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Sample records for modulates folding mechanism

  1. Macromolecular Crowding Modulates Folding Mechanism of α/β Protein Apoflavodoxin

    Science.gov (United States)

    Homouz, D.; Stagg, L.; Wittungstafshede, P.; Cheung, M.

    2009-01-01

    Protein dynamics in cells may be different from that in dilute solutions in vitro since the environment in cells is highly concentrated with other macromolecules. This volume exclusion due to macromolecular crowding is predicted to affect both equilibrium and kinetic processes involving protein conformational changes. To quantify macromolecular crowding effects on protein folding mechanisms, here we have investigated the folding energy landscape of an alpha/beta protein, apoflavodoxin, in the presence of inert macromolecular crowding agents using in silico and in vitro approaches. By coarse-grained molecular simulations and topology-based potential interactions, we probed the effects of increased volume fraction of crowding agents (phi_c) as well as of crowding agent geometry (sphere or spherocylinder) at high phi_c. Parallel kinetic folding experiments with purified Desulfovibro desulfuricans apoflavodoxin in vitro were performed in the presence of Ficoll (sphere) and Dextran (spherocylinder) synthetic crowding agents. In conclusion, we have identified in silico crowding conditions that best enhance protein stability and discovered that upon manipulation of the crowding conditions, folding routes experiencing topological frustrations can be either enhanced or relieved. The test-tube experiments confirmed that apoflavodoxin's time-resolved folding path is modulated by crowding agent geometry. We propose that macromolecular crowding effects may be a tool for manipulation of protein folding and function in living cells.

  2. Protein folding modulates the swapped dimerization mechanism of methyl-accepting chemotaxis heme sensors.

    Directory of Open Access Journals (Sweden)

    Marta A Silva

    Full Text Available The periplasmic sensor domains GSU0582 and GSU0935 are part of methyl accepting chemotaxis proteins in the bacterium Geobacter sulfurreducens. Both contain one c-type heme group and their crystal structures revealed that these domains form swapped dimers with a PAS fold formed from the two protein chains. The swapped dimerization of these sensors is related to the mechanism of signal transduction and the formation of the swapped dimer involves significant folding changes and conformational rearrangements within each monomeric component. However, the structural changes occurring during this process are poorly understood and lack a mechanistic framework. To address this issue, we have studied the folding and stability properties of two distinct heme-sensor PAS domains, using biophysical spectroscopies. We observed substantial differences in the thermodynamic stability (ΔG = 14.6 kJ.mol(-1 for GSU0935 and ΔG = 26.3 kJ.mol(-1 for GSU0582, and demonstrated that the heme moiety undergoes conformational changes that match those occurring at the global protein structure. This indicates that sensing by the heme cofactor induces conformational changes that rapidly propagate to the protein structure, an effect which is directly linked to the signal transduction mechanism. Interestingly, the two analyzed proteins have distinct levels of intrinsic disorder (25% for GSU0935 and 13% for GSU0582, which correlate with conformational stability differences. This provides evidence that the sensing threshold and intensity of the propagated allosteric effect is linked to the stability of the PAS-fold, as this property modulates domain swapping and dimerization. Analysis of the PAS-domain shows that disorder segments are found either at the hinge region that controls helix motions or in connecting segments of the β-sheet interface. The latter is known to be widely involved in both intra- and intermolecular interactions, supporting the view that it's folding

  3. Kinetic partitioning mechanism of HDV ribozyme folding

    Science.gov (United States)

    Chen, Jiawen; Gong, Sha; Wang, Yujie; Zhang, Wenbing

    2014-01-01

    RNA folding kinetics is directly tied to RNA biological functions. We introduce here a new approach for predicting the folding kinetics of RNA secondary structure with pseudoknots. This approach is based on our previous established helix-based method for predicting the folding kinetics of RNA secondary structure. In this approach, the transition rates for an elementary step: (1) formation, (2) disruption of a helix stem, and (3) helix formation with concomitant partial melting of an incompatible helix, are calculated with the free energy landscape. The folding kinetics of the Hepatitis delta virus (HDV) ribozyme and the mutated sequences are studied with this method. The folding pathways are identified by recursive searching the states with high net flux-in(out) population starting from the native state. The theory results are in good agreement with that of the experiments. The results indicate that the bi-phasic folding kinetics for the wt HDV sequence is ascribed to the kinetic partitioning mechanism: Part of the population will quickly fold to the native state along the fast pathway, while another part of the population will fold along the slow pathway, in which the population is trapped in a non-native state. Single mutation not only changes the folding rate but also the folding pathway.

  4. Kinetic partitioning mechanism of HDV ribozyme folding

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Jiawen; Gong, Sha; Wang, Yujie; Zhang, Wenbing, E-mail: wbzhang@whu.edu.cn [Department of Physics, Wuhan University, Wuhan, Hubei 430072 (China)

    2014-01-14

    RNA folding kinetics is directly tied to RNA biological functions. We introduce here a new approach for predicting the folding kinetics of RNA secondary structure with pseudoknots. This approach is based on our previous established helix-based method for predicting the folding kinetics of RNA secondary structure. In this approach, the transition rates for an elementary step: (1) formation, (2) disruption of a helix stem, and (3) helix formation with concomitant partial melting of an incompatible helix, are calculated with the free energy landscape. The folding kinetics of the Hepatitis delta virus (HDV) ribozyme and the mutated sequences are studied with this method. The folding pathways are identified by recursive searching the states with high net flux-in(out) population starting from the native state. The theory results are in good agreement with that of the experiments. The results indicate that the bi-phasic folding kinetics for the wt HDV sequence is ascribed to the kinetic partitioning mechanism: Part of the population will quickly fold to the native state along the fast pathway, while another part of the population will fold along the slow pathway, in which the population is trapped in a non-native state. Single mutation not only changes the folding rate but also the folding pathway.

  5. Mechanical Models of Fault-Related Folding

    Energy Technology Data Exchange (ETDEWEB)

    Johnson, A. M.

    2003-01-09

    The subject of the proposed research is fault-related folding and ground deformation. The results are relevant to oil-producing structures throughout the world, to understanding of damage that has been observed along and near earthquake ruptures, and to earthquake-producing structures in California and other tectonically-active areas. The objectives of the proposed research were to provide both a unified, mechanical infrastructure for studies of fault-related foldings and to present the results in computer programs that have graphical users interfaces (GUIs) so that structural geologists and geophysicists can model a wide variety of fault-related folds (FaRFs).

  6. Exploring the mechanisms of protein folding

    CERN Document Server

    Xu, Ji; Ren, Ying; Li, Jinghai

    2013-01-01

    Neither of the two prevalent theories, namely thermodynamic stability and kinetic stability, provides a comprehensive understanding of protein folding. The thermodynamic theory is misleading because it assumes that free energy is the exclusive dominant mechanism of protein folding, and attributes the structural transition from one characteristic state to another to energy barriers. Conversely, the concept of kinetic stability overemphasizes dominant mechanisms that are related to kinetic factors. This article explores the stability condition of protein structures from the viewpoint of meso-science, paying attention to the compromise in the competition between minimum free energy and other dominant mechanisms. Based on our study of complex systems, we propose that protein folding is a meso-scale, dissipative, nonlinear and non-equilibrium process that is dominated by the compromise between free energy and other dominant mechanisms such as environmental factors. Consequently, a protein shows dynamic structures,...

  7. Stretching and folding mechanism in foams

    Energy Technology Data Exchange (ETDEWEB)

    Tufaile, Alberto [Escola de Artes, Ciencias e Humanidades, Soft Matter Laboratory, Universidade de Sao Paulo, 03828-000 Sao Paulo, SP (Brazil)], E-mail: tufaile@usp.br; Pedrosa Biscaia Tufaile, Adriana [Escola de Artes, Ciencias e Humanidades, Soft Matter Laboratory, Universidade de Sao Paulo, 03828-000 Sao Paulo, SP (Brazil)

    2008-10-13

    We have described the stretching and folding of foams in a vertical Hele-Shaw cell containing air and a surfactant solution, from a sequence of upside-down flips. Besides the fractal dimension of the foam, we have observed the logistic growth for the soap film length. The stretching and folding mechanism is present during the foam formation, and this mechanism is observed even after the foam has reached its respective maximum fractal dimension. Observing the motion of bubbles inside the foam, large bubbles present power spectrum associated with random walk motion in both directions, while the small bubbles are scattered like balls in a Galton board.

  8. Modulation of the multistate folding of designed TPR proteins through intrinsic and extrinsic factors.

    Science.gov (United States)

    Phillips, J J; Javadi, Y; Millership, C; Main, E R G

    2012-03-01

    Tetratricopeptide repeats (TPRs) are a class of all alpha-helical repeat proteins that are comprised of 34-aa helix-turn-helix motifs. These stack together to form nonglobular structures that are stabilized by short-range interactions from residues close in primary sequence. Unlike globular proteins, they have few, if any, long-range nonlocal stabilizing interactions. Several studies on designed TPR proteins have shown that this modular structure is reflected in their folding, that is, modular multistate folding is observed as opposed to two-state folding. Here we show that TPR multistate folding can be suppressed to approximate two-state folding through modulation of intrinsic stability or extrinsic environmental variables. This modulation was investigated by comparing the thermodynamic unfolding under differing buffer regimes of two distinct series of consensus-designed TPR proteins, which possess different intrinsic stabilities. A total of nine proteins of differing sizes and differing consensus TPR motifs were each thermally and chemically denatured and their unfolding monitored using differential scanning calorimetry (DSC) and CD/fluorescence, respectively. Analyses of both the DSC and chemical denaturation data show that reducing the total stability of each protein and repeat units leads to observable two-state unfolding. These data highlight the intimate link between global and intrinsic repeat stability that governs whether folding proceeds by an observably two-state mechanism, or whether partial unfolding yields stable intermediate structures which retain sufficient stability to be populated at equilibrium.

  9. Mechanics of large folds in thin interfacial films

    Science.gov (United States)

    Démery, Vincent; Davidovitch, Benny; Santangelo, Christian D.

    2014-10-01

    A thin film confined to a liquid interface responds to uniaxial compression by wrinkling, and then by folding, that has been solved exactly before self-contact. Here, we address the mechanics of large folds, i.e., folds that absorb a length much larger than the wrinkle wavelength. With scaling arguments and numerical simulations, we show that the antisymmetric fold is energetically favorable and can absorb any excess length at zero pressure. Then, motivated by puzzles arising in the comparison of this simple model to experiments on lipid monolayers or capillary rafts, we discuss how to incorporate film weight, self-adhesion, or energy dissipation.

  10. Energy landscapes, folding mechanisms, and kinetics of RNA tetraloop hairpins.

    Science.gov (United States)

    Chakraborty, Debayan; Collepardo-Guevara, Rosana; Wales, David J

    2014-12-31

    RNA hairpins play a pivotal role in a diverse range of cellular functions, and are integral components of ribozymes, mRNA, and riboswitches. However, the mechanistic and kinetic details of RNA hairpin folding, which are key determinants of most of its biological functions, are poorly understood. In this work, we use the discrete path sampling (DPS) approach to explore the energy landscapes of two RNA tetraloop hairpins, and provide insights into their folding mechanisms and kinetics in atomistic detail. Our results show that the potential energy landscapes have a distinct funnel-like bias toward the folded hairpin state, consistent with efficient structure-seeking properties. Mechanistic and kinetic information is analyzed in terms of kinetic transition networks. We find microsecond folding times, consistent with temperature jump experiments, for hairpin folding initiated from relatively compact unfolded states. This process is essentially driven by an initial collapse, followed by rapid zippering of the helix stem in the final phase. Much lower folding rates are predicted when the folding is initiated from extended chains, which undergo longer excursions on the energy landscape before nucleation events can occur. Our work therefore explains recent experiments and coarse-grained simulations, where the folding kinetics exhibit precisely this dependency on the initial conditions.

  11. The X-38 V-201 Fin Fold Actuation Mechanism

    Science.gov (United States)

    Lupo, Christian; Robertson, Brandan; Gafka, George

    2004-01-01

    The X-38 Vehicle 201 (V-201) is a space flight prototype lifting body vehicle that was designed to launch to orbit in the Space Shuttle orbiter payload bay. Although the project was cancelled in May 2003, many of the systems were nearly complete. This paper will describe the fin folding actuation mechanism flight subsystems and development units as well as lessons learned in the design, assembly, development testing, and qualification testing. The two vertical tail fins must be stowed (folded inboard) to allow the orbiter payload bay doors to close. The fin folding actuation mechanism is a remotely or extravehicular activity (EVA) actuated single fault tolerant system consisting of seven subsystems capable of repeatedly deploying or stowing the fins.

  12. Opsin stability and folding: modulation by phospholipid bicelles.

    Science.gov (United States)

    McKibbin, Craig; Farmer, Nicola A; Jeans, Chris; Reeves, Philip J; Khorana, H Gobind; Wallace, B A; Edwards, Patricia C; Villa, Claudio; Booth, Paula J

    2007-12-14

    Integral membrane proteins do not fare well when extracted from biological membranes and are unstable or lose activity in detergents commonly used for structure and function investigations. We show that phospholipid bicelles provide a valuable means of preserving alpha-helical membrane proteins in vitro by supplying a soluble lipid bilayer fragment. Both 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC)/3-[(cholamidopropyl)dimethyl-ammonio]-1-propane sulfonate (Chaps) and DMPC/l-alpha-1,2-dihexanoyl-sn-glycero-3-phosphocholine (DHPC) bicelles dramatically increase the stability of the mammalian vision receptor rhodopsin as well as its apoprotein, opsin. Opsin is particularly unstable in detergent solution but can be directly purified into DMPC/Chaps. We show that opsin can also be directly purified in DMPC/DHPC bicelles to give correctly folded functional opsin, as shown by the ability to regenerate rhodopsin to approximately 70% yield. These well-characterised DMPC/DHPC bicelles enable us to probe the influence of bicelle properties on opsin stability. These bicelles are thought to provide DMPC bilayer fragments with most DHPC capping the bilayer edge, giving a soluble bilayer disc. Opsin stability is shown to be modulated by the q value, the ratio of DMPC to DHPC, which reflects changes in the bicelle size and, thus, proportion of DMPC bilayer present. The observed changes in stability also correlate with loss of opsin secondary structure as determined by synchrotron far-UV circular dichroism spectroscopy; the most stable bicelle results in the least helix loss. The inclusion of Chaps rather than DHPC in the DMPC/Chaps bicelles, however, imparts the greatest stability. This suggests that it is not just the DMPC bilayer fragment in the bicelles that stabilises the protein, but that Chaps provides additional stability either through direct interaction with the protein or by altering the DMPC/Chaps bilayer properties within the bicelle. The significant stability

  13. Fold modulating function: bacterial toxins to functional amyloids

    OpenAIRE

    Adnan Khawaja Syed; Blaise R. Boles

    2014-01-01

    Many bacteria produce cytolytic toxins that target host cells or other competing microbes. It is well known that environmental factors control toxin expression, however, recent work suggests that some bacteria manipulate the fold of these protein toxins to control their function. The β-sheet rich amyloid fold is a highly stable ordered aggregate that many toxins form in response to specific environmental conditions. When in the amyloid state, toxins become inert, losing the cytolytic activity...

  14. Common folds and transport mechanisms of secondary active transporters.

    Science.gov (United States)

    Shi, Yigong

    2013-01-01

    Secondary active transporters exploit the electrochemical potential of solutes to shuttle specific substrate molecules across biological membranes, usually against their concentration gradient. Transporters of different functional families with little sequence similarity have repeatedly been found to exhibit similar folds, exemplified by the MFS, LeuT, and NhaA folds. Observations of multiple conformational states of the same transporter, represented by the LeuT superfamily members Mhp1, AdiC, vSGLT, and LeuT, led to proposals that structural changes are associated with substrate binding and transport. Despite recent biochemical and structural advances, our understanding of substrate recognition and energy coupling is rather preliminary. This review focuses on the common folds and shared transport mechanisms of secondary active transporters. Available structural information generally supports the alternating access model for substrate transport, with variations and extensions made by emerging structural, biochemical, and computational evidence.

  15. Fold modulating function: Bacterial toxins to functional amyloids

    Directory of Open Access Journals (Sweden)

    Adnan Khawaja Syed

    2014-08-01

    Full Text Available Many bacteria produce cytolytic toxins that target host cells or other competing microbes. It is well known that environmental factors control toxin expression, however recent work suggests that some bacteria manipulate the fold of these protein toxins to control their function. The β-sheet rich amyloid fold is a highly stable ordered aggregate that many toxins form in response to specific environmental conditions. When in the amyloid state, toxins become inert, losing the cytolytic activity they display in the soluble form. Emerging evidence suggest that some amyloids function as toxin storage systems until they are again needed, while other bacteria utilize amyloids as a structural matrix component of biofilms. This amyloid matrix component facilitates resistance to biofilm disruptive challenges. The bacterial amyloids discussed in this review reveal an elegant system where changes in protein fold and solubility dictate the function of proteins in response to the environment.

  16. Fold modulating function: bacterial toxins to functional amyloids.

    Science.gov (United States)

    Syed, Adnan K; Boles, Blaise R

    2014-01-01

    Many bacteria produce cytolytic toxins that target host cells or other competing microbes. It is well known that environmental factors control toxin expression, however, recent work suggests that some bacteria manipulate the fold of these protein toxins to control their function. The β-sheet rich amyloid fold is a highly stable ordered aggregate that many toxins form in response to specific environmental conditions. When in the amyloid state, toxins become inert, losing the cytolytic activity they display in the soluble form. Emerging evidence suggest that some amyloids function as toxin storage systems until they are again needed, while other bacteria utilize amyloids as a structural matrix component of biofilms. This amyloid matrix component facilitates resistance to biofilm disruptive challenges. The bacterial amyloids discussed in this review reveal an elegant system where changes in protein fold and solubility dictate the function of proteins in response to the environment.

  17. Cooperative folding of muscle myosins: I. Mechanical model

    CERN Document Server

    Caruel, Matthieu; Truskinovsky, Lev

    2013-01-01

    Mechanically induced folding of passive cross-linkers is a fundamental biological phenomenon. A typical example is a conformational change in myosin II responsible for the power-stroke in skeletal muscles. In this paper we present an athermal perspective on such folding by analyzing the simplest purely mechanical prototype: a parallel bundle of bi-stable units attached to a common backbone. We show that in this analytically transparent model, characterized by a rugged energy landscape, the ground states are always highly coherent, single-phase configurations. We argue that such cooperative behavior, ensuring collective conformational change, is due to the dominance of long- range interactions making the system non-additive. The detailed predictions of our model are in agreement with experimentally observed non-equivalence of fast force recovery in skeletal muscles loaded in soft and hard devices. Some features displayed by the model are also recognizable in the behavior of other biological systems with passiv...

  18. Insights into Coupled Folding and Binding Mechanisms from Kinetic Studies.

    Science.gov (United States)

    Shammas, Sarah L; Crabtree, Michael D; Dahal, Liza; Wicky, Basile I M; Clarke, Jane

    2016-03-25

    Intrinsically disordered proteins (IDPs) are characterized by a lack of persistent structure. Since their identification more than a decade ago, many questions regarding their functional relevance and interaction mechanisms remain unanswered. Although most experiments have taken equilibrium and structural perspectives, fewer studies have investigated the kinetics of their interactions. Here we review and highlight the type of information that can be gained from kinetic studies. In particular, we show how kinetic studies of coupled folding and binding reactions, an important class of signaling event, are needed to determine mechanisms.

  19. Glycoprotein folding and quality-control mechanisms in protein-folding diseases

    Directory of Open Access Journals (Sweden)

    Sean P. Ferris

    2014-03-01

    Full Text Available Biosynthesis of proteins – from translation to folding to export – encompasses a complex set of events that are exquisitely regulated and scrutinized to ensure the functional quality of the end products. Cells have evolved to capitalize on multiple post-translational modifications in addition to primary structure to indicate the folding status of nascent polypeptides to the chaperones and other proteins that assist in their folding and export. These modifications can also, in the case of irreversibly misfolded candidates, signal the need for dislocation and degradation. The current Review focuses on the glycoprotein quality-control (GQC system that utilizes protein N-glycosylation and N-glycan trimming to direct nascent glycopolypeptides through the folding, export and dislocation pathways in the endoplasmic reticulum (ER. A diverse set of pathological conditions rooted in defective as well as over-vigilant ER quality-control systems have been identified, underlining its importance in human health and disease. We describe the GQC pathways and highlight disease and animal models that have been instrumental in clarifying our current understanding of these processes.

  20. Mechanisms of CFTR folding at the endoplasmic reticulum

    Directory of Open Access Journals (Sweden)

    Soo Jung Kim

    2012-12-01

    Full Text Available In the past decade much has been learned about how CFTR folds and misfolds as the etiologic cause of cystic fibrosis (CF. CFTR folding is complex and hierarchical, takes place in multiple cellular compartments and physical environments, and involves several large networks of folding machineries. Insertion of transmembrane (TM segments into the endoplasmic reticulum (ER membrane and tertiary folding of cytosolic domains begin cotranslationally as the nascent polypeptide emerges from the ribosome, whereas posttranslational folding establishes critical domain-domain contacts needed to form a physiologically stable structure. Within the membrane, N- and C-terminal TM helices are sorted into bundles that project from the cytosol to form docking sites for nucleotide binding domains, NBD1 and NBD2, which in turn form a sandwich dimer for ATP binding. While tertiary folding is required for domain assembly, proper domain assembly also reciprocally affects folding of individual domains analogous to a jigsaw puzzle wherein the structure of each interlocking piece influences its neighbors. Superimposed on this process is an elaborate proteostatic network of cellular chaperones and folding machineries that facilitate the timing and coordination of specific folding steps in and across the ER membrane. While the details of this process require further refinement, we finally have a useful framework to understand key folding defect(s caused by ∆F508 that provides a molecular target(s for the next generation of CFTR small molecule correctors aimed at the specific defect present in the majority of CF patients.

  1. Structural Characterization of the Early Events in the Nucleation-Condensation Mechanism in a Protein Folding Process.

    Science.gov (United States)

    Kukic, Predrag; Pustovalova, Yulia; Camilloni, Carlo; Gianni, Stefano; Korzhnev, Dmitry M; Vendruscolo, Michele

    2017-05-24

    The nucleation-condensation mechanism represents a major paradigm to understand the folding process of many small globular proteins. Although substantial evidence has been acquired for this mechanism, it has remained very challenging to characterize the initial events leading to the formation of a folding nucleus. To achieve this goal, we used a combination of relaxation dispersion NMR spectroscopy and molecular dynamics simulations to determine ensembles of conformations corresponding to the denatured, transition, and native states in the folding of the activation domain of human procarboxypeptidase A2 (ADA2h). We found that the residues making up the folding nucleus tend to interact in the denatured state in a transient manner and not simultaneously, thereby forming incomplete and distorted versions of the folding nucleus. Only when all the contacts between these key residues are eventually formed can the protein reach the transition state and continue folding. Overall, our results elucidate the mechanism of formation of the folding nucleus of a protein and provide insights into how its folding rate can be modified during evolution by mutations that modulate the strength of the interactions between the residues forming the folding nucleus.

  2. Intradomain Confinement of Disulfides in the Folding of Two Consecutive Modules of the LDL Receptor

    Science.gov (United States)

    Martínez-Oliván, Juan; Fraga, Hugo; Arias-Moreno, Xabier; Ventura, Salvador; Sancho, Javier

    2015-01-01

    The LDL receptor internalizes circulating LDL and VLDL particles for degradation. Its extracellular binding domain contains ten (seven LA and three EGF) cysteine-rich modules, each bearing three disulfide bonds. Despite the enormous number of disulfide combinations possible, LDLR oxidative folding leads to a single native species with 30 unique intradomain disulfides. Previous folding studies of the LDLR have shown that non native disulfides are initially formed that lead to compact species. Accordingly, the folding of the LDLR has been described as a "coordinated nonvectorial” reaction, and it has been proposed that early compaction funnels the reaction toward the native structure. Here we analyze the oxidative folding of LA4 and LA5, the modules critical for ApoE binding, isolated and in the LA45 tandem. Compared to LA5, LA4 folding is slow and inefficient, resembling that of LA5 disease-linked mutants. Without Ca++, it leads to a mixture of many two-disulfide scrambled species and, with Ca++, to the native form plus two three-disulfide intermediates. The folding of the LA45 tandem seems to recapitulate that of the individual repeats. Importantly, although the folding of the LA45 tandem takes place through formation of scrambled isomers, no interdomain disulfides are detected, i.e. the two adjacent modules fold independently without the assistance of interdomain covalent interactions. Reduction of incredibly large disulfide combinatorial spaces, such as that in the LDLR, by intradomain confinement of disulfide bond formation might be also essential for the efficient folding of other homologous disulfide-rich receptors. PMID:26168158

  3. A new zinc binding fold underlines the versatility of zinc binding modules in protein evolution.

    Science.gov (United States)

    Sharpe, Belinda K; Matthews, Jacqueline M; Kwan, Ann H Y; Newton, Anthea; Gell, David A; Crossley, Merlin; Mackay, Joel P

    2002-05-01

    Many different zinc binding modules have been identified. Their abundance and variety suggests that the formation of zinc binding folds might be relatively common. We have determined the structure of CH1(1), a 27-residue peptide derived from the first cysteine/histidine-rich region (CH1) of CREB binding protein (CBP). This peptide forms a highly ordered zinc-dependent fold that is distinct from known folds. The structure differs from a subsequently determined structure of a larger region from the CH3 region of CBP, and the CH1(1) fold probably represents a nonphysiologically active form. Despite this, the fold is thermostable and tolerant to both multiple alanine mutations and changes in the zinc-ligand spacing. Our data support the idea that zinc binding domains may arise frequently. Additionally, such structures may prove useful as scaffolds for protein design, given their stability and robustness.

  4. When fast is better: protein folding fundamentals and mechanisms from ultrafast approaches.

    Science.gov (United States)

    Muñoz, Victor; Cerminara, Michele

    2016-09-01

    Protein folding research stalled for decades because conventional experiments indicated that proteins fold slowly and in single strokes, whereas theory predicted a complex interplay between dynamics and energetics resulting in myriad microscopic pathways. Ultrafast kinetic methods turned the field upside down by providing the means to probe fundamental aspects of folding, test theoretical predictions and benchmark simulations. Accordingly, experimentalists could measure the timescales for all relevant folding motions, determine the folding speed limit and confirm that folding barriers are entropic bottlenecks. Moreover, a catalogue of proteins that fold extremely fast (microseconds) could be identified. Such fast-folding proteins cross shallow free energy barriers or fold downhill, and thus unfold with minimal co-operativity (gradually). A new generation of thermodynamic methods has exploited this property to map folding landscapes, interaction networks and mechanisms at nearly atomic resolution. In parallel, modern molecular dynamics simulations have finally reached the timescales required to watch fast-folding proteins fold and unfold in silico All of these findings have buttressed the fundamentals of protein folding predicted by theory, and are now offering the first glimpses at the underlying mechanisms. Fast folding appears to also have functional implications as recent results connect downhill folding with intrinsically disordered proteins, their complex binding modes and ability to moonlight. These connections suggest that the coupling between downhill (un)folding and binding enables such protein domains to operate analogically as conformational rheostats.

  5. The Fast-Folding Mechanism of Villin Headpiece Subdomain Studied by Multiscale Distributed Computing.

    Science.gov (United States)

    Harada, Ryuhei; Kitao, Akio

    2012-01-10

    The fast-folding mechanism of a 35-residue mini-protein, villin headpiece subdomain (HP35), was investigated using folding free energy landscape analysis with the multiscale free energy landscape calculation method (MSFEL). A major and a minor folding pathway were deduced from the folding free energy landscape. In the major folding pathway, the formation of helices II and III was the rate-limiting step in the transition to an intermediate state, triggered by the folding of the PLWK motif. HP35 then folds into the native structure through the formation of the hydrophobic core located at the center of the three-helix bundle. Mutations in the motif and hydrophobic core that suppressed folding into the native state drastically changed the folding free energy landscape compared to the wild type protein. In the minor folding pathway, nucleation of the hydrophobic core preceded formation of the motif.

