in conformation space, where motions are largely governed by molecular junctions of unpaired nucleotides. On a large benchmark set, we show that our morphing procedure compares favorably to peer algorithms, and can approach goal conformations to within a low all-atom RMSD by directing fewer than 1% of its atoms. Furthermore, our results suggest that molecular junctions can modulate 3D structural rearrangements, while secondary structure elements guide large parts of the molecule along the transition to the correct final conformation.« less

Fast, clash-free RNA conformational morphing using molecular junctions

DOE PAGES

Heliou, Amelie; Budday, Dominik; Fonseca, Rasmus; ...

2017-03-13

Non-coding ribonucleic acids (ncRNA) are functional RNA molecules that are not translated into protein. They are extremely dynamic, adopting diverse conformational substates, which enables them to modulate their interaction with a large number of other molecules. The flexibility of ncRNA provides a challenge for probing their complex 3D conformational landscape, both experimentally and computationally. As a result, despite their conformational diversity, ncRNAs mostly preserve their secondary structure throughout the dynamic ensemble. Here we present a kinematics-based procedure to morph an RNA molecule between conformational substates, while avoiding inter-atomic clashes. We represent an RNA as a kinematic linkage, with fixed groupsmore » of atoms as rigid bodies and rotatable bonds as degrees of freedom. Our procedure maintains RNA secondary structure by treating hydrogen bonds between base pairs as constraints. The constraints define a lower-dimensional, secondary-structure constraint manifold in conformation space, where motions are largely governed by molecular junctions of unpaired nucleotides. On a large benchmark set, we show that our morphing procedure compares favorably to peer algorithms, and can approach goal conformations to within a low all-atom RMSD by directing fewer than 1% of its atoms. Furthermore, our results suggest that molecular junctions can modulate 3D structural rearrangements, while secondary structure elements guide large parts of the molecule along the transition to the correct final conformation.« less

Metal-graphene heterojunction modulation via H{sub 2} interaction

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

Cadore, A. R., E-mail: alissoncadore@gmail.com, E-mail: lccampos@fisica.ufmg.br; Mania, E.; Lacerda, R. G.

2016-07-18

Combining experiment and theory, we investigate how a naturally created heterojunction (pn junction) at a graphene and metallic contact interface is modulated via interaction with molecular hydrogen (H{sub 2}). Due to an electrostatic interaction, metallic electrodes induce pn junctions in graphene, leading to an asymmetrical resistance in electronic transport for electrons and holes. We report that the asymmetry in the resistance can be tuned in a reversible manner by exposing graphene devices to H{sub 2}. The interaction between the H{sub 2} and graphene occurs solely at the graphene-contact pn junction and induces a modification on the electrostatic interaction between graphenemore » and metallic contacts. We explain the experimental data with theory providing information concerning the length of the heterojunction and how it changes as a function of H{sub 2} adsorption. Our results are valuable for understanding the nature of the metal-graphene interfaces and have potential application for selective sensors of molecular hydrogen.« less

Conserved gene regulatory module specifies lateral neural borders across bilaterians.

PubMed

Li, Yongbin; Zhao, Di; Horie, Takeo; Chen, Geng; Bao, Hongcun; Chen, Siyu; Liu, Weihong; Horie, Ryoko; Liang, Tao; Dong, Biyu; Feng, Qianqian; Tao, Qinghua; Liu, Xiao

2017-08-01

The lateral neural plate border (NPB), the neural part of the vertebrate neural border, is composed of central nervous system (CNS) progenitors and peripheral nervous system (PNS) progenitors. In invertebrates, PNS progenitors are also juxtaposed to the lateral boundary of the CNS. Whether there are conserved molecular mechanisms determining vertebrate and invertebrate lateral neural borders remains unclear. Using single-cell-resolution gene-expression profiling and genetic analysis, we present evidence that orthologs of the NPB specification module specify the invertebrate lateral neural border, which is composed of CNS and PNS progenitors. First, like in vertebrates, the conserved neuroectoderm lateral border specifier Msx/vab-15 specifies lateral neuroblasts in Caenorhabditis elegans Second, orthologs of the vertebrate NPB specification module ( Msx/vab-15 , Pax3/7/pax-3 , and Zic/ref-2 ) are significantly enriched in worm lateral neuroblasts. In addition, like in other bilaterians, the expression domain of Msx/vab-15 is more lateral than those of Pax3/7/pax-3 and Zic/ref- 2 in C. elegans Third, we show that Msx/vab-15 regulates the development of mechanosensory neurons derived from lateral neural progenitors in multiple invertebrate species, including C. elegans , Drosophila melanogaster , and Ciona intestinalis We also identify a novel lateral neural border specifier, ZNF703/tlp-1 , which functions synergistically with Msx/vab- 15 in both C. elegans and Xenopus laevis These data suggest a common origin of the molecular mechanism specifying lateral neural borders across bilaterians.

Conserved gene regulatory module specifies lateral neural borders across bilaterians

PubMed Central

Li, Yongbin; Zhao, Di; Horie, Takeo; Chen, Geng; Bao, Hongcun; Chen, Siyu; Liu, Weihong; Horie, Ryoko; Liang, Tao; Dong, Biyu; Feng, Qianqian; Tao, Qinghua

2017-01-01

The lateral neural plate border (NPB), the neural part of the vertebrate neural border, is composed of central nervous system (CNS) progenitors and peripheral nervous system (PNS) progenitors. In invertebrates, PNS progenitors are also juxtaposed to the lateral boundary of the CNS. Whether there are conserved molecular mechanisms determining vertebrate and invertebrate lateral neural borders remains unclear. Using single-cell-resolution gene-expression profiling and genetic analysis, we present evidence that orthologs of the NPB specification module specify the invertebrate lateral neural border, which is composed of CNS and PNS progenitors. First, like in vertebrates, the conserved neuroectoderm lateral border specifier Msx/vab-15 specifies lateral neuroblasts in Caenorhabditis elegans. Second, orthologs of the vertebrate NPB specification module (Msx/vab-15, Pax3/7/pax-3, and Zic/ref-2) are significantly enriched in worm lateral neuroblasts. In addition, like in other bilaterians, the expression domain of Msx/vab-15 is more lateral than those of Pax3/7/pax-3 and Zic/ref-2 in C. elegans. Third, we show that Msx/vab-15 regulates the development of mechanosensory neurons derived from lateral neural progenitors in multiple invertebrate species, including C. elegans, Drosophila melanogaster, and Ciona intestinalis. We also identify a novel lateral neural border specifier, ZNF703/tlp-1, which functions synergistically with Msx/vab-15 in both C. elegans and Xenopus laevis. These data suggest a common origin of the molecular mechanism specifying lateral neural borders across bilaterians. PMID:28716930

Implications of Green Tea and Its Constituents in the Prevention of Cancer via the Modulation of Cell Signalling Pathway

PubMed Central

Rahmani, Arshad H.; Al shabrmi, Fahad M.; Allemailem, Khaled S.; Aly, Salah M.; Khan, Masood A.

2015-01-01

Green tea is commonly used as a beverage worldwide, especially in China, Japan, Morocco, and Saudi Arabia. Green tea and its constituents have been considered very effective in the prevention and treatment of various diseases. It contains a variety of catechins, which show a pivotal role in the modulation of biological activities and also act as chemopreventive agents. Earlier studies have confirmed that green tea and its chief constituent epigallocatechin gallate (EGCG) have a potential role in the management of cancer through the modulation of cell signaling pathways. In this review, we focused on the beneficial effects of green tea and its constituents in the cancer prevention and treatment and its impact on modulation of molecular pathways. PMID:25977926

First biological evaluation of developed 3-benzyloxyfluorenes as novel class of MDR modulators.

PubMed

Krug, Martin; Voigt, Burkhardt; Baumert, Christiane; Lüpken, Ralf; Molnár, Joséf; Hilgeroth, Andreas

2010-06-01

A series of 3-benzyloxy-1-aza-9-oxafluorenes has been synthesized and biologically evaluated as novel MDR modulators. The concentration dependent inhibition of the efflux pump ABCB1 (P-glycoprotein) has been characterized and is discussed in relation to calculated lipophilicity data. Instead of the molecular lipophilicity the exact positioning of functional groups was found decisive for the biological activities. Copyright (c) 2010 Elsevier Masson SAS. All rights reserved.

Effect of PEO molecular weight on the miscibility and dynamics in epoxy/PEO blends.

PubMed

Lu, Shoudong; Zhang, Rongchun; Wang, Xiaoliang; Sun, Pingchuan; Lv, Weifeng; Liu, Qingjie; Jia, Ninghong

2015-11-01

In this work, the effect of poly(ethylene oxide) (PEO) molecular weight in blends of epoxy (ER) and PEO on the miscibility, inter-chain weak interactions and local dynamics were systematically investigated by multi-frequency temperature modulation DSC and solid-state NMR techniques. We found that the molecular weight (M(w)) of PEO was a crucial factor in controlling the miscibility, chain dynamics and hydrogen bonding interactions between PEO and ER. A critical PEO molecular weight (M(crit)) around 4.5k was found. PEO was well miscible with ER when the molecular weight was below M(crit), where the chain motion of PEO was restricted due to strong inter-chain hydrogen bonding interactions. However, for the blends with high molecular weight PEO (M(w) > M(crit)), the miscibility between PEO and ER was poor, and most of PEO chains were considerably mobile. Finally, polarization inversion spin exchange at magic angle (PISEMA) solid-state NMR experiment further revealed the different mobility of the PEO in ER/PEO blends with different molecular weight of PEO at molecular level. Based on the DSC and NMR results, a tentative model was proposed to illustrate the miscibility in ER/PEO blends.

Architectonics: Design of Molecular Architecture for Functional Applications.

PubMed

Avinash, M B; Govindaraju, Thimmaiah

2018-02-20

biomolecules like amino acids and nucleobases as auxiliaries. Naphthalenediimide (NDI), perylenediimide (PDI), and few other molecular systems serve as functional modules. The effects of stereochemistry and minute structural modifications in the molecular designs on the supramolecular interactions, and construction of self-assembled zero-dimensional (OD), one-dimensional (1D), and two-dimensional (2D) nano- and microarchitectures like particles, spheres, cups, bowls, fibers, belts, helical belts, supercoiled helices, sheets, fractals, and honeycomb-like arrays are discussed in extensive detail. Additionally, we present molecular systems that showcase the elegant designs of coassembly, templated assembly, hierarchical assembly, transient self-assembly, chiral denaturation, retentive helical memory, self-replication, supramolecular regulation, supramolecular speciation, supernon linearity, dynamic pathway complexity, supramolecular heterojunction, living supramolecular polymerization, and molecular machines. Finally, we describe the molecular engineering principles learnt over the years that have led to several applications, namely, organic electronics, self-cleaning, high-mechanical strength, and tissue engineering.

Network-based differential gene expression analysis suggests cell cycle related genes regulated by E2F1 underlie the molecular difference between smoker and non-smoker lung adenocarcinoma

PubMed Central

2013-01-01

Background Differential gene expression (DGE) analysis is commonly used to reveal the deregulated molecular mechanisms of complex diseases. However, traditional DGE analysis (e.g., the t test or the rank sum test) tests each gene independently without considering interactions between them. Top-ranked differentially regulated genes prioritized by the analysis may not directly relate to the coherent molecular changes underlying complex diseases. Joint analyses of co-expression and DGE have been applied to reveal the deregulated molecular modules underlying complex diseases. Most of these methods consist of separate steps: first to identify gene-gene relationships under the studied phenotype then to integrate them with gene expression changes for prioritizing signature genes, or vice versa. It is warrant a method that can simultaneously consider gene-gene co-expression strength and corresponding expression level changes so that both types of information can be leveraged optimally. Results In this paper, we develop a gene module based method for differential gene expression analysis, named network-based differential gene expression (nDGE) analysis, a one-step integrative process for prioritizing deregulated genes and grouping them into gene modules. We demonstrate that nDGE outperforms existing methods in prioritizing deregulated genes and discovering deregulated gene modules using simulated data sets. When tested on a series of smoker and non-smoker lung adenocarcinoma data sets, we show that top differentially regulated genes identified by the rank sum test in different sets are not consistent while top ranked genes defined by nDGE in different data sets significantly overlap. nDGE results suggest that a differentially regulated gene module, which is enriched for cell cycle related genes and E2F1 targeted genes, plays a role in the molecular differences between smoker and non-smoker lung adenocarcinoma. Conclusions In this paper, we develop nDGE to prioritize

Molecular-Scale Features that Govern the Effects of O-Glycosylation on a Carbohydrate-Binding Module

DOE PAGES

Guan, Xiaoyang; Chaffey, Patrick K.; Zeng, Chen; ...

2015-09-21

The protein glycosylation is a ubiquitous post-translational modification in all kingdoms of life. Despite its importance in molecular and cellular biology, the molecular-level ramifications of O-glycosylation on biomolecular structure and function remain elusive. Here, we took a small model glycoprotein and changed the glycan structure and size, amino acid residues near the glycosylation site, and glycosidic linkage while monitoring any corresponding changes to physical stability and cellulose binding affinity. The results of this study reveal the collective importance of all the studied features in controlling the most pronounced effects of O-glycosylation in this system. This study suggests the possibility ofmore » designing proteins with multiple improved properties by simultaneously varying the structures of O-glycans and amino acids local to the glycosylation site.« less

Cellular and molecular specificity of pituitary gland physiology.

PubMed

Perez-Castro, Carolina; Renner, Ulrich; Haedo, Mariana R; Stalla, Gunter K; Arzt, Eduardo

2012-01-01

The anterior pituitary gland has the ability to respond to complex signals derived from central and peripheral systems. Perception of these signals and their integration are mediated by cell interactions and cross-talk of multiple signaling transduction pathways and transcriptional regulatory networks that cooperate for hormone secretion, cell plasticity, and ultimately specific pituitary responses that are essential for an appropriate physiological response. We discuss the physiopathological and molecular mechanisms related to this integrative regulatory system of the anterior pituitary gland and how it contributes to modulate the gland functions and impacts on body homeostasis.

Two-dimensional nuclear magnetic resonance structure determination module for introductory biochemistry: synthesis and structural characterization of lyso-glycerophospholipids.

PubMed

Garrett, Teresa A; Rose, Rebecca L; Bell, Sidney M

2013-01-01

In this laboratory module, introductory biochemistry students are exposed to two-dimensional (1) H-nuclear magnetic resonance of glycerophospholipids (GPLs). Working in groups of three, students enzymatically synthesized and purified a variety of 2-acyl lyso GPLs. The structure of the 2-acyl lyso GPL was verified using (1) H-correlation spectroscopy. Students scored significantly higher on an assessment of NMR knowledge after having participated in this lab module and in comparison to a similar cohort who did not participate. Inaddition, student confidence in their NMR knowledge and abilities increased 62% following the module and correlated with their ability to apply their NMR knowledge. Based on these results, the laboratory module was very effective at providing students with a more extensive understanding of the underlying concepts of NMR as a tool for structural determination. Copyright © 2013 International Union of Biochemistry and Molecular Biology, Inc.

Long Distance Modulation of Disorder-to-Order Transitions in Protein Allostery.

PubMed

Wang, Jingheng; Custer, Gregory; Beckett, Dorothy; Matysiak, Silvina

2017-08-29

Elucidation of the molecular details of allosteric communication between distant sites in a protein is key to understanding and manipulating many biological regulatory processes. Although protein disorder is acknowledged to play an important thermodynamic role in allostery, the molecular mechanisms by which this disorder is harnessed for long distance communication are known for a limited number of systems. Transcription repression by the Escherichia coli biotin repressor, BirA, is allosterically activated by binding of the small molecule effector biotinoyl-5'-AMP. The effector acts by promoting BirA dimerization, which is a prerequisite for sequence-specific binding to the biotin biosynthetic operon operator sequence. A 30 Å distance separates the effector binding and dimerization surfaces in BirA, and previous studies indicate that allostery is mediated, in part, by disorder-to-order transitions on the two coupled sites. In this work, combined experimental and computational methods have been applied to investigate the molecular basis of allosteric communication in BirA. Double-mutant cycle analysis coupled with thermodynamic measurements indicates functional coupling between residues in disordered loops on the two distant surfaces. All atom molecular dynamics simulations reveal that this coupling occurs through long distance reciprocal modulation of the structure and dynamics of disorder-to-order transitions on the two surfaces.

Penetration of Cosmic Rays into Dense Molecular Clouds: Role of Diffuse Envelopes

NASA Astrophysics Data System (ADS)

Ivlev, A. V.; Dogiel, V. A.; Chernyshov, D. O.; Caselli, P.; Ko, C.-M.; Cheng, K. S.

2018-03-01

A flux of cosmic rays (CRs) propagating through a diffuse ionized gas can excite MHD waves, thus generating magnetic disturbances. We propose a generic model of CR penetration into molecular clouds through their diffuse envelopes, and identify the leading physical processes controlling their transport on the way from a highly ionized interstellar medium to the dense interior of the cloud. The model allows us to describe a transition between a free streaming of CRs and their diffusive propagation, determined by the scattering on the self-generated disturbances. A self-consistent set of equations, governing the diffusive transport regime in an envelope and the MHD turbulence generated by the modulated CR flux, is characterized by two dimensionless numbers. We demonstrate a remarkable mutual complementarity of different mechanisms leading to the onset of the diffusive regime, which results in a universal energy spectrum of the modulated CRs. In conclusion, we briefly discuss implications of our results for several fundamental astrophysical problems, such as the spatial distribution of CRs in the Galaxy as well as the ionization, heating, and chemistry in dense molecular clouds. This paper is dedicated to the memory of Prof. Vadim Tsytovich.

Entropy in molecular recognition by proteins

PubMed Central

Caro, José A.; Harpole, Kyle W.; Kasinath, Vignesh; Lim, Jackwee; Granja, Jeffrey; Valentine, Kathleen G.; Sharp, Kim A.

2017-01-01

Molecular recognition by proteins is fundamental to molecular biology. Dissection of the thermodynamic energy terms governing protein–ligand interactions has proven difficult, with determination of entropic contributions being particularly elusive. NMR relaxation measurements have suggested that changes in protein conformational entropy can be quantitatively obtained through a dynamical proxy, but the generality of this relationship has not been shown. Twenty-eight protein–ligand complexes are used to show a quantitative relationship between measures of fast side-chain motion and the underlying conformational entropy. We find that the contribution of conformational entropy can range from favorable to unfavorable, which demonstrates the potential of this thermodynamic variable to modulate protein–ligand interactions. For about one-quarter of these complexes, the absence of conformational entropy would render the resulting affinity biologically meaningless. The dynamical proxy for conformational entropy or “entropy meter” also allows for refinement of the contributions of solvent entropy and the loss in rotational-translational entropy accompanying formation of high-affinity complexes. Furthermore, structure-based application of the approach can also provide insight into long-lived specific water–protein interactions that escape the generic treatments of solvent entropy based simply on changes in accessible surface area. These results provide a comprehensive and unified view of the general role of entropy in high-affinity molecular recognition by proteins. PMID:28584100

Entropy in molecular recognition by proteins.