  6. Mechanical Modeling and Computer Simulation of Protein Folding

    Science.gov (United States)

    Prigozhin, Maxim B.; Scott, Gregory E.; Denos, Sharlene

    2014-01-01

    In this activity, science education and modern technology are bridged to teach students at the high school and undergraduate levels about protein folding and to strengthen their model building skills. Students are guided from a textbook picture of a protein as a rigid crystal structure to a more realistic view: proteins are highly dynamic…

  7. Impaired folding and subunit assembly as disease mechanism

    DEFF Research Database (Denmark)

    Bross, P; Andresen, B S; Gregersen, N

    1998-01-01

    mutations. Characterization of the effect of these mutations is particularly important in order to establish that they are disease causing and to estimate their severity. We use the experiences with investigation of medium-chain acyl-CoA dehydrogenase deficiency as an example to illustrate that (i) impaired......Rapid progress in DNA technology has entailed the possibility of readily detecting mutations in disease genes. In contrast to this, techniques to characterize the effects of mutations are still very time consuming. It has turned out that many of the mutations detected in disease genes are missense...... folding is a common effect of missense mutations occurring in genetic diseases, (ii) increasing the level of available chaperones may augment the level of functional mutant protein in vivo, and (iii) one mutation may have multiple effects. The interplay between the chaperones assisting folding...

  8. Geometries and mechanism of folds in sediments on the southern Huanghai Sea shelf

    Institute of Scientific and Technical Information of China (English)

    LI Xishuang; LIU Baohua; ZHAO Yuexia; LI Sanzhong

    2006-01-01

    Most descriptions and studies about folds have been associated with consolidated strata; fold deformation in loosely-consolidated sediments, however, has been rarely discussed. Since the Pleistocene, tectonic activities have been intensive over the South Huanghai Sea (SHS) shelf, resulting in fold deformation features that are preserved in thick sediment layers. Four types of folds with different geometries have been identified on the basis of an analysis of single-channel seismic profiles from the SHS shelf region: (1) fault-propagation fold; (2) fault-drag fold; (3) transversal bending fold; and (4) multi-action-folding fold. Studies on the geometry and mechanism of the folds indicate that base faults and fault blocks control the folding patterns in loosely-consolidated sediments on the SHS shelf and a large quantity of pore water in sediments plays an important role in cansing the deformation of sediment layers. The continuity of deformations of fault-propagation fold and fault-drag fold indicates that there is a genetic relationship between these fold types. The potential of earthquakes induced by fault-propagation folding in the deformation zone should be taken into account in the assessment of the marine engineering geology conditions of the SHS shelf.

  9. From mechanical folding trajectories to intrinsic energy landscapes of biopolymers

    Science.gov (United States)

    Hinczewski, Michael; Gebhardt, J. Christof M.; Rief, Matthias; Thirumalai, D.

    2013-01-01

    In single-molecule laser optical tweezer (LOT) pulling experiments, a protein or RNA is juxtaposed between DNA handles that are attached to beads in optical traps. The LOT generates folding trajectories under force in terms of time-dependent changes in the distance between the beads. How to construct the full intrinsic folding landscape (without the handles and beads) from the measured time series is a major unsolved problem. By using rigorous theoretical methods—which account for fluctuations of the DNA handles, rotation of the optical beads, variations in applied tension due to finite trap stiffness, as well as environmental noise and limited bandwidth of the apparatus—we provide a tractable method to derive intrinsic free-energy profiles. We validate the method by showing that the exactly calculable intrinsic free-energy profile for a generalized Rouse model, which mimics the two-state behavior in nucleic acid hairpins, can be accurately extracted from simulated time series in a LOT setup regardless of the stiffness of the handles. We next apply the approach to trajectories from coarse-grained LOT molecular simulations of a coiled-coil protein based on the GCN4 leucine zipper and obtain a free-energy landscape that is in quantitative agreement with simulations performed without the beads and handles. Finally, we extract the intrinsic free-energy landscape from experimental LOT measurements for the leucine zipper. PMID:23487746

  10. Mechanical models of amplitude and frequency modulation

    Energy Technology Data Exchange (ETDEWEB)

    Bellomonte, L; Guastella, I; Sperandeo-Mineo, R M [GRIAF - Research Group on Teaching/Learning Physics, DI.F.TE.R. -Dipartimento di Fisica e Tecnologie Relative, University of Palermo, Viale delle Scienze, Edificio 18, 90128 Palermo (Italy)

    2005-05-01

    This paper presents some mechanical models for amplitude and frequency modulation. The equations governing both modulations are deduced alongside some necessary approximations. Computer simulations of the models are carried out by using available educational software. Amplitude modulation is achieved by using a system of two weakly coupled pendulums, whereas the frequency modulation is obtained by using a pendulum of variable length. Under suitable conditions (small oscillations, appropriate initial conditions, etc) both types of modulation result in significantly accurate and visualized simulations.

  11. Single-molecule folding mechanism of an EF-hand neuronal calcium sensor

    DEFF Research Database (Denmark)

    Heidarsson, P.O.; Otazo, M.R.; Bellucci, L.

    2013-01-01

    EF-hand calcium sensors respond structurally to changes in intracellular Ca2+ concentration, triggering diverse cellular responses and resulting in broad interactomes. Despite impressive advances in decoding their structure-function relationships, the folding mechanism of neuronal calcium sensors...... is still elusive. We used single-molecule optical tweezers to study the folding mechanism of the human neuronal calcium sensor 1 (NCS1). Two intermediate structures induced by Ca2+ binding to the EF-hands were observed during refolding. The complete folding of the C domain is obligatory for the folding...

  12. Extracting folding landscape characteristics of biomolecules using mechanical forces

    OpenAIRE

    2015-01-01

    In recent years single molecule force spectroscopy has opened a new avenue to provide profiles of the complex energy landscape of biomolecules. In this field, quantitative analyses of the data employing sound theoretical models, have played a major role in interpreting data and anticipating outcomes of experiments. Here, we explain how by using temperature as a variable in mechanical unfolding of biomolecules in force spectroscopy, the roughness of the energy landscape can be measured without...

  13. Bend, buckle, and fold: mechanical engineering with nanomembranes.

    Science.gov (United States)

    Kim, Dae-Hyeong; Rogers, John A

    2009-03-24

    Research on nanomembranes and graphene sheets represents the "third wave" of work on nanomaterials, following earlier studies of nanoparticles/fullerenes and, somewhat later, nanowires/nanotubes. Inorganic semiconductor nanomembranes are particularly appealing due to their materials diversity, the ease with which they can be grown with high quality over large areas, and the ability to exploit them in unique, high-performance electronic and optoelectronic systems. The mechanics of such nanomembranes and the coupling of strain to their electronic properties are topics of considerable current interest. A new paper by the Lagally group in this issue combines single-crystalline silicon nanomembranes with chemical vapor deposition techniques to form "mechano-electronic" superlattices whose properties could lead to unusual classes of electronic devices.

  14. Buttressing a new paradigm in protein folding: experimental tools to distinguish between downhill and multi-state folding mechanisms

    OpenAIRE

    Nagalakshmi, Tiruvarur Sooriyanarayanan

    2014-01-01

    Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biologíoa Molecular. Fecha de lectura: 15-07-2014 Many single-domain proteins fold in milliseconds or longer. However, the advent of fast folding kinetic techniques has permitted to identify many other proteins that fold in the order of (few) microseconds and thus very closely to the folding speed limit. This suggests that the proteins that fold in microsecond timescale either ...

  15. A bioreactor for the dynamic mechanical stimulation of vocal-fold fibroblasts based on vibro-acoustography

    Science.gov (United States)

    Chan, Roger W.; Rodriguez, Maritza

    2005-09-01

    During voice production, the vocal folds undergo airflow-induced self-sustained oscillation at a fundamental frequency of around 100-1000 Hz, with an amplitude of around 1-3 mm. The vocal-fold extracellular matrix (ECM), with appropriate tissue viscoelastic properties, is optimally tuned for such vibration. Vocal-fold fibroblasts regulate the gene expressions for key ECM proteins (e.g., collagen, fibronectin, fibromodulin, and hyaluronic acid), and these expressions are affected by the stress fields experi- enced by the fibroblasts. This study attempts to develop a bioreactor for cultivating cells under a micromechanical environment similar to that in vivo, based on the principle of vibro-acoustography. Vocal-fold fibroblasts from primary culture were grown in 3D, biodegradable scaffolds, and were excited dynamically by the radiation force generated by amplitude modulation of two confocal ultrasound beams of slightly different frequencies. Low-frequency acoustic radiation force was applied to the scaffold surface, and its vibratory response was imaged by videostroboscopy. A phantom tissue (standard viscoelastic material) with known elastic modulus was also excited and its vibratory frequency and amplitude were measured by videostroboscopy. Results showed that the bioreactor was capable of delivering mechanical stimuli to the tissue constructs in a physiological frequency range (100-1000 Hz), supporting its potential for vocal-fold tissue engineering applications. [Work supported by NIH Grant R01 DC006101.

  16. Mechanical versus kinematical shortening reconstructions of the Zagros High Folded Zone (Kurdistan region of Iraq)

    Science.gov (United States)

    Frehner, Marcel; Reif, Daniel; Grasemann, Bernhard

    2012-06-01

    This paper compares kinematical and mechanical techniques for the palinspastic reconstruction of folded cross sections in collision orogens. The studied area and the reconstructed NE-SW trending, 55.5 km long cross section is located in the High Folded Zone of the Zagros fold-and-thrust belt in the Kurdistan region of Iraq. The present-day geometry of the cross section has been constructed from field as well as remote sensing data. In a first step, the structures and the stratigraphy are simplified and summarized in eight units trying to identify the main geometric and mechanical parameters. In a second step, the shortening is kinematically estimated using the dip domain method to 11%-15%. Then the same cross section is used in a numerical finite element model to perform dynamical unfolding simulations taking various rheological parameters into account. The main factor allowing for an efficient dynamic unfolding is the presence of interfacial slip conditions between the mechanically strong units. Other factors, such as Newtonian versus power law viscous rheology or the presence of a basement, affect the numerical simulations much less strongly. If interfacial slip is accounted for, fold amplitudes are reduced efficiently during the dynamical unfolding simulations, while welded layer interfaces lead to unrealistic shortening estimates. It is suggested that interfacial slip and decoupling of the deformation along detachment horizons is an important mechanical parameter that controlled the folding processes in the Zagros High Folded Zone.

  17. Folded-Cavity Resonators as Key Elements for Optical Filtering and Low-Voltage Electroabsorption Modulation

    Science.gov (United States)

    Djordjev, Kostadin D.; Lin, Chao-Kun; Zhu, Jintian; Bour, David; Tan, Michael R.

    2006-09-01

    Folded-cavity (FC) resonators, which are based on shallow-etched ridge waveguides combined with four deeply etched turning mirrors, are designed and fabricated. The device consists of a resonant FC and a bus waveguide coupled to it through a directional coupler. Optical passive filters, based on this technology, exhibit quality factors in the excess of 5000, with a low insertion loss of 5 dB (including the input coupling loss to a fiber) and more than 15-dB extinction at resonance. When the filter is combined with an electroabsorption active region and is designed to operate in the overcoupled regime, a low-voltage/high-extinction-ratio resonant modulation becomes feasible. The resonant modulator exhibits a low insertion loss (greater than 22-dB extinction at resonance) and offers a low-voltage operation. A change in the applied voltage by 0.7 V (close to the critically coupled conditions) leads to a transmission change of more than 16 dB. Open eye diagrams at 12 Gb/s are presented. To decrease the insertion loss, multiple material bangaps are further monolithically integrated across the wafer by utilizing the quantum-well-intermixing techniques.

  18. Tractor Mechanic Check Sheets for Modules.

    Science.gov (United States)

    Clemson Univ., SC. Vocational Education Media Center.

    Forms for student self-checks and the instructor's final checklist (student evaluation) are provided for use with thirty-three learning modules on maintaining and servicing fuel and electrical systems in tractor mechanics. The student self-check asks the students questions about their understanding of the modules' content. The instructor's…

  19. From the endoplasmic reticulum to the plasma membrane: mechanisms of CFTR folding and trafficking.

    Science.gov (United States)

    Farinha, Carlos M; Canato, Sara

    2017-01-01

    CFTR biogenesis starts with its co-translational insertion into the membrane of endoplasmic reticulum and folding of the cytosolic domains, towards the acquisition of a fully folded compact native structure. Efficiency of this process is assessed by the ER quality control system that allows the exit of folded proteins but targets unfolded/misfolded CFTR to degradation. If allowed to leave the ER, CFTR is modified at the Golgi and reaches the post-Golgi compartments to be delivered to the plasma membrane where it functions as a cAMP- and phosphorylation-regulated chloride/bicarbonate channel. CFTR residence at the membrane is a balance of membrane delivery, endocytosis, and recycling. Several adaptors, motor, and scaffold proteins contribute to the regulation of CFTR stability and are involved in continuously assessing its structure through peripheral quality control systems. Regulation of CFTR biogenesis and traffic (and its dysregulation by mutations, such as the most common F508del) determine its overall activity and thus contribute to the fine modulation of chloride secretion and hydration of epithelial surfaces. This review covers old and recent knowledge on CFTR folding and trafficking from its synthesis to the regulation of its stability at the plasma membrane and highlights how several of these steps can be modulated to promote the rescue of mutant CFTR.

  20. Ring Separation Highlights the Protein-Folding Mechanism Used by the Phage EL-Encoded Chaperonin.

    Science.gov (United States)

    Molugu, Sudheer K; Hildenbrand, Zacariah L; Morgan, David Gene; Sherman, Michael B; He, Lilin; Georgopoulos, Costa; Sernova, Natalia V; Kurochkina, Lidia P; Mesyanzhinov, Vadim V; Miroshnikov, Konstantin A; Bernal, Ricardo A

    2016-04-05

    Chaperonins are ubiquitous, ATP-dependent protein-folding molecular machines that are essential for all forms of life. Bacteriophage φEL encodes its own chaperonin to presumably fold exceedingly large viral proteins via profoundly different nucleotide-binding conformations. Our structural investigations indicate that ATP likely binds to both rings simultaneously and that a misfolded substrate acts as the trigger for ATP hydrolysis. More importantly, the φEL complex dissociates into two single rings resulting from an evolutionarily altered residue in the highly conserved ATP-binding pocket. Conformational changes also more than double the volume of the single-ring internal chamber such that larger viral proteins are accommodated. This is illustrated by the fact that φEL is capable of folding β-galactosidase, a 116-kDa protein. Collectively, the architecture and protein-folding mechanism of the φEL chaperonin are significantly different from those observed in group I and II chaperonins.

  1. Modulation of STAT3 folding and function by TRiC/CCT chaperonin.

    Directory of Open Access Journals (Sweden)

    Moses Kasembeli

    2014-04-01

    Full Text Available Signal transducer and activator of transcription 3 (Stat3 transduces signals of many peptide hormones from the cell surface to the nucleus and functions as an oncoprotein in many types of cancers, yet little is known about how it achieves its native folded state within the cell. Here we show that Stat3 is a novel substrate of the ring-shaped hetero-oligomeric eukaryotic chaperonin, TRiC/CCT, which contributes to its biosynthesis and activity in vitro and in vivo. TRiC binding to Stat3 was mediated, at least in part, by TRiC subunit CCT3. Stat3 binding to TRiC mapped predominantly to the β-strand rich, DNA-binding domain of Stat3. Notably, enhancing Stat3 binding to TRiC by engineering an additional TRiC-binding domain from the von Hippel-Lindau protein (vTBD, at the N-terminus of Stat3, further increased its affinity for TRiC as well as its function, as determined by Stat3's ability to bind to its phosphotyrosyl-peptide ligand, an interaction critical for Stat3 activation. Thus, Stat3 levels and function are regulated by TRiC and can be modulated by manipulating its interaction with TRiC.

  2. Universality and diversity of folding mechanics for three-helix bundle proteins.

    Science.gov (United States)

    Yang, Jae Shick; Wallin, Stefan; Shakhnovich, Eugene I

    2008-01-22

    In this study we evaluate, at full atomic detail, the folding processes of two small helical proteins, the B domain of protein A and the Villin headpiece. Folding kinetics are studied by performing a large number of ab initio Monte Carlo folding simulations using a single transferable all-atom potential. Using these trajectories, we examine the relaxation behavior, secondary structure formation, and transition-state ensembles (TSEs) of the two proteins and compare our results with experimental data and previous computational studies. To obtain a detailed structural information on the folding dynamics viewed as an ensemble process, we perform a clustering analysis procedure based on graph theory. Moreover, rigorous p(fold) analysis is used to obtain representative samples of the TSEs and a good quantitative agreement between experimental and simulated Phi values is obtained for protein A. Phi values for Villin also are obtained and left as predictions to be tested by future experiments. Our analysis shows that the two-helix hairpin is a common partially stable structural motif that gets formed before entering the TSE in the studied proteins. These results together with our earlier study of Engrailed Homeodomain and recent experimental studies provide a comprehensive, atomic-level picture of folding mechanics of three-helix bundle proteins.

  3. Mechanical modulation of cardiac microtubules.

    Science.gov (United States)

    White, Ed

    2011-07-01

    Microtubules are a major component of the cardiac myocyte cytoskeleton. Interventions that alter it may influence cardiac mechanical and electrical activity by disrupting the trafficking of proteins to and from the surface membrane by molecular motors such as dynein, which use microtubules as tracks to step along. Free tubulin dimers may transfer GTP to the α-subunits of G-proteins, thus an increase in free tubulin could increase the activity of G-proteins; evidence for and against such a role exists. There is more general agreement that microtubules act as compression-resisting structures within myocytes, influencing visco-elasticity of myocytes and increasing resistance to shortening when proliferated and resisting deformation from longitudinal shear stress. In response to pressure overload, there can be post-translational modifications resulting in more stable microtubules and an increase in microtubule density. This is accompanied by contractile dysfunction of myocytes which can be reversed by microtubule disruption. There are reports of mechanically induced changes in electrical activity that are dependent upon microtubules, but at present, a consensus is lacking on whether disruption or proliferation would be beneficial in the prevention of arrhythmias. Microtubules certainly play a role in the response of cardiac myocytes to mechanical stimulation, the exact nature and significance of this role is still to be fully determined.

  4. Comparison of the Folding Mechanism of Highly Homologous Proteins in the Lipid-binding Protein Family

    Science.gov (United States)

    The folding mechanism of two closely related proteins in the intracellular lipid binding protein family, human bile acid binding protein (hBABP) and rat bile acid binding protein (rBABP) were examined. These proteins are 77% identical (93% similar) in sequence Both of these singl...

  5. Comparison of the Folding Mechanism of Highly Homologous Proteins in the Lipid-binding Protein Family

    Science.gov (United States)

    The folding mechanism of two closely related proteins in the intracellular lipid binding protein family, human bile acid binding protein (hBABP) and rat bile acid binding protein (rBABP) were examined. These proteins are 77% identical (93% similar) in sequence Both of these singl...

  6. Detecting Selection on Protein Stability through Statistical Mechanical Models of Folding and Evolution

    Directory of Open Access Journals (Sweden)

    Ugo Bastolla

    2014-03-01

    Full Text Available The properties of biomolecules depend both on physics and on the evolutionary process that formed them. These two points of view produce a powerful synergism. Physics sets the stage and the constraints that molecular evolution has to obey, and evolutionary theory helps in rationalizing the physical properties of biomolecules, including protein folding thermodynamics. To complete the parallelism, protein thermodynamics is founded on the statistical mechanics in the space of protein structures, and molecular evolution can be viewed as statistical mechanics in the space of protein sequences. In this review, we will integrate both points of view, applying them to detecting selection on the stability of the folded state of proteins. We will start discussing positive design, which strengthens the stability of the folded against the unfolded state of proteins. Positive design justifies why statistical potentials for protein folding can be obtained from the frequencies of structural motifs. Stability against unfolding is easier to achieve for longer proteins. On the contrary, negative design, which consists in destabilizing frequently formed misfolded conformations, is more difficult to achieve for longer proteins. The folding rate can be enhanced by strengthening short-range native interactions, but this requirement contrasts with negative design, and evolution has to trade-off between them. Finally, selection can accelerate functional movements by favoring low frequency normal modes of the dynamics of the native state that strongly correlate with the functional conformation change.

  7. New light on protein folding: Unraveling folding and unfolding mechanisms using time-resolved and two-dimensional vibrational spectroscopy

    NARCIS (Netherlands)

    H. Meuzelaar

    2015-01-01

    How a protein folds from its one-dimensional sequence of amino acids into its three-dimensional, functional structure on biologically relevant time scales (typically on the micro- to millisecond time scale) is one of the most challenging questions currently investigated in several scientific discipl

  8. New light on protein folding: Unraveling folding and unfolding mechanisms using time-resolved and two-dimensional vibrational spectroscopy

    NARCIS (Netherlands)

    Meuzelaar, H.

    2015-01-01

    How a protein folds from its one-dimensional sequence of amino acids into its three-dimensional, functional structure on biologically relevant time scales (typically on the micro- to millisecond time scale) is one of the most challenging questions currently investigated in several scientific

  9. Field failure mechanisms for photovoltaic modules

    Science.gov (United States)

    Dumas, L. N.; Shumka, A.

    1981-01-01

    Beginning in 1976, Department of Energy field centers have installed and monitored a number of field tests and application experiments using current state-of-the-art photovoltaic modules. On-site observations of module physical and electrical degradation, together with in-depth laboratory analysis of failed modules, permits an overall assessment of the nature and causes of early field failures. Data on failure rates are presented, and key failure mechanisms are analyzed with respect to origin, effect, and prospects for correction. It is concluded that all failure modes identified to date are avoidable or controllable through sound design and production practices.

  10. Single-molecule folding mechanism of an EF-hand neuronal calcium sensor

    DEFF Research Database (Denmark)

    Heidarsson, P.O.; Otazo, M.R.; Bellucci, L.;

    2013-01-01

    of the N domain, showing striking interdomain dependence. Molecular dynamics results reveal the atomistic details of the unfolding process and rationalize the different domain stabilities during mechanical unfolding. Through constant-force experiments and hidden Markov model analysis, the free energy...... landscape of the protein was reconstructed. Our results emphasize that NCS1 has evolved a remarkable complex interdomain cooperativity and a fundamentally different folding mechanism compared to structurally related proteins....

  11. Downhill versus two-state protein folding in a statistical mechanical model

    Science.gov (United States)

    Bruscolini, Pierpaolo; Pelizzola, Alessandro; Zamparo, Marco

    2007-06-01

    The authors address the problem of downhill protein folding in the framework of a simple statistical mechanical model, which allows an exact solution for the equilibrium and a semianalytical treatment of the kinetics. Focusing on protein 1BBL, a candidate for downhill folding behavior, and comparing it to the WW domain of protein PIN1, a two-state folder of comparable size, the authors show that there are qualitative differences in both the equilibrium and kinetic properties of the two molecules. However, the barrierless scenario which would be expected if 1BBL were a true downhill folder is observed only at low enough temperature.

  12. Histaminergic Mechanisms for Modulation of Memory Systems

    Directory of Open Access Journals (Sweden)

    Cristiano André Köhler

    2011-01-01

    Full Text Available Encoding for several memory types requires neural changes and the activity of distinct regions across the brain. These areas receive broad projections originating in nuclei located in the brainstem which are capable of modulating the activity of a particular area. The histaminergic system is one of the major modulatory systems, and it regulates basic homeostatic and higher functions including arousal, circadian, and feeding rhythms, and cognition. There is now evidence that histamine can modulate learning in different types of behavioral tasks, but the exact course of modulation and its mechanisms are controversial. In the present paper we review the involvement of the histaminergic system and the effects histaminergic receptor agonists/antagonists have on the performance of tasks associated with the main memory types as well as evidence provided by studies with knockout models. Thus, we aim to summarize the possible effects histamine has on modulation of circuits involved in memory formation.

  13. Optomechanical laser cooling with mechanical modulations

    OpenAIRE

    Bienert, Marc; Barberis-Blostein, Pablo

    2014-01-01

    We theoretically study the laser cooling of cavity optomechanics when the mechanical resonance frequency and damping depend on time. In the regime of weak optomechanical coupling we extend the theory of laser cooling using an adiabatic approximation. We discuss the modifications of the cooling dynamics and compare it with numerical simulations in a wide range of modulation frequencies.

  14. Catastrophe mechanism & classification of discontinuity behavior in thermal science (Ⅰ) --Fold catastrophe

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    The mechanism of discontinuity behavior has important significance in the study of thermal science,such as fire,combustion,explosion and heat transfer.This sort of discontinuity behavior and the catastrophe caused by system nonlinearity may be equivalently classified according to the catastrophe model promulgated by catastrophe theory.Under the conditions of uniform temperature and thermal isolation,the self-ignition behavior of a Semenov System can be viewed as a result of the fold catastrophe of the system.

  15. Optical Measurements of Vocal Fold Tensile Properties: Implications for Phonatory Mechanics

    Science.gov (United States)

    Kelleher, Jordan E.; Siegmund, Thomas; Chan, Roger W.; Henslee, Erin A.

    2011-01-01

    In voice research, in vitro tensile stretch experiments of vocal fold tissues are commonly employed to determine the tissue biomechanical properties. In the standard stretch-release protocol, tissue deformation is computed from displacements applied to sutures inserted through the thyroid and arytenoid cartilages, with the cartilages assumed to be rigid. Here, a non-contact optical method was employed to determine the actual tissue deformation of vocal fold lamina propria specimens from three excised human larynges in uniaxial tensile tests. Specimen deformation was found to consist not only of deformation of the tissue itself, but also deformation of the cartilages, as well as suture alignment and tightening. Stress-stretch curves of a representative load cycle were characterized by an incompressible Ogden model. The initial longitudinal elastic modulus was found to be considerably higher if determined based on optical displacement measurements than typical values reported in the literature. The present findings could change the understanding of the mechanics underlying vocal fold vibration. Given the high longitudinal elastic modulus the lamina propria appeared to demonstrate a substantial level of anisotropy. Consequently, transverse shear could play a significant role in vocal fold vibration, and fundamental frequencies of phonation should be predicted by beam theories accounting for such effects. PMID:21497355

  16. Single-Molecule Approaches for the Characterization of Riboswitch Folding Mechanisms.

    Science.gov (United States)

    Boudreault, Julien; Perez-Gonzalez, D Cibran; Penedo, J Carlos; Lafontaine, Daniel A

    2015-01-01

    Riboswitches are highly structured RNA molecules that control genetic expression by altering their structure as a function of metabolite binding. Accumulating evidence suggests that riboswitch structures are highly dynamic and perform conformational exchange between structural states that are important for the outcome of genetic regulation. To understand how ligand binding influences the folding of riboswitches, it is important to monitor in real time the riboswitch folding pathway as a function of experimental conditions. Single-molecule FRET (sm-FRET) is unique among biophysical techniques to study riboswitch conformational changes as it allows to both monitor steady-state populations of riboswitch conformers and associated interconversion dynamics. Since FRET fluorophores can be attached to virtually any nucleotide position, FRET assays can be adapted to monitor specific conformational changes, thus enabling to deduce complex riboswitch folding pathways. Herein, we show how to employ sm-FRET to study the folding pathway of the S-adenosylmethionine (SAM) and how this can be used to understand very specific conformational changes that are at the heart of riboswitch regulation mechanism.

  17. Mechanism of Coupled Folding and Binding in the siRNA-PAZ Complex.

    Science.gov (United States)

    Chen, Hai-Feng

    2008-08-01

    The PAZ domain plays a key role in gene silencing pathway. The PAZ domain binds with siRNAs to form the multimeric RNA-induced silencing complex (RISC). RISC identifies mRNAs homologous to the siRNAs and promotes their degradation. It was found that binding with siRNA significantly enhances apo-PAZ folding. However, the mechanism by which folding is coupled to binding is poorly understood. Thus, the coupling relationship between binding and folding is very important for understanding the function of gene silencing. We have performed molecular dynamics (MD) of both bound and apo-PAZ to study the coupling mechanism between binding and folding in the siRNA-PAZ complex. Room-temperature MD simulations suggest that both PAZ and siRNA become more rigid and stable upon siRNA binding. Kinetic analysis of high-temperature MD simulations shows that both bound and apo-PAZ unfold via a two-state process. The unfolding pathways are different between bound and apo-PAZ: the order of helix III and helices I & II unfolding is switched. Furthermore, transition probability was used to determine the transition state ensemble for both bound and apo-PAZ. It was found that the transition state of bound PAZ is more compact than that of apo-PAZ. The predicted Φ-values suggest that the Φ-values of helix III and sheets of β3-β7 for bound PAZ are more native-like than those of apo-PAZ upon the binding of siRNA. The results can help us to understand the mechanism of gene silencing.

  18. Growth and development: hereditary and mechanical modulations.

    Science.gov (United States)

    Mao, Jeremy J; Nah, Hyun-Duck

    2004-06-01

    Growth and development is the net result of environmental modulation of genetic inheritance. Mesenchymal cells differentiate into chondrogenic, osteogenic, and fibrogenic cells: the first 2 are chiefly responsible for endochondral ossification, and the last 2 for sutural growth. Cells are influenced by genes and environmental cues to migrate, proliferate, differentiate, and synthesize extracellular matrix in specific directions and magnitudes, ultimately resulting in macroscopic shapes such as the nose and the chin. Mechanical forces, the most studied environmental cues, readily modulate bone and cartilage growth. Recent experimental evidence demonstrates that cyclic forces evoke greater anabolic responses of not only craniofacial sutures, but also cranial base cartilage. Mechanical forces are transmitted as tissue-borne and cell-borne mechanical strain that in turn regulates gene expression, cell proliferation, differentiation, maturation, and matrix synthesis, the totality of which is growth and development. Thus, hereditary and mechanical modulations of growth and development share a common pathway via genes. Combined approaches using genetics, bioengineering, and quantitative biology are expected to bring new insight into growth and development, and might lead to innovative therapies for craniofacial skeletal dysplasia including malocclusion, dentofacial deformities, and craniofacial anomalies such as cleft palate and craniosynostosis, as well as disorders associated with the temporomandibular joint.

  19. Applied origami. Using origami design principles to fold reprogrammable mechanical metamaterials.

    Science.gov (United States)

    Silverberg, Jesse L; Evans, Arthur A; McLeod, Lauren; Hayward, Ryan C; Hull, Thomas; Santangelo, Christian D; Cohen, Itai

    2014-08-08

    Although broadly admired for its aesthetic qualities, the art of origami is now being recognized also as a framework for mechanical metamaterial design. Working with the Miura-ori tessellation, we find that each unit cell of this crease pattern is mechanically bistable, and by switching between states, the compressive modulus of the overall structure can be rationally and reversibly tuned. By virtue of their interactions, these mechanically stable lattice defects also lead to emergent crystallographic structures such as vacancies, dislocations, and grain boundaries. Each of these structures comes from an arrangement of reversible folds, highlighting a connection between mechanical metamaterials and programmable matter. Given origami's scale-free geometric character, this framework for metamaterial design can be directly transferred to milli-, micro-, and nanometer-size systems.

  20. The folding catalyst protein disulfide isomerase is constructed of active and inactive thioredoxin modules

    NARCIS (Netherlands)

    Kemmink, J; Darby, NJ; Dijkstra, K; Nilges, M; Creighton, TE

    1997-01-01

    Background: Protein disulfide isomerase (PDI), a multifunctional protein of the endoplasmic reticulum, catalyzes the formation, breakage and rearrangement of disulfide bonds during protein folding. Dissection of this protein into its individual domains has confirmed the presence of the a and a' doma

  1. GroEL mediates protein folding with a two successive timer mechanism.

    Science.gov (United States)

    Ueno, Taro; Taguchi, Hideki; Tadakuma, Hisashi; Yoshida, Masasuke; Funatsu, Takashi

    2004-05-21

    GroEL encapsulates nonnative substrate proteins in a central cavity capped by GroES, providing a safe folding cage. Conventional models assume that a single timer lasting approximately 8 s governs the ATP hydrolysis-driven GroEL chaperonin cycle. We examine single molecule imaging of GFP folding within the cavity, binding release dynamics of GroEL-GroES, ensemble measurements of GroEL/substrate FRET, and the initial kinetics of GroEL ATPase activity. We conclude that the cycle consists of two successive timers of approximately 3 s and approximately 5 s duration. During the first timer, GroEL is bound to ATP, substrate protein, and GroES. When the first timer ends, the substrate protein is released into the central cavity and folding begins. ATP hydrolysis and phosphate release immediately follow this transition. ADP, GroES, and substrate depart GroEL after the second timer is complete. This mechanism explains how GroES binding to a GroEL-substrate complex encapsulates the substrate rather than allowing it to escape into solution.

  2. Large inverted duplications in the human genome form via a fold-back mechanism.

    Directory of Open Access Journals (Sweden)

    Karen E Hermetz

    2014-01-01

    Full Text Available Inverted duplications are a common type of copy number variation (CNV in germline and somatic genomes. Large duplications that include many genes can lead to both neurodevelopmental phenotypes in children and gene amplifications in tumors. There are several models for inverted duplication formation, most of which include a dicentric chromosome intermediate followed by breakage-fusion-bridge (BFB cycles, but the mechanisms that give rise to the inverted dicentric chromosome in most inverted duplications remain unknown. Here we have combined high-resolution array CGH, custom sequence capture, next-generation sequencing, and long-range PCR to analyze the breakpoints of 50 nonrecurrent inverted duplications in patients with intellectual disability, autism, and congenital anomalies. For half of the rearrangements in our study, we sequenced at least one breakpoint junction. Sequence analysis of breakpoint junctions reveals a normal-copy disomic spacer between inverted and non-inverted copies of the duplication. Further, short inverted sequences are present at the boundary of the disomic spacer and the inverted duplication. These data support a mechanism of inverted duplication formation whereby a chromosome with a double-strand break intrastrand pairs with itself to form a "fold-back" intermediate that, after DNA replication, produces a dicentric inverted chromosome with a disomic spacer corresponding to the site of the fold-back loop. This process can lead to inverted duplications adjacent to terminal deletions, inverted duplications juxtaposed to translocations, and inverted duplication ring chromosomes.

  3. Origami mechanical metamaterials based on the Miura-derivative fold patterns

    Science.gov (United States)

    Zhou, Xiang; Zang, Shixi; You, Zhong

    2016-07-01

    This paper presents two new types of origami-inspired mechanical metamaterials based on the Miura-derivative fold patterns that consist of non-identical parallelogram facets. The analytical models to predict dimension changes and deformation kinematics of the proposed metamaterials are developed. Furthermore, by modelling the creases as revolute hinges with certain rotational spring constants, we derived analytical models for stretching and bulk moduli. The analytical models are validated through finite-element simulation results. Numerical examples reveal that the proposed metamaterials possess some intriguing properties, including negative Poisson's ratios and bulk modulus. The work presented in this paper can provide a highly flexible framework for the design of versatile tunable mechanical metamaterials.

  4. Biophysical characterisation of calumenin as a charged F508del-CFTR folding modulator.

    Science.gov (United States)

    Tripathi, Rashmi; Benz, Nathalie; Culleton, Bridget; Trouvé, Pascal; Férec, Claude

    2014-01-01

    The cystic fibrosis transmembrane regulator (CFTR) is a cyclic-AMP dependent chloride channel expressed at the apical surface of epithelial cells lining various organs such as the respiratory tract. Defective processing and functioning of this protein caused by mutations in the CFTR gene results in loss of ionic balance, defective mucus clearance, increased proliferation of biofilms and inflammation of human airways observed in cystic fibrosis (CF) patients. The process by which CFTR folds and matures under the influence of various chaperones in the secretory pathway remains incompletely understood. Recently, calumenin, a secretory protein, belonging to the CREC family of low affinity calcium binding proteins has been identified as a putative CFTR chaperone whose biophysical properties and functions remain uncharacterized. We compared hydropathy, instability, charge, unfoldability, disorder and aggregation propensity of calumenin and other CREC family members with CFTR associated chaperones and calcium binding proteins, wild-type and mutant CFTR proteins and intrinsically disordered proteins (IDPs). We observed that calumenin, along with other CREC proteins, was significantly more charged and less folded compared to CFTR associated chaperones. Moreover like IDPs, calumenin and other CREC proteins were found to be less hydrophobic and aggregation prone. Phylogenetic analysis revealed a close link between calumenin and other CREC proteins indicating how evolution might have shaped their similar biophysical properties. Experimentally, calumenin was observed to significantly reduce F508del-CFTR aggregation in a manner similar to AavLEA1, a well-characterized IDP. Fluorescence microscopy based imaging analysis also revealed altered trafficking of calumenin in bronchial cells expressing F508del-CFTR, indicating its direct role in the pathophysiology of CF. In conclusion, calumenin is characterized as a charged protein exhibiting close similarity with IDPs and is

  5. Biophysical characterisation of calumenin as a charged F508del-CFTR folding modulator.

    Directory of Open Access Journals (Sweden)

    Rashmi Tripathi

    Full Text Available The cystic fibrosis transmembrane regulator (CFTR is a cyclic-AMP dependent chloride channel expressed at the apical surface of epithelial cells lining various organs such as the respiratory tract. Defective processing and functioning of this protein caused by mutations in the CFTR gene results in loss of ionic balance, defective mucus clearance, increased proliferation of biofilms and inflammation of human airways observed in cystic fibrosis (CF patients. The process by which CFTR folds and matures under the influence of various chaperones in the secretory pathway remains incompletely understood. Recently, calumenin, a secretory protein, belonging to the CREC family of low affinity calcium binding proteins has been identified as a putative CFTR chaperone whose biophysical properties and functions remain uncharacterized. We compared hydropathy, instability, charge, unfoldability, disorder and aggregation propensity of calumenin and other CREC family members with CFTR associated chaperones and calcium binding proteins, wild-type and mutant CFTR proteins and intrinsically disordered proteins (IDPs. We observed that calumenin, along with other CREC proteins, was significantly more charged and less folded compared to CFTR associated chaperones. Moreover like IDPs, calumenin and other CREC proteins were found to be less hydrophobic and aggregation prone. Phylogenetic analysis revealed a close link between calumenin and other CREC proteins indicating how evolution might have shaped their similar biophysical properties. Experimentally, calumenin was observed to significantly reduce F508del-CFTR aggregation in a manner similar to AavLEA1, a well-characterized IDP. Fluorescence microscopy based imaging analysis also revealed altered trafficking of calumenin in bronchial cells expressing F508del-CFTR, indicating its direct role in the pathophysiology of CF. In conclusion, calumenin is characterized as a charged protein exhibiting close similarity with

  6. Folding to Curved Surfaces: A Generalized Design Method and Mechanics of Origami-based Cylindrical Structures

    Science.gov (United States)

    Wang, Fei; Gong, Haoran; Chen, Xi; Chen, C. Q.

    2016-01-01

    Origami structures enrich the field of mechanical metamaterials with the ability to convert morphologically and systematically between two-dimensional (2D) thin sheets and three-dimensional (3D) spatial structures. In this study, an in-plane design method is proposed to approximate curved surfaces of interest with generalized Miura-ori units. Using this method, two combination types of crease lines are unified in one reprogrammable procedure, generating multiple types of cylindrical structures. Structural completeness conditions of the finite-thickness counterparts to the two types are also proposed. As an example of the design method, the kinematics and elastic properties of an origami-based circular cylindrical shell are analysed. The concept of Poisson’s ratio is extended to the cylindrical structures, demonstrating their auxetic property. An analytical model of rigid plates linked by elastic hinges, consistent with numerical simulations, is employed to describe the mechanical response of the structures. Under particular load patterns, the circular shells display novel mechanical behaviour such as snap-through and limiting folding positions. By analysing the geometry and mechanics of the origami structures, we extend the design space of mechanical metamaterials and provide a basis for their practical applications in science and engineering. PMID:27624892

  7. Folding to Curved Surfaces: A Generalized Design Method and Mechanics of Origami-based Cylindrical Structures

    Science.gov (United States)

    Wang, Fei; Gong, Haoran; Chen, Xi; Chen, C. Q.

    2016-09-01

    Origami structures enrich the field of mechanical metamaterials with the ability to convert morphologically and systematically between two-dimensional (2D) thin sheets and three-dimensional (3D) spatial structures. In this study, an in-plane design method is proposed to approximate curved surfaces of interest with generalized Miura-ori units. Using this method, two combination types of crease lines are unified in one reprogrammable procedure, generating multiple types of cylindrical structures. Structural completeness conditions of the finite-thickness counterparts to the two types are also proposed. As an example of the design method, the kinematics and elastic properties of an origami-based circular cylindrical shell are analysed. The concept of Poisson’s ratio is extended to the cylindrical structures, demonstrating their auxetic property. An analytical model of rigid plates linked by elastic hinges, consistent with numerical simulations, is employed to describe the mechanical response of the structures. Under particular load patterns, the circular shells display novel mechanical behaviour such as snap-through and limiting folding positions. By analysing the geometry and mechanics of the origami structures, we extend the design space of mechanical metamaterials and provide a basis for their practical applications in science and engineering.

  8. Folding to Curved Surfaces: A Generalized Design Method and Mechanics of Origami-based Cylindrical Structures.

    Science.gov (United States)

    Wang, Fei; Gong, Haoran; Chen, Xi; Chen, C Q

    2016-09-14

    Origami structures enrich the field of mechanical metamaterials with the ability to convert morphologically and systematically between two-dimensional (2D) thin sheets and three-dimensional (3D) spatial structures. In this study, an in-plane design method is proposed to approximate curved surfaces of interest with generalized Miura-ori units. Using this method, two combination types of crease lines are unified in one reprogrammable procedure, generating multiple types of cylindrical structures. Structural completeness conditions of the finite-thickness counterparts to the two types are also proposed. As an example of the design method, the kinematics and elastic properties of an origami-based circular cylindrical shell are analysed. The concept of Poisson's ratio is extended to the cylindrical structures, demonstrating their auxetic property. An analytical model of rigid plates linked by elastic hinges, consistent with numerical simulations, is employed to describe the mechanical response of the structures. Under particular load patterns, the circular shells display novel mechanical behaviour such as snap-through and limiting folding positions. By analysing the geometry and mechanics of the origami structures, we extend the design space of mechanical metamaterials and provide a basis for their practical applications in science and engineering.

  9. Role of five-fold twin boundary on the enhanced mechanical properties of fcc Fe nanowires.

    Science.gov (United States)

    Wu, J Y; Nagao, S; He, J Y; Zhang, Z L

    2011-12-14

    The role of 5-fold twin boundary on the structural and mechanical properties of fcc Fe nanowire under tension is explored by classical molecular dynamics. Twin-stabilized fcc nanowire with various diameters (6-24 nm) are examined by tension tests at several temperatures ranging from 0.01 to 1100 K. Significant increase in the Young's modulus of the smaller nanowires is revealed to originate from the central area of quinquefoliolate-like stress-distribution over the 5-fold twin, rather than from the surface tension that is often considered as the main source of such size-effects found in nanostructures. Because of the excess compressive stress caused by crossing twin-boundaries, the atoms in the center behave stiffer than those in bulk and even expand laterally under axial tension, providing locally negative Poisson's ratio. The yield strength of nanowire is also enhanced by the twin boundary that suppresses dislocation nucleation within a fcc twin-domain; therefore, the plasticity of nanowire is initiated by strain-induced fcc→bcc phase transformation that destroys the twin structure. After the yield, the nucleated bcc phase immediately spreads to the entire area, and forms a multigrain structure to realize ductile deformation followed by necking. As temperature elevated close to the critical temperature between bcc and fcc phases, the increased stability of fcc phase competes with the phase transformation under tension, and hence dislocation nucleations in fcc phase are observed exclusively at the highest temperature in our study.

  10. Alternating access mechanisms of LeuT-fold transporters: trailblazing towards the promised energy landscapes.

    Science.gov (United States)

    Kazmier, Kelli; Claxton, Derek P; Mchaourab, Hassane S

    2016-12-29

    Secondary active transporters couple the uphill translocation of substrates to electrochemical ion gradients. Transporter conformational motion, generically referred to as alternating access, enables a central ligand binding site to change its orientation relative to the membrane. Here we review themes of alternating access and the transduction of ion gradient energy to power this process in the LeuT-fold class of transporters where crystallographic, computational and spectroscopic approaches have converged to yield detailed models of transport cycles. Specifically, we compare findings for the Na(+)-coupled amino acid transporter LeuT and the Na(+)-coupled hydantoin transporter Mhp1. Although these studies have illuminated multiple aspects of transporter structures and dynamics, a number of questions remain unresolved that so far hinder understanding transport mechanisms in an energy landscape perspective.

  11. Anterior Cingulate epilepsy: mechanism and modulation

    Directory of Open Access Journals (Sweden)

    Bai-Chuang eShyu

    2014-01-01

    Full Text Available Epilepsy is a common neurological disorder, about 1% population worldwide suffered from this disease. In 1989, the International League Against Epilepsy (ILAE classified anterior cingulate epilepsy as a form of frontal lobe epilepsy (FLE. FLE is the second most common type of epilepsy. Previous clinical studies showed that FLE account an important cause in refractory epilepsy, therefore to find alternative approach to modulate FLE is very important. Basic research using animal models and brain slice have revealed some insights on the epileptogenesis and modulation of seizure in anterior cingulate cortex (ACC. Interneurons play an important role in the synchronization of cingulate epilepsy. Research has shown that the epileptogenesis of seizure originated from mesial frontal lobe might be caused by a selective increase in nicotine-evoked -aminobutyric acid (GABA inhibition, because the application of the GABAA receptor antagonist picrotoxin inhibited epileptic discharges. Gap junctions are also involved in the regulation of cingulate epilepsy. Previous studies have shown that the application of gap junction blockers could attenuate ACC seizures, while gap junction opener could enhance them in an in vitro preparation. -Opioid receptors have been shown to be involved in the epileptic synchronization mechanism in ACC seizures in a brain slice preparation. Application of the -Opioid agonist DAMGO significantly abolished the ictal discharges in a 4-aminopyridine (4-AP induced electrographic seizure model in ACC. Basic research has also found that thalamic modulation has an inhibitory effect on ACC seizures. Studies have shown that the medial thalamus may be a target for deep brain stimulation to cure ACC seizures.

  12. Predicting Folding Sequences Based on the Maximum Rock Strength and Mechanical Equilibrium

    Science.gov (United States)

    Cubas, N.; Souloumiac, P.; Maillot, B.; Leroy, Y. M.

    2007-12-01

    The objective is to propose and validate simple procedures, compared to the finite-element method, to select and optimize the dominant mode of folding in fold-and-thrust belts and accretionary wedges, and to determine its stress distribution. Mechanical equilibrium as well as the constraints due to the limited rock strength of the bulk material and of major discontinuities, such as décollements, are accounted for. The first part of the proposed procedure, which is at the core of the external approach of classical limit analysis, consists in estimating the least upper bound on the tectonic force by minimisation of the internal dissipation and part of the external work. The new twist to the method is that the optimization is also done with respect to the geometry of the evolving fold. If several folding events are possible, the dominant mode is the one leading to the least upper bound. The second part of the procedure is based on the Equilibrium Element Method, which is an application of the internal approach of limit analysis. The optimum stress field, obtained by spatial discretisation of the fold, provides the best lower bound on the tectonic force. The difference between the two bounds defines an error estimate of the exact unknown tectonic force. To show the merits of the proposed procedure, its first part is applied to predict the life span of a thrust within an accretionary prism, from its onset, its development with a relief build up and its arrest because of the onset of a more favorable new thrust (Cubas et al., 2007). This life span is sensitive to the friction angles over the ramp and the décollement. It is shown how the normal sequence of thrusting in a supercritical wedge is ended with the first out-of sequence event. The second part of the procedure provides the stress state over each thrust showing that the active back thrust is a narrow fan which dip is sensitive to the friction angle over the ramp and the amount of relief build up (Souloumiac et

  13. Effect of hydrogen bond networks on the nucleation mechanism of protein folding

    Science.gov (United States)

    Djikaev, Y. S.; Ruckenstein, Eli

    2009-12-01

    We have recently developed a kinetic model for the nucleation mechanism of protein folding (NMPF) in terms of ternary nucleation by using the first passage time analysis. A protein was considered as a random heteropolymer consisting of hydrophobic, hydrophilic (some of which are negatively or positively ionizable), and neutral beads. The main idea of the NMPF model consisted of averaging the dihedral potential in which a selected residue is involved over all possible configurations of all neighboring residues along the protein chain. The combination of the average dihedral, effective pairwise (due to Lennard-Jones-type and electrostatic interactions), and confining (due to the polymer connectivity constraint) potentials gives rise to an overall potential around the cluster that, as a function of the distance from the cluster center, has a double-well shape. This allows one to evaluate the protein folding time. In the original NMPF model hydrogen bonding was not taken into account explicitly. To improve the NMPF model and make it more realistic, in this paper we modify our (previously developed) probabilistic hydrogen bond model and combine it with the former. Thus, a contribution due to the disruption of hydrogen bond networks around the interacting particles (cluster of native residues and residue in the protein unfolded part) appears in the overall potential field around a cluster. The modified model is applied to the folding of the same model proteins that were examined in the original model: a short protein consisting of 124 residues (roughly mimicking bovine pancreatic ribonuclease) and a long one consisting of 2500 residues (as a representative of large proteins with superlong polypeptide chains), at pH=8.3 , 7.3, and 6.3. The hydrogen bond contribution now plays a dominant role in the total potential field around the cluster (except for very short distances thereto where the repulsive energy tends to infinity). It is by an order of magnitude stronger for

  14. A review on the molecular mechanism of plants rooting modulated ...

    African Journals Online (AJOL)

    A review on the molecular mechanism of plants rooting modulated by auxin. ... rooting modulated by auxin. H Han, S Zhang, X Sun ... Phytohormones, especially auxin, played an essential role in regulating roots developments. This review ...

  15. Unraveling protein folding mechanism by analyzing the hierarchy of models with increasing level of detail

    Science.gov (United States)

    Hayashi, Tomohiko; Yasuda, Satoshi; Škrbić, Tatjana; Giacometti, Achille; Kinoshita, Masahiro

    2017-09-01

    Taking protein G with 56 residues for a case study, we investigate the mechanism of protein folding. In addition to its native structure possessing α-helix and β-sheet contents of 27% and 39%, respectively, we construct a number of misfolded decoys with a wide variety of α-helix and β-sheet contents. We then consider a hierarchy of 8 different models with increasing level of detail in terms of the number of entropic and energetic physical factors incorporated. The polyatomic structure is always taken into account, but the side chains are removed in half of the models. The solvent is formed by either neutral hard spheres or water molecules. Protein intramolecular hydrogen bonds (H-bonds) and protein-solvent H-bonds (the latter is present only in water) are accounted for or not, depending on the model considered. We then apply a physics-based free-energy function (FEF) corresponding to each model and investigate which structures are most stabilized. This special approach taken on a step-by-step basis enables us to clarify the role of each physical factor in contributing to the structural stability and separately elucidate its effect. Depending on the model employed, significantly different structures such as very compact configurations with no secondary structures and configurations of associated α-helices are optimally stabilized. The native structure can be identified as that with lowest FEF only when the most detailed model is employed. This result is significant for at least the two reasons: The most detailed model considered here is able to capture the fundamental aspects of protein folding notwithstanding its simplicity; and it is shown that the native structure is stabilized by a complex interplay of minimal multiple factors that must be all included in the description. In the absence of even a single of these factors, the protein is likely to be driven towards a different, more stable state.

  16. A new mechanism for producing cleavage in preexisting folds: The translation mechanism. An example in the Burela section (Variscan belt, NW Spain)

    Science.gov (United States)

    Bobillo-Ares, Nilo C.; Bastida, Fernando; Aller, Jesús; Lisle, Richard J.

    2017-01-01

    An outcrop on the Cantabrian coast (Burela section) shows a long train of tight meter-scale folds developed in Cambrian siliciclastic rocks. These folds have been shortened in the axial trace direction on the fold profile, developing a cleavage in the incompetent layers which obliterates the primary cleavage and crosscuts the folds. Several mechanisms have been analyzed to explain the development and attitude of this cleavage, some of them being the same as those that have previously been proposed to form folds but operating in a reverse sense. They are: anti-flexural flow, anti-reverse tangential longitudinal strain and homogeneous strain. The sole operation of these mechanisms cannot explain this cleavage and a new one has been defined with this aim. This mechanism consists of deformation of the incompetent layers by translation of the competent ones (translation mechanism), and it involves an area decrease within the incompetent layers in the fold profile plane and, if there is no important volume decrease, a stretching in the hinge direction that must affect both competent and incompetent layers. The geometrical properties of this mechanism have been analyzed in detail and it is concluded that, combined with a small amount of homogeneous flattening, this mechanism can explain the distribution of the cleavage through the folds.

  17. Significance of first-order faults in folding mechanically isotropic layers: Evidence from the Sudbury Basin, Canada

    Science.gov (United States)

    Clark, Martin D.; Riller, Ulrich

    2017-02-01

    The Sudbury Basin is a non-cylindrical fold basin demarcated by the layered Sudbury Igneous Complex (SIC), the eastern part of which is transected by prominent curved faults. Folding of the SIC and adjacent rock units occurred in the brittle field and is peculiar due to its petrographically distinct, but initially mechanically similar layers. Overall, the layers are characterized by low levels of solid-state strain raising the question how the layer contacts acquired their curvature. We addressed this question by developing a G.I.S.-based workflow to analyze the orientation and slip vectors of the faults. Slip vectors form clusters of normal and reverse slip along a given fault. The clustering is best interpreted in terms of successive slip events during folding of the SIC. As the faults formed most likely as planar reverse faults prior to folding of the SIC they subsequently served as mechanically anisotropic elements to fold the SIC. The results contribute to (1) better understand the folding mechanisms of thick melt sheets in the upper crust, (2) explain apparently incompatible principal strain axes during progressive deformation, and (3) efficiently analyze the orientation and kinematics of fault zones close to the Earth's surface.

  18. Early Events, Kinetic Intermediates and the Mechanism of Protein Folding in Cytochrome c

    Directory of Open Access Journals (Sweden)

    David S. Kliger

    2009-04-01

    Full Text Available Kinetic studies of the early events in cytochrome c folding are reviewed with a focus on the evidence for folding intermediates on the submillisecond timescale. Evidence from time-resolved absorption, circular dichroism, magnetic circular dichroism, fluorescence energy and electron transfer, small-angle X-ray scattering and amide hydrogen exchange studies on the t £ 1 ms timescale reveals a picture of cytochrome c folding that starts with the ~ 1-ms conformational diffusion dynamics of the unfolded chains. A fractional population of the unfolded chains collapses on the 1 – 100 ms timescale to a compact intermediate IC containing some native-like secondary structure. Although the existence and nature of IC as a discrete folding intermediate remains controversial, there is extensive high time-resolution kinetic evidence for the rapid formation of IC as a true intermediate, i.e., a metastable state separated from the unfolded state by a discrete free energy barrier. Final folding to the native state takes place on millisecond and longer timescales, depending on the presence of kinetic traps such as heme misligation and proline mis-isomerization. The high folding rates observed in equilibrium molten globule models suggest that IC may be a productive folding intermediate. Whether it is an obligatory step on the pathway to the high free energy barrier associated with millisecond timescale folding to the native state, however, remains to be determined.