PubMed

Caro, José A; Harpole, Kyle W; Kasinath, Vignesh; Lim, Jackwee; Granja, Jeffrey; Valentine, Kathleen G; Sharp, Kim A; Wand, A Joshua

2017-06-20

Molecular recognition by proteins is fundamental to molecular biology. Dissection of the thermodynamic energy terms governing protein-ligand interactions has proven difficult, with determination of entropic contributions being particularly elusive. NMR relaxation measurements have suggested that changes in protein conformational entropy can be quantitatively obtained through a dynamical proxy, but the generality of this relationship has not been shown. Twenty-eight protein-ligand complexes are used to show a quantitative relationship between measures of fast side-chain motion and the underlying conformational entropy. We find that the contribution of conformational entropy can range from favorable to unfavorable, which demonstrates the potential of this thermodynamic variable to modulate protein-ligand interactions. For about one-quarter of these complexes, the absence of conformational entropy would render the resulting affinity biologically meaningless. The dynamical proxy for conformational entropy or "entropy meter" also allows for refinement of the contributions of solvent entropy and the loss in rotational-translational entropy accompanying formation of high-affinity complexes. Furthermore, structure-based application of the approach can also provide insight into long-lived specific water-protein interactions that escape the generic treatments of solvent entropy based simply on changes in accessible surface area. These results provide a comprehensive and unified view of the general role of entropy in high-affinity molecular recognition by proteins.

Electrostatic potential profiles of molecular conductors

NASA Astrophysics Data System (ADS)

Liang, G. C.; Ghosh, A. W.; Paulsson, M.; Datta, S.

2004-03-01

The electrostatic potential across a short ballistic molecular conductor depends sensitively on the geometry of its environment, and can affect its conduction significantly by influencing its energy levels and wave functions. We illustrate some of the issues involved by evaluating the potential profiles for a conducting gold wire and an aromatic phenyl dithiol molecule in various geometries. The potential profile is obtained by solving Poisson’s equation with boundary conditions set by the contact electrochemical potentials and coupling the result self-consistently with a nonequilibrium Green’s function formulation of transport. The overall shape of the potential profile (ramp versus flat) depends on the feasibility of transverse screening of electric fields. Accordingly, the screening is better for a thick wire, a multiwalled nanotube, or a close-packed self-assembled monolayer, in comparison to a thin wire, a single-walled nanotube, or an isolated molecular conductor. The electrostatic potential further governs the alignment or misalignment of intramolecular levels, which can strongly influence the molecular current voltage (I V) characteristic. An external gate voltage can modify the overall potential profile, changing the I V characteristic from a resonant conducting to a saturating one. The degree of saturation and gate modulation depends on the availability of metal-induced-gap states and on the electrostatic gate control parameter set by the ratio of the gate oxide thickness to the channel length.

Genomic biomarkers for molecular imaging: predicting the future.

PubMed

Thakur, Mathew L

2009-07-01

Over the past few decades, great strides have been made in anatomical imaging of disease that has led to their diagnosis with minimal invasion. Despite these advances, diseases such as cancer continue to take one human life every minute in the United States. Complimentary approaches that pertain directly to the genesis of the disease might contribute to its early diagnosis and subsequent management. In cancer, an array of molecular abnormalities leading to the modulations in expression of key proteins important in the cellular signaling pathways and cell proliferation has been identified. These specific disease fingerprints, biomarkers, are overexpressed on malignant cell surfaces or within the cytoplasm, and they provide unique targets that are promising for improving cancer diagnosis and therapy. We and others have designed, synthesized, and evaluated some novel probes specific for those oncogenes and oncogene product biomarkers for PET and SPECT molecular imaging of certain types of cancers. This article briefly describes this approach and gives specific examples that depict the ability of molecular imaging to detect occult lesions not detectable by current scintigraphic approaches. The article also outlines a few examples predicting other possible applications of targeting such specific probes not yet used.

Module utilization committee

NASA Technical Reports Server (NTRS)

Volkmer, K.; Praver, G.

1984-01-01

Photovoltaic collector modules were declared surplus to the needs of the U.S. Dept. of Energy. The Module Utilization Committee was formed to make appropriate disposition of the surplus modules on a national basis and to act as a broker for requests for these modules originating outside of the National Photovoltaics Program.

Nanoscale molecular communication networks: a game-theoretic perspective

NASA Astrophysics Data System (ADS)

Jiang, Chunxiao; Chen, Yan; Ray Liu, K. J.

2015-12-01

Currently, communication between nanomachines is an important topic for the development of novel devices. To implement a nanocommunication system, diffusion-based molecular communication is considered as a promising bio-inspired approach. Various technical issues about molecular communications, including channel capacity, noise and interference, and modulation and coding, have been studied in the literature, while the resource allocation problem among multiple nanomachines has not been well investigated, which is a very important issue since all the nanomachines share the same propagation medium. Considering the limited computation capability of nanomachines and the expensive information exchange cost among them, in this paper, we propose a game-theoretic framework for distributed resource allocation in nanoscale molecular communication systems. We first analyze the inter-symbol and inter-user interference, as well as bit error rate performance, in the molecular communication system. Based on the interference analysis, we formulate the resource allocation problem as a non-cooperative molecule emission control game, where the Nash equilibrium is found and proved to be unique. In order to improve the system efficiency while guaranteeing fairness, we further model the resource allocation problem using a cooperative game based on the Nash bargaining solution, which is proved to be proportionally fair. Simulation results show that the Nash bargaining solution can effectively ensure fairness among multiple nanomachines while achieving comparable social welfare performance with the centralized scheme.

Modulation of Immune Response by Organophosphorus Pesticides: Fishes as a Potential Model in Immunotoxicology

PubMed Central

Díaz-Resendiz, K. J. G.; Toledo-Ibarra, G. A.; Girón-Pérez, M. I.

2015-01-01

Immune response is modulated by different substances that are present in the environment. Nevertheless, some of these may cause an immunotoxic effect. In this paper, the effect of organophosphorus pesticides (frequent substances spilled in aquatic ecosystems) on the immune system of fishes and in immunotoxicology is reviewed. Furthermore, some cellular and molecular mechanisms that might be involved in immunoregulation mechanisms of organophosphorus pesticides are discussed. PMID:25973431

The molecular basis of bacterial-insect symbiosis.

PubMed

Douglas, Angela E

2014-11-25

Insects provide experimentally tractable and cost-effective model systems to investigate the molecular basis of animal-bacterial interactions. Recent research is revealing the central role of the insect innate immune system, especially anti-microbial peptides and reactive oxygen species, in regulating the abundance and composition of the microbiota in various insects, including Drosophila and the mosquitoes Aedes and Anopheles. Interactions between the immune system and microbiota are, however, bidirectional with evidence that members of the resident microbiota can promote immune function, conferring resistance to pathogens and parasites by both activation of immune effectors and production of toxins. Antagonistic and mutualistic interactions among bacteria have also been implicated as determinants of the microbiota composition, including exclusion of pathogens, but the molecular mechanisms are largely unknown. Some bacteria are crucial for insect nutrition, through provisioning of specific nutrients (e.g., B vitamins, essential amino acids) and modulation of the insect nutritional sensing and signaling pathways (e.g., insulin signaling) that regulate nutrient allocation, especially to lipid and other energy reserves. A key challenge for future research is to identify the molecular interaction between specific bacterial effectors and animal receptors, as well as to determine how these interactions translate into microbiota-dependent signaling, metabolism, and immune function in the host. Copyright © 2014. Published by Elsevier Ltd.

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

Multi-scale reflection modulator-based optical interconnects

NASA Astrophysics Data System (ADS)

Nair, Rohit

. The rationale behind using on-chip modulators rather than VCSELs is to avoid VCSEL thermal loads on chip, and because of higher reliability of modulators than VCSELs. Particularly above 10Gbps, an empirical model developed shows the rapid decrease of VCSEL median time to failure vs. data rate. Thus the proposed interconnect scheme which utilizes continuous wave VCSELs that are externally modulated by on-chip multiple quantum well modulators is applicable for chip-to-chip optical interconnects at 20Gbps and higher line data rates. Finally, for applications such as remote telemetry, where the interrogation distances can vary from a few meters to tens or even hundreds of meters we demonstrate a modulated retroreflector that utilizes InGaAs/InAlAs-based large-area multiple quantum well modulators on all three faces of a retroreflector. The large-area devices, fabricated by metalorganic chemical vapor deposition, are characterized in terms of the yield and leakage currents. A yield higher than that achieved previously using devices fabricated by molecular beam epitaxy is observed. The retroreflector module is constructed using standard FR4 printed circuit boards, thereby simplifying the wiring issue. A high optical contrast ratio of 8.23dB is observed for a drive of 20V. A free-standing PCB retroreflector is explored and found to have insufficient angular tolerances (+/-0.5 degrees). We show that the angular errors in the corner-cube construction can be corrected for using off-the-shelf optical components as opposed to mounting the PCBs on a precision corner cube, as has been done previously.

Ultrasensitive detection of atmospheric trace gases using frequency modulation spectroscopy

NASA Technical Reports Server (NTRS)

Cooper, David E.

1986-01-01

Frequency modulation (FM) spectroscopy is a new technique that promises to significantly extend the state-of-the-art in point detection of atmospheric trace gases. FM spectroscopy is essentially a balanced bridge optical heterodyne approach in which a small optical absorption or dispersion from an atomic or molecular species of interest generates an easily detected radio frequency (RF) signal. This signal can be monitored using standard RF signal processing techniques and is, in principle, limited only by the shot noise generated in the photodetector by the laser source employed. The use of very high modulation frequencies which exceed the spectral width of the probed absorption line distinguishes this technique from the well-known derivative spectroscopy which makes use of low (kHz) modulation frequencies. FM spectroscopy was recently extended to the 10 micron infrared (IR) spectral region where numerous polyatomic molecules exhibit characteristic vibrational-rotational bands. In conjunction with tunable semiconductor diode lasers, the quantum-noise-limited sensitivity of the technique should allow for the detection of absorptions as small as .00000001 in the IR spectral region. This sensitivity would allow for the detection of H2O2 at concentrations as low as 1 pptv with an integration time of 10 seconds.

Amplitude modulation detection with concurrent frequency modulation.

PubMed

Nagaraj, Naveen K

2016-09-01

Human speech consists of concomitant temporal modulations in amplitude and frequency that are crucial for speech perception. In this study, amplitude modulation (AM) detection thresholds were measured for 550 and 5000 Hz carriers with and without concurrent frequency modulation (FM), at AM rates crucial for speech perception. Results indicate that adding 40 Hz FM interferes with AM detection, more so for 5000 Hz carrier and for frequency deviations exceeding the critical bandwidth of the carrier frequency. These findings suggest that future cochlear implant processors, encoding speech fine-structures may consider limiting the FM to narrow bandwidth and to low frequencies.

Molecular pathophysiology and pharmacology of the voltage-sensing module of neuronal ion channels.

PubMed

Miceli, Francesco; Soldovieri, Maria Virginia; Ambrosino, Paolo; De Maria, Michela; Manocchio, Laura; Medoro, Alessandro; Taglialatela, Maurizio

2015-01-01

Voltage-gated ion channels (VGICs) are membrane proteins that switch from a closed to open state in response to changes in membrane potential, thus enabling ion fluxes across the cell membranes. The mechanism that regulate the structural rearrangements occurring in VGICs in response to changes in membrane potential still remains one of the most challenging topic of modern biophysics. Na(+), Ca(2+) and K(+) voltage-gated channels are structurally formed by the assembly of four similar domains, each comprising six transmembrane segments. Each domain can be divided into two main regions: the Pore Module (PM) and the Voltage-Sensing Module (VSM). The PM (helices S5 and S6 and intervening linker) is responsible for gate opening and ion selectivity; by contrast, the VSM, comprising the first four transmembrane helices (S1-S4), undergoes the first conformational changes in response to membrane voltage variations. In particular, the S4 segment of each domain, which contains several positively charged residues interspersed with hydrophobic amino acids, is located within the membrane electric field and plays an essential role in voltage sensing. In neurons, specific gating properties of each channel subtype underlie a variety of biological events, ranging from the generation and propagation of electrical impulses, to the secretion of neurotransmitters and to the regulation of gene expression. Given the important functional role played by the VSM in neuronal VGICs, it is not surprising that various VSM mutations affecting the gating process of these channels are responsible for human diseases, and that compounds acting on the VSM have emerged as important investigational tools with great therapeutic potential. In the present review we will briefly describe the most recent discoveries concerning how the VSM exerts its function, how genetically inherited diseases caused by mutations occurring in the VSM affects gating in VGICs, and how several classes of drugs and toxins

Identification of glia phenotype modulators based on select glial function regulatory signaling pathways.

PubMed

Lee, Sun-Hwa; Suk, Kyoungho

2018-04-20

Despite the considerable social and economic burden on the healthcare system worldwide due to neurodegenerative diseases, there are currently few disease-altering treatment options for many of these conditions. Therefore, new approaches for both prevention and intervention for neurodegenerative diseases are urgently required. Microglia-mediated neurotoxicity is one of the pathologic hallmarks common to Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Current therapeutic approaches to target microglia-mediated neurotoxicity are focused on the identification of glia phenotype modulators (GPMs), which can inhibit the 'classical' pro-inflammatory and neurotoxic phenotypes of microglia. Areas covered: This article reviews selected microglial molecular targets and pathways involved in either neurotoxicity or neuroprotection and how their identification. Expert opinion: Microglial activation and their signaling pathways have important implications in the neurotoxicity and brain disorders. Pharmacological modulation of microglial activation may serve as a potential therapeutic approach for targeting microglia-mediated neurotoxicity. However, given that microglia change their activation states depending on the timing, stage, and severity of disease, and even aging, the appropriate window should be considered for this approach to be clinically effective. In the future, the identification of unknown extracellular signals and intracellular molecular switches that control phenotypic shifts may facilitate the development of novel therapeutics targeting microglia-mediated neurotoxicity.

Whole Module Offgas Test Report: Space-Xl Dragon Module

NASA Technical Reports Server (NTRS)

James, John T.

2012-01-01

On September 26 and September 28,2012 a chemist from the JSC Toxicology Group acquired samples of air in 500 m1 evacuated canisters from the sealed Space-Xl Dragon Module. One sample was also acquired from Space-X Facility near the module at the start of the test. Samples of the module air were taken in triplicate once the module had been sealed, and then taken again in triplicate 1.98 days later. Ofthe triplicate samples, the first served as a line purge, and the last two were analyzed. The results of 5 samples are reported.

The Role of HCG in Implantation: A Mini-Review of Molecular and Clinical Evidence

PubMed Central

Makrigiannakis, Antonis; Vrekoussis, Thomas; Zoumakis, Emmanouel; Kalantaridou, Sophia N.; Jeschke, Udo

2017-01-01

Embryo implantation is a complex process involving continuous molecular cross-talk between the embryo and the decidua. One of the key molecules during this process is human chorionic gonadotropin (HCG). HCG effectively modulates several metabolic pathways within the decidua contributing to endometrial receptivity. Herein, a brief overview of the molecular mechanisms regulated by HCG is presented. Furthermore, we summarize the existing evidence regarding the clinical impact on reproductive outcomes after endometrial priming with HCG prior to embryo transfer. Although promising, further evidence is needed to clarify the protocol that would lead to beneficial outcomes. PMID:28629172

Molecular Profiles for Lung Cancer Pathogenesis and Detection in U.S. Veterans

DTIC Science & Technology

2014-12-01

smokers [7]. In addition, modulation of global gene expression in the normal epithelium in health smokers is similar in the large and small airways...previously shown that gene-expression profiles in cytologically normal mainstem bronchus epithelium can distinguish smokers with and without lung cancer...spatially mapping the molecular field of injury associated with smoking-related lung cancer. In smokers undergoing resection of lung lesions, high

Control of liquid crystal molecular orientation using ultrasound vibration

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

Taniguchi, Satoki; Wave Electronics Research Center, Doshisha University, 1-3 Tataramiyakodani, Kyotanabe, Kyoto 610-0321; Koyama, Daisuke

2016-03-07

We propose a technique to control the orientation of nematic liquid crystals using ultrasound and investigate the optical characteristics of the oriented samples. An ultrasonic liquid crystal cell with a thickness of 5–25 μm and two ultrasonic lead zirconate titanate transducers was fabricated. By exciting the ultrasonic transducers, the flexural vibration modes were generated on the cell. An acoustic radiation force to the liquid crystal layer was generated, changing the molecular orientation and thus the light transmission. By modulating the ultrasonic driving frequency and voltage, the spatial distribution of the molecular orientation of the liquid crystals could be controlled. The distributionmore » of the transmitted light intensity depends on the thickness of the liquid crystal layer because the acoustic field in the liquid crystal layer is changed by the orientational film.« less

Solvent induced rapid modulation of micro/nano structures of metal carboxylates coordination polymers: mechanism and morphology dependent magnetism.

PubMed

Liu, Kun; Shen, Zhu-Rui; Li, Yue; Han, Song-De; Hu, Tong-Liang; Zhang, Da-Shuai; Bu, Xian-He; Ruan, Wen-Juan

2014-08-12

Rational modulation of morphology is very important for functional coordination polymers (CPs) micro/nanostructures, and new strategies are still desired to achieve this challenging target. Herein, organic solvents have been established as the capping agents for rapid modulating the growth of metal-carboxylates CPs in organic solvent/water mixtures at ambient conditions. Co-3,5-pyridinedicarboxylate (pydc) CPs was studied here as the example. During the reaction, the organic solvents exhibited three types of modulation effect: anisotropic growth, anisotropic growth/formation of new crystalline phase and the formation of new crystalline phase solely, which was due to the variation of their binding ability with metal cations. The following study revealed that the binding ability was critically affected by their functional groups and molecular size. Moreover, their modulation effect could be finely tuned by changing volume ratios of solvent mixtures. Furthermore, they could be applied for modulating other metal-carboxylates CPs: Co-1,3,5-benzenetricarboxylic (BTC), Zn-pydc and Eu-pydc etc. Additionally, the as-prepared Co-pydc CPs showed a fascinating morphology-dependent antiferromagnetic behavior.

Solvent induced rapid modulation of micro/nano structures of metal carboxylates coordination polymers: mechanism and morphology dependent magnetism

NASA Astrophysics Data System (ADS)

Liu, Kun; Shen, Zhu-Rui; Li, Yue; Han, Song-De; Hu, Tong-Liang; Zhang, Da-Shuai; Bu, Xian-He; Ruan, Wen-Juan

2014-08-01

Rational modulation of morphology is very important for functional coordination polymers (CPs) micro/nanostructures, and new strategies are still desired to achieve this challenging target. Herein, organic solvents have been established as the capping agents for rapid modulating the growth of metal-carboxylates CPs in organic solvent/water mixtures at ambient conditions. Co-3,5-pyridinedicarboxylate (pydc) CPs was studied here as the example. During the reaction, the organic solvents exhibited three types of modulation effect: anisotropic growth, anisotropic growth/formation of new crystalline phase and the formation of new crystalline phase solely, which was due to the variation of their binding ability with metal cations. The following study revealed that the binding ability was critically affected by their functional groups and molecular size. Moreover, their modulation effect could be finely tuned by changing volume ratios of solvent mixtures. Furthermore, they could be applied for modulating other metal-carboxylates CPs: Co-1,3,5-benzenetricarboxylic (BTC), Zn-pydc and Eu-pydc etc. Additionally, the as-prepared Co-pydc CPs showed a fascinating morphology-dependent antiferromagnetic behavior.

Solvent induced rapid modulation of micro/nano structures of metal carboxylates coordination polymers: mechanism and morphology dependent magnetism

PubMed Central

Liu, Kun; Shen, Zhu-Rui; Li, Yue; Han, Song-De; Hu, Tong-Liang; Zhang, Da-Shuai; Bu, Xian-He; Ruan, Wen-Juan

2014-01-01

Rational modulation of morphology is very important for functional coordination polymers (CPs) micro/nanostructures, and new strategies are still desired to achieve this challenging target. Herein, organic solvents have been established as the capping agents for rapid modulating the growth of metal-carboxylates CPs in organic solvent/water mixtures at ambient conditions. Co-3,5-pyridinedicarboxylate (pydc) CPs was studied here as the example. During the reaction, the organic solvents exhibited three types of modulation effect: anisotropic growth, anisotropic growth/formation of new crystalline phase and the formation of new crystalline phase solely, which was due to the variation of their binding ability with metal cations. The following study revealed that the binding ability was critically affected by their functional groups and molecular size. Moreover, their modulation effect could be finely tuned by changing volume ratios of solvent mixtures. Furthermore, they could be applied for modulating other metal-carboxylates CPs: Co-1,3,5-benzenetricarboxylic (BTC), Zn-pydc and Eu-pydc etc. Additionally, the as-prepared Co-pydc CPs showed a fascinating morphology-dependent antiferromagnetic behavior. PMID:25113225

Molecular neurobiology of Drosophila taste

PubMed Central

Freeman, Erica Gene; Dahanukar, Anupama

2015-01-01

Drosophila is a powerful model in which to study the molecular and cellular basis of taste coding. Flies sense tastants via populations of taste neurons that are activated by compounds of distinct categories. The past few years have borne witness to studies that define the properties of taste neurons, identifying functionally distinct classes of sweet and bitter taste neurons that express unique subsets of gustatory receptor (Gr) genes, as well as water, salt, and pheromone sensing neurons that express members of the pickpocket (ppk) or ionotropic receptor (Ir) families. There has also been significant progress in terms of understanding how tastant information is processed and conveyed to higher brain centers, and modulated by prior dietary experience or starvation. PMID:26102453

Discovery and SAR of muscarinic receptor subtype 1 (M1) allosteric activators from a molecular libraries high throughput screen. Part 1: 2,5-dibenzyl-2H-pyrazolo[4,3-c]quinolin-3(5H)-ones as positive allosteric modulators.

PubMed

Han, Changho; Chatterjee, Arindam; Noetzel, Meredith J; Panarese, Joseph D; Smith, Emery; Chase, Peter; Hodder, Peter; Niswender, Colleen; Conn, P Jeffrey; Lindsley, Craig W; Stauffer, Shaun R

2015-01-15

Results from a 2012 high-throughput screen of the NIH Molecular Libraries Small Molecule Repository (MLSMR) against the human muscarinic receptor subtype 1 (M1) for positive allosteric modulators is reported. A content-rich screen utilizing an intracellular calcium mobilization triple-addition protocol allowed for assessment of all three modes of pharmacology at M1, including agonist, positive allosteric modulator, and antagonist activities in a single screening platform. We disclose a dibenzyl-2H-pyrazolo[4,3-c]quinolin-3(5H)-one hit (DBPQ, CID 915409) and examine N-benzyl pharmacophore/SAR relationships versus previously reported quinolin-3(5H)-ones and isatins, including ML137. SAR and consideration of recently reported crystal structures, homology modeling, and structure-function relationships using point mutations suggests a shared binding mode orientation at the putative common allosteric binding site directed by the pendant N-benzyl substructure. Copyright © 2014 Elsevier Ltd. All rights reserved.

Galois Module Structure of Lubin-Tate Modules

NASA Astrophysics Data System (ADS)

Tomaskovic-Moore, Sebastian

Let L/K be a finite, Galois extension of local or global fields. In the classical setting of additive Galois modules, the ring of integers OL of L is studied as a module for the group ring OKG, where G is the Galois group of L/K. When K is a p-adic field, we also find a structure of OKG module when we replace OL with the group of points in OL of a Lubin-Tate formal group defined over K. For this new Galois module we find an analogue of the normal basis theorem. When K is a proper unramified extension of Qp , we show that some eigenspaces for the Teichmuller character are not free. We also adapt certain cases of E. Noether's result on normal integral bases for tame extensions. Finally, for wild extensions we define a version of Leopoldt's associated order and demonstrate in a specific case that it is strictly larger than the integral group ring.

Pharmacophore-based virtual screening, molecular docking, molecular dynamics simulation, and biological evaluation for the discovery of novel BRD4 inhibitors.

PubMed

Yan, Guoyi; Hou, Manzhou; Luo, Jiang; Pu, Chunlan; Hou, Xueyan; Lan, Suke; Li, Rui

2018-02-01

Bromodomain is a recognition module in the signal transduction of acetylated histone. BRD4, one of the bromodomain members, is emerging as an attractive therapeutic target for several types of cancer. Therefore, in this study, an attempt has been made to screen compounds from an integrated database containing 5.5 million compounds for BRD4 inhibitors using pharmacophore-based virtual screening, molecular docking, and molecular dynamics simulations. As a result, two molecules of twelve hits were found to be active in bioactivity tests. Among the molecules, compound 5 exhibited potent anticancer activity, and the IC 50 values against human cancer cell lines MV4-11, A375, and HeLa were 4.2, 7.1, and 11.6 μm, respectively. After that, colony formation assay, cell cycle, apoptosis analysis, wound-healing migration assay, and Western blotting were carried out to learn the bioactivity of compound 5. © 2017 John Wiley & Sons A/S.

Molecular Basis for Phosphorylation-dependent SUMO Recognition by the DNA Repair Protein RAP80.

PubMed

Anamika; Spyracopoulos, Leo

2016-02-26

Recognition and repair of double-stranded DNA breaks (DSB) involves the targeted recruitment of BRCA tumor suppressors to damage foci through binding of both ubiquitin (Ub) and the Ub-like modifier SUMO. RAP80 is a component of the BRCA1 A complex, and plays a key role in the recruitment process through the binding of Lys(63)-linked poly-Ub chains by tandem Ub interacting motifs (UIM). RAP80 also contains a SUMO interacting motif (SIM) just upstream of the tandem UIMs that has been shown to specifically bind the SUMO-2 isoform. The RAP80 tandem UIMs and SIM function collectively for optimal recruitment of BRCA1 to DSBs, although the molecular basis of this process is not well understood. Using NMR spectroscopy, we demonstrate that the RAP80 SIM binds SUMO-2, and that both specificity and affinity are enhanced through phosphorylation of the canonical CK2 site within the SIM. The affinity increase results from an enhancement of electrostatic interactions between the phosphoserines of RAP80 and the SIM recognition module within SUMO-2. The NMR structure of the SUMO-2·phospho-RAP80 complex reveals that the molecular basis for SUMO-2 specificity is due to isoform-specific sequence differences in electrostatic SIM recognition modules. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Cavity-Enhanced Spectroscopy of Molecular Ions in the Mid-Infrared with Up-Conversion Detection and Brewster-Plate Spoilers

NASA Astrophysics Data System (ADS)

Markus, Charles R.; McCollum, Jefferson E.; Hodges, James Neil; Perry, Adam J.; McCall, Benjamin J.

2017-06-01

Molecular ions are challenging to study with conventional spectroscopic methods. Laboratory discharges produce ions in trace quantities which can be obscured by the abundant neutral molecules present. The technique Noise Immune Cavity Enhanced Optical Heterodyne Velocity Modulation Spectroscopy (NICE-OHVMS) overcomes these challenges by combining the ion-neutral discrimination of velocity modulation spectroscopy with the sensitivity of Noise-Immune Cavity-Enhanced Optical Heterodyne Molecular Spectroscopy (NICE-OHMS), and has been able to determine transition frequencies of molecular ions in the mid-infrared (mid-IR) with sub-MHz uncertainties when calibrated with an optical frequency comb. However, the extent of these studies was limited by the presence of fringes due to parasitic etalons and the speed and noise characteristics of mid-IR detectors. Recently, we have overcome these limitations by implementing up-conversion detection and dithered optics. We performed up-conversion using periodically poled lithium niobate to convert light from the mid-IR to the visible to be within the coverage of sensitive and fast silicon detectors while maintaining our heterodyne and velocity modulation signals. The parasitic etalons were removed by rapidly rotating CaF_2 windows with galvanometers, which is known as a Brewster-plate spoiler, which averaged out the fringes in detection. Together, these improved the sensitivity by more than an order of magnitude and have enabled extended spectroscopic surveys of molecular ions in the mid-IR. J. N. Hodges, A. J. Perry, P. A. Jenkins II, B. M. Siller, and B. J. McCall, J. Chem. Phys. (2013), 139, 164201. C. R. Webster, J. Opt. Soc. Am. B (1985), 2, 1464. C. R. Markus, A. J. Perry, J. N. Hodges, and B. J. McCall, Opt. Express (2017), 25, 3709-3721.

Molecular and Cellular Biology Animations: Development and Impact on Student Learning

PubMed Central

2005-01-01

Educators often struggle when teaching cellular and molecular processes because typically they have only two-dimensional tools to teach something that plays out in four dimensions. Learning research has demonstrated that visualizing processes in three dimensions aids learning, and animations are effective visualization tools for novice learners and aid with long-term memory retention. The World Wide Web Instructional Committee at North Dakota State University has used these research results as an inspiration to develop a suite of high-quality animations of molecular and cellular processes. Currently, these animations represent transcription, translation, bacterial gene expression, messenger RNA (mRNA) processing, mRNA splicing, protein transport into an organelle, the electron transport chain, and the use of a biological gradient to drive adenosine triphosphate synthesis. These animations are integrated with an educational module that consists of First Look and Advanced Look components that feature captioned stills from the animation representing the key steps in the processes at varying levels of complexity. These animation-based educational modules are available via the World Wide Web at http://vcell.ndsu.edu/animations. An in-class research experiment demonstrated that student retention of content material was significantly better when students received a lecture coupled with the animations and then used the animation as an individual study activity. PMID:15917875

Ultrasound neuro-modulation chip: activation of sensory neurons in Caenorhabditis elegans by surface acoustic waves.

PubMed

Zhou, Wei; Wang, Jingjing; Wang, Kaiyue; Huang, Bin; Niu, Lili; Li, Fei; Cai, Feiyan; Chen, Yan; Liu, Xin; Zhang, Xiaoyan; Cheng, Hankui; Kang, Lijun; Meng, Long; Zheng, Hairong

2017-05-16

Ultrasound neuro-modulation has gained increasing attention as a non-invasive method. In this paper, we present an ultrasound neuro-modulation chip, capable of initiating reversal behaviour and activating neurons of C. elegans under the stimulation of a single-shot, short-pulsed ultrasound. About 85.29% ± 6.17% of worms respond to the ultrasound stimulation exhibiting reversal behaviour. Furthermore, the worms can adapt to the ultrasound stimulation with a lower acoustic pulse duration of stimulation. In vivo calcium imaging shows that the activity of ASH, a polymodal sensory neuron in C. elegans, can be directly evoked by the ultrasound stimulation. On the other hand, AFD, a thermal sensitive neuron, cannot be activated by the ultrasound stimulation using the same parameter and the temperature elevation during the stimulation process is relatively small. Consistent with the calcium imaging results, the tax-4 mutants, which are insensitive to temperature increase, do not show a significant difference in avoidance probability compared to the wild type. Therefore, the mechanical effects induced by ultrasound are the main reason for neural and behavioural modulation of C. elegans. With the advantages of confined acoustic energy on the surface, compatible with standard calcium imaging, this neuro-modulation chip could be a powerful tool for revealing the molecular mechanisms of ultrasound neuro-modulation.

Molecular ecological network analyses.

PubMed

Deng, Ye; Jiang, Yi-Huei; Yang, Yunfeng; He, Zhili; Luo, Feng; Zhou, Jizhong

2012-05-30

Understanding the interaction among different species within a community and their responses to environmental changes is a central goal in ecology. However, defining the network structure in a microbial community is very challenging due to their extremely high diversity and as-yet uncultivated status. Although recent advance of metagenomic technologies, such as high throughout sequencing and functional gene arrays, provide revolutionary tools for analyzing microbial community structure, it is still difficult to examine network interactions in a microbial community based on high-throughput metagenomics data. Here, we describe a novel mathematical and bioinformatics framework to construct ecological association networks named molecular ecological networks (MENs) through Random Matrix Theory (RMT)-based methods. Compared to other network construction methods, this approach is remarkable in that the network is automatically defined and robust to noise, thus providing excellent solutions to several common issues associated with high-throughput metagenomics data. We applied it to determine the network structure of microbial communities subjected to long-term experimental warming based on pyrosequencing data of 16 S rRNA genes. We showed that the constructed MENs under both warming and unwarming conditions exhibited topological features of scale free, small world and modularity, which were consistent with previously described molecular ecological networks. Eigengene analysis indicated that the eigengenes represented the module profiles relatively well. In consistency with many other studies, several major environmental traits including temperature and soil pH were found to be important in determining network interactions in the microbial communities examined. To facilitate its application by the scientific community, all these methods and statistical tools have been integrated into a comprehensive Molecular Ecological Network Analysis Pipeline (MENAP), which is open

Magnetic nanoparticles as contrast agents for molecular imaging in medicine

NASA Astrophysics Data System (ADS)

O'Donnell, Matthew

2018-05-01

For over twenty years, superparamagnetic nanoparticles have been developed for a number of medical applications ranging from bioseparations, magnetic drug targeting, hyperthermia and imaging. Recent studies have shown that they can be functionalized for in vivo biological targeting, potentially enabling nanoagents for molecular imaging and site-localized drug delivery. Here we review several imaging technologies developed using functionalized superparamagnetic iron oxide nanoparticles (SPIONs) as targeted molecular agents. Several imaging modalities have exploited the large induced magnetic moment of SPIONs to create local mechanical force. Magnetic force microscopy can probe nanoparticle uptake in single cells. For in vivo applications, magnetomotive modulation of primary images in ultrasound (US), photoacoustics (PA), and optical coherence tomography (OCT) can help identify very small concentrations of nanoagents while simultaneously suppressing intrinsic background signals from tissue.

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

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.

Vertical resonant tunneling transistors with molecular quantum dots for large-scale integration.

PubMed

Hayakawa, Ryoma; Chikyow, Toyohiro; Wakayama, Yutaka

2017-08-10

Quantum molecular devices have a potential for the construction of new data processing architectures that cannot be achieved using current complementary metal-oxide-semiconductor (CMOS) technology. The relevant basic quantum transport properties have been examined by specific methods such as scanning probe and break-junction techniques. However, these methodologies are not compatible with current CMOS applications, and the development of practical molecular devices remains a persistent challenge. Here, we demonstrate a new vertical resonant tunneling transistor for large-scale integration. The transistor channel is comprised of a MOS structure with C 60 molecules as quantum dots, and the structure behaves like a double tunnel junction. Notably, the transistors enabled the observation of stepwise drain currents, which originated from resonant tunneling via the discrete molecular orbitals. Applying side-gate voltages produced depletion layers in Si substrates, to achieve effective modulation of the drain currents and obvious peak shifts in the differential conductance curves. Our device configuration thus provides a promising means of integrating molecular functions into future CMOS applications.

Structural Basis for Prereceptor Modulation of Plant Hormones by GH3 Proteins

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

Westfall, Corey S.; Zubieta, Chloe; Herrmann, Jonathan

Acyl acid amido synthetases of the GH3 family act as critical prereceptor modulators of plant hormone action; however, the molecular basis for their hormone selectivity is unclear. Here, we report the crystal structures of benzoate-specific Arabidopsis thaliana AtGH3.12/PBS3 and jasmonic acid-specific AtGH3.11/JAR1. These structures, combined with biochemical analysis, define features for the conjugation of amino acids to diverse acyl acid substrates and highlight the importance of conformational changes in the carboxyl-terminal domain for catalysis. We also identify residues forming the acyl acid binding site across the GH3 family and residues critical for amino acid recognition. Our results demonstrate how amore » highly adaptable three-dimensional scaffold is used for the evolution of promiscuous activity across an enzyme family for modulation of plant signaling molecules.« less

Discovery and development of small molecule SHIP phosphatase modulators.

PubMed

Viernes, Dennis R; Choi, Lydia B; Kerr, William G; Chisholm, John D

2014-07-01

Inositol phospholipids play an important role in the transfer of signaling information across the cell membrane in eukaryotes. These signals are often governed by the phosphorylation patterns on the inositols, which are mediated by a number of inositol kinases and phosphatases. The src homology 2 (SH2) containing inositol 5-phosphatase (SHIP) plays a central role in these processes, influencing signals delivered through the PI3K/Akt/mTOR pathway. SHIP modulation by small molecules has been implicated as a treatment in a number of human disease states, including cancer, inflammatory diseases, diabetes, atherosclerosis, and Alzheimer's disease. In addition, alteration of SHIP phosphatase activity may provide a means to facilitate bone marrow transplantation and increase blood cell production. This review discusses the cellular signaling pathways and protein-protein interactions that provide the molecular basis for targeting the SHIP enzyme in these disease states. In addition, a comprehensive survey of small molecule modulators of SHIP1 and SHIP2 is provided, with a focus on the structure, potency, selectivity, and solubility properties of these compounds. © 2013 Wiley Periodicals, Inc.

Using MD simulations to calculate how solvents modulate solubility

PubMed Central

Liu, Shuai; Cao, Shannon; Hoang, Kevin; Young, Kayla L.; Paluch, Andrew S.; Mobley, David L.

2016-01-01

Here, our interest is in predicting solubility in general, and we focus particularly on predicting how the solubility of particular solutes is modulated by the solvent environment. Solubility in general is extremely important, both for theoretical reasons – it provides an important probe of the balance between solute-solute and solute-solvent interactions – and for more practical reasons, such as how to control the solubility of a given solute via modulation of its environment, as in process chemistry and separations. Here, we study how the change of solvent affects the solubility of a given compound. That is, we calculate relative solubilities. We use MD simulations to calculate relative solubility and compare our calculated values with experiment as well as with results from several other methods, SMD and UNIFAC, the latter of which is commonly used in chemical engineering design. We find that straightforward solubility calculations based on molecular simulations using a general small-molecule force field outperform SMD and UNIFAC both in terms of accuracy and coverage of the relevant chemical space. PMID:26878198

Graphene optical modulator

NASA Astrophysics Data System (ADS)

Liu, Ming; Yin, Xiaobo; Wang, Feng; Zhang, Xiang

2011-10-01

Data communications have been growing at a speed even faster than Moore's Law, with a 44-fold increase expected within the next 10 years. Data Transfer on such scale would have to recruit optical communication technology and inspire new designs of light sources, modulators, and photodetectors. An ideal optical modulator will require high modulation speed, small device footprint and large operating bandwidth. Silicon modulators based on free carrier plasma dispersion effect and compound semiconductors utilizing direct bandgap transition have seen rapid improvement over the past decade. One of the key limitations for using silicon as modulator material is its weak refractive index change, which limits the footprint of silicon Mach-Zehnder interferometer modulators to millimeters. Other approaches such as silicon microring modulators reduce the operation wavelength range to around 100 pm and are highly sensitive to typical fabrication tolerances and temperature fluctuations. Growing large, high quality wafers of compound semiconductors, and integrating them on silicon or other substrates is expensive, which also restricts their commercialization. In this work, we demonstrate that graphene can be used as the active media for electroabsorption modulators. By tuning the Fermi energy level of the graphene layer, we induced changes in the absorption coefficient of graphene at communication wavelength and achieve a modulation depth above 3 dB. This integrated device also has the potential of working at high speed.

Modulation of apoptosis sensitivity through the interplay with autophagic and proteasomal degradation pathways

PubMed Central

Delgado, M E; Dyck, L; Laussmann, M A; Rehm, M

2014-01-01

Autophagic and proteasomal degradation constitute the major cellular proteolysis pathways. Their physiological and pathophysiological adaptation and perturbation modulates the relative abundance of apoptosis-transducing proteins and thereby can positively or negatively adjust cell death susceptibility. In addition to balancing protein expression amounts, components of the autophagic and proteasomal degradation machineries directly interact with and co-regulate apoptosis signal transduction. The influence of autophagic and proteasomal activity on apoptosis susceptibility is now rapidly gaining more attention as a significant modulator of cell death signalling in the context of human health and disease. Here we present a concise and critical overview of the latest knowledge on the molecular interplay between apoptosis signalling, autophagy and proteasomal protein degradation. We highlight that these three pathways constitute an intricate signalling triangle that can govern and modulate cell fate decisions between death and survival. Owing to rapid research progress in recent years, it is now possible to provide detailed insight into the mechanisms of pathway crosstalk, common signalling nodes and the role of multi-functional proteins in co-regulating both protein degradation and cell death. PMID:24457955

Modulation of learning and memory by cytokines: signaling mechanisms and long term consequences.