  19. Electrothermal Frequency Modulated Resonator for Mechanical Memory

    KAUST Repository

    Hafiz, Md Abdullah Al

    2016-08-18

    In this paper, we experimentally demonstrate a mechanical memory device based on the nonlinear dynamics of an electrostatically actuated microelectromechanical resonator utilizing an electrothermal frequency modulation scheme. The microstructure is deliberately fabricated as an in-plane shallow arch to achieve geometric quadratic nonlinearity. We exploit this inherent nonlinearity of the arch and drive it at resonance with minimal actuation voltage into the nonlinear regime, thereby creating softening behavior, hysteresis, and coexistence of states. The hysteretic frequency band is controlled by the electrothermal actuation voltage. Binary values are assigned to the two allowed dynamical states on the hysteretic response curve of the arch resonator with respect to the electrothermal actuation voltage. Set-and-reset operations of the memory states are performed by applying controlled dc pulses provided through the electrothermal actuation scheme, while the read-out operation is performed simultaneously by measuring the motional current through a capacitive detection technique. This novel memory device has the advantages of operating at low voltages and under room temperature. [2016-0043

  20. Numerical study of mechanism of fold formation in a laminated rock

    Indian Academy of Sciences (India)

    P K Saini; T Kumar; T N Singh; N Singh; V K Keshr

    2011-12-01

    A set of large deformation experiments are presented to simulate folding pattern at various energy states during formation. In order to numerically simulate this phenomenon, a rectangular layer of shale is generated and compressed at various strain rates. The results reveal the variation in distribution of stress along the length of the bed. The stress distribution during elastic behaviour of shale bed at low compression rate and the change in stress distribution leading to rupture at high compression rates is discussed. Wavelength, limb length, bulk shortening, stress distribution, displacement of particles along the length of the bed is considered for comparative study of the fold pattern generated at various compression rates. The nature and position of crack generated during the formation of fold is also explained. After rupture in shale bed, the generation of fault and stress distribution in limbs of fold sliding over one another is also described.

  1. Precursory signatures of protein folding/unfolding: From time series correlation analysis to atomistic mechanisms

    Energy Technology Data Exchange (ETDEWEB)

    Hsu, P. J.; Lai, S. K., E-mail: sklai@coll.phy.ncu.edu.tw [Complex Liquids Laboratory, Department of Physics, National Central University, Chungli 320 Taiwan (China); Molecular Science and Technology Program, Taiwan International Graduate Program, Academia Sinica, Taipei 115, Taiwan (China); Cheong, S. A. [Division of Physics and Applied Physics, School of Physical and Mathematical Sciences, Nanyang Technological University, 21 Nanyang Link, Singapore 637371 (Singapore)

    2014-05-28

    Folded conformations of proteins in thermodynamically stable states have long lifetimes. Before it folds into a stable conformation, or after unfolding from a stable conformation, the protein will generally stray from one random conformation to another leading thus to rapid fluctuations. Brief structural changes therefore occur before folding and unfolding events. These short-lived movements are easily overlooked in studies of folding/unfolding for they represent momentary excursions of the protein to explore conformations in the neighborhood of the stable conformation. The present study looks for precursory signatures of protein folding/unfolding within these rapid fluctuations through a combination of three techniques: (1) ultrafast shape recognition, (2) time series segmentation, and (3) time series correlation analysis. The first procedure measures the differences between statistical distance distributions of atoms in different conformations by calculating shape similarity indices from molecular dynamics simulation trajectories. The second procedure is used to discover the times at which the protein makes transitions from one conformation to another. Finally, we employ the third technique to exploit spatial fingerprints of the stable conformations; this procedure is to map out the sequences of changes preceding the actual folding and unfolding events, since strongly correlated atoms in different conformations are different due to bond and steric constraints. The aforementioned high-frequency fluctuations are therefore characterized by distinct correlational and structural changes that are associated with rate-limiting precursors that translate into brief segments. Guided by these technical procedures, we choose a model system, a fragment of the protein transthyretin, for identifying in this system not only the precursory signatures of transitions associated with α helix and β hairpin, but also the important role played by weaker correlations in such protein

  2. Mechanical Modulation of Hybrid Graphene Microfiber Structure

    CERN Document Server

    Xu, Fei; Lu, Yan-qing

    2015-01-01

    Recently, the strain engineering of two-dimensional materials such as graphene has attracted considerable attention for its great potential in functional nanodevices. Here, we theoretically and experimentally investigate the strain manipulation of a graphene-integrated microfiber system for the first time. We analyze the influential factors of strain tuning, i.e., the geometrical parameters of the microfiber, the strain magnitude, and the probe-light wavelength. Moreover, we experimentally achieve in-line modulation as high as 30% with a moderate strain of ~5%, which is two orders of magnitude larger than previous results. The dynamic vibration response is also researched. The broadband, polarization-independent, cost-effective, strain-based modulator may find applications in low-speed modulation and strain sensing. Further, we believe that our platform may allow for all-in fiber engineering of graphene-analogue materials and provide new ideas for graphene-integrated flexible device design.

  3. A mechanical experimental setup to simulate vocal folds vibrations. Preliminary results

    CERN Document Server

    Ruty, Nicolas; Pelorson, Xavier; Lopez-Arteaga, Ines; Hirschberg, Avraham

    2005-01-01

    This paper contributes to the understanding of vocal folds oscillation during phonation. In order to test theoretical models of phonation, a new experimental set-up using a deformable vocal folds replica is presented. The replica is shown to be able to produce self sustained oscillations under controlled experimental conditions. Therefore different parameters, such as those related to elasticity, to acoustical coupling or to the subglottal pressure can be quantitatively studied. In this work we focused on the oscillation fundamental frequency and the upstream pressure in order to start (on-set threshold) either end (off-set threshold) oscillations in presence of a downstream acoustical resonator. As an example, it is shown how this data can be used in order to test the theoretical predictions of a simple one-mass model.

  4. A disorder-induced domino-like destabilization mechanism governs the folding and functional dynamics of the repeat protein IκBα.

    Directory of Open Access Journals (Sweden)

    Srinivasan Sivanandan

    Full Text Available The stability of the repeat protein IκBα, a transcriptional inhibitor in mammalian cells, is critical in the functioning of the NF-κB signaling module implicated in an array of cellular processes, including cell growth, disease, immunity and apoptosis. Structurally, IκBα is complex, with both ordered and disordered regions, thus posing a challenge to the available computational protocols to model its conformational behavior. Here, we introduce a simple procedure to model disorder in systems that undergo binding-induced folding that involves modulation of the contact map guided by equilibrium experimental observables in combination with an Ising-like Wako-Saitô-Muñoz-Eaton model. This one-step procedure alone is able to reproduce a variety of experimental observables, including ensemble thermodynamics (scanning calorimetry, pre-transitions, m-values and kinetics (roll-over in chevron plot, intermediates and their identity, and is consistent with hydrogen-deuterium exchange measurements. We further capture the intricate distance-dynamics between the domains as measured by single-molecule FRET by combining the model predictions with simple polymer physics arguments. Our results reveal a unique mechanism at work in IκBα folding, wherein disorder in one domain initiates a domino-like effect partially destabilizing neighboring domains, thus highlighting the effect of symmetry-breaking at the level of primary sequences. The offshoot is a multi-state and a dynamic conformational landscape that is populated by increasingly partially folded ensembles upon destabilization. Our results provide, in a straightforward fashion, a rationale to the promiscuous binding and short intracellular half-life of IκBα evolutionarily engineered into it through repeats with variable stabilities and expand the functional repertoire of disordered regions in proteins.

  5. Defective folding and rapid degradation of mutant proteins is a common disease mechanism in genetic disorders

    DEFF Research Database (Denmark)

    Gregersen, N; Bross, P; Jørgensen, M M

    2000-01-01

    of such 'conformational disease' are illustrated by reference to cystic fibrosis, phenylketonuria and short-chain acyl-CoA dehydrogenase deficiency. Other cellular components such as chaperones and proteases, as well as environmental factors, may combine to modulate the phenotype of such disorders and this may open up...

  6. Effect of hydrophobic interactions on the folding mechanism of β-hairpins.

    Science.gov (United States)

    Popp, Alexander; Wu, Ling; Keiderling, Timothy A; Hauser, Karin

    2014-12-11

    Hydrophobic interactions are essential in stabilizing protein structures. How they affect the folding pathway and kinetics, however, is less clear. We used time-resolved infrared spectroscopy to study the dynamics of hydrophobic interactions of β-hairpin variants of the sequence Trpzip2 (SWTWENGKWTWK-NH2) that is stabilized by two cross-strand Trp-Trp pairs. The hydrophobicity strength was varied by substituting the tryptophans pairwise by either tyrosines or valines. Relaxation dynamics were induced by a laser-excited temperature jump, which separately probed for the loss of the cross-strand β-hairpin interaction and the rise of the disordered structure. All substitutions tested result in reduced thermal stability, lower transition temperatures, and faster dynamics compared to Trpzip2. However, the changes in folding dynamics depend on the amino acid substituted for Trp. The aromatic substitution of Tyr for Trp results in the same kinetics for the unfolding of sheet and growth of disorder, with similar activation energies, independent of the substitution position. Substitution of Trp with a solely hydrophobic Val results in even faster kinetics than substitution with Tyr but is additionally site-dependent. If the hairpin has a Val pair close to its termini, the rate constants for loss of sheet and gain of disorder are the same, but if the pair is close to the turn, the sheet and disorder components show different relaxation kinetics. The Trp → Val substitutions reveal that hydrophobic interactions alone weakly stabilize the hairpin structure, but adding edge-to-face aromatic interaction strengthens it, and both modify the complex folding process.

  7. Nanomaterial-modulated autophagy: underlying mechanisms and functional consequences.

    Science.gov (United States)

    Zheng, Wei; Wei, Min; Li, Song; Le, Weidong

    2016-06-01

    Autophagy is an essential lysosome-dependent process that controls the quality of the cytoplasm and maintains cellular homeostasis, and dysfunction of this protein degradation system is correlated with various disorders. A growing body of evidence suggests that nanomaterials (NMs) have autophagy-modulating effects, thus predicting a valuable and promising application potential of NMs in the diagnosis and treatment of autophagy-related diseases. NMs exhibit unique physical, chemical and biofunctional properties, which may endow NMs with capabilities to modulate autophagy via various mechanisms. The present review highlights the impacts of various NMs on autophagy and their functional consequences. The possible underlying mechanisms for NM-modulated autophagy are also discussed.

  8. Influences of heterogeneous native contact energy and many-body interactions on the prediction of protein folding mechanisms.

    Science.gov (United States)

    Zhang, Zhuqing; Ouyang, Yanhua; Chen, Tao

    2016-11-16

    Since single-point mutant perturbation has been used to probe protein folding mechanisms in experiments, the ϕ-value has become a critical parameter to infer the transition state (TS) for two-state proteins. Experimentally, large scale analysis has shown a nearly single uniform ϕ-value with normally distributed error from 24 different proteins; moreover, in zero stability conditions, the intrinsic variable ϕ(0) is around 0.36. To explore how and to what extent theoretical models can capture experimental phenomena, we here use structure-based explicit chain coarse-grained models to investigate the influence of single-point mutant perturbation on protein folding for single domain two-state proteins. Our results indicate that uniform, additive contact energetic interactions cannot predict experimental Brønsted plots well. Those points deviate largely from the main data sets in Brønsted plots, are mostly hydrophobic, and are located in N- and C-terminal contacting regions. Heterogenous contact energy, which is dependent on sequence separation, can narrow the point dispersion in a Brønsted plot. Moreover, we demonstrate that combining many-body interactions with heterogeneous native contact energy can present mean ϕ-values consistent with experimental findings, with a comparable distributed error. This indicates that for more accurate elucidation of protein folding mechanisms by residue-level structure-based models, these elements should be considered.

  9. Self-oscillating Vocal Fold Model Mechanics: Healthy, Diseased, and Aging

    Science.gov (United States)

    Hiubler, Elizabeth P.; Pollok, Lucas F. E.; Apostoli, Adam G.; Hancock, Adrienne B.; Plesniak, Michael W.

    2014-11-01

    Voice disorders have been estimated to have a substantial economic impact of 2.5 billion annually. Approximately 30% of people will suffer from a voice disorder at some point in their lives. Life-sized, self-oscillating, synthetic vocal fold (VF) models are fabricated to exhibit material properties representative of human VFs. These models are created both with and without a polyp-like structure, a pathology that has been shown to produce rich viscous flow structures not normally observed for healthy VFs during normal phonation. Pressure measurements are acquired upstream of the VFs and high-speed images are captured at varying flow rates during VF oscillation to facilitate an understanding of the characteristics of healthy and diseased VFs. The images are analyzed using a videokymography line-scan technique. Clinically-relevant parameters calculated from the volume-velocity output of a circumferentially-vented mask (Rothenberg mask) are compared to human data collected from two groups of males aged 18-30 and 60-80. This study extends the use of synthetic VF models by assessing their ability to replicate behaviors observed in human subject data to advance a means of investigating changes associated with normal, pathological, and the aging voice. Supported by the GWU Institute for Biomedical Engineering (GWIBE) and GWU Center for Biomimetics and Bioinspired Engineering (COBRE).

  10. On the mechanism of electrochemical modulation of plasmonic resonances

    Science.gov (United States)

    Shao, L.-H.; Ruther, M.; Linden, S.; Wegener, M.; Weissmüller, J.

    2012-09-01

    Recent electrochemical experiments on gold-based photonic metamaterials have shown a sizable reversible tuning and modulation of plasmonic resonances. Here, we study the mechanism of the electrochemical modulation by measuring the change of the resonance transmittance and resonance frequency during underpotential deposition of Pb, Cu, and electrosorption of OH. The electric resistance change of the resonators is identified as decisive for the resonance transmittance change, while the space-charge layer at the metal surface shifts the resonance frequency.

  11. Functional and Structural Analysis of Wing Folding Mechanism Based on Cockchafer (Melolontha Melolontha

    Directory of Open Access Journals (Sweden)

    Geisler Tomasz

    2014-09-01

    Full Text Available Insects are among nature’s most nimble flyers. In this paper we present the functional and structural analysis of wing joint mechanism. Detailed action of the axillary plates and their mutual interaction was also described. Because of the small dimensions of the wing joint elements and the limited resolution of the light microscope, the authors used a scanning electron microscope. Based upon the knowledge of working principles of beetle flight apparatus a wing joint mechanism kinematics model has been developed.

  12. Understanding the mechanical properties of DNA origami tiles and controlling the kinetics of their folding and unfolding reconfiguration.

    Science.gov (United States)

    Chen, Haorong; Weng, Te-Wei; Riccitelli, Molly M; Cui, Yi; Irudayaraj, Joseph; Choi, Jong Hyun

    2014-05-14

    DNA origami represents a class of highly programmable macromolecules that can go through conformational changes in response to external signals. Here we show that a two-dimensional origami rectangle can be effectively folded into a short, cylindrical tube by connecting the two opposite edges through the hybridization of linker strands and that this process can be efficiently reversed via toehold-mediated strand displacement. The reconfiguration kinetics was experimentally studied as a function of incubation temperature, initial origami concentration, missing staples, and origami geometry. A kinetic model was developed by introducing the j factor to describe the reaction rates in the cyclization process. We found that the cyclization efficiency (j factor) increases sharply with temperature and depends strongly on the structural flexibility and geometry. A simple mechanical model was used to correlate the observed cyclization efficiency with origami structure details. The mechanical analysis suggests two sources of the energy barrier for DNA origami folding: overcoming global twisting and bending the structure into a circular conformation. It also provides the first semiquantitative estimation of the rigidity of DNA interhelix crossovers, an essential element in structural DNA nanotechnology. This work demonstrates efficient DNA origami reconfiguration, advances our understanding of the dynamics and mechanical properties of self-assembled DNA structures, and should be valuable to the field of DNA nanotechnology.

  13. Huntington's disease induced cardiac amyloidosis is reversed by modulating protein folding and oxidative stress pathways in the Drosophila heart.

    Directory of Open Access Journals (Sweden)

    Girish C Melkani

    organization of contractile proteins, leads to mitochondrial dysfunction and increases oxidative stress in cardiomyocytes leading to abnormal cardiac function. We conclude that modulation of both protein unfolding and oxidative stress pathways in the Drosophila heart model can ameliorate the detrimental PolyQ effects, thus providing unique insights into the genetic mechanisms underlying amyloid-induced cardiac failure in HD patients.

  14. On the cascade mechanism of short surface wave modulation

    Directory of Open Access Journals (Sweden)

    M. Charnotskii

    2002-01-01

    Full Text Available Modulation of short surface ripples by long surface or internal waves by a cascade mechanism is considered. At the first stage, the orbital velocity of the long wave (LW adiabatically modulates an intermediate length nonlinear gravity wave (GW, which generates a bound (parasitic capillary wave (CW near its crest in a wide spatial frequency band. Due to strong dependence of the CW amplitude on that of the GW, the resulting ripple modulation by LW can be strong. Adiabatic modulation at the first stage is calculated for an arbitrarily strong LW current. The CWs are calculated based on the Lonquet-Higgins theory, in the framework of a steady periodic solution, which proves to be sufficient for the cases considered. Theoretical results are compared with data from laboratory experiments. A discussion of related sea clutter data is given in the conclusion.

  15. Analyses of simulations of three-dimensional lattice proteins in comparison with a simplified statistical mechanical model of protein folding.

    Science.gov (United States)

    Abe, H; Wako, H

    2006-07-01

    Folding and unfolding simulations of three-dimensional lattice proteins were analyzed using a simplified statistical mechanical model in which their amino acid sequences and native conformations were incorporated explicitly. Using this statistical mechanical model, under the assumption that only interactions between amino acid residues within a local structure in a native state are considered, the partition function of the system can be calculated for a given native conformation without any adjustable parameter. The simulations were carried out for two different native conformations, for each of which two foldable amino acid sequences were considered. The native and non-native contacts between amino acid residues occurring in the simulations were examined in detail and compared with the results derived from the theoretical model. The equilibrium thermodynamic quantities (free energy, enthalpy, entropy, and the probability of each amino acid residue being in the native state) at various temperatures obtained from the simulations and the theoretical model were also examined in order to characterize the folding processes that depend on the native conformations and the amino acid sequences. Finally, the free energy landscapes were discussed based on these analyses.

  16. Using RNA nanoparticles with thermostable motifs and fluorogenic modules for real-time detection of RNA folding and turnover in prokaryotic and eukaryotic cells.

    Science.gov (United States)

    Zhang, Hui; Pi, Fengmei; Shu, Dan; Vieweger, Mario; Guo, Peixuan

    2015-01-01

    RNA nanotechnology is an emerging field at the interface of biochemistry and nanomaterials that shows immense promise for applications in nanomedicines, therapeutics and nanotechnology. Noncoding RNAs, such as siRNA, miRNA, ribozymes, and riboswitches, play important roles in the regulation of cellular processes. They carry out highly specific functions on a compact and efficient footprint. The properties of specificity and small size make them excellent modules in the construction of multifaceted RNA nanoparticles for targeted delivery and therapy. Biological activity of RNA molecules, however, relies on their proper folding. Therefore their thermodynamic and biochemical stability in the cellular environment is critical. Consequently, it is essential to assess global fold and intracellular lifetime of multifaceted RNA nanoparticles to optimize their therapeutic effectiveness. Here, we describe a method to express and assemble stable RNA nanoparticles in cells, and to assess the folding and turnover rate of RNA nanoparticles in vitro as well as in vivo in real time using a thermostable core motif derived from pRNA of bacteriophage Phi29 DNA packaging motor and fluorogenic RNA modules.

  17. Mechanics of neurulation: From classical to current perspectives on the physical mechanics that shape, fold, and form the neural tube.

    Science.gov (United States)

    Vijayraghavan, Deepthi S; Davidson, Lance A

    2016-09-13

    Neural tube defects arise from mechanical failures in the process of neurulation. At the most fundamental level, formation of the neural tube relies on coordinated, complex tissue movements that mechanically transform the flat neural epithelium into a lumenized epithelial tube (Davidson, 2012). The nature of this mechanical transformation has mystified embryologists, geneticists, and clinicians for more than 100 years. Early embryologists pondered the physical mechanisms that guide this transformation. Detailed observations of cell and tissue movements as well as experimental embryological manipulations allowed researchers to generate and test elementary hypotheses of the intrinsic and extrinsic forces acting on the neural tissue. Current research has turned toward understanding the molecular mechanisms underlying neurulation. Genetic and molecular perturbation have identified a multitude of subcellular components that correlate with cell behaviors and tissue movements during neural tube formation. In this review, we focus on methods and conceptual frameworks that have been applied to the study of amphibian neurulation that can be used to determine how molecular and physical mechanisms are integrated and responsible for neurulation. We will describe how qualitative descriptions and quantitative measurements of strain, force generation, and tissue material properties as well as simulations can be used to understand how embryos use morphogenetic programs to drive neurulation. Birth Defects Research (Part A), 2016. © 2016 Wiley Periodicals, Inc.

  18. MODELS OF PROTEIN FOLDING

    Directory of Open Access Journals (Sweden)

    Unnati Ahluwalia

    2012-12-01

    Full Text Available In an attempt to explore the understanding of protein folding mechanism, various models have been proposed in the literature. Advances in recent experimental and computational techniques rationalized our understanding on some of the fundamental features of the protein folding pathways. The goal of this review is to revisit the various models and outline the essential aspects of the folding reaction.

  19. Conserved inhibitory mechanism and competent ATP binding mode for adenylyltransferases with Fic fold.

    Directory of Open Access Journals (Sweden)

    Arnaud Goepfert

    Full Text Available The ubiquitous FIC domain is evolutionarily conserved from bacteria to human and has been shown to catalyze AMP transfer onto protein side-chain hydroxyl groups. Recently, it was predicted that most catalytically competent Fic proteins are inhibited by the presence of an inhibitory helix αinh that is provided by a cognate anti-toxin (class I, or is part of the N- or C-terminal part of the Fic protein itself (classes II and III. In vitro, inhibition is relieved by mutation of a conserved glutamate of αinh to glycine. For the class III bacterial Fic protein NmFic from Neisseria meningitidis, the inhibitory mechanism has been elucidated. Here, we extend above study by including bacterial class I and II Fic proteins VbhT from Bartonella schoenbuchensis and SoFic from Shewanella oneidensis, respectively, and the respective E->G mutants. Comparative enzymatic and crystallographic analyses show that, in all three classes, the ATP substrate binds to the wild-type FIC domains, but with the α-phosphate in disparate and non-competent orientations. In the E->G mutants, however, the tri-phosphate moiety is found reorganized to the same tightly bound structure through a unique set of hydrogen bonds with Fic signature motif residues. The γ-phosphate adopts the location that is taken by the inhibitory glutamate in wild-type resulting in an α-phosphate orientation that can be attacked in-line by a target side-chain hydroxyl group. The latter is properly registered to the Fic active center by main-chain β-interactions with the β-hairpin flap. These data indicate that the active site motif and the exposed edge of the flap are both required to form an adenylylation-competent Fic protein.

  20. Extreme Folding

    Science.gov (United States)

    Demaine, Erik

    2012-02-01

    Our understanding of the mathematics and algorithms behind paper folding, and geometric folding in general, has increased dramatically over the past several years. These developments have found a surprisingly broad range of applications. In the art of origami, it has helped spur the technical origami revolution. In engineering and science, it has helped solve problems in areas such as manufacturing, robotics, graphics, and protein folding. On the recreational side, it has led to new kinds of folding puzzles and magic. I will give an overview of the mathematics and algorithms of folding, with a focus on new mathematics and sculpture.

  1. Modulation of folding and assembly of the membrane protein bacteriorhodopsin by intermolecular forces within the lipid bilayer.

    Science.gov (United States)

    Curran, A R; Templer, R H; Booth, P J

    1999-07-20

    Three different lipid systems have been developed to investigate the effect of physicochemical forces within the lipid bilayer on the folding of the integral membrane protein bacteriorhodopsin. Each system consists of lipid vesicles containing two lipid species, one with phosphatidylcholine and the other with phosphatidylethanolamine headgroups, but the same hydrocarbon chains: either L-alpha-1, 2-dioleoyl, L-alpha-1,2-dipalmitoleoyl, or L-alpha-1,2-dimyristoyl. Increasing the mole fraction of the phosphatidylethanolamine lipid increases the desire of each monolayer leaflet in the bilayer to curve toward water. This increases the torque tension of such monolayers, when they are constrained to remain flat in the vesicle bilayer. Consequently, the lateral pressure in the hydrocarbon chain region increases, and we have used excimer fluorescence from pyrene-labeled phosphatidylcholine lipids to probe these pressure changes. We show that bacteriorhodopsin regenerates to about 95% yield in vesicles of 100% phosphatidylcholine. The regeneration yield decreases as the mole fraction of the corresponding phosphatidylethanolamine component is increased. The decrease in yield correlates with the increase in lateral pressure which the lipid chains exert on the refolding protein. We suggest that the increase in lipid chain pressure either hinders insertion of the denatured state of bacterioopsin into the bilayer or slows a folding step within the bilayer, to the extent that an intermediate involved in bacteriorhodopsin regeneration is effectively trapped.

  2. Transformation of the mechanism of triple-helix peptide folding in the absence of a C-terminal nucleation domain and its implications for mutations in collagen disorders.

    Science.gov (United States)

    Buevich, Alexei V; Silva, Teresita; Brodsky, Barbara; Baum, Jean

    2004-11-05

    Folding abnormalities of the triple helix have been demonstrated in collagen diseases such as osteogenesis imperfecta in which the mutation leads to the substitution of a single Gly in the (Gly-X-Y)n sequence pattern by a larger residue. Model peptides can be used to clarify the details of normal collagen folding and the consequences of the interruption of that folding by a Gly substitution. NMR and CD studies show that placement of a (GPO)4 nucleation domain at the N terminus rather than the C terminus of a native collagen sequence allows the formation of a stable triple helix but alters the folding mechanism. Although C- to N-terminal directional folding occurs when the nucleation domain is at the C terminus, there is no preferential folding direction when the nucleation domain is at the N terminus. The lack of zipper-like directional folding does not interfere with triple-helix formation, and when a Gly residue is replaced by Ser to model an osteogenesis imperfecta mutation, the peptide with the N-terminal (GPO)4 domain can still form a good triple helix N-terminal to the mutation site. These peptide studies raise the possibility that mutant collagen could fold in a C to N direction in a zipper-like manner up to the mutation site and that completion of the triple helix N-terminal to the mutation would involve an alternative mechanism.

  3. Electrical power generation by mechanically modulating electrical double layers.

    Science.gov (United States)

    Moon, Jong Kyun; Jeong, Jaeki; Lee, Dongyun; Pak, Hyuk Kyu

    2013-01-01

    Since Michael Faraday and Joseph Henry made their great discovery of electromagnetic induction, there have been continuous developments in electrical power generation. Most people today get electricity from thermal, hydroelectric, or nuclear power generation systems, which use this electromagnetic induction phenomenon. Here we propose a new method for electrical power generation, without using electromagnetic induction, by mechanically modulating the electrical double layers at the interfacial areas of a water bridge between two conducting plates. We find that when the height of the water bridge is mechanically modulated, the electrical double layer capacitors formed on the two interfacial areas are continuously charged and discharged at different phases from each other, thus generating an AC electric current across the plates. We use a resistor-capacitor circuit model to explain the results of this experiment. This observation could be useful for constructing a micro-fluidic power generation system in the near future.

  4. Mechanical stress and glucose concentration modulate glucose transport in cultured rat podocytes.

    Science.gov (United States)

    Lewko, Barbara; Bryl, Ewa; Witkowski, Jacek M; Latawiec, Elzbieta; Angielski, Stefan; Stepinski, Jan

    2005-02-01

    Recent studies show that mechanical stress modifies both morphology and protein expression in podocytes. Ambient glucose is another factor modulating protein synthesis in these cells. In diabetes, podocytes experience elevated glucose concentrations as well as mechanical strain generated by high intracapillary pressures. Both these factors are responsible for podocyte injury, leading to impairment of kidney glomerular function. In the present study, we examined the effects of glucose concentration and mechanical stress on glucose uptake in podocytes. Following a 24 h pre-incubation in low (2.5 mM, LG), normal (5.6 mM, NG) or high (30 mM, HG) glucose media, cultured rat podocytes were exposed to 4 h mechanical stress. We used the labelled glucose analogue, [3H]2-deoxy-D-glucose, to measure glucose uptake. The distribution of facilitative glucose transporters GLUT2 and GLUT4 was assessed by flow cytometry. In the control (static) cells, glucose uptake was similar in the three glucose groups. In mechanically stressed podocytes, glucose uptake increased 2-fold in the LG and NG groups but increased 3-fold in the HG group. In the NG cells, mechanical load increased the membrane expression of GLUT2 and reduced the membrane-bound GLUT4. In stretched HG cells, the membrane expression of both GLUT2 and GLUT4 was decreased. High glucose decreased the plasma membrane GLUT2 content in the stretched cells, whereas both static and stretched podocytes showed an elevation in GLUT4. Mechanical stress potentiated glucose uptake in podocytes and this effect was enhanced by high ambient glucose. The decreased expression of GLUT2 and GLUT4 on the surface of stretched cells suggests that the activity of other glucose transporters may be regulated by mechanical stress in podocytes.

  5. The peripheral modulation of duodenal and colonic motility in rats by the pancreatic polypeptide-fold family: neuropeptide Y, peptide YY, and pancreatic polypeptide.

    Science.gov (United States)

    Wager-Pagé, S A; Ghazali, B; Anderson, W; Veale, W L; Davison, J S

    1993-01-01

    Neuropeptide Y (NPY), peptide YY (PYY), and pancreatic polypeptide (PP) altered intraluminal pressure in the duodenum and colon of fasted anesthetized rats following intravenous bolus administration. There were rapid increases in intraluminal pressure of the duodenum and colon of anesthetized rats following peripheral injections of NPY, PYY and PP. Administration (IV) of NPY, PYY, and PP increased intraduodenal pressure +1.8, +3.2, and +3.7 mmHg compared to saline baseline. Prazosin, an alpha-2 adrenergic antagonist, did not alter the response of the duodenum of urethane-anesthesized rats to any of the PP-fold peptides following peripheral administration. Yohimbine, an alpha 2-adrenergic antagonist, attenuated the excitatory response of rat duodenum following NPY (IV) but did not alter the duodenal response to PP (IV). Intravenous NPY, PYY, and PP increased intracolonic pressure +2.0, +3.3, and +6.2 mmHg compared to saline baseline. In the presence of prazosin, an alpha 1-adrenergic antagonist, the intraluminal pressure of the colon increased +2.6, +2.4, and +8.1 mmHg compared to saline baseline by NPY, PYY, and PP (IV), respectively. In the presence of alpha 2-adrenergic blockade by yohimbine, NPY, PYY, and PP (IV) increased intraluminal pressure of the colon +4.2, +2.9, and +2.5 mmHg compared to saline baseline. The response of the duodenum to the excitatory effect of PYY (IV) was enhanced in the presence of yohimbine. Duodenal and colonic tone were modulated by the PP-fold peptides following peripheral administration. The alpha-adrenergic nervous system played only a minor role in the modulation of GI motility by the PP-fold peptides at peripheral sites.

  6. Standard Test Methods for Determining Mechanical Integrity of Photovoltaic Modules

    CERN Document Server

    American Society for Testing and Materials. Philadelphia

    2009-01-01

    1.1 These test methods cover procedures for determining the ability of photovoltaic modules to withstand the mechanical loads, stresses and deflections used to simulate, on an accelerated basis, high wind conditions, heavy snow and ice accumulation, and non-planar installation effects. 1.1.1 A static load test to 2400 Pa is used to simulate wind loads on both module surfaces 1.1.2 A static load test to 5400 Pa is used to simulate heavy snow and ice accumulation on the module front surface. 1.1.3 A twist test is used to simulate the non-planar mounting of a photovoltaic module by subjecting it to a twist angle of 1.2°. 1.1.4 A cyclic load test of 10 000 cycles duration and peak loading to 1440 Pa is used to simulate dynamic wind or other flexural loading. Such loading might occur during shipment or after installation at a particular location. 1.2 These test methods define photovoltaic test specimens and mounting methods, and specify parameters that must be recorded and reported. 1.3 Any individual mech...

  7. The mechanical environment modulates intracellular calcium oscillation activities of myofibroblasts.

    Directory of Open Access Journals (Sweden)

    Charles Godbout

    Full Text Available Myofibroblast contraction is fundamental in the excessive tissue remodeling that is characteristic of fibrotic tissue contractures. Tissue remodeling during development of fibrosis leads to gradually increasing stiffness of the extracellular matrix. We propose that this increased stiffness positively feeds back on the contractile activities of myofibroblasts. We have previously shown that cycles of contraction directly correlate with periodic intracellular calcium oscillations in cultured myofibroblasts. We analyze cytosolic calcium dynamics using fluorescent calcium indicators to evaluate the possible impact of mechanical stress on myofibroblast contractile activity. To modulate extracellular mechanics, we seeded primary rat subcutaneous myofibroblasts on silicone substrates and into collagen gels of different elastic modulus. We modulated cell stress by cell growth on differently adhesive culture substrates, by restricting cell spreading area on micro-printed adhesive islands, and depolymerizing actin with Cytochalasin D. In general, calcium oscillation frequencies in myofibroblasts increased with increasing mechanical challenge. These results provide new insight on how changing mechanical conditions for myofibroblasts are encoded in calcium oscillations and possibly explain how reparative cells adapt their contractile behavior to the stresses occurring in normal and pathological tissue repair.

  8. Fracture mechanics in new designed power module under thermo-mechanical loads

    Directory of Open Access Journals (Sweden)

    Durand Camille

    2014-06-01

    Full Text Available Thermo-mechanically induced failure is a major reliability issue in the microelectronic industry. On this account, a new type of Assembly Interconnected Technology used to connect MOSFETs in power modules has been developed. The reliability is increased by using a copper clip soldered on the top side of the chip, avoiding the use of aluminium wire bonds, often responsible for the failure of the device. Thus the new designed MOSFET package does not follow the same failure mechanisms as standard modules. Thermal and power cycling tests were performed on these new packages and resulting failures were analyzed. Thermo-mechanical simulations including cracks in the aluminium metallization and intermetallics (IMC were performed using Finite Element Analysis in order to better understand crack propagation and module behaviour.

  9. Mechanism and modulation of terahertz generation from a semimetal - graphite

    CERN Document Server

    Ye, Tong; Zhang, Jin; E, Yiwen; Yang, Yuping; Liu, Wuming; Yin, Yan; Wang, Li

    2015-01-01

    Semi-metals might offer a stronger interaction and a better confinement for terahertz wave than semiconductors, while preserve tunability. Particularly, graphene-based materials are envisioned as terahertz modulators, filters and ultra-broadband sources. However, the understanding of terahertz generation from those materials is still not clear, thus limits us recognizing the potential and improving device performances. Graphite, the mother material of graphene and a typical bulk semi-metal, is a good system to study semi-metals and graphene-based materials. Here we experimentally modulate and maximize the terahertz signal from graphite surface, thus reveal the mechanism - surface field driving photon induced carriers into transient current to radiate terahertz wave. We also discuss the differences between graphite and semiconductors; particularly graphite shows no temperature dependency from room temperature to 80C. Above knowledge will help us understand terahertz generations, achieve maximum output and elec...

  10. A galaxy of folds.

    Science.gov (United States)

    Alva, Vikram; Remmert, Michael; Biegert, Andreas; Lupas, Andrei N; Söding, Johannes

    2010-01-01

    Many protein classification systems capture homologous relationships by grouping domains into families and superfamilies on the basis of sequence similarity. Superfamilies with similar 3D structures are further grouped into folds. In the absence of discernable sequence similarity, these structural similarities were long thought to have originated independently, by convergent evolution. However, the growth of databases and advances in sequence comparison methods have led to the discovery of many distant evolutionary relationships that transcend the boundaries of superfamilies and folds. To investigate the contributions of convergent versus divergent evolution in the origin of protein folds, we clustered representative domains of known structure by their sequence similarity, treating them as point masses in a virtual 2D space which attract or repel each other depending on their pairwise sequence similarities. As expected, families in the same superfamily form tight clusters. But often, superfamilies of the same fold are linked with each other, suggesting that the entire fold evolved from an ancient prototype. Strikingly, some links connect superfamilies with different folds. They arise from modular peptide fragments of between 20 and 40 residues that co-occur in the connected folds in disparate structural contexts. These may be descendants of an ancestral pool of peptide modules that evolved as cofactors in the RNA world and from which the first folded proteins arose by amplification and recombination. Our galaxy of folds summarizes, in a single image, most known and many yet undescribed homologous relationships between protein superfamilies, providing new insights into the evolution of protein domains.

  11. Characterization of unfolding mechanism of human lamin A Ig fold by single-molecule force spectroscopy-implications in EDMD.

    Science.gov (United States)

    Bera, Manindra; Kotamarthi, Hema Chandra; Dutta, Subarna; Ray, Angana; Ghosh, Saptaparni; Bhattacharyya, Dhananjay; Ainavarapu, Sri Rama Koti; Sengupta, Kaushik

    2014-11-25

    A- and B-type lamins are intermediate filament proteins constituting the nuclear lamina underneath the nuclear envelope thereby conferring proper shape and mechanical rigidity to the nucleus. Lamin proteins are also shown to be related diversely to basic nuclear processes. More than 400 mutations in human lamin A protein alone have been reported to produce at least 11 different disease conditions jointly termed as laminopathies. These mutations in lamin A are scattered throughout its helical rod domain, as well as the C-terminal domain containing the conserved Ig-fold region. The commonality of phenotypes in all these diseases is characterized by misshapen nuclei of the affected tissues which might stem from altered rigidity of the supporting lamina hence lamins. Here we have focused on autosomal dominant Emery-Dreifuss Muscular Dystrophy, one such laminopathy where R453W is the causative mutation located in the Ig domain of lamin A. We have investigated by single-molecule force spectroscopy how a stretching mechanical perturbation senses the destabilizing effect of the mutation in the lamin A Ig domain and compared the mechanoelastic properties of the mutant R453W with that of the wild-type in conjunction with steered molecular dynamics. Furthermore, we have shown the interaction of Ig domain with emerin, another key player and interacting partner in the pathogenesis of EDMD, is disrupted in the R453W mutant. This altered mechanoresistance of Ig domain itself and consequent uncoupling of lamin A-emerin interaction might underlie the altered mechanotransduction properties of EDMD affected nuclei.

  12. The structure of cytomegalovirus immune modulator UL141 highlights structural Ig-fold versatility for receptor binding

    Energy Technology Data Exchange (ETDEWEB)

    Nemčovičová, Ivana [La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92037 (United States); Slovak Academy of Sciences, Dúbravská cesta 9, SK 84505 Bratislava (Slovakia); Zajonc, Dirk M., E-mail: dzajonc@liai.org [La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92037 (United States)

    2014-03-01

    The crystal structure of Human cytomegalovirus immune modulator UL141 was solved at 3.25 Å resolution. Here, a detailed analysis of its intimate dimerization interface and the biophysical properties of its receptor (TRAIL-R2 and CD155) binding interactions are presented. Natural killer (NK) cells are critical components of the innate immune system as they rapidly detect and destroy infected cells. To avoid immune recognition and to allow long-term persistence in the host, Human cytomegalovirus (HCMV) has evolved a number of genes to evade or inhibit immune effector pathways. In particular, UL141 can inhibit cell-surface expression of both the NK cell-activating ligand CD155 as well as the TRAIL death receptors (TRAIL-R1 and TRAIL-R2). The crystal structure of unliganded HCMV UL141 refined to 3.25 Å resolution allowed analysis of its head-to-tail dimerization interface. A ‘dimerization-deficient’ mutant of UL141 (ddUL141) was further designed, which retained the ability to bind to TRAIL-R2 or CD155 while losing the ability to cross-link two receptor monomers. Structural comparison of unliganded UL141 with UL141 bound to TRAIL-R2 further identified a mobile loop that makes intimate contacts with TRAIL-R2 upon receptor engagement. Superposition of the Ig-like domain of UL141 on the CD155 ligand T-cell immunoreceptor with Ig and ITIM domains (TIGIT) revealed that UL141 can potentially engage CD155 similar to TIGIT by using the C′C′′ and GF loops. Further mutations in the TIGIT binding site of CD155 (Q63R and F128R) abrogated UL141 binding, suggesting that the Ig-like domain of UL141 is a viral mimic of TIGIT, as it targets the same binding site on CD155 using similar ‘lock-and-key’ interactions. Sequence alignment of the UL141 gene and its orthologues also showed conservation in this highly hydrophobic (L/A)X{sub 6}G ‘lock’ motif for CD155 binding as well as conservation of the TRAIL-R2 binding patches, suggesting that these host

  13. Mechanical modulation method for ultrasensitive phase measurements in photonics biosensing.

    Science.gov (United States)

    Patskovsky, S; Maisonneuve, M; Meunier, M; Kabashin, A V

    2008-12-22

    A novel polarimetry methodology for phase-sensitive measurements in single reflection geometry is proposed for applications in optical transduction-based biological sensing. The methodology uses altering step-like chopper-based mechanical phase modulation for orthogonal s- and p- polarizations of light reflected from the sensing interface and the extraction of phase information at different harmonics of the modulation. We show that even under a relatively simple experimental arrangement, the methodology provides the resolution of phase measurements as low as 0.007 deg. We also examine the proposed approach using Total Internal Reflection (TIR) and Surface Plasmon Resonance (SPR) geometries. For TIR geometry, the response appears to be strongly dependent on the prism material with the best values for high refractive index Si. The detection limit for Si-based TIR is estimated as 10(-5) in terms Refractive Index Units (RIU) change. SPR geometry offers much stronger phase response due to a much sharper phase characteristics. With the detection limit of 3.2*10(-7) RIU, the proposed methodology provides one of best sensitivities for phase-sensitive SPR devices. Advantages of the proposed method include high sensitivity, simplicity of experimental setup and noise immunity as a result of a high stability modulation.

  14. Modulation of mechanical resonance by chemical potential oscillation in graphene

    Science.gov (United States)

    Chen, Changyao; Deshpande, Vikram V.; Koshino, Mikito; Lee, Sunwoo; Gondarenko, Alexander; MacDonald, Allan H.; Kim, Philip; Hone, James

    2016-03-01

    The classical picture of the force on a capacitor assumes a large density of electronic states, such that the electrochemical potential of charges added to the capacitor is given by the external electrostatic potential and the capacitance is determined purely by geometry. Here we consider capacitively driven motion of a nano-mechanical resonator with a low density of states, in which these assumptions can break down. We find three leading-order corrections to the classical picture: the first of which is a modulation in the static force due to variation in the internal chemical potential; the second and third are changes in the static force and dynamic spring constant due to the rate of change of chemical potential, expressed as the quantum (density of states) capacitance. As a demonstration, we study capacitively driven graphene mechanical resonators, where the chemical potential is modulated independently of the gate voltage using an applied magnetic field to manipulate the energy of electrons residing in discrete Landau levels. In these devices, we observe large periodic frequency shifts consistent with the three corrections to the classical picture. In devices with extremely low strain and disorder, the first correction term dominates and the resonant frequency closely follows the chemical potential. The theoretical model fits the data with only one adjustable parameter representing disorder-broadening of the Landau levels. The underlying electromechanical coupling mechanism is not limited by the particular choice of material, geometry, or mechanism for variation in the chemical potential, and can thus be extended to other low-dimensional systems.

  15. Evolving Stress State and Deformation Mechanism in the Himalayan Foreland Fold-and-Thrust Belt, Northern Pakistan

    Science.gov (United States)

    Ahmad, I.; Dasti, N.

    2010-12-01

    Crustal deformation along with shortening due to northward under-thrusting of the Indian plate beneath the Eurasian plate continues to create active tectonic features on the northern fringes of the Indian craton since major collision began in the Eocene. Here the study provides insights on the evolving stress state and deformation mechanism of the Salt Range and Potwar area of Northern Pakistan. This part of Himalayan foreland fold-and-thrust-belt has severe history of deformation during 5.1 Ma and 2 Ma. This foreland area lies between Main Boundary Thrust (MBT) in the north, Himalayan Frontal Thrust (HFT) in the south and Jhelum fault of sinistral nature in the east & Kalabagh fault of dextral nature in the west. An integrated data from seismic reflection profiles and drilling logs reveal that the subsurface deformation encompasses pop-ups, imbricates, duplexes with in-sequence and out-of-sequence thrusting. It also depicts that intensity of deformation increases from the northern margin of Soan geosyncline towards north due to lacking of evaporites while in the south it decreases due to gradual increase in salt thickness. Surface geologic mapping glimpses a series of thrust sheets and anticlines trending ENE-SWS in the eastern and central part of the study area; whereas in the western part, the trend is almost E-W. This variation in the trend of structures is the result of counter clock rotational behaviour (~10°deviation from north to the west) of north-western part of the Indian lithospheric plate. Current outcrop-scale natural fracture data collected from selected anticlinal structures of the study area is presented to manifest the stress evolution and deformation styles under the established tectonic framework. Collected data is analysed for the evaluation of tectonic stress direction and deformation mechanism. The genetic arrangement and types of fractures observed in the study area indicate that the whole area is under compression. The data also testify

  16. Different mechanisms of resistance modulate sulfite tolerance in wine yeasts.

    Science.gov (United States)

    Nadai, Chiara; Treu, Laura; Campanaro, Stefano; Giacomini, Alessio; Corich, Viviana

    2016-01-01

    From a technological point of view, yeast resistance to sulfite is of great interest and represents an important technological character for winemaking. Several mechanisms are involved, and strain-dependent strategies to obtain SO2 resistance can deeply influence wine quality, although this choice is less relevant in determining the technological performance of the strain during fermentation. In this study, to better understand the strain-specific mechanisms of resistance, 11 Saccharomyces cerevisiae strains, whose genomes have been previously sequenced, were selected. Their attitude towards sulfites, in terms of resistance and production, was evaluated, and RNA-sequencing of four selected strains was performed during fermentation process in synthetic grape must in the presence of SO2. Results demonstrated that at molecular level, the physical effect of SO2 triggered multiple stress responses in the cell and high tolerance to general enological stressing condition increased SO2 resistance. Adaptation mechanism due to high basal gene expression level rather than specific gene induction in the presence of sulfite seemed to be responsible in modulating strain resistance. This mechanism involved higher basal gene expression level of specific cell wall proteins, enzymes for lipid biosynthesis, and enzymes directly involved in SO2 assimilation pathway and efflux.

  17. Progress on modelling of the thermo-mechanical behavior of the CLIC two-beam module

    CERN Document Server

    Raatikainen, R; Niinikoski, T; Riddone, G

    2011-01-01

    under study, imposes micrometer mechanical stability of the 2-m long two-beam modules, the shortest repetitive elements of the main linacs. These modules will be exposed to variable high power dissipation during operation resulting in mechanical distortions in and between module components. The stability of the CLIC module will be tested in laboratory conditions at CERN in a full-scale prototype module. In this paper, the FEA model developed for CLIC prototype module is described. The thermal and structural results for the new module configuration are presented considering the thermo-mechanical behavior of the CLIC collider in its primary operation modes. These results will be compared to the laboratory measurements to be done during 2011 and 2012 with the full-scale prototype module. The experimental results will allow for better understanding of the module behaviour and they will be propagated back to the present thermo-mechanical model.

  18. The application of plastic compression to modulate fibrin hydrogel mechanical properties.

    Science.gov (United States)

    Haugh, Matthew G; Thorpe, Stephen D; Vinardell, Tatiana; Buckley, Conor T; Kelly, Daniel J

    2012-12-01

    The inherent biocompatibility of fibrin hydrogels makes them an attractive material for use in a wide range of tissue engineering applications. Despite this, their relatively low stiffness and high compliance limits their potential for certain orthopaedic applications. Enhanced mechanical properties are desirable so as to withstand surgical handling and in vivo loading after implantation and additionally, can provide important cues to cells seeded within the hydrogel. Standard methods used to enhance the mechanical properties of biological scaffolds such as chemical or thermal crosslinking cannot be used with fibrin hydrogels as cell seeding and gel formation occurs simultaneously. The objective of this study was to investigate the use of plastic compression as a means to improve the mechanical properties of chondrocyte-seeded fibrin hydrogels and to determine the influence of such compression on cell viability within these constructs. It was found that the application of 80% strain to fibrin hydrogels for 30 min (which resulted in a permanent strain of 47.4%) produced a 2.1-fold increase in the subsequent compressive modulus. Additionally, chondrocyte viability was maintained in the plastically compressed gels with significant cellular proliferation and extracellular matrix accumulation observed over 28 days of culture. In conclusion, plastic compression can be used to modulate the density and mechanical properties of cell-seeded fibrin hydrogels and represents a useful tool for both in theatre and in vitro tissue engineering applications.

  19. Folding Thermodynamics and Mechanism of Five Trp-Cage Variants from Replica-Exchange MD Simulations with RSFF2 Force Field.

    Science.gov (United States)

    Zhou, Chen-Yang; Jiang, Fan; Wu, Yun-Dong

    2015-11-10

    To test whether our recently developed residue-specific force field RSFF2 can reproduce the mutational effect on the thermal stability of Trp-cage mini-protein and decipher its detailed folding mechanism, we carried out long-time replica-exchange molecular dynamics (REMD) simulations on five Trp-cage variants, including TC5b and TC10b. Initiated from their unfolded structures, the simulations not only well-reproduce their experimental structures but also their melting temperatures and folding enthalpies reasonably well. For each Trp-cage variant, the overall folding free energy landscape is apparently two-state, but some intermediate states can be observed when projected on more detailed coordinates. We also found different variants have the same major folding pathway, including the well formed PII-helix in the unfolded state, the formation of W6-P12/P18/P19 contacts and the α-helix before the transition state, the following formation of most native contacts, and the final native loop formation. The folding mechanism derived here is consistent with many previous simulations and experiments.

  20. Neural mechanism of acupuncture-modulated gastric motility

    Institute of Scientific and Technical Information of China (English)

    Yu-Qing Li; Bing Zhu; Pei-Jing Rong; Hui Ben; Yan-Hua Li

    2007-01-01

    AIM: To investigate the acupuncture-modulated gastric motility and its underlying neural mechanism.METHODS: Intragastric pressure and/or waves of gastric contraction in rats were recorded by intrapyloric balloon and changes of gastric motility induced by acupuncture stimulation were compared with the background activity before any stimulation. Gastrovagal or splanchnic-sympathetic nerves were recorded or cut respectively for investigating the involvement of autonomic nerve pathways. Spinalization experiment was also performed.RESULTS: Acupuncture-stimulation by exciting Aδ and/or C afferent fibers, could only modulate gastric motility.Acupuncture-stimulation on fore- and hind-limbs evoked a moderate gastric motility followed by increased vagus discharges with unchanged sympathetic activity, while the same stimulus to the acupoints in abdomen resulted in reversed effects on gastric motility and autonomic nervous activities. The inhibitory gastric response was completely abolished by splanchnic denervation, but the facilitative gastric response to stimulation of acupoints in limbs was not influenced, which was opposite to the effect when vagotomy was performed. The similar depressive effects were produced by the stimulation at the acupoints homo-segmental to the gastric innervation in the animals with or without spinalization. However, the facilitation induced by the stimulation at the acupoints heteto-segmental to the gastric innervation was not observed in the spinalized animals.CONCLUSION: Facilitative effects of stimulating hetero-segmental acupoints are involved in the intact preparation of vagal nerves and spinal cord, while the inhibitory response induced by stimulating homosegmental acupoints is involved in the intact preparation of sympathetic nerves. Only the acupuncture-stimulation with intensity over the threshold of Aδ and/or C afferent fibers can markedly modulate gastrointestinal motility.

  1. Fast protein folding kinetics

    Science.gov (United States)

    Gelman, Hannah; Gruebele, Martin

    2014-01-01

    Fast folding proteins have been a major focus of computational and experimental study because they are accessible to both techniques: they are small and fast enough to be reasonably simulated with current computational power, but have dynamics slow enough to be observed with specially developed experimental techniques. This coupled study of fast folding proteins has provided insight into the mechanisms which allow some proteins to find their native conformation well less than 1 ms and has uncovered examples of theoretically predicted phenomena such as downhill folding. The study of fast folders also informs our understanding of even “slow” folding processes: fast folders are small, relatively simple protein domains and the principles that govern their folding also govern the folding of more complex systems. This review summarizes the major theoretical and experimental techniques used to study fast folding proteins and provides an overview of the major findings of fast folding research. Finally, we examine the themes that have emerged from studying fast folders and briefly summarize their application to protein folding in general as well as some work that is left to do. PMID:24641816

  2. Unstart coupling mechanism analysis of multiple-modules hypersonic inlet.

    Science.gov (United States)

    Hu, Jichao; Chang, Juntao; Wang, Lei; Cao, Shibin; Bao, Wen

    2013-01-01

    The combination of multiplemodules in parallel manner is an important way to achieve the much higher thrust of scramjet engine. For the multiple-modules scramjet engine, when inlet unstarted oscillatory flow appears in a single-module engine due to high backpressure, how to interact with each module by massflow spillage, and whether inlet unstart occurs in other modules are important issues. The unstarted flowfield and coupling characteristic for a three-module hypersonic inlet caused by center module II and side module III were, conducted respectively. The results indicate that the other two hypersonic inlets are forced into unstarted flow when unstarted phenomenon appears on a single-module hypersonic inlet due to high backpressure, and the reversed flow in the isolator dominates the formation, expansion, shrinkage, and disappearance of the vortexes, and thus, it is the major factor of unstart coupling of multiple-modules hypersonic inlet. The coupling effect among multiple modules makes hypersonic inlet be more likely unstarted.

  3. A mechanism for frequency modulation in songbirds shared with humans.

    Science.gov (United States)

    Amador, Ana; Margoliash, Daniel

    2013-07-03

    In most animals that vocalize, control of fundamental frequency is a key element for effective communication. In humans, subglottal pressure controls vocal intensity but also influences fundamental frequency during phonation. Given the underlying similarities in the biomechanical mechanisms of vocalization in humans and songbirds, songbirds offer an attractive opportunity to study frequency modulation by pressure. Here, we present a novel technique for dynamic control of subsyringeal pressure in zebra finches. By regulating the opening of a custom-built fast valve connected to the air sac system, we achieved partial or total silencing of specific syllables, and could modify syllabic acoustics through more complex manipulations of air sac pressure. We also observed that more nuanced pressure variations over a limited interval during production of a syllable concomitantly affected the frequency of that syllable segment. These results can be explained in terms of a mathematical model for phonation that incorporates a nonlinear description for the vocal source capable of generating the observed frequency modulations induced by pressure variations. We conclude that the observed interaction between pressure and frequency was a feature of the source, not a result of feedback control. Our results indicate that, beyond regulating phonation or its absence, regulation of pressure is important for control of fundamental frequencies of vocalizations. Thus, although there are separate brainstem pathways for syringeal and respiratory control of song production, both can affect airflow and frequency. We hypothesize that the control of pressure and frequency is combined holistically at higher levels of the vocalization pathways.

  4. Microcantilever Displacement Measurement Using a Mechanically Modulated Optical Feedback Interferometer

    Directory of Open Access Journals (Sweden)

    Francisco J. Azcona

    2016-06-01

    Full Text Available Microcantilever motion detection is a useful tool for the characterization of the physical, chemical and biological properties of materials. In the past, different approaches have been proposed and tested to enhance the behavior, size and simplicity of microcantilever motion detectors. In this paper, a new approach to measure microcantilever motion with nanometric resolution is presented. The proposed approach is based on the concept of mechanically-modulated optical feedback interferometry, a technique that has shown displacement measurement capabilities well within the nanometric scale and that, due to its size, compactness and low cost, may be a suitable choice for measuring nanometric motions in cantilever-like sensors. It will be shown that the sensor, in its current state of development, is capable of following a cantilever sinusoidal trajectory at different sets of frequencies ranging up to 200 Hz and peak to peak amplitudes up to λ / 2 with experimental resolutions in the λ / 100 range.