PubMed

Donzis, Elissa J; Tronson, Natalie C

2014-11-01

This review describes the role of cytokines and their downstream signaling cascades on the modulation of learning and memory. Immune proteins are required for many key neural processes and dysregulation of these functions by systemic inflammation can result in impairments of memory that persist long after the resolution of inflammation. Recent research has demonstrated that manipulations of individual cytokines can modulate learning, memory, and synaptic plasticity. The many conflicting findings, however, have prevented a clear understanding of the precise role of cytokines in memory. Given the complexity of inflammatory signaling, understanding its modulatory role requires a shift in focus from single cytokines to a network of cytokine interactions and elucidation of the cytokine-dependent intracellular signaling cascades. Finally, we propose that whereas signal transduction and transcription may mediate short-term modulation of memory, long-lasting cellular and molecular mechanisms such as epigenetic modifications and altered neurogenesis may be required for the long lasting impact of inflammation on memory and cognition. Copyright © 2014 Elsevier Inc. All rights reserved.

Geminiviruses and Plant Hosts: A Closer Examination of the Molecular Arms Race.

PubMed

Ramesh, Shunmugiah V; Sahu, Pranav P; Prasad, Manoj; Praveen, Shelly; Pappu, Hanu R

2017-09-15

Geminiviruses are plant-infecting viruses characterized by a single-stranded DNA (ssDNA) genome. Geminivirus-derived proteins are multifunctional and effective regulators in modulating the host cellular processes resulting in successful infection. Virus-host interactions result in changes in host gene expression patterns, reprogram plant signaling controls, disrupt central cellular metabolic pathways, impair plant's defense system, and effectively evade RNA silencing response leading to host susceptibility. This review summarizes what is known about the cellular processes in the continuing tug of war between geminiviruses and their plant hosts at the molecular level. In addition, implications for engineered resistance to geminivirus infection in the context of a greater understanding of the molecular processes are also discussed. Finally, the prospect of employing geminivirus-based vectors in plant genome engineering and the emergence of powerful genome editing tools to confer geminivirus resistance are highlighted to complete the perspective on geminivirus-plant molecular interactions.

An auto-bias control scheme for IQ-modulator with various modulation formats

NASA Astrophysics Data System (ADS)

Zhang, Wenqi; Yuan, Xueguang; Zhang, Yang'an

2016-10-01

We propose and demonstrate an auto-bias control scheme for the IQ-modulator of a flexible optical PSK or QAM or other modulation formats transmitter in this paper. Due to IQ-modulators usually producing higher-order modulation format, these modulation formats involve phase mostly. It is based on that the bias drift will change the operating point and result in varying the output optical phase. This technology has no restrictions on modulation formats, so it has good flexibility. The experimental result show the three biases can be stabilized when the proposed scheme is implemented.

View of docked Apollo 9 Command/Service Module and Lunar Module

NASA Image and Video Library

1969-03-06

AS09-20-3064 (6 March 1969) --- Excellent view of the docked Apollo 9 Command and Service Modules (CSM) and Lunar Module (LM), with Earth in the background, during astronaut David R. Scott's stand-up extravehicular activity (EVA), on the fourth day of the Apollo 9 Earth-orbital mission. Scott, command module pilot, is standing in the open hatch of the Command Module (CM). Astronaut Russell L. Schweickart, lunar module pilot, took this photograph of Scott from the porch of the LM. Inside the LM was astronaut James A. McDivitt, Apollo 9 commander.

Lunar Module 4 moved for mating with Lunar Module Adapter at KSC

NASA Technical Reports Server (NTRS)

1969-01-01

Lunar Module 4 in the Kennedy Space Center's Manned Spacecraft Operations Bldg being moved into position for mating with Spacecraft Lunar Module Adapter (SLA) 13 (17809);Lunar Module 4 being moved for mating with the Spacecraft Lunar Module Adapter in the Kennedy Space Center's (KSC) Manned Spacecraft Operations Building. Lunar module 4 will be flown on the Apollo 10 (Spacecraft 106/Saturn 505) lunar orbit mission (17810).

Ligand-Receptor Interaction Modulates the Energy Landscape of Enzyme-Instructed Self-Assembly of Small Molecules.

PubMed

Haburcak, Richard; Shi, Junfeng; Du, Xuewen; Yuan, Dan; Xu, Bing

2016-11-30

The concurrence of enzymatic reaction and ligand-receptor interactions is common for proteins, but rare for small molecules and has yet to be explored. Here we show that ligand-receptor interaction modulates the morphology of molecular assemblies formed by enzyme-instructed assembly of small molecules. While the absence of ligand-receptor interaction allows enzymatic dephosphorylation of a precursor to generate the hydrogelator that self-assembles to form long nanofibers, the presence of the ligand-receptor interaction biases the pathway to form precipitous aggregates containing short nanofibers. While the hydrogelators self-assemble to form nanofibers or nanoribbons that are unable to bind with the ligand (i.e., vancomycin), the addition of surfactant breaks up the assemblies to restore the ligand-receptor interaction. In addition, an excess amount of the ligands can disrupt the nanofibers and result in the precipitates. As the first example of the use of ligand-receptor interaction to modulate the kinetics of enzymatic self-assembly, this work not only provides a solution to evaluate the interaction between aggregates and target molecules but also offers new insight for understanding the emergent behavior of sophisticated molecular systems having multiple and parallel processes.

Lipid Interaction Sites on Channels, Transporters and Receptors: Recent Insights from Molecular Dynamics Simulations

PubMed Central

Hedger, George; Sansom, Mark S. P.

2017-01-01

Lipid molecules are able to selectively interact with specific sites on integral membrane proteins, and modulate their structure and function. Identification and characterisation of these sites is of importance for our understanding of the molecular basis of membrane protein function and stability, and may facilitate the design of lipid-like drug molecules. Molecular dynamics simulations provide a powerful tool for the identification of these sites, complementing advances in membrane protein structural biology and biophysics. We describe recent notable biomolecular simulation studies which have identified lipid interaction sites on a range of different membrane proteins. The sites identified in these simulation studies agree well with those identified by complementary experimental techniques. This demonstrates the power of the molecular dynamics approach in the prediction and characterization of lipid interaction sites on integral membrane proteins. PMID:26946244

P2X4 Receptor in Silico and Electrophysiological Approaches Reveal Insights of Ivermectin and Zinc Allosteric Modulation

PubMed Central

Latapiat, Verónica; Rodríguez, Felipe E.; Godoy, Francisca; Montenegro, Felipe A.; Barrera, Nelson P.; Huidobro-Toro, Juan P.

2017-01-01

Protein allosteric modulation is a pillar of metabolic regulatory mechanisms; this concept has been extended to include ion channel regulation. P2XRs are ligand-gated channels activated by extracellular ATP, sensitive to trace metals and other chemicals. By combining in silico calculations with electrophysiological recordings, we investigated the molecular basis of P2X4R modulation by Zn(II) and ivermectin, an antiparasite drug currently used in veterinary medicine. To this aim, docking studies, molecular dynamics simulations and non-bonded energy calculations for the P2X4R in the apo and holo states or in the presence of ivermectin and/or Zn(II) were accomplished. Based on the crystallized Danio rerio P2X4R, the rat P2X4R, P2X2R, and P2X7R structures were modeled, to determine ivermectin binding localization. Calculations revealed that its allosteric site is restricted to transmembrane domains of the P2X4R; the role of Y42 and W46 plus S341 and non-polar residues were revealed as essential, and are not present in the homologous P2X2R or P2X7R transmembrane domains. This finding was confirmed by preferential binding conformations and electrophysiological data, revealing P2X4R modulator specificity. Zn(II) acts in the P2X4R extracellular domain neighboring the SS3 bridge. Molecular dynamics in the different P2X4R states revealed allosterism-induced stability. Pore and lateral fenestration measurements of the P2X4R showed conformational changes in the presence of both modulators compatible with a larger opening of the extracellular vestibule. Electrophysiological studies demonstrated additive effects in the ATP-gated currents by joint applications of ivermectin plus Zn(II). The C132A P2X4R mutant was insensitive to Zn(II); but IVM caused a 4.9 ± 0.7-fold increase in the ATP-evoked currents. Likewise, the simultaneous application of both modulators elicited a 7.1 ± 1.7-fold increase in the ATP-gated current. Moreover, the C126A P2X4R mutant evoked similar ATP

Development and performance of pulse-width-modulated static inverter and converter modules

NASA Technical Reports Server (NTRS)

Pittman, P. F.; Gourash, F.; Birchenough, A. G.; Pittman, P. F.; Ravas, R. J.; Hall, W. G.

1971-01-01

Pulse-width-modulated inverter and converter modules are being developed for modular aerospace electrical power systems. The modules, rate 2.5 kilowatts per module and 10-minute - 150-percent overload, operate from 56 volts dc. The converter module provides two output voltages: a nominal link voltage of 200 volts dc when used with the inverter, and 150 volts dc to a load bus when used separately. The inverter module output is 400-hertz, sinusoidal, three-phase, 120/208 volts. Tests of breadboard models with standard parts and integrated circuits show rated power efficiencies of 71.4 and 85.1 percent and voltage regulation of 5 and 3.1 percent for inverter and converter modules, respectively. Sine-wave output distortion is 0.74 percent.

Pharmacological Modulation of Diacylglycerol-Sensitive TRPC3/6/7 Channels

PubMed Central

Harteneck, Christian; Gollasch, Maik

2011-01-01

Members of the classic type of transient receptor potential channels (TRPC) represent important molecules involved in hormonal signal transduction. TRPC3/6/7 channels are of particular interest as they are components of phospholipase C driven signalling pathways. Upon receptor-activation, G-protein-mediated stimulation of phospholipase C results in breakdown of phosphatidylinositides leading to increased intracellular diacylglycerol and inositol-trisphosphate levels. Diacylglycerol activates protein kinase C, but more interestingly diacylglycerol directly activates TRPC2/3/6/7 channels. Molecular cloning, expression and characterization of TRP channels enabled reassignment of traditional inhibitors of receptor-dependent calcium entry such as SKF-96365 and 2-APB as blockers of TRPC3/6/7 and several members of non-classic TRP channels. Furthermore, several enzyme inhibitors have also been identified as TRP channel blockers, such as ACA, a phospholipase A2 inhibitor, and W-7, a calmodulin antagonist. Finally, the naturally occurring secondary plant compound hyperforin has been identified as TRPC6-selective drug, providing an exciting proof of concept that it is possible to generate TRPC-selective channel modulators. The description of Pyr3 as the first TRPC3-selective inhibitor shows that not only nature but also man is able to generate TRP-selective modulators. The review sheds lights on the current knowledge and historical development of pharmacological modulators of TRPC3/6/7. Our analysis indicates that Pyr3 and hyperforin provide promising core structures for the development of new, selective and more potent modulators of TRPC3/6/7 activity. PMID:20932261

Modulators of heterogeneous protein surface water dynamics

NASA Astrophysics Data System (ADS)

Han, Songi

The hydration water that solvates proteins is a major factor in driving or enabling biological events, including protein-protein and protein-ligand interactions. We investigate the role of the protein surface in modulating the hydration water fluctuations on both the picosecond and nanosecond timescale with an emerging experimental NMR technique known as Overhauser Dynamic Nuclear Polarization (ODNP). We carry out site-specific ODNP measurements of the hydration water fluctuations along the surface of Chemotaxis Y (CheY), and correlate the measured fluctuations to hydropathic and topological properties of the CheY surface as derived from molecular dynamics (MD) simulation. Furthermore, we compare hydration water fluctuations measured on the CheY surface to that of other globular proteins, as well as intrinsically disordered proteins, peptides, and liposome surfaces to systematically test characteristic effects of the biomolecular surface on the hydration water dynamics. Our results suggest that the labile (ps) hydration water fluctuations are modulated by the chemical nature of the surface, while the bound (ns) water fluctuations are present on surfaces that feature a rough topology and chemical heterogeneity such as the surface of a folded and structured protein. In collaboration with: Ryan Barnes, Dept of Chemistry and Biochemistry, University of California Santa Barbara

Diverse feather shape evolution enabled by coupling anisotropic signalling modules with self-organizing branching programme

PubMed Central

Li, Ang; Figueroa, Seth; Jiang, Ting-Xin; Wu, Ping; Widelitz, Randall; Nie, Qing; Chuong, Cheng-Ming

2017-01-01

Adaptation of feathered dinosaurs and Mesozoic birds to new ecological niches was potentiated by rapid diversification of feather vane shapes. The molecular mechanism driving this spectacular process remains unclear. Here, through morphology analysis, transcriptome profiling, functional perturbations and mathematical simulations, we find that mesenchyme-derived GDF10 and GREM1 are major controllers for the topologies of rachidial and barb generative zones (setting vane boundaries), respectively, by tuning the periodic-branching programme of epithelial progenitors. Their interactions with the anterior–posterior WNT gradient establish the bilateral-symmetric vane configuration. Additionally, combinatory effects of CYP26B1, CRABP1 and RALDH3 establish dynamic retinoic acid (RA) landscapes in feather mesenchyme, which modulate GREM1 expression and epithelial cell shapes. Incremental changes of RA gradient slopes establish a continuum of asymmetric flight feathers along the wing, while switch-like modulation of RA signalling confers distinct vane shapes between feather tracts. Therefore, the co-option of anisotropic signalling modules introduced new dimensions of feather shape diversification. PMID:28106042

Modulation of inhibitory activity markers by intermittent theta-burst stimulation in rat cortex is NMDA-receptor dependent.

PubMed

Labedi, Adnan; Benali, Alia; Mix, Annika; Neubacher, Ute; Funke, Klaus

2014-01-01

Intermittent theta-burst stimulation (iTBS) applied via transcranial magnetic stimulation has been shown to increase cortical excitability in humans. In the rat brain it strongly reduced the number of neurons expressing the 67-kD isoform of the GABA-synthesizing enzyme glutamic acid decarboxylase (GAD67) and those expressing the calcium-binding proteins parvalbumin (PV) and calbindin (CB), specific markers of fast-spiking (FS) and non-FS inhibitory interneurons, respectively, an indication of modified cortical inhibition. Since iTBS effects in humans have been shown to be NMDA receptor sensitive, we wondered whether the iTBS-induced changes in the molecular phenotype of interneurons may be also sensitive to glutamatergic synaptic transmission mediated by NMDA receptors. In a sham-controlled fashion, five iTBS-blocks of 600 stimuli were applied to rats either lightly anesthetized by only urethane or by an additional low (subnarcotic) or high dose of the NMDA receptor antagonist ketamine before immunohistochemical analysis. iTBS reduced the number of neurons expressing GAD67, PV and CB. Except for CB, a low dose of ketamine partially prevented these effects while a higher dose almost completely abolished the iTBS effects. Our findings indicate that iTBS modulates the molecular, and likely also the electric, activity of cortical inhibitory interneurons and that the modulation of FS-type but less that of non-FS-type neurons is mediated by NMDA receptors. A combination of iTBS with pharmacological interventions affecting distinct receptor subtypes may thus offer options to enhance its selectivity in modulating the activity of distinct cell types and preventing others from being modulated. Copyright © 2014 Elsevier Inc. All rights reserved.

Seeking structural specificity: direct modulation of pentameric ligand-gated ion channels by alcohols and general anesthetics.

PubMed

Howard, Rebecca J; Trudell, James R; Harris, R Adron

2014-01-01

Alcohols and other anesthetic agents dramatically alter neurologic function in a wide range of organisms, yet their molecular sites of action remain poorly characterized. Pentameric ligand-gated ion channels, long implicated in important direct effects of alcohol and anesthetic binding, have recently been illuminated in renewed detail thanks to the determination of atomic-resolution structures of several family members from lower organisms. These structures provide valuable models for understanding and developing anesthetic agents and for allosteric modulation in general. This review surveys progress in this field from function to structure and back again, outlining early evidence for relevant modulation of pentameric ligand-gated ion channels and the development of early structural models for ion channel function and modulation. We highlight insights and challenges provided by recent crystal structures and resulting simulations, as well as opportunities for translation of these newly detailed models back to behavior and therapy.

Seeking Structural Specificity: Direct Modulation of Pentameric Ligand-Gated Ion Channels by Alcohols and General Anesthetics

PubMed Central

Trudell, James R.; Harris, R. Adron

2014-01-01

Alcohols and other anesthetic agents dramatically alter neurologic function in a wide range of organisms, yet their molecular sites of action remain poorly characterized. Pentameric ligand-gated ion channels, long implicated in important direct effects of alcohol and anesthetic binding, have recently been illuminated in renewed detail thanks to the determination of atomic-resolution structures of several family members from lower organisms. These structures provide valuable models for understanding and developing anesthetic agents and for allosteric modulation in general. This review surveys progress in this field from function to structure and back again, outlining early evidence for relevant modulation of pentameric ligand-gated ion channels and the development of early structural models for ion channel function and modulation. We highlight insights and challenges provided by recent crystal structures and resulting simulations, as well as opportunities for translation of these newly detailed models back to behavior and therapy. PMID:24515646

PIM1: A Molecular Target to Modulate Cellular Resistance to Therapy in Prostate Cancer

DTIC Science & Technology

2008-10-31

2007) C«t Pr. T«K:J1 r. 587-605 CaUtr«M, F. I . |200S> Oil . te- Tx\\u< 35.443-582 I ..-:tiatr.-ir, C.Iixo;, X. Cfitniti t,B<nor V..Dcrtgovsu, V,Chat...control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. I . REPORT DATE (DD-MM-YYYY) 31-10-2008 2. REPORT TYPE Annual 3. DATES COVERED...reporting period a number of studies were undertaken to characterize Fig. 4. Modulation of docetaxel cell kill by enforced expression of pim-1 cDNAs. 1 i

Modulation of prion polymerization and toxicity by rationally designed peptidomimetics.

PubMed

Srivastava, Ankit; Sharma, Sakshi; Sadanandan, Sandhya; Gupta, Sakshi; Singh, Jasdeep; Gupta, Sarika; Haridas, V; Kundu, Bishwajit

2017-01-01

Misfolding and aggregation of cellular prion protein is associated with a large array of neurological disorders commonly called the transmissible spongiform encephalopathies. Designing inhibitors against prions has remained a daunting task owing to limited information about mechanism(s) of their pathogenic self-assembly. Here, we explore the anti-prion properties of a combinatorial library of bispidine-based peptidomimetics (BPMs) that conjugate amino acids with hydrophobic and aromatic side chains. Keeping the bispidine unit unaltered, a series of structurally diverse BPMs were synthesized and tested for their prion-modulating properties. Administration of Leu- and Trp-BPMs delayed and completely inhibited the amyloidogenic conversion of human prion protein (HuPrP), respectively. We found that each BPM induced the HuPrP to form unique oligomeric nanostructures differing in their biophysical properties, cellular toxicities and response to conformation-specific antibodies. While Leu-BPMs were found to stabilize the oligomers, Trp-BPMs effected transient oligomerization, resulting in the formation of non-toxic, non-fibrillar aggregates. Yet another aromatic residue, Phe, however, accelerated the aggregation process in HuPrP. Molecular insights obtained through MD (molecular dynamics) simulations suggested that each BPM differently engages a conserved Tyr 169 residue at the α2-β2 loop of HuPrP and affects the stability of α2 and α3 helices. Our results demonstrate that this new class of molecules having chemical scaffolds conjugating hydrophobic/aromatic residues could effectively modulate prion aggregation and toxicity. © 2017 The Author(s); published by Portland Press Limited on behalf of the Biochemical Society.