  5. Strain modulations as a mechanism to reduce stress relaxation in laryngeal tissues.

    Directory of Open Access Journals (Sweden)

    Eric J Hunter

    Full Text Available Vocal fold tissues in animal and human species undergo deformation processes at several types of loading rates: a slow strain involved in vocal fold posturing (on the order of 1 Hz or so, cyclic and faster posturing often found in speech tasks or vocal embellishment (1-10 Hz, and shear strain associated with vocal fold vibration during phonation (100 Hz and higher. Relevant to these deformation patterns are the viscous properties of laryngeal tissues, which exhibit non-linear stress relaxation and recovery. In the current study, a large strain time-dependent constitutive model of human vocal fold tissue is used to investigate effects of phonatory posturing cyclic strain in the range of 1 Hz to 10 Hz. Tissue data for two subjects are considered and used to contrast the potential effects of age. Results suggest that modulation frequency and extent (amplitude, as well as the amount of vocal fold overall strain, all affect the change in stress relaxation with modulation added. Generally, the vocal fold cover reduces the rate of relaxation while the opposite is true for the vocal ligament. Further, higher modulation frequencies appear to reduce the rate of relaxation, primarily affecting the ligament. The potential benefits of cyclic strain, often found in vibrato (around 5 Hz modulation and intonational inflection, are discussed in terms of vocal effort and vocal pitch maintenance. Additionally, elderly tissue appears to not exhibit these benefits to modulation. The exacerbating effect such modulations may have on certain voice disorders, such as muscle tension dysphonia, are explored.

  6. (Un)folding mechanisms of the FBP28 WW domain in explicit solvent revealed by multiple rare event simulation methods

    NARCIS (Netherlands)

    Juraszek, J.; Bolhuis, P.G.

    2010-01-01

    We report a numerical study of the (un)folding routes of the truncated FBP28 WW domain at ambient conditions using a combination of four advanced rare event molecular simulation techniques. We explore the free energy landscape of the native state, the unfolded state, and possible intermediates, with

  7. Folding by Design

    Science.gov (United States)

    Dodd, Paul; Damasceno, Pablo; Glotzer, Sharon

    2014-03-01

    A form of self-assembly, ``self-folding'' presents an alternative approach to the creation of reconfigurable, responsive materials with applications ranging from robotics to drug design. However, the complexity of interactions present in biological and engineered systems that undergo folding makes it challenging to isolate the main factors controlling their assembly and dis-assembly. Here we use computer simulations of simple, minimalistic self-foldable structures and investigate their stochastic folding process. By dynamically accessing all the states that lead to, or inhibit, successful folding, we show that the mechanisms by which general stochastic systems can achieve their ``native'' structures can be identified and used to design rules for optimized folding propensity. Research supported by the National Science Foundation, Emerging Frontiers in Research and Innovation Award # EFRI-1240264.

  8. Signal modulation as a mechanism for handicap disposal

    Science.gov (United States)

    Gavassa, Sat; Silva, Ana C.; Gonzalez, Emmanuel; Stoddard, Philip K.

    2012-01-01

    Signal honesty may be compromised when heightened competition provides incentive for signal exaggeration. Some degree of honesty might be maintained by intrinsic handicap costs on signalling or through imposition of extrinsic costs, such as social punishment of low quality cheaters. Thus, theory predicts a delicate balance between signal enhancement and signal reliability that varies with degree of social competition, handicap cost, and social cost. We investigated whether male sexual signals of the electric fish Brachyhypopomus gauderio would become less reliable predictors of body length when competition provides incentives for males to boost electric signal amplitude. As expected, social competition under natural field conditions and in controlled lab experiments drove males to enhance their signals. However, signal enhancement improved the reliability of the information conveyed by the signal, as revealed in the tightening of the relationship between signal amplitude and body length. Signal augmentation in male B. gauderio was independent of body length, and thus appeared not to be curtailed through punishment of low quality (small) individuals. Rather, all individuals boosted their signals under high competition, but those whose signals were farthest from the predicted value under low competition boosted signal amplitude the most. By elimination, intrinsic handicap cost of signal production, rather than extrinsic social cost, appears to be the basis for the unexpected reinforcement of electric signal honesty under social competition. Signal modulation may provide its greatest advantage to the signaller as a mechanism for handicap disposal under low competition rather than as a mechanism for exaggeration of quality under high competition. PMID:22665940

  9. Basal forebrain thermoregulatory mechanism modulates auto-regulated sleep

    Directory of Open Access Journals (Sweden)

    Hruda N Mallick

    2012-06-01

    Full Text Available Regulation of body temperature and sleep are two physiological mechanisms that are vital for our survival. Interestingly neural structures implicated in both these functions are common. These areas include the medial preoptic area, the lateral preoptic area, the ventrolateral preoptic area, the median preoptic nucleus and the medial septum, which form part of the basal forebrain.When given a choice, rats prefer to stay at an ambient temperature of 270C, though the maximum sleep was observed when they were placed at 300C. Ambient temperature around 270C should be considered as the thermoneutral temperature for rats in all sleep studies. At this temperature the diurnal oscillations of sleep and body temperature are properly expressed. The warm sensitive neurons of the preoptic area mediate the increase in sleep at 300C. Promotion of sleep during the rise in ambient temperature from 270C to 300C, serve a thermoregulatory function. Autonomous thermoregulatory changes in core body temperature and skin temperature could act as an input signal to modulate neuronal activity in sleep-promoting brain areas. The studies presented here show that the neurons of the basal forebrain play a key role in regulating sleep. Basal forebrain thermoregulatory system is a part of the global homeostatic sleep regulatory mechanism, which is auto-regulated.

  10. Fast protein folding kinetics.

    Science.gov (United States)

    Gelman, Hannah; Gruebele, Martin

    2014-05-01

    Fast-folding proteins have been a major focus of computational and experimental study because they are accessible to both techniques: they are small and fast enough to be reasonably simulated with current computational power, but have dynamics slow enough to be observed with specially developed experimental techniques. This coupled study of fast-folding proteins has provided insight into the mechanisms, which allow some proteins to find their native conformation well fast folders also informs our understanding of even 'slow' folding processes: fast folders are small; relatively simple protein domains and the principles that govern their folding also govern the folding of more complex systems. This review summarizes the major theoretical and experimental techniques used to study fast-folding proteins and provides an overview of the major findings of fast-folding research. Finally, we examine the themes that have emerged from studying fast folders and briefly summarize their application to protein folding in general, as well as some work that is left to do.

  11. Probing the folded state and mechanical unfolding pathways of T4 lysozyme using all-atom and coarse-grained molecular simulation

    Energy Technology Data Exchange (ETDEWEB)

    Zheng, Wenjun, E-mail: wjzheng@buffalo.edu; Glenn, Paul [Department of Physics, University at Buffalo, Buffalo, New York 14260 (United States)

    2015-01-21

    The Bacteriophage T4 Lysozyme (T4L) is a prototype modular protein comprised of an N-terminal and a C-domain domain, which was extensively studied to understand the folding/unfolding mechanism of modular proteins. To offer detailed structural and dynamic insights to the folded-state stability and the mechanical unfolding behaviors of T4L, we have performed extensive equilibrium and steered molecular dynamics simulations of both the wild-type (WT) and a circular permutation (CP) variant of T4L using all-atom and coarse-grained force fields. Our all-atom and coarse-grained simulations of the folded state have consistently found greater stability of the C-domain than the N-domain in isolation, which is in agreement with past thermostatic studies of T4L. While the all-atom simulation cannot fully explain the mechanical unfolding behaviors of the WT and the CP variant observed in an optical tweezers study, the coarse-grained simulations based on the Go model or a modified elastic network model (mENM) are in qualitative agreement with the experimental finding of greater unfolding cooperativity in the WT than the CP variant. Interestingly, the two coarse-grained models predict different structural mechanisms for the observed change in cooperativity between the WT and the CP variant—while the Go model predicts minor modification of the unfolding pathways by circular permutation (i.e., preserving the general order that the N-domain unfolds before the C-domain), the mENM predicts a dramatic change in unfolding pathways (e.g., different order of N/C-domain unfolding in the WT and the CP variant). Based on our simulations, we have analyzed the limitations of and the key differences between these models and offered testable predictions for future experiments to resolve the structural mechanism for cooperative folding/unfolding of T4L.

  12. Unstart Coupling Mechanism Analysis of Multiple-Modules Hypersonic Inlet

    Directory of Open Access Journals (Sweden)

    Jichao Hu

    2013-01-01

    Full Text Available The combination of multiplemodules in parallel manner is an important way to achieve the much higher thrust of scramjet engine. For the multiple-modules scramjet engine, when inlet unstarted oscillatory flow appears in a single-module engine due to high backpressure, how to interact with each module by massflow spillage, and whether inlet unstart occurs in other modules are important issues. The unstarted flowfield and coupling characteristic for a three-module hypersonic inlet caused by center module II and side module III were, conducted respectively. The results indicate that the other two hypersonic inlets are forced into unstarted flow when unstarted phenomenon appears on a single-module hypersonic inlet due to high backpressure, and the reversed flow in the isolator dominates the formation, expansion, shrinkage, and disappearance of the vortexes, and thus, it is the major factor of unstart coupling of multiple-modules hypersonic inlet. The coupling effect among multiple modules makes hypersonic inlet be more likely unstarted.

  13. Mechanical compaction directly modulates the dynamics of bile canaliculi formation.

    Science.gov (United States)

    Wang, Yan; Toh, Yi-Chin; Li, Qiushi; Nugraha, Bramasta; Zheng, Baixue; Lu, Thong Beng; Gao, Yi; Ng, Mary Mah Lee; Yu, Hanry

    2013-02-01

    Homeostatic pressure-driven compaction is a ubiquitous mechanical force in multicellular organisms and is proposed to be important in the maintenance of multicellular tissue integrity and function. Previous cell-free biochemical models have demonstrated that there are cross-talks between compaction forces and tissue structural functions, such as cell-cell adhesion. However, its involvement in physiological tissue function has yet to be directly demonstrated. Here, we use the bile canaliculus (BC) as a physiological example of a multicellular functional structure in the liver, and employ a novel 3D microfluidic hepatocyte culture system to provide an unprecedented opportunity to experimentally modulate the compaction states of primary hepatocyte aggregates in a 3D physiological-mimicking environment. Mechanical compaction alters the physical attributes of the hepatocyte aggregates, including cell shape, cell packing density and cell-cell contact area, but does not impair the hepatocytes' remodeling and functional capabilities. Characterization of structural and functional polarity shows that BC formation in compact hepatocyte aggregates is accelerated to as early as 12 hours post-seeding; whereas non-compact control requires 48 hours for functional BC formation. Further dynamic immunofluorescence imaging and gene expression profiling reveal that compaction accelerated BC formation is accompanied by changes in actin cytoskeleton remodeling dynamics and transcriptional levels of hepatic nuclear factor 4α and Annexin A2. Our report not only provides a novel strategy of modeling BC formation for in vitro hepatology research, but also shows a first instance that homeostatic pressure-driven compaction force is directly coupled to the higher-order multicellular functions.

  14. Mechanism of Folding and Activation of Subtilisin Kexin Isozyme-1 (SKI-1)/Site-1 Protease (S1P).

    Science.gov (United States)

    da Palma, Joel Ramos; Cendron, Laura; Seidah, Nabil Georges; Pasquato, Antonella; Kunz, Stefan

    2016-01-29

    The proprotein convertase subtilisin kexin isozyme-1 (SKI-1)/site-1 protease (S1P) is implicated in lipid homeostasis, the unfolded protein response, and lysosome biogenesis. The protease is further hijacked by highly pathogenic emerging viruses for the processing of their envelope glycoproteins. Zymogen activation of SKI-1/S1P requires removal of an N-terminal prodomain, by a multistep process, generating the mature enzyme. Here, we uncover a modular structure of the human SKI-1/S1P prodomain and define its function in folding and activation. We provide evidence that the N-terminal AB fragment of the prodomain represents an autonomous structural and functional unit that is necessary and sufficient for folding and partial activation. In contrast, the C-terminal BC fragment lacks a defined structure but is crucial for autoprocessing and full catalytic activity. Phylogenetic analysis revealed that the sequence of the AB domain is highly conserved, whereas the BC fragment shows considerable variation and seems even absent in some species. Notably, SKI-1/S1P of arthropods, like the fruit fly Drosophila melanogaster, contains a shorter prodomain comprised of full-length AB and truncated BC regions. Swapping the prodomain fragments between fly and human resulted in a fully mature and active SKI-1/S1P chimera. Our study suggests that primordial SKI-1/S1P likely contained a simpler prodomain consisting of the highly conserved AB fragment that represents an independent folding unit. The BC region appears as a later evolutionary acquisition, possibly allowing more subtle fine-tuning of the maturation process.

  15. Bilingualism modulates dual mechanisms of cognitive control: Evidence from ERPs.

    Science.gov (United States)

    Morales, Julia; Yudes, Carolina; Gómez-Ariza, Carlos J; Bajo, M Teresa

    2015-01-01

    Recent behavioral findings with the AX-Continous Performance Task (AX-CPT; Morales et al., 2013) show that bilinguals only outperform monolinguals under conditions that require the highest adjustment between monitoring (proactive) and inhibitory (reactive) control, which supports the idea that bilingualism modulates the coordination of different control mechanisms. In an ERP experiment we aimed to further investigate the role that bilingualism plays in the dynamic combination of proactive and reactive control in the AX-CPT. Our results strongly indicate that bilingualism facilitates an effective adjustment between both components of cognitive control. First, we replicated previous behavioral results. Second, ERP components indicated that bilingualism influences the conflict monitoring, response inhibition and error monitoring components of control (as indexed by the N2 and P3a elicited by the probe and the error-related negativity following incorrect responses, respectively). Thus, bilinguals exerted higher reactive control than monolinguals but only when they needed to overcome the competing cue-information. These findings join others in suggesting that a better understanding of the cognitive benefits of bilingualism may require consideration of a multi-component perspective. Copyright © 2014 Elsevier Ltd. All rights reserved.

  16. Modulation of mechanical and muscular load by footwear during catering.

    Science.gov (United States)

    Kersting, U G; Janshen, L; Böhm, H; Morey-Klapsing, G M; Brüggemann, G-P

    2005-03-15

    The BGN (Berufsgenossenschaft Nahrungsmithl und Gaststätten) reports 70% of job induced days off work to be connected with traumas of the ankle joint or overloading of the leg, knee and lower back, with an increased incidence in service areas outdoors (R. Grieshaber, personal communication). Workspace environments usually contain narrow passages, slopes or stairs and sudden changes between different surfaces. The aim of this study was to investigate the biomechanical load on the lower extremity and the low back during catering service when wearing different types of footwear. Thus, the potential for altering mechanical stress experienced during catering by variations in footwear was explored. Sixteen experienced waiters followed a course typical for a combined indoor-outdoor service area. Three different types of footwear were investigated using pressure distribution measurements, rearfoot goniometry and electromyography. A discriminant analysis revealed that the factors subject, shoe and surface affect rear foot movement or pressure distribution in different ways. A MANOVA demonstrated significant differences in loading parameters between footwear types. In general, these differences increased in magnitude in critical situations, such as climbing stairs or crossing slippery surfaces. The results of this study demonstrate that manipulations to footwear offer a great potential for modulating loads experienced during catering. Based on the results, the effects of constructional features are discussed. The method proposed can be applied to evaluate shoe modifications under realistic workplace conditions.

  17. Mechanized Off-Road Equipment Safety. Module SH-17. Safety and Health.

    Science.gov (United States)

    Center for Occupational Research and Development, Inc., Waco, TX.

    This student module on mechanized off-road equipment safety is one of 50 modules concerned with job safety and health. This module aims to encourage the development of a positive approach to safety as it concerns the heavy equipment industry. Following the introduction, 15 objectives (each keyed to a page in the text) the student is expected to…

  18. Heating and Air Conditioning. Auto Mechanics Curriculum Guide Module 9. Instructor's Guide.

    Science.gov (United States)

    Hevel, David

    This unit of instruction is one of a series of modules in the Missouri Auto Mechanics Curriculum Guide. The module's format was developed for competency-based teaching and testing. The module contains 11 units, each of which contains the following components: a competency profile, objective sheets, references, notes to the instructor, lesson…

  19. Nuclear Technology. Course 30: Mechanical Inspection. Module 30-7, Pressure Vessel Inspection.

    Science.gov (United States)

    Kupiec, Chet; Espy, John

    This seventh in a series of eight modules for a course titled Mechanical Inspection is devoted to the design and fabrication of the reactor pressure vessel. The module follows a typical format that includes the following sections: (1) introduction, (2) module prerequisites, (3) objectives, (4) notes to instructor/student, (5) subject matter, (6)…

  20. Heating and Air Conditioning. Auto Mechanics Curriculum Guide Module 9. Instructor's Guide.

    Science.gov (United States)

    Hevel, David

    This unit of instruction is one of a series of modules in the Missouri Auto Mechanics Curriculum Guide. The module's format was developed for competency-based teaching and testing. The module contains 11 units, each of which contains the following components: a competency profile, objective sheets, references, notes to the instructor, lesson…

  1. Nuclear Technology. Course 30: Mechanical Inspection. Module 30-5, Surface Cleaning Inspection.

    Science.gov (United States)

    Wasel, Ed; Espy, John

    This fifth in a series of eight modules for a course titled Mechanical Inspection describes cleaning activities which typically apply to construction, maintenance, and modification activities at the nuclear power plant site. The module follows a typical format that includes the following sections: (1) introduction, (2) module prerequisites, (3)…

  2. Nuclear Technology. Course 27: Metrology. Module 27-3, Gage Blocks, Mechanical Comparators and Electronic Comparators.

    Science.gov (United States)

    Selleck, Ben; Espy, John

    This third in a series of eight modules for a course titled Metrology describes gage blocks and mechanical and electronic comparators. The module follows a typical format that includes the following sections: (1) introduction, (2) module prerequisites, (3) objectives, (4) notes to instructor/student, (5) subject matter, (6) materials needed, (7)…

  3. Engine Performance (Section C: Emission Control Systems). Auto Mechanics Curriculum Guide. Module 3. Instructor's Guide.

    Science.gov (United States)

    Rains, Larry

    This engine performance (emission control systems) module is one of a series of competency-based modules in the Missouri Auto Mechanics Curriculum Guide. Topics of this module's five units are: positive crankcase ventilation (PCV) and evaporative emission control systems; exhaust gas recirculation (EGR); air injection and catalytic converters;…

  4. Optimization of the Mechanical and Electrical Performance of a Thermoelectric Module

    DEFF Research Database (Denmark)

    Sarhadi, Ali; Bjørk, Rasmus; Pryds, Nini

    2015-01-01

    Finite element (FE) simulation of a thermoelectric (TE) module was conducted to optimize its geometrical dimensions in terms of mechanical reliability and performance. The TE module consisted of bismuth telluride, nand p-type legs. The geometrical dimensions of the module, i.e. leg length and leg...

  5. Modulation mechanism and disorder structure in hollandite-type crystals

    Energy Technology Data Exchange (ETDEWEB)

    Wu Xiaojing; Fujiki, Yoshiki; Horiuchi, Shigeo (National Inst. for Research in Inorganic Materials, Ibaraki (Japan)); Ishigame, Mareo (Research Inst. for Scientific Measurements, Tohoku Univ., Sendai (Japan))

    1991-07-01

    The structural modulation in some hollandite-type crystals is explained by a vacancy-displacive modulation model. In this model the large cations located in the tetragonal channels along the c axis deviate from the average position to form a modulation wave. Three types of disorder in the initial phase of the modulation wave have been introduced to interpret apparently different diffraction patterns in hollandite-type crystals. A mathematical analysis as well as optical diffraction give results similar to those experimentally observed. High-resolution transmission electron microscope images have been observed to confirm the discussion further. (orig.).

  6. Experimental Identification of Downhill Protein Folding

    Science.gov (United States)

    Garcia-Mira, Maria M.; Sadqi, Mourad; Fischer, Niels; Sanchez-Ruiz, Jose M.; Muñoz, Victor

    2002-12-01

    Theory predicts the existence of barrierless protein folding. Without barriers, folding should be noncooperative and the degree of native structure should be coupled to overall protein stability. We investigated the thermal unfolding of the peripheral subunit binding domain from Escherichia coli's 2-oxoglutarate dehydrogenase multienzyme complex (termed BBL) with a combination of spectroscopic techniques and calorimetry. Each technique probed a different feature of protein structure. BBL has a defined three-dimensional structure at low temperatures. However, each technique showed a distinct unfolding transition. Global analysis with a statistical mechanical model identified BBL as a downhill-folding protein. Because of BBL's biological function, we propose that downhill folders may be molecular rheostats, in which effects could be modulated by altering the distribution of an ensemble of structures.

  7. Vocal Fold Collision Modeling

    DEFF Research Database (Denmark)

    Granados, Alba; Brunskog, Jonas; Misztal, M. K.

    2015-01-01

    When vocal folds vibrate at normal speaking frequencies, collisions occurs. The numerics and formulations behind a position-based continuum model of contact is an active field of research in the contact mechanics community. In this paper, a frictionless three-dimensional finite element model...... of the vocal fold collision is proposed, which incorporates different procedures used in contact mechanics and mathematical optimization theories. The penalty approach and the Lagrange multiplier method are investigated. The contact force solution obtained by the penalty formulation is highly dependent...

  8. Improved Standard Electronic Modules, Thermal and Mechanical Analyses and Design

    Science.gov (United States)

    1978-09-01

    the flow meter. A listing of test equipment is as follows: Flow Meter - Meriam Instruments Model 5OMW20 Flow Meter Manometer - Meriam Instruments Type...WM Module Array Duct Manometer - Meriam Instruments Type TM Air Moving Device - Dayton Model 2Z-563 Each load module contained twelve (12) 16-pin DIP

  9. A Peripheral Mechanism for CB1 Cannabinoid Receptor-Dependent Modulation of Feeding

    National Research Council Canada - National Science Library

    Gomez, Raquel; Navarro, Miguel; Ferrer, Belen; Trigo, Jose M; Bilbao, Ainhoa; Del Arco, Ignacio; Cippitelli, Andrea; Nava, Felice; Piomelli, Daniele; Rodriguez de Fonseca, Fernando

    2002-01-01

    Recent studies suggest that the endocannabinoid system modulates feeding. Despite the existence of central mechanisms for the regulation of food intake by endocannabinoids, evidence indicates that peripheral mechanisms may also exist...

  10. Studies on the thermo-mechanical behavior of the CLIC two-beam module

    CERN Document Server

    Nousiainen, R; Österberg, K

    2010-01-01

    To fulfil the mechanical requirements set by the luminosity goals of the CLIC collider, currently under study, the 2-m two-beam modules, the shortest repetitive elements in the main linac, have to be controlled at micrometer level. At the same time these modules are exposed to variable high power dissipation while the accelerator is ramped up to nominal power as well as when the mode of CLIC operation is varied. This will result into inevitable temperature excursions driving mechanical distortions in and between different module components. A FEM model is essential to estimate and simulate the fundamental thermo-mechanical behaviour of the CLIC two-beam module to facilitate its design and development. In this paper, the fundamental thermal environments for the RF-components of the module are described. Also the thermal and structural results for the studied module configuration are presented showing the fundamental thermo-mechanical behaviour under the main CLIC collider operation conditions.

  11. Modelling "reality" in tectonics: Simulation of the mechanical evolution of the Jura Mountains-Molasse Basin system, and routes to forward-inverse modelling of fold thrust belts.

    Science.gov (United States)

    Hindle, David; Kley, Jonas

    2016-04-01

    The ultimate validation of any numerical model of any geological process comes when it can accurately forward model a case study from the geological record. However, as the example of the Jura-Molasse fold thrust belt demonstrates, geological information on even the most basic aspects of the present day state of such systems is highly incomplete and usually known only with large uncertainties. Fold thrust-belts are studied and understood by geologists in an iterative process of constructing their subsurface geometries and structures (folds, faults, bedding etc) based on limited subsurface information from boreholes, tunnels or seismic data where available, and surface information on outcrops of different layers and their dips. This data is usually processed through geometric models which involve conservation of line length of different beds over the length of an entire cross section. Constructing such sections is the art of cross section balancing. A balanced cross section can be easily restored to its pre-deformation state, assuming (usually) originally horizontal bedding to remove the effects of folding and faulting. Such a pre-deformation state can then form an initial condition for a forward mechanical model of the section. A mechanical model introduces new parameters into the system such as rock elasticity, cohesion, and frictional properties. However, a forward mechanical model can also potentially show the continuous evolution of a fold thrust belt, including dynamic quantities like stress. Moreover, a forward mechanical model, if correct in most aspects, should match in its final state, the present day geological cross section it is simulating. However, when attempting to achieve a match between geometric and mechanical models, it becomes clear that many more aspects of the geodynamic history of a fold thrust belt have to be taken into account. Erosion of the uppermost layers of an evolving thrust belt is the most obvious one of these. This can potentially

  12. Efficient molecular mechanics simulations of the folding, orientation, and assembly of peptides in lipid bilayers using an implicit atomic solvation model

    Science.gov (United States)

    Bordner, Andrew J.; Zorman, Barry; Abagyan, Ruben

    2011-10-01

    Membrane proteins comprise a significant fraction of the proteomes of sequenced organisms and are the targets of approximately half of marketed drugs. However, in spite of their prevalence and biomedical importance, relatively few experimental structures are available due to technical challenges. Computational simulations can potentially address this deficit by providing structural models of membrane proteins. Solvation within the spatially heterogeneous membrane/solvent environment provides a major component of the energetics driving protein folding and association within the membrane. We have developed an implicit solvation model for membranes that is both computationally efficient and accurate enough to enable molecular mechanics predictions for the folding and association of peptides within the membrane. We derived the new atomic solvation model parameters using an unbiased fitting procedure to experimental data and have applied it to diverse problems in order to test its accuracy and to gain insight into membrane protein folding. First, we predicted the positions and orientations of peptides and complexes within the lipid bilayer and compared the simulation results with solid-state NMR structures. Additionally, we performed folding simulations for a series of host-guest peptides with varying propensities to form alpha helices in a hydrophobic environment and compared the structures with experimental measurements. We were also able to successfully predict the structures of amphipathic peptides as well as the structures for dimeric complexes of short hexapeptides that have experimentally characterized propensities to form beta sheets within the membrane. Finally, we compared calculated relative transfer energies with data from experiments measuring the effects of mutations on the free energies of translocon-mediated insertion of proteins into lipid bilayers and of combined folding and membrane insertion of a beta barrel protein.

  13. Thermo-mechanical controls on intraplate deformation and the role of plume – folding interactions in continental topography

    NARCIS (Netherlands)

    Cloetingh, S.; Burov, E.; Francois, T.

    2013-01-01

    Thermo-tectonic age and inherited structure exert the main controls on the bulk strength of the lithosphere in intraplate settings. Mechanical decoupling within the lithosphere strongly affects the interaction between deep Earth and surface processes. Thermo-mechanical models demonstrate the particu

  14. Module Degradation Mechanisms Studied by a Multi-Scale Approach

    Energy Technology Data Exchange (ETDEWEB)

    Johnston, Steve; Al-Jassim, Mowafak; Hacke, Peter; Harvey, Steven P.; Jiang, Chun-Sheng; Gerber, Andreas; Guthrey, Harvey; Moutinho, Helio; Albin, David; To, Bobby; Tynan, Jerry; Moseley, John; Aguiar, Jeffery; Xiao, Chuanxiao; Waddle, John; Nardone, Marco

    2016-11-21

    A key pathway to meeting the Department of Energy SunShot 2020 goals is to reduce financing costs by improving investor confidence through improved photovoltaic (PV) module reliability. A comprehensive approach to further understand and improve PV reliability includes characterization techniques and modeling from module to atomic scale. Imaging techniques, which include photoluminescence, electroluminescence, and lock-in thermography, are used to locate localized defects responsible for module degradation. Small area samples containing such defects are prepared using coring techniques and are then suitable and available for microscopic study and specific defect modeling and analysis.

  15. Design of thermoelectric modules for both mechanical reliability and performance using FE simulation

    DEFF Research Database (Denmark)

    Sarhadi, Ali; Bjørk, Rasmus; Pryds, Nini

    Thermo-mechanical modeling of the TE modules provides an efficient tool for assessing the mechanical strength of the modules against the induced thermal stresses and subsequently optimizing them in terms of the mechanical reliability. However, the design of TE modules in terms of mechanical......, the geometrical dimensions of the TE elements for both mechanical reliability and performance are optimized to obtain a compromise design. The present work provides a basis for optimizing the TE modules in terms of their life time and performance....... reliability cannot be separated completely from the design for performance. These two objectives may conflict such that the improvement of the design parameters for one objective can deteriorate the other one. This trade off can be seen particularly when the geometrical dimensions of a TE module is optimized...

  16. Changes in the folding landscape of the WW domain provide a molecular mechanism for an inherited genetic syndrome

    Science.gov (United States)

    Pucheta-Martinez, Encarna; D’Amelio, Nicola; Lelli, Moreno; Martinez-Torrecuadrada, Jorge L.; Sudol, Marius; Saladino, Giorgio; Gervasio, Francesco Luigi

    2016-07-01

    WW domains are small domains present in many human proteins with a wide array of functions and acting through the recognition of proline-rich sequences. The WW domain belonging to polyglutamine tract-binding protein 1 (PQBP1) is of particular interest due to its direct involvement in several X chromosome-linked intellectual disabilities, including Golabi-Ito-Hall (GIH) syndrome, where a single point mutation (Y65C) correlates with the development of the disease. The mutant cannot bind to its natural ligand WBP11, which regulates mRNA processing. In this work we use high-field high-resolution NMR and enhanced sampling molecular dynamics simulations to gain insight into the molecular causes the disease. We find that the wild type protein is partially unfolded exchanging among multiple beta-strand-like conformations in solution. The Y65C mutation further destabilizes the residual fold and primes the protein for the formation of a disulphide bridge, which could be at the origin of the loss of function.

  17. Uncovering signals from measurement noise by electro mechanical amplitude modulation

    NARCIS (Netherlands)

    Droogendijk, H.; Sanders, Remco G.P.; Krijnen, Gijsbertus J.M.

    2013-01-01

    We present an electromechanical parametric scheme to improve the low-frequency signal-to-noise ratio of energy buffering type transducers. The method is based on periodic modulation of the stiffness in the sensory system which produces upconverted replicas of the signals of interest at frequencies

  18. Mechanical stability model of progradational carbonate platform margins under tectonic loads: Deformation of Cretaceous carbonate platforms in the Sierra Madre Oriental fold-thrust belt (east central Mexico)

    Science.gov (United States)

    Contreras, Juan; Suter, Max

    2015-02-01

    Shortening in the Sierra Madre Oriental fold-thrust belt (east central Mexico) is localized along the margins of Cretaceous carbonate platforms and controlled by mechanical stratigraphy. The platform margins are deformed by imbricate series of thrust ramps, whereas the coeval basins and platform interiors are deformed by map-scale detachment folds. Here we present a finite element model to evaluate the influence of the boundary geometry and boundary conditions on the style of deformation observed at these basinward progradational platform margins. We calculate the stress distribution in a linearly elastic platform-basin transition zone under the action of horizontal tectonic stress, taking into account changes of rock mechanical properties across the platform margin, as well as their dependence on direction, and infer the resulting fracture patterns based on the Mohr-Coulomb failure criterion. Stress concentrations are predicted at the contacts between the massive rocks of the platform margin and the well-layered rocks of both, the platform interior and the adjacent basin. Brittle failure of the platform border can be mostly attributed to three effects: mechanical coupling between the carbonate platform and a substratum of moderate to low viscosity, variations in layering and texture that governed the mechanical properties of the involved carbonates as well as their dependence on direction, and the development of sharp domain boundary corners associated with progradational facies changes. In contrast, the dip of the basement and a possible taper of the overlying Upper Cretaceous shale toward the basin appear to have little influence on the mechanical failure of the platform margin.

  19. Growth plate cartilage shows different strain patterns in response to static versus dynamic mechanical modulation.

    Science.gov (United States)

    Kaviani, Rosa; Londono, Irene; Parent, Stefan; Moldovan, Florina; Villemure, Isabelle

    2016-08-01

    Longitudinal growth of long bones and vertebrae occurs in growth plate cartilage. This process is partly regulated by mechanical forces, which are one of the underlying reasons for progression of growth deformities such as idiopathic adolescent scoliosis and early-onset scoliosis. This concept of mechanical modulation of bone growth is also exploited in the development of fusionless treatments of these deformities. However, the optimal loading condition for the mechanical modulation of growth plate remains to be identified. The objective of this study was to evaluate the effects of in vitro static versus dynamic modulation and of dynamic loading parameters, such as frequency and amplitude, on the mechanical responses and histomorphology of growth plate explants. Growth plate explants from distal ulnae of 4-week-old swines were extracted and randomly distributed among six experimental groups: baseline ([Formula: see text]), control ([Formula: see text]), static ([Formula: see text]) and dynamic ([Formula: see text]). For static and dynamic groups, mechanical modulation was performed in vitro using an Indexed CartiGen bioreactor. A stress relaxation test combined with confocal microscopy and digital image correlation was used to characterize the mechanical responses of each explant in terms of peak stress, equilibrium stress, equilibrium modulus of elasticity and strain pattern. Histomorphometrical measurements were performed on toluidine blue tissue sections using a semi-automatic custom-developed MATLAB toolbox. Results suggest that compared to dynamic modulation, static modulation changes the strain pattern of the tissue and thus is more detrimental for tissue biomechanics, while the histomorphological parameters are not affected by mechanical modulation. Also, under dynamic modulation, changing the frequency or amplitude does not affect the biomechanical response of the tissue. Results of this study will be useful in finding optimal and non-damaging parameters

  20. Graphene folding on flat substrates

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Xiaoming; Zhao, Yadong; Ke, Changhong, E-mail: cke@binghamton.edu [Department of Mechanical Engineering, State University of New York at Binghamton, Binghamton, New York 13902 (United States); Zhang, Liuyang; Wang, Xianqiao [College of Engineering, University of Georgia, Athens, Georgia 30602 (United States)

    2014-10-28

    We present a combined experimental-theoretical study of graphene folding on flat substrates. The structure and deformation of the folded graphene sheet are experimentally characterized by atomic force microscopy. The local graphene folding behaviors are interpreted based on nonlinear continuum mechanics modeling and molecular dynamics simulations. Our study on self-folding of a trilayer graphene sheet reports a bending stiffness of about 6.57 eV, which is about four times the reported values for monolayer graphene. Our results reveal that an intriguing free sliding phenomenon occurs at the interlayer van der Waals interfaces during the graphene folding process. This work demonstrates that it is a plausible venue to quantify the bending stiffness of graphene based on its self-folding conformation on flat substrates. The findings reported in this work are useful to a better understanding of the mechanical properties of graphene and in the pursuit of its applications.

  1. Nuclear Technology. Course 30: Mechanical Inspection. Module 30-4, Piping Inspection.

    Science.gov (United States)

    Kinne, Bruce

    This fourth in a series of eight modules for a course titled Mechanical Inspection describes the classifications of pipe and fittings, the types of connections used in the installation of piping systems, the typical marking schemes, the preinstallation and installation verifications, and the tests of the completed installation. The module follows…

  2. Characterization of PV modules by combining results of mechanical and electrical analysis methods

    Science.gov (United States)

    Sander, Martin; Henke, Bastian; Schwarz, Hannes; Dietrich, Sascha; Schweizer, Stefan; Ebert, Matthias; Bagdahn, Jörg

    2010-08-01

    Photovoltaic modules (PV modules) are supposed to have a lifetime of more than 20 years under various environmental conditions like temperature changes, mechanical loads, etc. Common outdoor exposure may influence efficiency and lifetime which necessitates assessment of PV module performance and detection of output deficits. For this purpose reliable and nondestructive testing methods are desirable. Commercially available PV modules were tested by different analysis methods. The PV module's electrical properties were investigated by thermography and electroluminescence measurements. The combination of these two techniques is well-suited to detect many cell and module defects. A crystalline module showed significant cell breakage after temperature cycle test. To observe the mechanisms of this specific defect type laminated test specimens on smaller scales were produced and analyzed over production process and during temperature cycles derived from the international standards IEC 61215 and IEC 61646. The defect study on small scales allows conclusions about the defect's influence on larger PV modules. Further methods capable for mechanical characterization like Laser Doppler vibrometry, surface geometry scan and digital image correlation are presented briefly. The combination of the methods mentioned above allows a very precise assessment of the mechanical and electrical capability which is essential for reliability and lifetime concepts.

  3. Engine Performance (Section B: Fuel and Exhaust Systems). Auto Mechanics Curriculum Guide. Module 3. Instructor's Guide.

    Science.gov (United States)

    Rains, Larry

    This module is the third of nine modules in the competency-based Missouri Auto Mechanics Curriculum Guide. Six units cover: fuel supply systems; carburetion; carburetor service; gasoline engine electronic fuel injection; diesel fuel injection; and exhaust systems and turbochargers. Introductory materials include a competency profile and…

  4. Nuclear Technology. Course 30: Mechanical Inspection. Module 30-3, Valve Inspection.

    Science.gov (United States)

    Wasil, Ed; Espy, John

    This third in a series of eight modules for a course titled Mechanical Inspection describes all the major types of valves utilized in a nuclear power plant and the purposes of the preinstallation and installation inspections; also describes the valve testing required for particular valves. The module follows a typical format that includes the…

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

    Science.gov (United States)

    Wasel, Ed; Espy, John

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

  6. Mechanism of cytokine modulation of epithelial tight junction barrier

    OpenAIRE

    Al-Sadi, Rana; Boivin, Michel; Ma, Thomas

    2009-01-01

    Cytokines play a crucial role in the modulation of inflammatory response in the gastrointestinal tract. Pro-inflammatory cytokines including tumor necrosis factor-α, interferon-γ, interleukin-1β (IL-1β), and interleukin-12 are essential in mediating the inflammatory response, while anti-inflammatory cytokines including interleukin-10 and transforming growth factor-β are important in the attenuation or containment of inflammatory process. It is increasingly recognized that cytokines have an im...

  7. Quark-lepton unification and eight-fold ambiguity in the left-right symmetric seesaw mechanism

    Energy Technology Data Exchange (ETDEWEB)

    Hosteins, Pierre [Service de Physique Theorique, CEA-Saclay, F-91191 Gif-sur-Yvette cedex, Laboratoire de la Direction des Sciences de la Matiere du Commissariat a l' Energie Atomique et Unite de Recherche associee au CNRS (URA 2306) (France); Lavignac, Stephane [Service de Physique Theorique, CEA-Saclay, F-91191 Gif-sur-Yvette cedex, Laboratoire de la Direction des Sciences de la Matiere du Commissariat a l' Energie Atomique et Unite de Recherche associee au CNRS (URA 2306) (France)]. E-mail: lavignac@spht.saclay.cea.fr; Savoy, Carlos A. [Service de Physique Theorique, CEA-Saclay, F-91191 Gif-sur-Yvette cedex, Laboratoire de la Direction des Sciences de la Matiere du Commissariat a l' Energie Atomique et Unite de Recherche associee au CNRS (URA 2306) (France)

    2006-10-30

    In many extensions of the Standard Model, including a broad class of left-right symmetric and grand unified theories, the light neutrino mass matrix is given by the left-right symmetric seesaw formula M{sub {nu}}=fv{sub L}-v{sup 2}v{sub R}Y{sub {nu}}f{sup -1}Y{sub {nu}}, in which the right-handed neutrino mass matrix and the SU(2){sub L} triplet couplings are proportional to the same matrix f. We propose a systematic procedure for reconstructing the 2{sup n} solutions (in the n-family case) for the matrix f as a function of the Dirac neutrino couplings (Y{sub {nu}}){sub ij} and of the light neutrino mass parameters, which can be used in both analytical and numerical studies. We apply this procedure to a particular class of supersymmetric SO(10) models with two 10-dimensional and a pair of 126-bar 126-bar representations in the Higgs sector, and study the properties of the corresponding 8 right-handed neutrino spectra. Then, using the reconstructed right-handed neutrino and triplet parameters, we study leptogenesis and lepton flavour violation in these models, and comment on flavour effects in leptogenesis in the type I limit. We find that the mixed solutions where both the type I and the type II seesaw mechanisms give a significant contribution to neutrino masses provide new opportunities for successful leptogenesis in SO(10) GUTs.

  8. Crystal structure of Arabidopsis cyclophilin38 reveals a previously uncharacterized immunophilin fold and a possible autoinhibitory mechanism.

    Science.gov (United States)

    Vasudevan, Dileep; Fu, Aigen; Luan, Sheng; Swaminathan, Kunchithapadam

    2012-06-01

    Cyclophilin38 (CYP38) is one of the highly divergent cyclophilins from Arabidopsis thaliana. Here, we report the crystal structure of the At-CYP38 protein (residues 83 to 437 of 437 amino acids) at 2.39-Å resolution. The structure reveals two distinct domains: an N-terminal helical bundle and a C-terminal cyclophilin β-barrel, connected by an acidic loop. Two N-terminal β-strands become part of the C-terminal cyclophilin β-barrel, thereby making a previously undiscovered domain organization. This study shows that CYP38 does not possess peptidyl-prolyl cis/trans isomerase activity and identifies a possible interaction of CYP38 with the E-loop of chlorophyll protein47 (CP47), a component of photosystem II. The interaction of CYP38 with the E-loop of CP47 is mediated through its cyclophilin domain. The N-terminal helical domain is closely packed together with the putative C-terminal cyclophilin domain and establishes a strong intramolecular interaction, thereby preventing the access of the cyclophilin domain to other proteins. This was further verified by protein-protein interaction assays using the yeast two-hybrid system. Furthermore, the non-Leucine zipper N-terminal helical bundle contains several new elements for protein-protein interaction that may be of functional significance. Together, this study provides the structure of a plant cyclophilin and explains a possible mechanism for autoinhibition of its function through an intramolecular interaction.

  9. New N-Acetyltransferase Fold in the Structure and Mechanism of the Phosphonate Biosynthetic Enzyme FrbF

    Energy Technology Data Exchange (ETDEWEB)

    Bae, Brian; Cobb, Ryan E.; DeSieno, Matthew A.; Zhao, Huimin; Nair, Satish K. (UIUC)

    2015-10-15

    The enzyme FrbF from Streptomyces rubellomurinus has attracted significant attention due to its role in the biosynthesis of the antimalarial phosphonate FR-900098. The enzyme catalyzes acetyl transfer onto the hydroxamate of the FR-900098 precursors cytidine 5'-monophosphate-3-aminopropylphosphonate and cytidine 5'-monophosphate-N-hydroxy-3-aminopropylphosphonate. Despite the established function as a bona fide N-acetyltransferase, FrbF shows no sequence similarity to any member of the GCN5-like N-acetyltransferase (GNAT) superfamily. Here, we present the 2.0 {angstrom} resolution crystal structure of FrbF in complex with acetyl-CoA, which demonstrates a unique architecture that is distinct from those of canonical GNAT-like acetyltransferases. We also utilized the co-crystal structure to guide structure-function studies that identified the roles of putative active site residues in the acetyltransferase mechanism. The combined biochemical and structural analyses of FrbF provide insights into this previously uncharacterized family of N-acetyltransferases and also provide a molecular framework toward the production of novel N-acyl derivatives of FR-900098.

  10. Detecting loss mechanisms of c-Si PV modules in-situ I-V measurement

    Science.gov (United States)

    Guo, Siyu; Schneller, Eric; Walters, Joe; Davis, Kristopher O.; Schoenfeld, Winston V.

    2016-09-01

    PV module reliability is alsways an important issue for PV industry. In an outdoor PV system, PV modules suffer from degradation due to different factors. It is then very important to determine the loss mechanisms of a PV module and making improvement based on this. It is found in this work that due to mismatch effect, using fitting method to extract I-V characteristics might not be well applied on a PV module, especially when it has non-uniform degradation problem. This work proposes a method to accurately quantify the power loss of PV modules due to different degradation mechanisms, including series resistance (Rs) loss, non-uniform shunting loss and number of shunted cells, uniform shunting loss, uniform current loss, non-uniform current (mismatch) loss, recombination current (J01 and J02) losses of a PV module. All required input information are the measured current-voltage (I-V) curves and short circuit current- open circuit voltage (Isc-Voc) of PV module initial state and final state. The method is first applied to a simulated PV module with various degradation problems. Power loss due to each loss mechanism for the simulated PV module is then extracted using the proposed method and a pie chart can be generated. Comparing with the actual power loss on each loss mechanism, the method proposed in this work is proved to be very accurate. The method is then further applied to a degradated PV module istalled in an outdoor PV system. The power loss on series resistance, shunting and current mismatch are effectively identified and the number of shunted cells is accurately calculated. In the real application, this method can be used in both indoor and outdoor characterization, which can be very beneficial for PV degradation analysis of PV modules and systems.

  11. Design of tissue engineering scaffolds as delivery devices for mechanical and mechanically modulated signals.

    Science.gov (United States)

    Anderson, Eric J; Knothe Tate, Melissa L

    2007-10-01

    New approaches to tissue engineering aim to exploit endogenous strategies such as those occurring in prenatal development and recapitulated during postnatal healing. Defining tissue template specifications to mimic the environment of the condensed mesenchyme during development allows for exploitation of tissue scaffolds as delivery devices for extrinsic cues, including biochemical and mechanical signals, to drive the fate of mesenchymal stem cells seeded within. Although a variety of biochemical signals that modulate stem cell fate have been identified, the mechanical signals conducive to guiding pluripotent cells toward specific lineages are less well characterized. Furthermore, not only is spatial and temporal control of mechanical stimuli to cells challenging, but also tissue template geometries vary with time due to tissue ingrowth and/or scaffold degradation. Hence, a case study was carried out to analyze flow regimes in a testbed scaffold as a first step toward optimizing scaffold architecture. A pressure gradient was applied to produce local (nm-micron) flow fields conducive to migration, adhesion, proliferation, and differentiation of cells seeded within, as well as global flow parameters (micron-mm), including flow velocity and permeability, to enhance directed cell infiltration and augment mass transport. Iterative occlusion of flow channel dimensions was carried out to predict virtually the effect of temporal geometric variation (e.g., due to tissue development and growth) on delivery of local and global mechanical signals. Thereafter, insights from the case study were generalized to present an optimization scheme for future development of scaffolds to be implemented in vitro or in vivo. Although it is likely that manufacture and testing will be required to finalize design specifications, it is expected that the use of the rational design optimization will reduce the number of iterations required to determine final prototype geometries and flow

  12. Quark-lepton unification and eight-fold ambiguity in the left-right symmetric seesaw mechanism

    Energy Technology Data Exchange (ETDEWEB)

    Hosteins, P.; Lavignac, St.; Savoy, C.A

    2006-07-01

    In many extensions of the Standard Model, including a broad class of left-right symmetric and Grand United theories, the light neutrino mass matrix is given by the left-right symmetric seesaw formula M{sub {nu}} = f*v{sub L} - v{sup 2}/v{sub R}*Y{sub {nu}}*f{sup -1}*Y{sub {nu}}, in which the right-handed neutrino mass matrix and the SU(2){sub L} triplet couplings are proportional to the same matrix f. We propose a systematic procedure for reconstructing the 2{sup n} solutions (in the n-family case) for the matrix f as a function of the Dirac neutrino couplings (Y{sub {nu}}){sub ij} and of the light neutrino mass parameters, which can be used in both analytical and numerical studies. We apply this procedure to a particular class of supersymmetric SO(10) models with two 10-dimensional and a pair of 126 + 126 representations in the Higgs sector, and study the properties of the corresponding 8 right-handed neutrino spectra. Then, using the reconstructed right-handed neutrino and triplet parameters, we study lepton-genesis and lepton flavour violation in these models, and comment on flavour effects in lepton-genesis in the type I limit. We find that the mixed solutions where both the type I and the type II seesaw mechanisms give a significant contribution to neutrino masses provide new opportunities for successful lepton-genesis in SO(10) Great Unified Theories. (authors)

  13. Mechanical study of the Chartreuse Fold-and-Thrust Belt: relationships between fluids overpressure and decollement within the Toarcian source-rock

    Science.gov (United States)

    Berthelon, Josselin; Sassi, William; Burov, Evgueni

    2016-04-01

    Many source-rocks are shale and constitute potential detachment levels in Fold-and-Thrust Belts (FTB): the toarcian Schistes-Cartons in the French Chartreuse FTB for example. Their mechanical properties can change during their burial and thermal maturation, as for example when large amount of hydrocarbon fluids are generated. A structural reconstruction of the Chartreuse FTB geo-history places the Toarcian Formation as the major decollement horizon. In this work, a mechanical analysis integrating the fluids overpressuring development is proposed to discuss on the validity of the structural interpretation. At first, an analogue of the Chartreuse Toarcian Fm, the albanian Posidonia Schist, is documented as it can provide insights on its initial properties and composition of its kerogen content. Laboratory characterisation documents the vertical evolution of the mineralogical, geochemical and mechanical parameters of this potential decollement layer. These physical parameters (i.e. Total Organic Carbon (TOC), porosity/permeability relationship, friction coefficient) are used to address overpressure buildup in the frontal part of the Chartreuse FTB with TEMISFlow Arctem Basin modelling approach (Faille et al, 2014) and the structural emplacement of the Chartreuse thrust units using the FLAMAR thermo-mechanical model (Burov et al, 2014). The hydro-mechanical modeling results highlight the calendar, distribution and magnitude of the overpressure that developed within the source-rock in the footwall of a simple fault-bend fold structure localized in the frontal part of the Chartreuse FTB. Several key geological conditions are required to create an overpressure able to fracture the shale-rocks and induce a significant change in the rheological behaviour: high TOC, low permeability, favourable structural evolution. These models highlight the importance of modeling the impact of a diffuse natural hydraulic fracturing to explain fluids propagation toward the foreland within

  14. Sandbox modelling of sequential thrusting in a mechanically two-layered system and its implications in fold-and-thrust belts

    Science.gov (United States)

    Saha, Puspendu; Bose, Santanu; Mandal, Nibir

    2016-10-01

    Many fold-and-thrust belts display multi-storied thrust sequences, characterizing a composite architecture of the thrust wedges. Despite dramatic progress in sandbox modelling over the last three decades, our understanding of such composite thrust-wedge mechanics is limited and demands a re-visit to the problem of sequential thrusting in mechanically layered systems. This study offers a new approach to sandbox modelling, designed with a two-layered sandpack simulating a mechanically weak Coulomb layer, resting coherently upon a stronger Coulomb layer. Our experimental models reproduce strikingly similar styles of the multi-storied frontal thrust sequences observed in natural fold-and- thrust belts. The upper weak horizon undergoes sequential thrusting at a high spatial frequency, forming numerous, closely spaced frontal thrusts, whereas the lower strong horizon produces widely spaced thrusts with progressive horizontal shortening. This contrasting thrust progression behaviour gives rise to composite thrust architecture in the layered sandpack. We show the evolution of such composite thrust sequences as a function of frictional strength (μb) at the basal detachment and thickness ratio (Tr) between the weak and strong layers. For any given values of Tr and μb, the two thrust sequences progress at different rates; the closely-spaced, upper thrust sequence advances forelandward at a faster rate than the widely-spaced, lower thrust sequence. Basal friction (μb) has little effects on the vergence of thrusts in the upper weak layer; they verge always towards foreland, irrespective of Tr values. But, the lower strong layer develops back-vergent thrusts when μb is low (∼0.36). In our experiments, closely spaced thrusts in the upper sequence experience intense reactivation due to their interaction with widely spaced thrusts in the lower sequence. The interaction eventually affects the wedge topography, leading to two distinct parts: inner and outer wedges

  15. Thermo-Mechanical tests for the CLIC two-beam module study

    CERN Document Server

    Xydou, A; Riddone, G; Daskalaki, E

    2014-01-01

    The luminosity goal of CLIC requires micron level precision with respect to the alignment of the components on its two-meter long modules, composing the two main linacs. The power dissipated inside the module components introduces mechanical deformations affecting their alignment and therefore the resulting machine performance. Several two-beam prototype modules must be assembled to extensively measure their thermo-mechanical behavior under different operation modes. In parallel, the real environmental conditions present in the CLIC tunnel should be studied. The air conditioning and ventilation system providing specified air temperature and flow has been installed in the dedicated laboratory. The power dissipation occurring in the modules is being reproduced by the electrical heaters inserted inside the RF structure mock-ups and the quadrupoles. The efficiency of the cooling systems is being verified and the alignment of module components is monitored. The measurement results will be compared to finite elemen...

  16. First and second generation γ-secretase modulators (GSMs) modulate amyloid-β (Aβ) peptide production through different mechanisms.

    Science.gov (United States)

    Borgegard, Tomas; Juréus, Anders; Olsson, Fredrik; Rosqvist, Susanne; Sabirsh, Alan; Rotticci, Didier; Paulsen, Kim; Klintenberg, Rebecka; Yan, Hongmei; Waldman, Magnus; Stromberg, Kia; Nord, Johan; Johansson, Jonas; Regner, Anna; Parpal, Santiago; Malinowsky, David; Radesater, Ann-Cathrin; Li, Tingsheng; Singh, Rajeshwar; Eriksson, Hakan; Lundkvist, Johan

    2012-04-01

    γ-Secretase-mediated cleavage of amyloid precursor protein (APP) results in the production of Alzheimer disease-related amyloid-β (Aβ) peptides. The Aβ42 peptide in particular plays a pivotal role in Alzheimer disease pathogenesis and represents a major drug target. Several γ-secretase modulators (GSMs), such as the nonsteroidal anti-inflammatory drugs (R)-flurbiprofen and sulindac sulfide, have been suggested to modulate the Alzheimer-related Aβ production by targeting the APP. Here, we describe novel GSMs that are selective for Aβ modulation and do not impair processing of Notch, EphB2, or EphA4. The GSMs modulate Aβ both in cell and cell-free systems as well as lower amyloidogenic Aβ42 levels in the mouse brain. Both radioligand binding and cellular cross-competition experiments reveal a competitive relationship between the AstraZeneca (AZ) GSMs and the established second generation GSM, E2012, but a noncompetitive interaction between AZ GSMs and the first generation GSMs (R)-flurbiprofen and sulindac sulfide. The binding of a (3)H-labeled AZ GSM analog does not co-localize with APP but overlaps anatomically with a γ-secretase targeting inhibitor in rodent brains. Combined, these data provide compelling evidence of a growing class of in vivo active GSMs, which are selective for Aβ modulation and have a different mechanism of action compared with the original class of GSMs described.

  17. Thermo-mechanical modelling and experimental validation of CLIC prototype module type 0

    CERN Document Server

    Kortelainen, Lauri; Koivurova, Hannu; Riddone, Germana; Österberg, Kenneth

    Micron level stability of the two-meter repetitive modules constituting the two main linacs is one of the most important requirements to achieve the luminosity goal for the Compact Linear Collider. Structural deformations due to thermal loads and related to the RF power dissipated inside the modules affect the alignment of the linacs and therefore the resulting luminosity performance. A CLIC prototype module has been assembled in a dedicated laboratory and a thermal test program has been started in order to study its thermo-mechanical behaviour. This thesis focuses on the finite elements modelling of the first CLIC prototype module 0. The aim of the modelling is to examine the temperature distributions and the resulting deformations of the module in different operating conditions defined in the thermal test program. The theoretical results have been compared to the experimental ones; the comparison shows that the results are in good agreement both for the thermal behaviour of the module and for the resulting ...

  18. Chemical reactions modulated by mechanical stress: extended Bell theory.

    Science.gov (United States)

    Konda, Sai Sriharsha M; Brantley, Johnathan N; Bielawski, Christopher W; Makarov, Dmitrii E

    2011-10-28

    A number of recent studies have shown that mechanical stress can significantly lower or raise the activation barrier of a chemical reaction. Within a common approximation due to Bell [Science 200, 618 (1978)], this barrier is linearly dependent on the applied force. A simple extension of Bell's theory that includes higher order corrections in the force predicts that the force-induced change in the activation energy will be given by -FΔR - ΔχF(2)∕2. Here, ΔR is the change of the distance between the atoms, at which the force F is applied, from the reactant to the transition state, and Δχ is the corresponding change in the mechanical compliance of the molecule. Application of this formula to the electrocyclic ring-opening of cis and trans 1,2-dimethylbenzocyclobutene shows that this extension of Bell's theory essentially recovers the force dependence of the barrier, while the original Bell formula exhibits significant errors. Because the extended Bell theory avoids explicit inclusion of the mechanical stress or strain in electronic structure calculations, it allows a computationally efficient characterization of the effect of mechanical forces on chemical processes. That is, the mechanical susceptibility of any reaction pathway is described in terms of two parameters, ΔR and Δχ, both readily computable at zero force.