Versatile Molecular Functionalization for Inhibiting Concentration Quenching of Thermally Activated Delayed Fluorescence.

PubMed

Lee, Jiyoung; Aizawa, Naoya; Numata, Masaki; Adachi, Chihaya; Yasuda, Takuma

2017-01-01

Concentration quenching of thermally activated delayed fluorescence is found to be dominated by electron-exchange interactions, as described by the Dexter energy-transfer model. Owing to the short-range nature of the electron-exchange interactions, even a small modulation in the molecular geometric structure drastically affects the concentration-quenching, leading to enhanced solid-state photoluminescence and electroluminescence quantum efficiencies. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Electro-optic modulator with ultra-low residual amplitude modulation for frequency modulation and laser stabilization.

PubMed

Tai, Zhaoyang; Yan, Lulu; Zhang, Yanyan; Zhang, Xiaofei; Guo, Wenge; Zhang, Shougang; Jiang, Haifeng

2016-12-01

The reduction of the residual amplitude modulation (RAM) induced by electro-optic modulation is essential for many applications of frequency modulation spectroscopy requiring a lower system noise floor. Here, we demonstrate a simple passive approach employing an electro-optic modulator (EOM) cut at Brewster's angle. The proposed EOM exhibits a RAM of a few parts per million, which is comparable with that achieved by a common EOM under critical active temperature and bias voltage controls. The frequency instability of a 10 cm cavity-stabilized laser induced by the RAM effect of the proposed EOM is below 3×10^-17 for integration times from 1 to 1000 s, and below 4×10^-16 for comprehensive noise contributions for integration times from 1 to 100 s.

Weakly Coretractable Modules

NASA Astrophysics Data System (ADS)

Hadi, Inaam M. A.; Al-aeashi, Shukur N.

2018-05-01

If R is a ring with identity and M is a unitary right R-module. Here we introduce the class of weakly coretractable module. Some basic properties are investigated and some relationships between these modules and other related one are introduced.

Modulation of low-voltage-activated T-type Ca²⁺ channels.

PubMed

Zhang, Yuan; Jiang, Xinghong; Snutch, Terrance P; Tao, Jin

2013-07-01

Low-voltage-activated T-type Ca²⁺ channels contribute to a wide variety of physiological functions, most predominantly in the nervous, cardiovascular and endocrine systems. Studies have documented the roles of T-type channels in sleep, neuropathic pain, absence epilepsy, cell proliferation and cardiovascular function. Importantly, novel aspects of the modulation of T-type channels have been identified over the last few years, providing new insights into their physiological and pathophysiological roles. Although there is substantial literature regarding modulation of native T-type channels, the underlying molecular mechanisms have only recently begun to be addressed. This review focuses on recent evidence that the Ca(v)3 subunits of T-type channels, Ca(v)3.1, Ca(v)3.2 and Ca(v)3.3, are differentially modulated by a multitude of endogenous ligands including anandamide, monocyte chemoattractant protein-1, endostatin, and redox and oxidizing agents. The review also provides an overview of recent knowledge gained concerning downstream pathways involving G-protein-coupled receptors. This article is part of a Special Issue entitled: Calcium channels. Copyright © 2012 Elsevier B.V. All rights reserved.

Network-Based Disease Module Discovery by a Novel Seed Connector Algorithm with Pathobiological Implications.

PubMed

Wang, Rui-Sheng; Loscalzo, Joseph

2018-05-20

Understanding the genetic basis of complex diseases is challenging. Prior work shows that disease-related proteins do not typically function in isolation. Rather, they often interact with each other to form a network module that underlies dysfunctional mechanistic pathways. Identifying such disease modules will provide insights into a systems-level understanding of molecular mechanisms of diseases. Owing to the incompleteness of our knowledge of disease proteins and limited information on the biological mediators of pathobiological processes, the key proteins (seed proteins) for many diseases appear scattered over the human protein-protein interactome and form a few small branches, rather than coherent network modules. In this paper, we develop a network-based algorithm, called the Seed Connector algorithm (SCA), to pinpoint disease modules by adding as few additional linking proteins (seed connectors) to the seed protein pool as possible. Such seed connectors are hidden disease module elements that are critical for interpreting the functional context of disease proteins. The SCA aims to connect seed disease proteins so that disease mechanisms and pathways can be decoded based on predicted coherent network modules. We validate the algorithm using a large corpus of 70 complex diseases and binding targets of over 200 drugs, and demonstrate the biological relevance of the seed connectors. Lastly, as a specific proof of concept, we apply the SCA to a set of seed proteins for coronary artery disease derived from a meta-analysis of large-scale genome-wide association studies and obtain a coronary artery disease module enriched with important disease-related signaling pathways and drug targets not previously recognized. Copyright © 2018 Elsevier Ltd. All rights reserved.

Synthesis, biological evaluation and molecular modelling of diversely functionalized heterocyclic derivatives as inhibitors of acetylcholinesterase/butyrylcholinesterase and modulators of Ca2+ channels and nicotinic receptors.

PubMed

Marco, José L; de los Ríos, Cristóbal; García, Antonio G; Villarroya, Mercedes; Carreiras, M Carmo; Martins, Carla; Eleutério, Ana; Morreale, Antonio; Orozco, M; Luque, F Javier

2004-05-01

The synthesis and the biological activity of compounds 5-40 as inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), as well as modulators of voltage-dependent Ca(2+) channels and nicotinic receptors, are described. These molecules are tacrine analogues, which have been prepared from polyfunctionalized 6-amino-5-cyano-4H-pyrans, 6-amino-5-cyano-pyridines and 5-amino-2-aryl-3-cyano-1,3-oxazoles via Friedländer reaction with selected cycloalkanones. These compounds are moderate acetylcholinesterase and butyrylcholinesterase inhibitors, the BuChE/AChE selectivity of the most active molecules ranges from 10.0 (compound 29) to 76.9 (compound 16). Interestingly, the 'oxazolo-tacrine' derivatives are devoid of any activity. All compounds showed an important inhibitory effect on the nicotinic acetylcholine receptor. Most of them also blocked L-type Ca(2+) channels, and three of them, 64, 19 and 67, the non-L type of Ca(2+) channels. Molecular modelling studies suggest that these compounds might bind at the peripheral binding site of AChE, which opens the possibility to design inhibitors able to bind at both, the catalytic and peripheral binding sites of the enzyme.

Molecular architecture and function of the SEA complex, a modulator of the TORC1 pathway.

PubMed

Algret, Romain; Fernandez-Martinez, Javier; Shi, Yi; Kim, Seung Joong; Pellarin, Riccardo; Cimermancic, Peter; Cochet, Emilie; Sali, Andrej; Chait, Brian T; Rout, Michael P; Dokudovskaya, Svetlana

2014-11-01

The TORC1 signaling pathway plays a major role in the control of cell growth and response to stress. Here we demonstrate that the SEA complex physically interacts with TORC1 and is an important regulator of its activity. During nitrogen starvation, deletions of SEA complex components lead to Tor1 kinase delocalization, defects in autophagy, and vacuolar fragmentation. TORC1 inactivation, via nitrogen deprivation or rapamycin treatment, changes cellular levels of SEA complex members. We used affinity purification and chemical cross-linking to generate the data for an integrative structure modeling approach, which produced a well-defined molecular architecture of the SEA complex and showed that the SEA complex comprises two regions that are structurally and functionally distinct. The SEA complex emerges as a platform that can coordinate both structural and enzymatic activities necessary for the effective functioning of the TORC1 pathway. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Simulating the control of molecular reactions via modulated light fields: from gas phase to solution

NASA Astrophysics Data System (ADS)

Thallmair, Sebastian; Keefer, Daniel; Rott, Florian; de Vivie-Riedle, Regina

2017-04-01

Over the past few years quantum control has proven to be very successful in steering molecular processes. By combining theory with experiment, even highly complex control aims were realized in the gas phase. In this topical review, we illustrate the past achievements on several examples in the molecular context. The next step for the quantum control of chemical processes is to translate the fruitful interplay between theory and experiment to the condensed phase and thus to the regime where chemical synthesis can be supported. On the theory side, increased efforts to include solvent effects in quantum control simulations were made recently. We discuss two major concepts, namely an implicit description of the environment via the density matrix algorithm and an explicit inclusion of solvent molecules. By application to chemical reactions, both concepts conclude that despite environmental perturbations leading to more complex control tasks, efficient quantum control in the condensed phase is still feasible.

Enhanced modulation rates via field modulation in spin torque nano-oscillators

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

Purbawati, A.; Garcia-Sanchez, F.; Buda-Prejbeanu, L. D.

Spin Transfer Nano-Oscillators (STNOs) are promising candidates for telecommunications applications due to their frequency tuning capabilities via either a dc current or an applied field. This frequency tuning is of interest for Frequency Shift Keying concepts to be used in wireless communication schemes or in read head applications. For these technological applications, one important parameter is the characterization of the maximum achievable rate at which an STNO can respond to a modulating signal, such as current or field. Previous studies of in-plane magnetized STNOs on frequency modulation via an rf current revealed that the maximum achievable rate is limited bymore » the amplitude relaxation rate Γ{sub p}, which gives the time scale over which amplitude fluctuations are damped out. This might be a limitation for applications. Here, we demonstrate via numerical simulation that application of an additional rf field is an alternative way for modulation of the in-plane magnetized STNO configuration, which has the advantage that frequency modulation is not limited by the amplitude relaxation rate, so that higher modulation rates above GHz are achievable. This occurs when the modulating rf field is oriented along the easy axis (longitudinal rf field). Tilting the direction of the modulating rf field in-plane and perpendicularly with respect to the easy axis (transverse rf field), the modulation is again limited by the amplitude relaxation rate similar to the response observed in current modulation.« less

Cholecystokinin: A multi-functional molecular switch of neuronal circuits

PubMed Central

Lee, Soo Yeun; Soltesz, Ivan

2010-01-01

Cholecystokinin (CCK), a peptide originally discovered in the gastrointestinal tract, is one of the most the abundant and widely distributed neuropeptides in the brain. In spite of its abundance, recent data indicate that that CCK modulates intrinsic neuronal excitability and synaptic transmission in a surprisingly cell-type specific manner, acting as a key molecular switch to regulate the functional output of neuronal circuits. The central importance of CCK in neuronal networks is also reflected in its involvement in a variety of neuropsychiatric and neurological disorders including panic attacks and epilepsy. PMID:21154912

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.

Boolean and fuzzy logic implemented at the molecular level

NASA Astrophysics Data System (ADS)

Gentili, Pier Luigi

2007-07-01

In this work, it is shown how to implement both hard and soft computing by means of two structurally related heterocyclic compounds: flindersine (FL) and 6(5H)-phenanthridinone (PH). Since FL and PH have a carbonyl group in their molecular skeletons, they exhibit Proximity Effects in their photophysics. In other words, they have an emission power that can be modulated through external inputs such as temperature ( T) and hydrogen-bonding donation (HBD) ability of solvents. This phenomenology can be exploited to implement both crisp and fuzzy logic. Fuzzy Logic Systems (FLSs) wherein the antecedents of the rules are connected through the AND operator, are built by both the Mamdani's and Sugeno's models. Finally, they are adopted as approximators of the proximity effect phenomenon and tested for their prediction capabilities. Moreover, FL as photochromic compound is also a multiply configurable crisp logic molecular element.

Single-molecular diodes based on opioid derivatives.

PubMed

Siqueira, M R S; Corrêa, S M; Gester, R M; Del Nero, J; Neto, A M J C

2015-12-01

We propose an efficient single-molecule rectifier based on a derivative of opioid. Electron transport properties are investigated within the non-equilibrium Green's function formalism combined with density functional theory. The analysis of the current-voltage characteristics indicates obvious diode-like behavior. While heroin presents rectification coefficient R>1, indicating preferential electronic current from electron-donating to electron-withdrawing, 3 and 6-acetylmorphine and morphine exhibit contrary behavior, R<1. Our calculations indicate that the simple inclusion of acetyl groups modulate a range of devices, which varies from simple rectifying to resonant-tunneling diodes. In particular, the rectification rations for heroin diodes show microampere electron current with a maximum of rectification (R=9.1) at very low bias voltage of ∼0.6 V and (R=14.3)∼1.8 V with resistance varying between 0.4 and 1.5 M Ω. Once most of the current single-molecule diodes usually rectifies in nanoampere, are not stable over 1.0 V and present electrical resistance around 10 M. Molecular devices based on opioid derivatives are promising in molecular electronics.

Phenotypic modulation of corpus cavernosum smooth muscle cells in a rat model of cavernous neurectomy.

PubMed

Yang, Fan; Zhao, Jian F; Shou, Qi Y; Huang, Xiao J; Chen, Gang; Yang, Ke B; Zhang, Shi G; Lv, Bo D; Fu, Hui Y

2014-01-01

Patients undergoing radical prostatectomy (RP) are at high risk for erectile dysfunction (ED) due to potential cavernous nerve (CN) damage during surgery. Penile hypoxia after RP is thought to significantly contribute to ED pathogenesis. We previously showed that corpora cavernosum smooth muscle cells (CCSMCs) undergo phenotypic modulation under hypoxic conditions in vitro. Here, we studied such changes in an in vivo post-RP ED model by investigating CCSMCs in bilateral cavernous neurectomy (BCN) rats. Sprague-Dawley rats underwent sham (n = 12) or BCN (n = 12) surgery. After 12 weeks, they were injected with apomorphine to determine erectile function. The penile tissues were harvested and assessed for fibrosis using Masson trichrome staining and for molecular markers of phenotypic modulation using immunohistochemistry and western blotting. CCSMC morphological structure was evaluated by hematoxylin-eosin (H&E) staining and transmission electron microscopy (TEM). Erectile function was significantly lower in BCN rats than in sham rats. BCN increased hypoxia-inducible factor-1α and collagen protein expression in corpora cavernous tissue. H&E staining and TEM showed that CCSMCs in BCN rats underwent hypertrophy and showed rough endoplasmic reticulum formation. The expression of CCSMC phenotypic markers, such as smooth muscle α-actin, smooth muscle myosin heavy chain, and desmin, was markedly lower, whereas vimentin protein expression was significantly higher in BCN rats than in control rats. CCSMCs undergo phenotype modulation in rats with cavernous neurectomy. The results have unveiled physiological transformations that occur at the cellular and molecular levels and have helped characterize CN injury-induced ED.

Phytochemicals modulate carcinogenic signaling pathways in breast and hormone-related cancers

PubMed Central

Cojocneanu Petric, Roxana; Braicu, Cornelia; Raduly, Lajos; Zanoaga, Oana; Dragos, Nicolae; Monroig, Paloma; Dumitrascu, Dan; Berindan-Neagoe, Ioana

2015-01-01

Over the years, nutrition and environmental factors have been demonstrated to influence human health, specifically cancer. Owing to the fact that cancer is a leading cause of death worldwide, efforts are being made to elucidate molecular mechanisms that trigger or delay carcinogenesis. Phytochemicals, in particular, have been shown to modulate oncogenic processes through their antioxidant and anti-inflammatory activities and their ability to mimic the chemical structure and activity of hormones. These compounds can act not only by influencing oncogenic proteins, but also by modulating noncoding RNAs such as microRNAs and long noncoding RNAs. Although we are only beginning to understand the complete effects of many natural compounds, such as phytochemicals, researchers are motivated to combine these agents with traditional, chemo-based, or hormone-based therapies to fight against cancer. Since ongoing studies continue to prove effective, herein we exalt the importance of improving dietary choices as a chemo-preventive strategy. PMID:26273208

Rab7-a novel redox target that modulates inflammatory pain processing.

PubMed

Kallenborn-Gerhardt, Wiebke; Möser, Christine V; Lorenz, Jana E; Steger, Mirco; Heidler, Juliana; Scheving, Reynir; Petersen, Jonas; Kennel, Lea; Flauaus, Cathrin; Lu, Ruirui; Edinger, Aimee L; Tegeder, Irmgard; Geisslinger, Gerd; Heide, Heinrich; Wittig, Ilka; Schmidtko, Achim

2017-07-01

Chronic pain is accompanied by production of reactive oxygen species (ROS) in various cells that are important for nociceptive processing. Recent data indicate that ROS can trigger specific redox-dependent signaling processes, but the molecular targets of ROS signaling in the nociceptive system remain largely elusive. Here, we performed a proteome screen for pain-dependent redox regulation using an OxICAT approach, thereby identifying the small GTPase Rab7 as a redox-modified target during inflammatory pain in mice. Prevention of Rab7 oxidation by replacement of the redox-sensing thiols modulates its GTPase activity. Immunofluorescence studies revealed Rab7 expression to be enriched in central terminals of sensory neurons. Knockout mice lacking Rab7 in sensory neurons showed normal responses to noxious thermal and mechanical stimuli; however, their pain behavior during inflammatory pain and in response to ROS donors was reduced. The data suggest that redox-dependent changes in Rab7 activity modulate inflammatory pain sensitivity.

Adaptive Detection and ISI Mitigation for Mobile Molecular Communication.

PubMed

Chang, Ge; Lin, Lin; Yan, Hao

2018-03-01

Current studies on modulation and detection schemes in molecular communication mainly focus on the scenarios with static transmitters and receivers. However, mobile molecular communication is needed in many envisioned applications, such as target tracking and drug delivery. Until now, investigations about mobile molecular communication have been limited. In this paper, a static transmitter and a mobile bacterium-based receiver performing random walk are considered. In this mobile scenario, the channel impulse response changes due to the dynamic change of the distance between the transmitter and the receiver. Detection schemes based on fixed distance fail in signal detection in such a scenario. Furthermore, the intersymbol interference (ISI) effect becomes more complex due to the dynamic character of the signal which makes the estimation and mitigation of the ISI even more difficult. In this paper, an adaptive ISI mitigation method and two adaptive detection schemes are proposed for this mobile scenario. In the proposed scheme, adaptive ISI mitigation, estimation of dynamic distance, and the corresponding impulse response reconstruction are performed in each symbol interval. Based on the dynamic channel impulse response in each interval, two adaptive detection schemes, concentration-based adaptive threshold detection and peak-time-based adaptive detection, are proposed for signal detection. Simulations demonstrate that the ISI effect is significantly reduced and the adaptive detection schemes are reliable and robust for mobile molecular communication.

Epithelial Folding Driven by Apical or Basal-Lateral Modulation: Geometric Features, Mechanical Inference, and Boundary Effects.

PubMed

Wen, Fu-Lai; Wang, Yu-Chiun; Shibata, Tatsuo

2017-06-20

During embryonic development, epithelial sheets fold into complex structures required for tissue and organ functions. Although substantial efforts have been devoted to identifying molecular mechanisms underlying epithelial folding, far less is understood about how forces deform individual cells to sculpt the overall sheet morphology. Here we describe a simple and general theoretical model for the autonomous folding of monolayered epithelial sheets. We show that active modulation of intracellular mechanics along the basal-lateral as well as the apical surfaces is capable of inducing fold formation in the absence of buckling instability. Apical modulation sculpts epithelia into shallow and V-shaped folds, whereas basal-lateral modulation generates deep and U-shaped folds. These characteristic tissue shapes remain unchanged when subject to mechanical perturbations from the surroundings, illustrating that the autonomous folding is robust against environmental variabilities. At the cellular scale, how cells change shape depends on their initial aspect ratios and the modulation mechanisms. Such cell deformation characteristics are verified via experimental measurements for a canonical folding process driven by apical modulation, indicating that our theory could be used to infer the underlying folding mechanisms based on experimental data. The mechanical principles revealed in our model could potentially guide future studies on epithelial folding in diverse systems. Copyright © 2017. Published by Elsevier Inc.

The Transcriptional Complex Between the BCL2 i-Motif and hnRNP LL Is a Molecular Switch for Control of Gene Expression That Can Be Modulated by Small Molecules

PubMed Central

2015-01-01

In a companion paper (DOI: 10.021/ja410934b) we demonstrate that the C-rich strand of the cis-regulatory element in the BCL2 promoter element is highly dynamic in nature and can form either an i-motif or a flexible hairpin. Under physiological conditions these two secondary DNA structures are found in an equilibrium mixture, which can be shifted by the addition of small molecules that trap out either the i-motif (IMC-48) or the flexible hairpin (IMC-76). In cellular experiments we demonstrate that the addition of these molecules has opposite effects on BCL2 gene expression and furthermore that these effects are antagonistic. In this contribution we have identified a transcriptional factor that recognizes and binds to the BCL2 i-motif to activate transcription. The molecular basis for the recognition of the i-motif by hnRNP LL is determined, and we demonstrate that the protein unfolds the i-motif structure to form a stable single-stranded complex. In subsequent experiments we show that IMC-48 and IMC-76 have opposite, antagonistic effects on the formation of the hnRNP LL–i-motif complex as well as on the transcription factor occupancy at the BCL2 promoter. For the first time we propose that the i-motif acts as a molecular switch that controls gene expression and that small molecules that target the dynamic equilibrium of the i-motif and the flexible hairpin can differentially modulate gene expression. PMID:24559432

Modulated nematic structures induced by chirality and steric polarization

NASA Astrophysics Data System (ADS)

Longa, Lech; PajÄ k, Grzegorz

2016-04-01

What kind of one-dimensional modulated nematic structures (ODMNS) can form nonchiral and chiral bent-core and dimeric materials? Here, using the Landau-de Gennes theory of nematics, extended to account for molecular steric polarization, we study a possibility of formation of ODMNS, both in nonchiral and intrinsically chiral liquid crystalline materials. Besides nematic and cholesteric phases, we find four bulk ODMNS for nonchiral materials, two of which, to the best of our knowledge, have not been reported so far. These two structures are longitudinal (NLP) and transverse (NTP) periodic waves where the polarization field being periodic in one dimension stays parallel and perpendicular, respectively, to the wave vector. The other two phases are the twist-bend nematic phase (NTB) and the splay-bend nematic phase (NSB), but their fine structure appears more complex than that considered so far. The presence of molecular chirality converts nonchiral NTP and NSB into new NTB phases. Surprisingly, the nonchiral NLP phase can stay stable even in the presence of intrinsic chirality.

Molecular pathophysiology and pharmacology of the voltage-sensing module of neuronal ion channels

PubMed Central

Miceli, Francesco; Soldovieri, Maria Virginia; Ambrosino, Paolo; De Maria, Michela; Manocchio, Laura; Medoro, Alessandro; Taglialatela, Maurizio

2015-01-01

Voltage-gated ion channels (VGICs) are membrane proteins that switch from a closed to open state in response to changes in membrane potential, thus enabling ion fluxes across the cell membranes. The mechanism that regulate the structural rearrangements occurring in VGICs in response to changes in membrane potential still remains one of the most challenging topic of modern biophysics. Na+, Ca2+ and K+ voltage-gated channels are structurally formed by the assembly of four similar domains, each comprising six transmembrane segments. Each domain can be divided into two main regions: the Pore Module (PM) and the Voltage-Sensing Module (VSM). The PM (helices S5 and S6 and intervening linker) is responsible for gate opening and ion selectivity; by contrast, the VSM, comprising the first four transmembrane helices (S1–S4), undergoes the first conformational changes in response to membrane voltage variations. In particular, the S4 segment of each domain, which contains several positively charged residues interspersed with hydrophobic amino acids, is located within the membrane electric field and plays an essential role in voltage sensing. In neurons, specific gating properties of each channel subtype underlie a variety of biological events, ranging from the generation and propagation of electrical impulses, to the secretion of neurotransmitters and to the regulation of gene expression. Given the important functional role played by the VSM in neuronal VGICs, it is not surprising that various VSM mutations affecting the gating process of these channels are responsible for human diseases, and that compounds acting on the VSM have emerged as important investigational tools with great therapeutic potential. In the present review we will briefly describe the most recent discoveries concerning how the VSM exerts its function, how genetically inherited diseases caused by mutations occurring in the VSM affects gating in VGICs, and how several classes of drugs and toxins

Molecular design toward highly efficient photovoltaic polymers based on two-dimensional conjugated benzodithiophene.

PubMed

Ye, Long; Zhang, Shaoqing; Huo, Lijun; Zhang, Maojie; Hou, Jianhui

2014-05-20

As researchers continue to develop new organic materials for solar cells, benzo[1,2-b:4,5-b']dithiophene (BDT)-based polymers have come to the fore. To improve the photovoltaic properties of BDT-based polymers, researchers have developed and applied various strategies leading to the successful molecular design of highly efficient photovoltaic polymers. Novel polymer materials composed of two-dimensional conjugated BDT (2D-conjugated BDT) have boosted the power conversion efficiency of polymer solar cells (PSCs) to levels that exceed 9%. In this Account, we summarize recent progress related to the design and synthesis of 2D-conjugated BDT-based polymers and discuss their applications in highly efficient photovoltaic devices. We introduce the basic considerations for the construction of 2D-conjugated BDT-based polymers and systematic molecular design guidelines. For example, simply modifying an alkoxyl-substituted BDT to form an alkylthienyl-substituted BDT can improve the polymer hole mobilities substantially with little effect on their molecular energy level. Secondly, the addition of a variety of chemical moieties to the polymer can produce a 2D-conjugated BDT unit with more functions. For example, the introduction of a conjugated side chain with electron deficient groups (such as para-alkyl-phenyl, meta-alkoxyl-phenyl, and 2-alkyl-3-fluoro-thienyl) allowed us to modulate the molecular energy levels of 2D-conjugated BDT-based polymers. Through the rational design of BDT analogues such as dithienobenzodithiophene (DTBDT) or the insertion of larger π bridges, we can tune the backbone conformations of these polymers and modulate their photovoltaic properties. We also discuss the influence of 2D-conjugated BDT on polymer morphology and the blends of these polymers with phenyl-C61 (or C71)-butyric acid methyl ester (PCBM). Finally, we summarize the various applications of the 2D-conjugated BDT-based polymers in highly efficient PSC devices. Overall, this Account

Chemodiversity and molecular plasticity: recognition processes as explored by property spaces.

PubMed

Vistoli, Giulio; Pedretti, Alessandro; Testa, Bernard

2011-06-01

In the last few years, a need to account for molecular flexibility in drug-design methodologies has emerged, even if the dynamic behavior of molecular properties is seldom made explicit. For a flexible molecule, it is indeed possible to compute different values for a given conformation-dependent property and the ensemble of such values defines a property space that can be used to describe its molecular variability; a most representative case is the lipophilicity space. In this review, a number of applications of lipophilicity space and other property spaces are presented, showing that this concept can be fruitfully exploited: to investigate the constraints exerted by media of different levels of structural organization, to examine processes of molecular recognition and binding at an atomic level, to derive informative descriptors to be included in quantitative structure--activity relationships and to analyze protein simulations extracting the relevant information. Much molecular information is neglected in the descriptors used by medicinal chemists, while the concept of property space can fill this gap by accounting for the often-disregarded dynamic behavior of both small ligands and biomacromolecules. Property space also introduces some innovative concepts such as molecular sensitivity and plasticity, which appear best suited to explore the ability of a molecule to adapt itself to the environment variously modulating its property and conformational profiles. Globally, such concepts can enhance our understanding of biological phenomena providing fruitful descriptors in drug-design and pharmaceutical sciences.

Biochemical factors modulating female genital sexual arousal physiology.

PubMed

Traish, Abdulmaged M; Botchevar, Ella; Kim, Noel N

2010-09-01

Female genital sexual arousal responses are complex neurophysiological processes consisting of central and peripheral components that occur following sexual stimulation. The peripheral responses in sexual arousal include genital vasocongestion, engorgement and lubrication resulting from a surge of vaginal and clitoral blood flow. These hemodynamic events are mediated by a host of neurotransmitters and vasoactive agents. To discuss the role of various biochemical factors modulating female genital sexual arousal responses. A comprehensive literature review was conducted using the PubMed database and citations were selected, based on topical relevance, and examined for study methodology and major findings. Data from peer-reviewed publications. Adrenergic as well as non-adrenergic non-cholinergic neurotransmitters play an important role in regulating genital physiological responses by mediating vascular and non-vascular smooth muscle contractility. Vasoactive peptides and neuropeptides also modulate genital sexual responses by regulating vascular and non-vascular smooth muscle cells and epithelial function. The endocrine milieu, particularly sex steroid hormones, is critical in the maintenance of tissue structure and function. Reduced levels of estrogens and androgen are associated with dramatic alterations in genital tissue structure, including the nerve network, as well as the response to physiological modulators. Furthermore, estrogen and androgen deficiency is associated with reduced expression of sex steroid receptors and most importantly with attenuated genital blood flow and lubrication in response to pelvic nerve stimulation. This article provides an integrated framework describing the physiological and molecular basis of various pathophysiological conditions associated with female genital sexual arousal dysfunction. © 2010 International Society for Sexual Medicine.

Trichomonas vaginalis origins, molecular pathobiology and clinical considerations.

PubMed

Hirt, Robert P; Sherrard, Jackie

2015-02-01

To integrate a selection of the most recent data on Trichomonas vaginalis origins, molecular cell biology and T. vaginalis interactions with the urogenital tract microbiota with trichomoniasis symptoms and clinical management. Transcriptomics and proteomics datasets are accumulating, facilitating the identification and prioritization of key target genes to study T. vaginalis pathobiology. Proteins involved in host sensing and cytoskeletal plasticity during T. vaginalis amoeboid transformation were identified. T. vaginalis was shown to secrete exosomes and a macrophage migration inhibitory factor-like protein that both influence host-parasite interactions. T. vaginalis co-infections with Mycoplasma species and viruses were shown to modulate the inflammatory responses, whereas T. vaginalis interactions with various Lactobacillus species inhibit parasite interactions with human cells. T. vaginalis infections were also shown to be associated with bacterial vaginosis. A broader range of health sequelae is also becoming apparent. Diagnostics for both women and men based on the molecular approaches are being refined, in particular for men. New developments in the molecular and cellular basis of T. vaginalis pathobiology combined with data on the urogenital tract microbiota and immunology have enriched our knowledge on human-microbe interactions that will contribute to increasing our capacity to prevent and treat T. vaginalis and other sexually transmitted infections.

Geminiviruses and Plant Hosts: A Closer Examination of the Molecular Arms Race

PubMed Central

Ramesh, Shunmugiah V.; Sahu, Pranav P.; Prasad, Manoj; Praveen, Shelly; Pappu, Hanu R.

2017-01-01

Geminiviruses are plant-infecting viruses characterized by a single-stranded DNA (ssDNA) genome. Geminivirus-derived proteins are multifunctional and effective regulators in modulating the host cellular processes resulting in successful infection. Virus-host interactions result in changes in host gene expression patterns, reprogram plant signaling controls, disrupt central cellular metabolic pathways, impair plant’s defense system, and effectively evade RNA silencing response leading to host susceptibility. This review summarizes what is known about the cellular processes in the continuing tug of war between geminiviruses and their plant hosts at the molecular level. In addition, implications for engineered resistance to geminivirus infection in the context of a greater understanding of the molecular processes are also discussed. Finally, the prospect of employing geminivirus-based vectors in plant genome engineering and the emergence of powerful genome editing tools to confer geminivirus resistance are highlighted to complete the perspective on geminivirus-plant molecular interactions. PMID:28914771

Directed network modules

NASA Astrophysics Data System (ADS)

Palla, Gergely; Farkas, Illés J.; Pollner, Péter; Derényi, Imre; Vicsek, Tamás

2007-06-01

A search technique locating network modules, i.e. internally densely connected groups of nodes in directed networks is introduced by extending the clique percolation method originally proposed for undirected networks. After giving a suitable definition for directed modules we investigate their percolation transition in the Erdos-Rényi graph both analytically and numerically. We also analyse four real-world directed networks, including Google's own web-pages, an email network, a word association graph and the transcriptional regulatory network of the yeast Saccharomyces cerevisiae. The obtained directed modules are validated by additional information available for the nodes. We find that directed modules of real-world graphs inherently overlap and the investigated networks can be classified into two major groups in terms of the overlaps between the modules. Accordingly, in the word-association network and Google's web-pages, overlaps are likely to contain in-hubs, whereas the modules in the email and transcriptional regulatory network tend to overlap via out-hubs.

Molecular Biology and Pathogenicity of Mycoplasmas

PubMed Central

Razin, Shmuel; Yogev, David; Naot, Yehudith

1998-01-01

The recent sequencing of the entire genomes of Mycoplasma genitalium and M. pneumoniae has attracted considerable attention to the molecular biology of mycoplasmas, the smallest self-replicating organisms. It appears that we are now much closer to the goal of defining, in molecular terms, the entire machinery of a self-replicating cell. Comparative genomics based on comparison of the genomic makeup of mycoplasmal genomes with those of other bacteria, has opened new ways of looking at the evolutionary history of the mycoplasmas. There is now solid genetic support for the hypothesis that mycoplasmas have evolved as a branch of gram-positive bacteria by a process of reductive evolution. During this process, the mycoplasmas lost considerable portions of their ancestors’ chromosomes but retained the genes essential for life. Thus, the mycoplasmal genomes carry a high percentage of conserved genes, greatly facilitating gene annotation. The significant genome compaction that occurred in mycoplasmas was made possible by adopting a parasitic mode of life. The supply of nutrients from their hosts apparently enabled mycoplasmas to lose, during evolution, the genes for many assimilative processes. During their evolution and adaptation to a parasitic mode of life, the mycoplasmas have developed various genetic systems providing a highly plastic set of variable surface proteins to evade the host immune system. The uniqueness of the mycoplasmal systems is manifested by the presence of highly mutable modules combined with an ability to expand the antigenic repertoire by generating structural alternatives, all compressed into limited genomic sequences. In the absence of a cell wall and a periplasmic space, the majority of surface variable antigens in mycoplasmas are lipoproteins. Apart from providing specific antimycoplasmal defense, the host immune system is also involved in the development of pathogenic lesions and exacerbation of mycoplasma induced diseases. Mycoplasmas are

Inorganic Phosphate Limitation Modulates Capsular Polysaccharide Composition in Mycobacteria.

PubMed

van de Weerd, Robert; Boot, Maikel; Maaskant, Janneke; Sparrius, Marion; Verboom, Theo; van Leeuwen, Lisanne M; Burggraaf, Maroeska J; Paauw, Nanne J; Dainese, Elisa; Manganelli, Riccardo; Bitter, Wilbert; Appelmelk, Ben J; Geurtsen, Jeroen

2016-05-27

Mycobacterium tuberculosis is protected by an unusual and highly impermeable cell envelope that is critically important for the successful colonization of the host. The outermost surface of this cell envelope is formed by capsular polysaccharides that play an important role in modulating the initial interactions once the bacillus enters the body. Although the bioenzymatic steps involved in the production of the capsular polysaccharides are emerging, information regarding the ability of the bacterium to modulate the composition of the capsule is still unknown. Here, we study the mechanisms involved in regulation of mycobacterial capsule biosynthesis using a high throughput screen for gene products involved in capsular α-glucan production. Utilizing this approach we identified a group of mutants that all carried mutations in the ATP-binding cassette phosphate transport locus pst These mutants collectively exhibited a strong overproduction of capsular polysaccharides, including α-glucan and arabinomannan, suggestive of a role for inorganic phosphate (Pi) metabolism in modulating capsular polysaccharide production. These findings were corroborated by the observation that growth under low Pi conditions as well as chemical activation of the stringent response induces capsule production in a number of mycobacterial species. This induction is, in part, dependent on σ factor E. Finally, we show that Mycobacterium marinum, a model organism for M. tuberculosis, encounters Pi stress during infection, which shows the relevance of our findings in vivo. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

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…

Molecular and Cellular Mechanisms of Axonal Regeneration After Spinal Cord Injury*

PubMed Central

van Niekerk, Erna A.; Tuszynski, Mark H.; Lu, Paul; Dulin, Jennifer N.

2016-01-01

Following axotomy, a complex temporal and spatial coordination of molecular events enables regeneration of the peripheral nerve. In contrast, multiple intrinsic and extrinsic factors contribute to the general failure of axonal regeneration in the central nervous system. In this review, we examine the current understanding of differences in protein expression and post-translational modifications, activation of signaling networks, and environmental cues that may underlie the divergent regenerative capacity of central and peripheral axons. We also highlight key experimental strategies to enhance axonal regeneration via modulation of intraneuronal signaling networks and the extracellular milieu. Finally, we explore potential applications of proteomics to fill gaps in the current understanding of molecular mechanisms underlying regeneration, and to provide insight into the development of more effective approaches to promote axonal regeneration following injury to the nervous system. PMID:26695766

From molecular evolution to biobricks and synthetic modules: a lesson by the bacterial flagellum.

PubMed

Altegoer, Florian; Schuhmacher, Jan; Pausch, Patrick; Bange, Gert

2014-10-01

The bacterial flagellum is a motility structure and represents one of the most sophisticated nanomachines in the biosphere. Here, we review the current knowledge on the flagellum, its architecture with respect to differences between Gram-negative and Gram-positive bacteria and other species-specific variations (e.g. the flagellar filament protein, Flagellin). We further focus on the mechanism by which the two nucleotide-binding proteins FlhF and FlhG ensure the correct reproduction of flagella place and number (the flagellation pattern). We will finish the review with an overview of current biotechnological applications, and a perspective of how understanding flagella can contribute to developing modules for synthetic approaches.

Modulation of lung molecular biomarkers by beta-carotene in the Physicians' Health Study.

PubMed

Liu, Chun; Wang, Xiang-Dong; Mucci, Lorelei; Gaziano, J Michael; Zhang, Shumin M

2009-03-01

Beta-Carotene supplementation showed neither benefit nor harm among apparently healthy physicians (all men) in the Physicians' Health Study (PHS) trial. The objective of the current investigation was to evaluate how long-term beta-carotene supplementation affects molecular markers of lung carcinogenesis in the PHS. The protein levels of total p53, cyclin D1, proliferating cellular nuclear antigen (PCNA), retinoic acid receptor beta (RARbeta), and cytochrome p450 enzyme 1A1 (CYP1A1) were measured using the immunohistochemical method in 40 available archival lung tissue samples from patients who were diagnosed with lung cancer in the PHS. The protein levels of these markers were compared by category of beta-carotene treatment assignment and other characteristics using unconditional logistic regression models. The positivity for total p53, RARbeta, cyclin D1, and PCNA was nonsignificantly lower among lung cancer patients who were assigned to receive beta-carotene than those who were assigned to receive beta-carotene placebo. There was a borderline significant difference in CYP1A1 positivity with an OR of 0.2 (95% confidence interval, 0.2-1.1; P = .06) in a comparison of men who received beta-carotene and men who received beta-carotene placebo. The 50-mg beta-carotene supplementation on alternate days had no significant influence on molecular markers of lung carcinogenesis that were evaluated in the PHS. This finding provides mechanistic support for the main PHS trial results of beta-carotene, which demonstrated no benefit or harm to the risk of developing lung cancer. (c) 2009 American Cancer Society.

Steroidal androgens and nonsteroidal, tissue-selective androgen receptor modulator, S-22, regulate androgen receptor function through distinct genomic and nongenomic signaling pathways.

PubMed

Narayanan, Ramesh; Coss, Christopher C; Yepuru, Muralimohan; Kearbey, Jeffrey D; Miller, Duane D; Dalton, James T

2008-11-01

Androgen receptor (AR) ligands are important for the development and function of several tissues and organs. However, the poor oral bioavailability, pharmacokinetic properties, and receptor cross-reactivity of testosterone, coupled with side effects, place limits on its clinical use. Selective AR modulators (SARMs) elicit anabolic effects in muscle and bone, sparing reproductive organs like the prostate. However, molecular mechanisms underlying the tissue selectivity remain ambiguous. We performed a variety of in vitro studies to compare and define the molecular mechanisms of an aryl propionamide SARM, S-22, as compared with dihydrotestosterone (DHT). Studies indicated that S-22 increased levator ani muscle weight but decreased the size of prostate in rats. Analysis of the upstream intracellular signaling events indicated that S-22 and DHT mediated their actions through distinct pathways. Modulation of these pathways altered the recruitment of AR and its cofactors to the PSA enhancer in a ligand-dependent fashion. In addition, S-22 induced Xenopus laevis oocyte maturation and rapid phosphorylation of several kinases, through pathways distinct from steroids. These studies reveal novel differences in the molecular mechanisms by which S-22, a nonsteroidal SARM, and DHT mediate their pharmacological effects.

Immune and cell modulation by amino acids.

PubMed

Roth, Erich

2007-10-01

Sir David Cuthbertson was the first to define metabolic alterations in post-aggression syndrome (PAS). From basic measurements of nitrogen loss and total protein synthesis/degradation, the current research has moved to genomics, proteomics and metabolomics. In this respect, first evidence was accumulated for the influence of acute catabolism, immobilisation by bed rest and sarcopenia of old age on the muscle-cell genome and proteome. Moreover, in post-aggression syndrome specific amino acids such as glutamine, arginine, glycine, taurine, tryptophan and cysteine are used for cell and immune modulation. Our laboratory has focused on the regulative capacity of glutamine. Glutamine deficiency as found in post-aggression syndrome reduces lymphocyte proliferation, alters monocyte/macrophage activity, decreases the formation of heat-shock proteins, stimulates cell apoptosis, shifts the cellular redox potential by altering the glutathione synthesis and increases the activity of the AMPK system. Investigating the molecular effect of glutamine on Hsp 70 induction, we tested the glutamine dependence on the formation of transfer-RNA and of heat-shock factor 1 (HSF 1), and on transcription and translation of Hsp 70. We could demonstrate that glutamine stabilises the mRNA of Hsp 70 thereby prolonging its half-life. The lecture also discusses the principal molecular targets of administered arginine, glycine, cysteine, taurine and tryptophan.

Modulation of natriuretic peptide receptors in human adipose tissue: molecular mechanisms behind the "natriuretic handicap" in morbidly obese patients.

PubMed

Gentili, Alessandra; Frangione, Maria Rosaria; Albini, Elisa; Vacca, Carmine; Ricci, Maria Anastasia; De Vuono, Stefano; Boni, Marcello; Rondelli, Fabio; Rotelli, Luciana; Lupattelli, Graziana; Orabona, Ciriana

2017-08-01

The B-type natriuretic peptide (BNP) hormone plays a crucial role in the regulation of cardiovascular and energy homeostasis. Obesity is associated with low circulating levels of BNP, a condition known as "natriuretic handicap." Recent evidences suggest an altered expression of BNP receptors-both the signaling natriuretic peptide receptors (NPR)-A and the clearance NPR-C receptor-in adipose tissue (AT) as one of the putative causes of natriuretic handicap. The current study aims at clarifying the molecular mechanisms behind the natriuretic handicap, focusing on NPR modulation in the AT of obese and control subjects. The study enrolled 34 obese and 20 control subjects undergoing bariatric or abdominal surgery, respectively. The main clinical and biochemical parameters, including circulating BNP, were assessed. In visceral (VAT) and subcutaneous AT (SAT) samples, collected during surgery, the adipocytes and stromal vascular fraction (SVF) expression of NPR-A and NPR-C and the SVF secretion of interleukin 6 (IL-6) were determined. Both VAT and SAT from obese patients expressed a lower NPR-A/NPR-C ratio in adipocytes and the SVF secreted a higher level of IL-6, compared with the controls. Moreover, NPR-A/NPR-C ratio expressed by VAT and SAT adipocytes negatively correlated with body mass index, insulin, the Homeostasis Model Assessment of Insulin resistance, and IL-6 secreted by SVF, and the expression of the clearance receptor NPR-C, in both the VAT and SAT adipocytes, showed a negative correlation with circulating BNP. Overall, insulin resistance/hyperinsulinemia and AT inflammation (ie, high level of IL-6) are the major determinants of the lower NPR-A/NPR-C ratio in adipocytes, thus contributing to the natriuretic handicap in obese subjects. Copyright © 2017 Elsevier Inc. All rights reserved.

Receiver bandwidth effects on complex modulation and detection using directly modulated lasers.

PubMed

Yuan, Feng; Che, Di; Shieh, William

2016-05-01

Directly modulated lasers (DMLs) have long been employed for short- and medium-reach optical communications due to their low cost. Recently, a new modulation scheme called complex modulated DMLs has been demonstrated showing a significant optical signal to noise ratio sensitivity enhancement compared with the traditional intensity-only detection scheme. However, chirp-induced optical spectrum broadening is inevitable in complex modulated systems, which may imply a need for high-bandwidth receivers. In this Letter, we study the impact of receiver bandwidth effects on the performance of complex modulation and coherent detection systems based on DMLs. We experimentally demonstrate that such systems exhibit a reasonable tolerance for the reduced receiver bandwidth. For 10 Gbaud 4-level pulse amplitude modulation signals, the required electrical bandwidth is as low as 8.5 and 7.5 GHz for 7% and 20% forward error correction, respectively. Therefore, it is feasible to realize DML-based complex modulated systems using cost-effective receivers with narrow bandwidth.

Repressor logic modules assembled by rolling circle amplification platform to construct a set of logic gates

PubMed Central

Wei, Hua; Hu, Bo; Tang, Suming; Zhao, Guojie; Guan, Yifu

2016-01-01

Small molecule metabolites and their allosterically regulated repressors play an important role in many gene expression and metabolic disorder processes. These natural sensors, though valuable as good logic switches, have rarely been employed without transcription machinery in cells. Here, two pairs of repressors, which function in opposite ways, were cloned, purified and used to control DNA replication in rolling circle amplification (RCA) in vitro. By using metabolites and repressors as inputs, RCA signals as outputs, four basic logic modules were constructed successfully. To achieve various logic computations based on these basic modules, we designed series and parallel strategies of circular templates, which can further assemble these repressor modules in an RCA platform to realize twelve two-input Boolean logic gates and a three-input logic gate. The RCA-output and RCA-assembled platform was proved to be easy and flexible for complex logic processes and might have application potential in molecular computing and synthetic biology. PMID:27869177

Molecular epidemiology, cancer-related symptoms, and cytokines pathway

PubMed Central

Reyes-Gibby, Cielito C; Wu, Xifeng; Spitz, Margaret; Kurzrock, Razelle; Fisch, Michael; Bruera, Eduardo; Shete, Sanjay

2012-01-01

The Human Genome Project and HapMap have led to a better appreciation of the importance of common genetic variation in determining cancer risk, created potential for predicting response to therapy, and made possible the development of targeted prevention and therapeutic interventions. Advances in molecular epidemiology can be used to explore the role of genetic variation in modulating the risk for severe and persistent symptoms, such as pain, depression, and fatigue, in patients with cancer. The same genes that are implicated in cancer risk might also be involved in the modulation of therapeutic outcomes. For example, polymorphisms in several cytokine genes are potential markers for genetic susceptibility both for cancer risk and for cancer-related symptoms. These genetic polymorphisms are stable markers and easily and reliably assayed to explore the extent to which genetic variation might prove useful in identifying patients with cancer at high-risk of symptom development. Likewise, they could identify subgroups who might benefit most from symptom intervention, and contribute to developing personalised and more effective therapies for persistent symptoms. PMID:18672213

Optical modulator system

NASA Technical Reports Server (NTRS)

Brand, J.

1972-01-01

The fabrication, test, and delivery of an optical modulator system which will operate with a mode-locked Nd:YAG laser indicating at either 1.06 or 0.53 micrometers is discussed. The delivered hardware operates at data rates up to 400 Mbps and includes a 0.53 micrometer electrooptic modulator, a 1.06 micrometer electrooptic modulator with power supply and signal processing electronics with power supply. The modulators contain solid state drivers which accept digital signals with MECL logic levels, temperature controllers to maintain a stable thermal environment for the modulator crystals, and automatic electronic compensation to maximize the extinction ratio. The modulators use two lithium tantalate crystals cascaded in a double pass configuration. The signal processing electronics include encoding electronics which are capable of digitizing analog signals between the limit of + or - 0.75 volts at a maximum rate of 80 megasamples per second with 5 bit resolution. The digital samples are serialized and made available as a 400 Mbps serial NRZ data source for the modulators. A pseudorandom (PN) generator is also included in the signal processing electronics. This data source generates PN sequences with lengths between 31 bits and 32,767 bits in a serial NRZ format at rates up to 400 Mbps.

The choroid plexus harbors a circadian oscillator modulated by estrogens.

PubMed

Quintela, Telma; Albuquerque, Tânia; Lundkvist, Gabriella; Carmine Belin, Andrea; Talhada, Daniela; Gonçalves, Isabel; Carro, Eva; Santos, Cecília R A

2018-02-01

The suprachiasmatic nucleus (SCN) of the hypothalamus is considered the master circadian oscillator in mammals. However, extra-SCN structures in the brain also display daily rhythms. Recently, we have demonstrated that the choroid plexus (CP) expresses core clock genes that are subjected to circadian regulation in a sex-dependent manner. By using CP explants cultured from female knock-in mice carrying the Period-luciferase transgene, we show that CP exhibits endogenous circadian rhythms of PERIOD2::LUCIFERASE expression. Furthermore, we demonstrate that estrogen declines following ovariectomy modulates the daily rhythm expression of Bmal1, Per1 and Per2 in female rat CP, corroborating data obtained in experiments where rat CP epithelial cell (CPEC) cultures were incubated with 17β-estradiol (E2). The molecular mechanism underlying these effects was also investigated, and we provide evidence that the estrogen receptor (ER) mediates the response of clock genes to E2. In conclusion, our study proves that the CP harbors a circadian oscillator that is modulated by estrogens and demonstrates that E2 regulation occurs through an estrogen-receptor-dependent mechanism.

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

The C-module-binding factor supports amplification of TRE5-A retrotransposons in the Dictyostelium discoideum genome.

PubMed

Bilzer, Annika; Dölz, Heike; Reinhardt, Alexander; Schmith, Anika; Siol, Oliver; Winckler, Thomas

2011-01-01

Retrotransposable elements are molecular parasites that have invaded the genomes of virtually all organisms. Although retrotransposons encode essential proteins to mediate their amplification, they also require assistance by host cell-encoded machineries that perform functions such as DNA transcription and repair. The retrotransposon TRE5-A of the social amoeba Dictyostelium discoideum generates a notable amount of both sense and antisense RNAs, which are generated from element-internal promoters, located in the A module and the C module, respectively. We observed that TRE5-A retrotransposons depend on the C-module-binding factor (CbfA) to maintain high steady-state levels of TRE5-A transcripts and that CbfA supports the retrotransposition activity of TRE5-A elements. The carboxy-terminal domain of CbfA was found to be required and sufficient to mediate the accumulation of TRE5-A transcripts, but it did not support productive retrotransposition of TRE5-A. This result suggests different roles for CbfA protein domains in the regulation of TRE5-A retrotransposition frequency in D. discoideum cells. Although CbfA binds to the C module in vitro, the factor regulates neither C-module nor A-module promoter activity in vivo. We speculate that CbfA supports the amplification of TRE5-A retrotransposons by suppressing the expression of an as yet unidentified component of the cellular posttranscriptional gene silencing machinery.

Modulation Index Adjustment for Recovery of Pure Wavelength Modulation Spectroscopy Second Harmonic Signal Waveforms.

PubMed

Wei, Wei; Chang, Jun; Wang, Qiang; Qin, Zengguang

2017-01-15

A new technique of modulation index adjustment for pure wavelength modulation spectroscopy second harmonic signal waveforms recovery is presented. As the modulation index is a key parameter in determining the exact form of the signals generated by the technique of wavelength modulation spectroscopy, the method of modulation index adjustment is applied to recover the second harmonic signal with wavelength modulation spectroscopy. By comparing the measured profile with the theoretical profile by calculation, the relationship between the modulation index and average quantities of the scanning wavelength can be obtained. Furthermore, when the relationship is applied in the experimental setup by point-by-point modulation index modification for gas detection, the results show good agreement with the theoretical profile and signal waveform distortion (such as the amplitude modulation effect caused by diode laser) can be suppressed. Besides, the method of modulation index adjustment can be used in many other aspects which involve profile improvement. In practical applications, when the amplitude modulation effect can be neglected and the stability of the detection system is limited by the sampling rate of analog-to-digital, modulation index adjustment can be used to improve detection into softer inflection points and solve the insufficient sampling problem. As a result, measurement stability is improved by 40%.

Modulation Index Adjustment for Recovery of Pure Wavelength Modulation Spectroscopy Second Harmonic Signal Waveforms

PubMed Central

Wei, Wei; Chang, Jun; Wang, Qiang; Qin, Zengguang

2017-01-01

A new technique of modulation index adjustment for pure wavelength modulation spectroscopy second harmonic signal waveforms recovery is presented. As the modulation index is a key parameter in determining the exact form of the signals generated by the technique of wavelength modulation spectroscopy, the method of modulation index adjustment is applied to recover the second harmonic signal with wavelength modulation spectroscopy. By comparing the measured profile with the theoretical profile by calculation, the relationship between the modulation index and average quantities of the scanning wavelength can be obtained. Furthermore, when the relationship is applied in the experimental setup by point-by-point modulation index modification for gas detection, the results show good agreement with the theoretical profile and signal waveform distortion (such as the amplitude modulation effect caused by diode laser) can be suppressed. Besides, the method of modulation index adjustment can be used in many other aspects which involve profile improvement. In practical applications, when the amplitude modulation effect can be neglected and the stability of the detection system is limited by the sampling rate of analog-to-digital, modulation index adjustment can be used to improve detection into softer inflection points and solve the insufficient sampling problem. As a result, measurement stability is improved by 40%. PMID:28098842

Improvement of laser molecular beam epitaxy grown SrTiO3 thin film properties by temperature gradient modulation growth

NASA Astrophysics Data System (ADS)

Li, Jin Long; Hao, J. H.; Li, Y. R.

2007-09-01

Oxygen diffusion at the SrTiO3/Si interface was analyzed. A method called temperature gradient modulation growth was introduced to control oxygen diffusion at the interface of SrTiO3/Si. Nanoscale multilayers were grown at different temperatures at the initial growing stage of films. Continuous growth of SrTiO3 films was followed to deposit on the grown sacrificial layers. The interface and crystallinity of SrTiO3/Si were investigated by in situ reflection high energy electron diffraction and x-ray diffraction measurements. It has been shown that the modulated multilayers may help suppress the interfacial diffusion, and therefore improve SrTiO3 thin film properties.

Molecular biology of pancreatic cancer: how useful is it in clinical practice?

PubMed

Sakorafas, George H; Smyrniotis, Vasileios

2012-07-10

During the recent two decades dramatic advances of molecular biology allowed an in-depth understanding of pancreatic carcinogenesis. It is currently accepted that pancreatic cancer has a genetic component. The real challenge is now how these impressive advances could be used in clinical practice. To critically present currently available data regarding clinical application of molecular biology in pancreatic cancer. Reports about clinical implications of molecular biology in patients with pancreatic cancer were retrieved from PubMed. These reports were selected on the basis of their clinical relevance, and the data of their publication (preferentially within the last 5 years). Emphasis was placed on reports investigating diagnostic, prognostic, and therapeutic implications. Molecular biology can be used to identify individuals at high-risk for pancreatic cancer development. Intensive surveillance is indicated in these patients to detect pancreatic neoplasia ideally at a preinvasive stage, when curative resection is still possible. Molecular biology can also be used in the diagnosis of pancreatic cancer, with molecular analysis on samples of biologic material, such as serum or plasma, duodenal fluid or preferentially pure pancreatic juice, pancreatic cells or tissue, and stools. Molecular indices have also prognostic significance. Finally, molecular biology may have therapeutic implications by using various therapeutic approaches, such as antiangiogenic factors, purine synthesis inhibitors, matrix metalloproteinase inhibitors, factors modulating tumor-stroma interaction, inactivation of the hedgehog pathway, gene therapy, oncolytic viral therapy, immunotherapy (both passive as well as active) etc. Molecular biology may have important clinical implications in patients with pancreatic cancer and represents one of the most active areas on cancer research. Hopefully clinical applications of molecular biology in pancreatic cancer will expand in the future, improving the

Modulation of Quorum Sensing in a Gram-Positive Pathogen by Linear Molecularly Imprinted Polymers with Anti-infective Properties.

PubMed

Motib, Anfal; Guerreiro, Antonio; Al-Bayati, Firas; Piletska, Elena; Manzoor, Irfan; Shafeeq, Sulman; Kadam, Anagha; Kuipers, Oscar; Hiller, Luisa; Cowen, Todd; Piletsky, Sergey; Andrew, Peter W; Yesilkaya, Hasan

2017-12-22

We describe the development, characterization, and biological testing of a new type of linear molecularly imprinted polymer (LMIP) designed to act as an anti-infective by blocking the quorum sensing (QS) mechanism and so abrogating the virulence of the pathogen Streptococcus pneumoniae. The LMIP is prepared (polymerized) in presence of a template molecule, but unlike in traditional molecular imprinting approaches, no cross-linker is used. This results in soluble low-molecular-weight oligomers that can act as a therapeutic agent in vitro and in vivo. The LMIP was characterized by mass spectrometry to determine its monomer composition. Fragments identified were then aligned along the peptide template by computer modeling to predict the possible monomer sequence of the LMIP. These findings provide a proof of principle that LMIPs can be used to block QS, thus setting the stage for the development of LMIPs a novel drug-discovery platform and class of materials to target Gram-positive pathogens. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Diffusion spectral imaging modules correlate with EEG LORETA neuroimaging modules.

PubMed

Thatcher, Robert W; North, Duane M; Biver, Carl J

2012-05-01

The purpose of this study was to test the hypothesis that the highest temporal correlations between 3-dimensional EEG current source density corresponds to anatomical Modules of high synaptic connectivity. Eyes closed and eyes open EEG was recorded from 19 scalp locations with a linked ears reference from 71 subjects age 13-42 years. LORETA was computed from 1 to 30 Hz in 2,394 cortical gray matter voxels that were grouped into six anatomical Modules corresponding to the ROIs in the Hagmann et al.'s [2008] diffusion spectral imaging (DSI) study. All possible cross-correlations between voxels within a DSI Module were compared with the correlations between Modules. The Hagmann et al. [ 2008] Module correlation structure was replicated in the correlation structure of EEG three-dimensional current source density. EEG Temporal correlation between brain regions is related to synaptic density as measured by diffusion spectral imaging. Copyright © 2011 Wiley-Liss, Inc.

MODUL-a multicenter randomized clinical trial of biomarker-driven maintenance therapy following first-line standard induction treatment of metastatic colorectal cancer: an adaptable signal-seeking approach.

PubMed

Schmoll, Hans-Joachim; Arnold, Dirk; de Gramont, Aimery; Ducreux, Michel; Grothey, Axel; O'Dwyer, Peter J; Van Cutsem, Eric; Hermann, Frank; Bosanac, Ivan; Bendahmane, Belguendouz; Mancao, Christoph; Tabernero, Josep

2018-06-01

The old approach of one therapeutic for all patients with mCRC is evolving with a need to target specific molecular aberrations or cell-signalling pathways. Molecular screening approaches and new biomarkers are required to fully characterize tumours, identify patients most likely to benefit, and predict treatment response. MODUL is a signal-seeking trial with a design that is highly adaptable, permitting modification of different treatment cohorts and inclusion of further additional cohorts based on novel evidence on new compounds/combinations that emerge during the study. MODUL is ongoing and its adaptable nature permits timely and efficient recruitment of patients into the most appropriate cohort. Recruitment will take place over approximately 5 years in Europe, Asia, Africa, and South America. The design of MODUL with ongoing parallel/sequential treatment cohorts means that the overall size and duration of the trial can be modified/prolonged based on accumulation of new data. The early success of the current trial suggests that the design may provide definitive leads in a patient-friendly and relatively economical trial structure. Along with other biomarker-driven trials that are currently underway, it is hoped that MODUL will contribute to the continuing evolution of clinical trial design and permit a more 'tailored' approach to the treatment of patients with mCRC.

A Synthetic Coiled-Coil Interactome Provides Heterospecific Modules for Molecular Engineering

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

Reinke, Aaron W.; Grant, Robert A.; Keating, Amy E.

2010-06-21

The versatile coiled-coil protein motif is widely used to induce and control macromolecular interactions in biology and materials science. Yet the types of interaction patterns that can be constructed using known coiled coils are limited. Here we greatly expand the coiled-coil toolkit by measuring the complete pairwise interactions of 48 synthetic coiled coils and 7 human bZIP coiled coils using peptide microarrays. The resulting 55-member protein 'interactome' includes 27 pairs of interacting peptides that preferentially heteroassociate. The 27 pairs can be used in combinations to assemble sets of 3 to 6 proteins that compose networks of varying topologies. Of specialmore » interest are heterospecific peptide pairs that participate in mutually orthogonal interactions. Such pairs provide the opportunity to dimerize two separate molecular systems without undesired crosstalk. Solution and structural characterization of two such sets of orthogonal heterodimers provide details of their interaction geometries. The orthogonal pair, along with the many other network motifs discovered in our screen, provide new capabilities for synthetic biology and other applications.« less

A design of optical modulation system with pixel-level modulation accuracy

NASA Astrophysics Data System (ADS)

Zheng, Shiwei; Qu, Xinghua; Feng, Wei; Liang, Baoqiu

2018-01-01

Vision measurement has been widely used in the field of dimensional measurement and surface metrology. However, traditional methods of vision measurement have many limits such as low dynamic range and poor reconfigurability. The optical modulation system before image formation has the advantage of high dynamic range, high accuracy and more flexibility, and the modulation accuracy is the key parameter which determines the accuracy and effectiveness of optical modulation system. In this paper, an optical modulation system with pixel level accuracy is designed and built based on multi-points reflective imaging theory and digital micromirror device (DMD). The system consisted of digital micromirror device, CCD camera and lens. Firstly we achieved accurate pixel-to-pixel correspondence between the DMD mirrors and the CCD pixels by moire fringe and an image processing of sampling and interpolation. Then we built three coordinate systems and calculated the mathematic relationship between the coordinate of digital micro-mirror and CCD pixels using a checkerboard pattern. A verification experiment proves that the correspondence error is less than 0.5 pixel. The results show that the modulation accuracy of system meets the requirements of modulation. Furthermore, the high reflecting edge of a metal circular piece can be detected using the system, which proves the effectiveness of the optical modulation system.

Programmable Thermostat Module Upgrade for the Multipurpose Logistics Module

NASA Technical Reports Server (NTRS)

Clark, D. W.; Glasgow, S. d.; Reagan, S. E.; Presson, K. H.; Howard, D. E.; Smith, D. A.

2007-01-01

The STS-121/ULF 1.1 mission was the maiden flight of the programmable thermostat module (PTM) system used to control the 28 V shell heaters on the multi-purpose logistics module (MPLM). These PTMs, in conjunction with a data recorder module (DRM), provide continuous closed loop temperature control and data recording of MPLM on-orbit heater operations. This Technical Memorandum discusses the hardware design, development, test, and verification (DDT&V) activities performed at the Marshall Space Flight Center as well as the operational implementation and mission performance.

Molecular characterization of a family 5 glycoside hydrolase suggests an induced-fit enzymatic mechanism.

PubMed

Liberato, Marcelo V; Silveira, Rodrigo L; Prates, Érica T; de Araujo, Evandro A; Pellegrini, Vanessa O A; Camilo, Cesar M; Kadowaki, Marco A; Neto, Mario de O; Popov, Alexander; Skaf, Munir S; Polikarpov, Igor

2016-04-01

Glycoside hydrolases (GHs) play fundamental roles in the decomposition of lignocellulosic biomaterials. Here, we report the full-length structure of a cellulase from Bacillus licheniformis (BlCel5B), a member of the GH5 subfamily 4 that is entirely dependent on its two ancillary modules (Ig-like module and CBM46) for catalytic activity. Using X-ray crystallography, small-angle X-ray scattering and molecular dynamics simulations, we propose that the C-terminal CBM46 caps the distal N-terminal catalytic domain (CD) to establish a fully functional active site via a combination of large-scale multidomain conformational selection and induced-fit mechanisms. The Ig-like module is pivoting the packing and unpacking motions of CBM46 relative to CD in the assembly of the binding subsite. This is the first example of a multidomain GH relying on large amplitude motions of the CBM46 for assembly of the catalytically competent form of the enzyme.

Molecular characterization of a family 5 glycoside hydrolase suggests an induced-fit enzymatic mechanism

NASA Astrophysics Data System (ADS)

Liberato, Marcelo V.; Silveira, Rodrigo L.; Prates, Érica T.; de Araujo, Evandro A.; Pellegrini, Vanessa O. A.; Camilo, Cesar M.; Kadowaki, Marco A.; Neto, Mario De O.; Popov, Alexander; Skaf, Munir S.; Polikarpov, Igor

2016-04-01

Glycoside hydrolases (GHs) play fundamental roles in the decomposition of lignocellulosic biomaterials. Here, we report the full-length structure of a cellulase from Bacillus licheniformis (BlCel5B), a member of the GH5 subfamily 4 that is entirely dependent on its two ancillary modules (Ig-like module and CBM46) for catalytic activity. Using X-ray crystallography, small-angle X-ray scattering and molecular dynamics simulations, we propose that the C-terminal CBM46 caps the distal N-terminal catalytic domain (CD) to establish a fully functional active site via a combination of large-scale multidomain conformational selection and induced-fit mechanisms. The Ig-like module is pivoting the packing and unpacking motions of CBM46 relative to CD in the assembly of the binding subsite. This is the first example of a multidomain GH relying on large amplitude motions of the CBM46 for assembly of the catalytically competent form of the enzyme.

Bubble memory module

NASA Technical Reports Server (NTRS)

Bohning, O. D.; Becker, F. J.

1980-01-01

Design, fabrication and test of partially populated prototype recorder using 100 kilobit serial chips is described. Electrical interface, operating modes, and mechanical design of several module configurations are discussed. Fabrication and test of the module demonstrated the practicality of multiplexing resulting in lower power, weight, and volume. This effort resulted in the completion of a module consisting of a fully engineered printed circuit storage board populated with 5 of 8 possible cells and a wire wrapped electronics board. Interface of the module is 16 bits parallel at a maximum of 1.33 megabits per second data rate on either of two interface buses.

Chitosan-triclosan particles modulate inflammatory signaling in gingival fibroblasts.

PubMed

Pavez, L; Tobar, N; Chacón, C; Arancibia, R; Martínez, C; Tapia, C; Pastor, A; González, M; Martínez, J; Smith, P C

2018-04-01

An important goal of periodontal therapy is the modulation of the inflammatory response. To this end, several pharmacological agents have been evaluated. Triclosan corresponds to an antibacterial and anti-inflammatory agent currently used in periodontal therapy. Chitosan is a natural polymer that may act as a drug delivery agent and exerts antibacterial and anti-inflammatory activities. Therefore, an association between both molecules might be useful to prevent inflammation and tissue destruction in periodontal tissues. In the present study, we have generated chitosan-triclosan particles and evaluated their morphology, charge, biocompatibility and gene expression analysis in human gingival fibroblasts. The chitosan-triclosan particles size and Z potential were 129 ± 47 nm and 51 ± 17 mV respectively. Human gingival fibroblast viability was not affected by chitosan-triclosan. A total of 1533 genes were upregulated by interleukin (IL)-1β. On the other hand, 943 were downregulated in fibroblasts stimulated with IL-1β plus chitosan-triclosan particles. Fifty-one genes were identified as molecular targets upregulated by IL-1 β and downregulated by the chitosan-triclosan particles. The gene ontology analysis revealed that these genes were enriched in categories related to biological processes, molecular function and cellular components. Furthermore, using real-time reverse transcription-polymerase chain reaction beta-actin, fibronectin, interleukin-6 and IL-1b genes were confirmed as targets upregulated by IL-1β and downregulated by chitosan-triclosan particles. Our results show that chitosan-triclosan particles are able to modulate the inflammatory response in gingival fibroblasts. This effect might be useful in the prevention and/or treatment of inflammation in periodontal diseases. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

A Family of Helminth Molecules that Modulate Innate Cell Responses via Molecular Mimicry of Host Antimicrobial Peptides

PubMed Central

Hutchinson, Andrew T.; To, Joyce; Taylor, Nicole L.; Norton, Raymond S.; Perugini, Matthew A.

2011-01-01

Over the last decade a significant number of studies have highlighted the central role of host antimicrobial (or defence) peptides in modulating the response of innate immune cells to pathogen-associated ligands. In humans, the most widely studied antimicrobial peptide is LL-37, a 37-residue peptide containing an amphipathic helix that is released via proteolytic cleavage of the precursor protein CAP18. Owing to its ability to protect against lethal endotoxaemia and clinically-relevant bacterial infections, LL-37 and its derivatives are seen as attractive candidates for anti-sepsis therapies. We have identified a novel family of molecules secreted by parasitic helminths (helminth defence molecules; HDMs) that exhibit similar biochemical and functional characteristics to human defence peptides, particularly CAP18. The HDM secreted by Fasciola hepatica (FhHDM-1) adopts a predominantly α-helical structure in solution. Processing of FhHDM-1 by F. hepatica cathepsin L1 releases a 34-residue C-terminal fragment containing a conserved amphipathic helix. This is analogous to the proteolytic processing of CAP18 to release LL-37, which modulates innate cell activation by classical toll-like receptor (TLR) ligands such as lipopolysaccharide (LPS). We show that full-length recombinant FhHDM-1 and a peptide analogue of the amphipathic C-terminus bind directly to LPS in a concentration-dependent manner, reducing its interaction with both LPS-binding protein (LBP) and the surface of macrophages. Furthermore, FhHDM-1 and the amphipathic C-terminal peptide protect mice against LPS-induced inflammation by significantly reducing the release of inflammatory mediators from macrophages. We propose that HDMs, by mimicking the function of host defence peptides, represent a novel family of innate cell modulators with therapeutic potential in anti-sepsis treatments and prevention of inflammation. PMID:21589904

Pharmacologic Targeting of Chromatin Modulators As Therapeutics of Acute Myeloid Leukemia.

PubMed

Lu, Rui; Wang, Gang Greg

2017-01-01

Acute myeloid leukemia (AML), a common hematological cancer of myeloid lineage cells, generally exhibits poor prognosis in the clinic and demands new treatment options. Recently, direct sequencing of samples from human AMLs and pre-leukemic diseases has unveiled their mutational landscapes and significantly advanced the molecular understanding of AML pathogenesis. The newly identified recurrent mutations frequently "hit" genes encoding epigenetic modulators, a wide range of chromatin-modifying enzymes and regulatory factors involved in gene expression regulation, supporting aberration of chromatin structure and epigenetic modification as a main oncogenic mechanism and cancer-initiating event. Increasing body of evidence demonstrates that chromatin modification aberrations underlying the formation of blood cancer can be reversed by pharmacological targeting of the responsible epigenetic modulators, thus providing new mechanism-based treatment strategies. Here, we summarize recent advances in development of small-molecule inhibitors specific to chromatin factors and their potential applications in the treatment of genetically defined AMLs. These compounds selectively inhibit various subclasses of "epigenetic writers" (such as histone methyltransferases MLL/KMT2A, G9A/KMT1C, EZH2/KMT6A, DOT1L/KMT4, and PRMT1), "epigenetic readers" (such as BRD4 and plant homeodomain finger proteins), and "epigenetic erasers" (such as histone demethylases LSD1/KDM1A and JMJD2C/KDM4C). We also discuss about the molecular mechanisms underpinning therapeutic effect of these epigenetic compounds in AML and favor their potential usage for combinational therapy and treatment of pre-leukemia diseases.

Solar energy modulator

NASA Technical Reports Server (NTRS)

Hale, R. R. (Inventor); Mcdougal, A. R.

1984-01-01

A module is described with a receiver having a solar energy acceptance opening and supported by a mounting ring along the optic axis of a parabolic mirror in coaxial alignment for receiving solar energy from the mirror, and a solar flux modulator plate for varying the quantity of solar energy flux received by the acceptance opening of the module. The modulator plate is characterized by an annular, plate-like body, the internal diameter of which is equal to or slightly greater than the diameter of the solar energy acceptance opening of the receiver. Slave cylinders are connected to the modulator plate for supporting the plate for axial displacement along the axis of the mirror, therby shading the opening with respect to solar energy flux reflected from the surface of the mirror to the solar energy acceptance opening.

Demonstration of β-(Al x Ga1- x )2O3/β-Ga2O3 modulation doped field-effect transistors with Ge as dopant grown via plasma-assisted molecular beam epitaxy

NASA Astrophysics Data System (ADS)

Ahmadi, Elaheh; Koksaldi, Onur S.; Zheng, Xun; Mates, Tom; Oshima, Yuichi; Mishra, Umesh K.; Speck, James S.

2017-07-01

β-(Al x Ga1- x )2O3/β-Ga2O3 heterostructures were grown via plasma-assisted molecular beam epitaxy. The β-(Al x Ga1- x )2O3 barrier was partially doped by Ge to achieve a two-dimensional electron gas (2DEG) in Ga2O3. The formation of the 2DEG was confirmed by capacitance-voltage measurements. The impact of Ga-polishing on both the surface morphology and the reduction of the unintentionally incorporated Si at the growth interface was investigated using atomic force microscopy and secondary-ion mass spectrometry. Modulation doped field-effect transistors were fabricated. A maximum current density of 20 mA/mm with a pinch-off voltage of -6 V was achieved on a sample with a 2DEG sheet charge density of 1.2 × 1013 cm-2.

Delta modulation

NASA Technical Reports Server (NTRS)

Schilling, D. L.

1971-01-01

The conclusions of the design research of the song adaptive delta modulator are presented for source encoding voice signals. The variation of output SNR vs input signal power/when 8, 9, and 10 bit internal arithmetic is employed. Voice intelligibility tapes to test the 10-bit system are used. An analysis of a delta modulator is also presented designed to minimize the in-band rms error. This is accomplished by frequency shaping the error signal in the modulator prior to hard limiting. The result is a significant increase in the output SNR measured after low pass filtering.

Japanese Experiment Module arrival

NASA Image and Video Library

2007-03-29

Several components for delivery to the International Space Station sit in test stands inside the Space Station Processing Facility highbay. To the right, from back to front, are the Japanese Experiment Module, the Raffaello multi-purpose logistics module, and the European Space Agency's Columbus scientific research module. To the left in front is the starboard truss segment S5. Behind it is the test stand that will hold the Experiment Logistics Module Pressurized Section for the Japanese Experiment Module. The logistics module is one of the components of the Japanese Experiment Module or JEM, also known as Kibo, which means "hope" in Japanese. Kibo comprises six components: two research facilities -- the Pressurized Module and Exposed Facility; a Logistics Module attached to each of them; a Remote Manipulator System; and an Inter-Orbit Communication System unit. Kibo also has a scientific airlock through which experiments are transferred and exposed to the external environment of space. Kibo is Japan's first human space facility and its primary contribution to the station. Kibo will enhance the unique research capabilities of the orbiting complex by providing an additional environment in which astronauts can conduct science experiments. The various components of JEM will be assembled in space over the course of three Space Shuttle missions. The first of those three missions, STS-123, will carry the Experiment Logistics Module Pressurized Section aboard the Space Shuttle Endeavour, targeted for launch in 2007.

Cancer Cell Biology: A Student-Centered Instructional Module Exploring the Use of Multimedia to Enrich Interactive, Constructivist Learning of Science

PubMed Central

Bockholt, Susanne M.; West, J. Paige; Bollenbacher, Walter E.

2003-01-01

Multimedia has the potential of providing bioscience education novel learning environments and pedagogy applications to foster student interest, involve students in the research process, advance critical thinking/problem-solving skills, and develop conceptual understanding of biological topics. Cancer Cell Biology, an interactive, multimedia, problem-based module, focuses on how mutations in protooncogenes and tumor suppressor genes can lead to uncontrolled cell proliferation by engaging students as research scientists/physicians with the task of diagnosing the molecular basis of tumor growth for a group of patients. The process of constructing the module, which was guided by scientist and student feedback/responses, is described. The completed module and insights gained from its development are presented as a potential “multimedia pedagogy” for the development of other multimedia science learning environments. PMID:12822037

Lunar Module 4 moved for mating with Lunar Module Adapter at KSC

NASA Technical Reports Server (NTRS)

1969-01-01

Lunar Module 4 being moved for mating with the Spacecraft Lunar Module Adapter in the Kennedy Space Center's (KSC) Manned Spacecraft Operations Building. Lunar module 4 will be flown on the Apollo 10 (Spacecraft 106/Saturn 505) lunar orbit mission.

FMRP acts as a key messenger for dopamine modulation in the forebrain.

PubMed

Wang, Hansen; Wu, Long-Jun; Kim, Susan S; Lee, Frank J S; Gong, Bo; Toyoda, Hiroki; Ren, Ming; Shang, Yu-Ze; Xu, Hui; Liu, Fang; Zhao, Ming-Gao; Zhuo, Min

2008-08-28

The fragile X mental retardation protein (FMRP) is an RNA-binding protein that controls translational efficiency and regulates synaptic plasticity. Here, we report that FMRP is involved in dopamine (DA) modulation of synaptic potentiation. AMPA glutamate receptor subtype 1 (GluR1) surface expression and phosphorylation in response to D1 receptor stimulation were reduced in cultured Fmr1(-/-) prefrontal cortex (PFC) neurons. Furthermore, D1 receptor signaling was impaired, accompanied by D1 receptor hyperphosphorylation at serine sites and subcellular redistribution of G protein-coupled receptor kinase 2 (GRK2) in both PFC and striatum of Fmr1(-/-) mice. FMRP interacted with GRK2, and pharmacological inhibition of GRK2 rescued D1 receptor signaling in Fmr1(-/-) neurons. Finally, D1 receptor agonist partially rescued hyperactivity and enhanced the motor function of Fmr1(-/-) mice. Our study has identified FMRP as a key messenger for DA modulation in the forebrain and may provide insights into the cellular and molecular mechanisms underlying fragile X syndrome.

Electro-Optic Modulator and Method

DTIC Science & Technology

An optical intensity modulator which uses a Sagnac interferometer having an electro - optic phase modulator therein. An electric modulation signal is...modulating the optical signals by the electrical signal, the electro - optic effect in the modulator phase shifts the optical signals with respect to one another