  19. Mechanical behavior of plastic materials for automobile cockpit module

    Science.gov (United States)

    Woo, Changsu.; Park, Hyunsung.; Jo, Jinho.

    2013-12-01

    Engineering plastics are used in instrument panels, interior trims, and other vehicle applications, and the thermo-mechanical behaviors of plastic materials are strongly influenced by many environmental factors such as temperature, sunlight, and rain. As the material properties change, the mechanical parts create unexpected noise. In this study, the dynamic mechanical property changes of plastics used in automobiles are measured to investigate the effect of temperature. Visco-elastic properties such as the glass transition temperature and storage modulus and loss factors under temperature and frequency sweeps were measured. The data results were compared with the original ones before aging to analyze the behavioral changes. It was found that as the temperature increased, the storage modulus decreased and the loss factor increased slightly.

  20. Mechanical Properties of Microcrystalline Metal-Organic Frameworks (MOFs) Measured by Bimodal Amplitude Modulated-Frequency Modulated Atomic Force Microscopy.

    Science.gov (United States)

    Sun, Yao; Hu, Zhigang; Zhao, Dan; Zeng, Kaiyang

    2017-09-08

    Direct measurement of the mechanical properties of microcrystalline metal-organic framework (MOF) nanoparticles is challenging and rarely explored. In this work, we apply an effective method to realize elastic modulus mapping of a series of isostructural single MOF nanoparticles (100-500 nm) via bimodal amplitude modulated-frequency modulated atomic force microscopy. By probing five types of zirconium (Zr) and hafnium (Hf) isostructural UiO-66-type MOFs, we experimentally found that UiO-66(Hf)-type MOFs possess the higher elastic modulus (46-104 GPa) than that of UiO-66(Zr)-type MOFs (34-100 GPa), both of which are higher than that of reported zinc/copper based MOFs (3-10 GPa). We also experimentally demonstrate that the mechanical properties of MOFs can be tuned by adjusting the chemical functionalities of the ligands or using different metal nodes. In detail, the sterically bulky functional groups increase the mechanical properties of the resultant UiO-66-type MOFs, possibly due to the increased atomic density. These results pave a way to the direct measurement of mechanical properties of MOFs crystalline particles and provide an incisive perspective to the design of MOFs with high mechanical properties.

  1. Heavy Duty Mechanics Apprenticeship Training, Module One. Volume I.

    Science.gov (United States)

    Batchelor, Leslie A.; Abercrombie, Richard, Ed.

    This training manual, the first of two volumes, comprises the first six blocks in a nine-block in-service training course for apprentices working in heavy duty mechanics. Addressed in the individual blocks included in this volume are the following topics: shop equipment and practices; procedures for starting, moving, and stopping equipment; the…

  2. Heavy Duty Mechanics Apprenticeship Training, Module One. Volume II.

    Science.gov (United States)

    Batchelor, Leslie A.; Abercrombie, Richard, Ed.

    This training manual, the second of two volumes, comprises the final three blocks in a nine-block in-service training course for apprentices working in heavy duty mechanics. Addressed in the individual blocks included in this volume are engines, basic electricity, and winches. Each block contains a section on parts theory that gives the purpose,…

  3. Thermal-mechanical analysis of actively cooled folded core sandwich panels%主动冷却皱褶芯材夹层板的热力分析

    Institute of Scientific and Technical Information of China (English)

    周晨; 王志瑾; 支骄杨

    2014-01-01

    A multifunctional sandwich panel with folded cellular cores was proposed for actively cooled load-bearing components in aerospace thermal protection systems. Thermal-mechanical responses of V-type and M-type folded core sandwich panels subjected to forced convection using kerosene as a coolant were studied numerically. First, a 3D fluid-solid coupling model was established and the temperature fields of fluid and structure were computed using the conjugate heat transfer model. Subsequently, the thermal stress and deformation of structure were obtained via sequential coupling method. The results show that the heat transfer perform-ances of folded core sandwich panels are evidently improved through active cooling. The temperature increases along the flow direc-tion and presents a periodic fluctuation. Heat convection is reinforced due to the folds which also cause serious stress concentrations. Cell topology and geometric dimensions have certain influences on the heat transfer characteristics and thermal structural behavior of the active cooled panels. A M-type folded core sandwich panel is superior to a V-type one for a much less severe stress concentra-tion.%提出了一种将皱褶芯材夹层板与主动冷却相结合的承载-热防护一体化结构形式。以煤油为冷却液,在强迫对流条件下,采用数值仿真方法对V-型和M-型皱褶芯材夹层板的热力响应进行了研究。首先,建立了主动冷却皱褶芯材夹层板的三维流固耦合模型,应用共轭传热数值计算方法,求解获得了冷却液和结构的温度场;采用顺序耦合求解,得到了相应的结构应力场和变形场。结果表明,实施主动冷却后皱褶结构的换热性能明显提高;沿流向温度上升,并呈现周期性波动;结构的皱褶在加强对流换热的同时,也导致了应力集中。芯材胞元拓扑构型及几何尺寸对结构的换热性能和应力应变具有一定程度的影响。与V-型相比

  4. Mechanical Genomics Identifies Diverse Modulators of Bacterial Cell Stiffness.

    Science.gov (United States)

    Auer, George K; Lee, Timothy K; Rajendram, Manohary; Cesar, Spencer; Miguel, Amanda; Huang, Kerwyn Casey; Weibel, Douglas B

    2016-06-22

    Bacteria must maintain mechanical integrity to withstand the large osmotic pressure differential across the cell membrane and wall. Although maintaining mechanical integrity is critical for proper cellular function, a fact exploited by prominent cell-wall-targeting antibiotics, the proteins that contribute to cellular mechanics remain unidentified. Here, we describe a high-throughput optical method for quantifying cell stiffness and apply this technique to a genome-wide collection of ∼4,000 Escherichia coli mutants. We identify genes with roles in diverse functional processes spanning cell-wall synthesis, energy production, and DNA replication and repair that significantly change cell stiffness when deleted. We observe that proteins with biochemically redundant roles in cell-wall synthesis exhibit different stiffness defects when deleted. Correlating our data with chemical screens reveals that reducing membrane potential generally increases cell stiffness. In total, our work demonstrates that bacterial cell stiffness is a property of both the cell wall and broader cell physiology and lays the groundwork for future systematic studies of mechanoregulation.

  5. Sub-microscopic modulation of mechanical properties in transparent insect wings

    CERN Document Server

    Arora, Ashima; Bhagavathi, Jithin; Singh, Kamal P; Sheet, Goutam

    2013-01-01

    We report on the measurement of mechanical properties of the transparent wings of an insect (popularly known as the 'rain fly') using an atomic force microscope (AFM) down to nanometer length scales. We observe that the frictional and adhesion properties on the surface of the wings are modulated in a semi-periodic fashion. From simultaneous measurement of AFM topography it is observed that the modulation of mechanical properties is correlated with the modulation of topography. Furthermore, the regions of higher friction are decorated with finer nanostructures with definite shape. From optical diffraction experiments we show that the observed modulation and its semi-periodic nature are distributed over the entire surface of the wing.

  6. Brain Mechanisms Supporting Modulation of Pain by Mindfulness Meditation

    Science.gov (United States)

    Zeidan, F.; Martucci, K.T.; Kraft, R.A.; Gordon, N.S.; McHaffie, J.G.; Coghill, R.C.

    2011-01-01

    The subjective experience of one’s environment is constructed by interactions among sensory, cognitive, and affective processes. For centuries, meditation has been thought to influence such processes by enabling a non-evaluative representation of sensory events. To better understand how meditation influences the sensory experience, we employed arterial spin labeling (ASL) functional magnetic resonance imaging to assess the neural mechanisms by which mindfulness meditation influences pain in healthy human participants. After four-days of mindfulness meditation training, meditating in the presence of noxious stimulation significantly reduced pain-unpleasantness by 57% and pain-intensity ratings by 40% when compared to rest. A two factor repeated measures analysis of variance was used to identify interactions between meditation and pain-related brain activation. Meditation reduced pain-related activation of the contra lateral primary somatosensory cortex. Multiple regression analysis was used to identify brain regions associated with individual differences in the magnitude of meditation-related pain reductions. Meditation-induced reductions in pain intensity ratings were associated with increased activity in the anterior cingulate cortex and anterior insula, areas involved in the cognitive regulation of nociceptive processing. Reductions in pain unpleasantness ratings were associated with orbitofrontal cortex activation, an area implicated in reframing the contextual evaluation of sensory events. Moreover, reductions in pain unpleasantness also were associated with thalamic deactivation, which may reflect a limbic gating mechanism involved in modifying interactions between afferent in put and executive-order brain areas. Taken together, these data indicate that meditation engages multiple brain mechanisms that alter the construction of the subjectively available pain experience from afferent information. PMID:21471390

  7. [Review: plant polyphenols modulate lipid metabolism and related molecular mechanism].

    Science.gov (United States)

    Dai, Yan-li; Zou, Yu-xiao; Liu, Fan; Li, Hong-zhi

    2015-11-01

    Lipid metabolism disorder is an important risk factor to obesity, hyperlipidemia and type 2 diabetes as well as other chronic metabolic disease. It is also a key target in preventing metabolic syndrome, chronic disease prevention. Plant polyphenol plays an important role in maintaining or improving lipid profile in a variety of ways. including regulating cholesterol absorption, inhibiting synthesis and secretion of triglyceride, and lowering plasma low density lipoprotein oxidation, etc. The purpose of this article is to review the lipid regulation effects of plant polyphenols and its related mechanisms.

  8. Neuro-cognitive mechanisms underlying the emotional modulation of word reading

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    A novel neural model for emotional modulation of word reading is proposed. This model has four principal hypotheses: the dominant activation region hypothesis, the emotional modulation hypothesis, the attentional level hypothesis, and the interaction hypothesis. Four lines of research were reviewed to provide evidence for these hypotheses: (1) neuro-cognitive studies on the mechanisms of word reading (i.e., neural networks for reading); (2) studies on the influence of words' emotional valence on word reading; (3) studies of the effect of attention on word reading; and (4) studies on emotional modulation of word reading under different attentional levels.

  9. Mechanical and Thermal Characterisation of a TT Half-Module Prototype

    CERN Document Server

    Lehner, F; Pangilinan, M; Siegler, M

    2005-01-01

    This note describes the mechanical effects of thermal cycles on a TT half-module, to demonstrate that the detectors can withstand the expected thermal gradients without damage. The stress transferred by the carbon fiber rails and the ceramic to the silicon sensors was investigated, and the deformation that occurred during these tests was measured by strain gauges that were attached to sensors on a test half-module. In addition, heat transfer through the carbon fiber rails was studied. Furthermore, we present a comparison of different materials proposed to build the carbon fiber rails of the modules.

  10. Length-Dependent Modulation of Cytoskeletal Remodeling and Mechanical Energetics in Airway Smooth Muscle

    OpenAIRE

    Kim, Hak Rim; Liu, Katrina; Roberts, Thomas J.; Hai, Chi-Ming

    2010-01-01

    Actin cytoskeletal remodeling is an important mechanism of airway smooth muscle (ASM) contraction. We tested the hypothesis that mechanical strain modulates the cholinergic receptor–mediated cytoskeletal recruitment of actin-binding and integrin-binding proteins in intact airway smooth muscle, thereby regulating the mechanical energetics of airway smooth muscle. We found that the carbachol-stimulated cytoskeletal recruitment of actin-related protein-3 (Arp3), metavinculin, and talin were up-r...

  11. Antimalarial Drugs as Immune Modulators: New Mechanisms for Old Drugs.

    Science.gov (United States)

    An, Jie; Minie, Mark; Sasaki, Tomikazu; Woodward, Joshua J; Elkon, Keith B

    2017-01-14

    The best known of the naturally occurring antimalarial compounds are quinine, extracted from cinchona bark, and artemisinin (qinghao), extracted from Artemisia annua in China. These and other derivatives are now chemically synthesized and remain the mainstay of therapy to treat malaria. The beneficial effects of several of the antimalarial drugs (AMDs) on clinical features of autoimmune disorders were discovered by chance during World War II. In this review, we discuss the chemistry of AMDs and their mechanisms of action, emphasizing how they may impact multiple pathways of innate immunity. These pathways include Toll-like receptors and the recently described cGAS-STING pathway. Finally, we discuss the current and future impact of AMDs on systemic lupus erythematosus, rheumatoid arthritis, and devastating monogenic disorders (interferonopathies) characterized by expression of type I interferon in the brain.

  12. The parallel universe of RNA folding.

    Science.gov (United States)

    Batey, R T; Doudna, J A

    1998-05-01

    How do large RNA molecules find their active conformations among a universe of possible structures? Two recent studies reveal that RNA folding is a rapid and ordered process, with surprising similarities to protein folding mechanisms.

  13. Folding of Pollen Grains

    Science.gov (United States)

    Katifori, Eleni; Alben, Silas; Cerda, Enrique; Nelson, David; Dumais, Jacques

    2008-03-01

    At dehiscence, which occurs when the anther reaches maturity and opens, pollen grains dehydrate and their volume is reduced. The pollen wall deforms to accommodate the volume loss, and the deformation pathway depends on the initial turgid pollen grain geometry and the mechanical properties of the pollen wall. We demonstrate, using both experimental and theoretical approaches, that the design of the apertures (areas on the pollen wall where the stretching and the bending modulus are reduced) is critical for controlling the folding pattern, and ensures the pollen grain viability. An excellent fit to the experiments is obtained using a discretized version of the theory of thin elastic shells.

  14. Molecular mechanism of fluoroquinolones modulation on corneal fibroblast motility.

    Science.gov (United States)

    Chen, Tsan-Chi; Tsai, Tzu-Yun; Chang, Shu-Wen

    2016-04-01

    Topical fluoroquinolones are widely used to prevent ocular infections after ophthalmic surgery. However, they have been shown to affect the corneal cell motility, whose mechanism remains indefinite. The purpose of this study was to investigate how fluoroquinolones affect corneal stromal cell motility. Human corneal fibroblasts (HCFs) were incubated in ciprofloxacin (CIP), levofloxacin (LEV), or moxifloxacin (MOX) at 0, 10, 50, and 100 μg/ml for up to 3 days. Effect of CIP, LEV, or MOX on HCF migration was monitored using migration assay. HCF viability was determined by WST-1 assay. Expression of focal adhesion kinase (FAK), paxillin (PXN), and their phosphorylated forms were analyzed by immunoblotting. Binding affinity between FAK and PXN was determined by co-immunoprecipitation. Our results revealed that CIP and MOX, but not LEV, noticeably retarded HCF migration. HCF proliferation was significantly reduced by CIP (38.2%), LEV (29.5%), and MOX (21.3%), respectively (p = 0.002). CIP and MOX suppressed the phosphorylation of PXN at tyrosines (10.2 ± 4.3%, p MOX diminished the binding affinity between FAK and PXN (8.2 ± 1.8%, p MOX, but not LEV, might delay corneal fibroblast migration via interfering with recruitment of PXN to focal adhesions and dephosphorylation of PXN at the tyrosines.

  15. Four-fold increase in users of time-wavelength division multiplexing (TWDM) passive optical network (PON) by delayed optical amplitude modulation (AM) upstream

    Science.gov (United States)

    Kachhatiya, Vivek; Prince, Shanthi

    2016-12-01

    In this paper, we have proposed and simulated optical time division multiplexed passive optical network (TDM-PON) using delayed optical amplitude modulation (AM). Eight upstream wavelengths are demonstrated to show optical time wavelength division multiplexed (TWDM) by combining optical network units (ONU) users data at the remote node (RN). Each ONU generates 2.5 Gb/s user data, and it is modulated using novel return to zero (RZ) delayed AM. Optical TDM aggregates 10 Gb/s data per wavelength from four 2.5 Gb/s upstream user data, which facilitates four different ONU data on the same wavelength as 10 Gb/s per upstream wavelength and, simplify the laser requirements (2.5 Gb/s) at each optical network unit (ONU) transmitter. Upstream optical TWDM-PON is investigated for eight wavelengths with wavelength spacing of 100 GHz. Novel optical TDM for upstream increased the number of the simultaneous user to fourfold from conventional TWDM-PON using delayed AM with a high-quality-factor of received signal. Despite performance degradation due to different fiber reach and dispersion compensation technique, Optical TWDM link shows significant improvement regarding receiver sensitivity when compared with common TWDM link. Hence, it offers optimistic thinking to show optical TDM at this phase as one of the future direction, where complex digital signal processing (DSP) and coherent optical communication are frequently demonstrated to serve the access network. Downstream side conventional TWDM eight wavelengths are multiplexed at the OLT and sent downstream to serve distributed tunable ONU receivers through an optical distribution network (ODN). Each downstream wavelengths are modulated at the peak rate of 10 Gb/s using non-return to zero external modulation (NRZ-EM). The proposed architecture is cost efficient and supports high data rates as well as ;pay as you grow; network for both service providers and the users perspectives. Users are classified into two categories viz home

  16. Compatibility conditions, modulation mechanisms and preferred modes in incompressible flow over a cavity

    CERN Document Server

    Delprat, Nathalie

    2010-01-01

    Self-sustained oscillations in cavity-flows can be strongly influenced by shear layer instability acting together with feedback and modulation mechanisms. When coherently organized, these oscillations lock-on at a fundamental frequency and compatibility conditions exist between shear layer forcing, non linear interactions and low-frequency modulations. Special attention is given to the frequency coincidence which may appear in spectral distributions due to combinations between the dominant peak and its sidebands. Hence, the possible existence of two preferred modes in incompressible cavity-flows at medium Reynolds numbers is shown. This leads to a detailed categorization of the flow modulated regimes and to the specification of a persistent mode involved in modulation process whatever the oscillation stage.

  17. Modulation index for VMAT considering both mechanical and dose calculation uncertainties

    Science.gov (United States)

    Park, Jong Min; Park, So-Yeon; Kim, Hyoungnyoun

    2015-09-01

    The aim of this study is to present a modulation index considering both mechanical and dose calculation uncertainties for volumetric modulated arc therapy (VMAT). As a modulation index considering only mechanical uncertainty of VMAT, MIt has been previously suggested. In this study, we developed a weighting factor which represents dose calculation uncertainty based on the aperture shapes of fluence maps at every control point of VMAT plans. In order to calculate the weighting factor, the thinning algorithm of image processing techniques was applied to measure field aperture irregularity. By combining this weighting factor with the previously suggested modulation index, MIt, comprehensive modulation index (MIc) was designed. To evaluate the performance of MIc, gamma passing rates, differences in mechanical parameters between plans and log files and differences in dose-volume parameters between plans and the plans reconstructed from log files were acquired with a total of 52 VMAT plans. Spearman’s correlation coefficients (rs) between the values of MIc and measures of VMAT delivery accuracy were calculated. The rs values of MIc (f = 0.5) to global gamma passing rates with 2%/2 mm, 1%/2 mm and 2%/1 mm were  -0.728,-0.847 and  -0.617, respectively (p  VMAT delivery accuracy showing strong correlations to various measures of VMAT delivery accuracy.

  18. Study of the Thermo-Mechanical Behavior of the CLIC Two-Beam Modules

    CERN Document Server

    Rossi, F; Riddone, G; Österberg, K; Kossyvakis, I; Gudkov, D; Samochkine, A

    2013-01-01

    The final luminosity target of the Compact LInear Collider (CLIC) imposes a micron-level stability requirement on the two-meter repetitive two-beam modules constituting the main linacs. Two-beam prototype modules are being assembled to extensively study their thermo-mechanical behaviour under different operation modes. The power dissipation occurring in the modules will be reproduced and the efficiency of the corresponding cooling systems validated. At the same time, the real environmental conditions present in the CLIC tunnel will be studied. Air conditioning and ventilation systems have been installed in the dedicated laboratory. The air temperature will be changed from 20 to 40°C, while the air flow rate will be varied up to 0.8 m/s. During all experimental tests, the alignment of the RF structures will be monitored to investigate the influence of power dissipation and air temperature on the overall thermo-mechanical behaviour. \

  19. Mechanisms of femtosecond LIPSS formation induced by periodic surface temperature modulation

    Science.gov (United States)

    Gurevich, Evgeny L.

    2016-06-01

    Here we analyze the formation of laser-induced periodic surface structures (LIPSS) on metal surfaces upon single femtosecond laser pulses. Most of the existing models of the femtosecond LIPSS formation discuss only the appearance of a periodic modulation of the electron and ion temperatures. However the mechanism how the inhomogeneous surface temperature distribution induces the periodically-modulated surface profile under the conditions corresponding to ultrashort-pulse laser ablation is still not clear. Estimations made on the basis of different hydrodynamic instabilities allow to sort out mechanisms, which can bridge the gap between the temperature modulation and the LIPSS. The proposed theory shows that the periodic structures can be generated by single ultrashort laser pulses due to ablative instabilities. The Marangoni and Rayleigh-Bénard convection on the contrary cannot cause the LIPSS formation.

  20. How Does Your Protein Fold? Elucidating the Apomyoglobin Folding Pathway.

    Science.gov (United States)

    Dyson, H Jane; Wright, Peter E

    2017-01-17

    Although each type of protein fold and in some cases individual proteins within a fold classification can have very different mechanisms of folding, the underlying biophysical and biochemical principles that operate to cause a linear polypeptide chain to fold into a globular structure must be the same. In an aqueous solution, the protein takes up the thermodynamically most stable structure, but the pathway along which the polypeptide proceeds in order to reach that structure is a function of the amino acid sequence, which must be the final determining factor, not only in shaping the final folded structure, but in dictating the folding pathway. A number of groups have focused on a single protein or group of proteins, to determine in detail the factors that influence the rate and mechanism of folding in a defined system, with the hope that hypothesis-driven experiments can elucidate the underlying principles governing the folding process. Our research group has focused on the folding of the globin family of proteins, and in particular on the monomeric protein apomyoglobin. Apomyoglobin (apoMb) folds relatively slowly (∼2 s) via an ensemble of obligatory intermediates that form rapidly after the initiation of folding. The folding pathway can be dissected using rapid-mixing techniques, which can probe processes in the millisecond time range. Stopped-flow measurements detected by circular dichroism (CD) or fluorescence spectroscopy give information on the rates of folding events. Quench-flow experiments utilize the differential rates of hydrogen-deuterium exchange of amide protons protected in parts of the structure that are folded early; protection of amides can be detected by mass spectrometry or proton nuclear magnetic resonance spectroscopy (NMR). In addition, apoMb forms an intermediate at equilibrium at pH ∼ 4, which is sufficiently stable for it to be structurally characterized by solution methods such as CD, fluorescence and NMR spectroscopies, and the

  1. Microbial modulation of bacoside A biosynthetic pathway and systemic defense mechanism in Bacopa monnieri under Meloidogyne incognita stress

    Science.gov (United States)

    Gupta, Rupali; Singh, Akanksha; Srivastava, Madhumita; Singh, Vivek; Gupta, M. M.; Pandey, Rakesh

    2017-01-01

    Plant-associated beneficial microbes have been explored to fulfill the imperative function for plant health. However, their impact on the host secondary metabolite production and nematode disease management remains elusive. Our present work has shown that chitinolytic microbes viz., Chitiniphilus sp. MTN22 and Streptomyces sp. MTN14 singly as well as in combination modulated the biosynthetic pathway of bacoside A and systemic defense mechanism against Meloidogyne incognita in Bacopa monnieri. Interestingly, expression of bacoside biosynthetic pathway genes (3-Hydroxy-3-methylglutaryl coenzyme A reductase, mevalonate diphosphate decarboxylase, and squalene synthase) were upregulated in plants treated with the microbial combination in the presence as well as in absence of M. incognita stress. These microbes not only augmented bacoside A production (1.5 fold) but also strengthened host resistance via enhancement in chlorophyll a, defense enzymes and phenolic compounds like gallic acid, syringic acid, ferulic acid and cinnamic acid. Furthermore, elevated lignification and callose deposition in the microbial combination treated plants corroborate well with the above findings. Overall, the results provide novel insights into the underlying mechanisms of priming by beneficial microbes and underscore their capacity to trigger bacoside A production in B. monnieri under biotic stress. PMID:28157221

  2. Thick-skinned tectonics and basement control on geometry, kinematics and mechanics of fold-and-thrust belts. Insights from some cenozoic belts worldwide

    Science.gov (United States)

    Lacombe, Olivier; Bellahsen, Nicolas

    2015-04-01

    Fold-and-thrust belts (FTBs) form either in lower and upper plates at the expense of proximal parts of former passive margins during collision or within the upper plate of subduction orogens. In contrast, inner parts of mountain belts are likely made of stacked units from the distal passive margin domains that have undergone continental subduction and HP-LT metamorphism. There are increasing lines of evidence that the basement is involved in shortening in many FTBs worldwide, either pervasively (across the entire belt; tectonic inversion may even occur more forelandward than the mountain front) or mainly in their innermore domains where this basement is commonly exhumed. For thick-skinned FTBs that developed from former passive margins, the occurrence of weak mechanical layers within the proximal margin lithosphere (the middle and most of the lower crust are expectedly ductile) may explain that contractional deformation be distributed within most of the crust giving rise to basement-involved tectonic style. In contrast, because these weak crustal levels are usually lacking in distal parts of the margins as a result of thinning, these stronger lithospheric domains are more prone to localized deformation/subduction. Less understandable this way is the occurrence of thick-skinned wide domains within cold and strong interiors of upper plates of subduction zones, such as the Paleocene Laramide orogenic belt or the active Sierras Pampeanas belt. Structural, geophysical and thermochronological investigations within Cenozoic thick-skinned (or basement-involved thin-skinned) FTBs provide evidence for how the pre-orogenic and syn-orogenic deformation of the basement may control the geometry, kinematics and mechanics of FTBs. In this contribution, we examine some examples of FTBs where the basement is known to be involved in shortening and we review some aspects of the control exerted by the basement on the deformation. This control is demonstrated (1) at the scale of the

  3. Modelling of the Thermo-Mechanical Behavior of the Two-Beam Module for the Compact Linear Collider

    CERN Document Server

    Raatikainen, Riku; Österberg, K; Lehtovaara, A; Pajunen, S

    2011-01-01

    To fulfil the mechanical requirements set by the luminosity goals of the compact linear collider, the 2-m long two-beam modules, the shortest repetitive elements in the main linear accelerator, have to be controlled at micrometer level. At the same time these modules are exposed to high power dissipation that varies while the accelerator is ramped up to nominal power and when the mode of the accelerator operation is modified. These variations will give rise to inevitable temperature transients driving mechanical distortions in and between different module components. Therefore, the thermo-mechanical behaviour of the module is of a high importance. This thesis describes a finite element method model for the two-beam compact linear collider module. The components are described in detail compared to earlier models, which should result in a realistic description of the module. Due to the complexity of the modules, the modelling is divided into several phases from geometrical simplification and modification to the...

  4. Covering folded shapes

    Directory of Open Access Journals (Sweden)

    Oswin Aichholzer

    2014-05-01

    Full Text Available Can folding a piece of paper flat make it larger? We explore whether a shape S must be scaled to cover a flat-folded copy of itself. We consider both single folds and arbitrary folds (continuous piecewise isometries \\(S\\to\\mathbb{R}^2\\. The underlying problem is motivated by computational origami, and is related to other covering and fixturing problems, such as Lebesgue's universal cover problem and force closure grasps. In addition to considering special shapes (squares, equilateral triangles, polygons and disks, we give upper and lower bounds on scale factors for single folds of convex objects and arbitrary folds of simply connected objects.

  5. Modulation index for VMAT considering both mechanical and dose calculation uncertainties

    Energy Technology Data Exchange (ETDEWEB)

    Park, Jong Min; Park, So Yeon; Kim, Jung In [Dept. of Radiation Oncology, Seoul National University Hospital, Seoul (Korea, Republic of); Ye, Sung Joon [Program in Biomedical Radiation Sciences, Department of Transdisciplinary Studies, Seoul National University Graduate School of Convergence Science and Technology, Seoul (Korea, Republic of); Wu, Hong Gyun [Dept. of Radiation Oncology, Seoul National University College of Medicine, Seoul (Korea, Republic of); Kim, Hyoung Nyoun [Graduate School of Information, Yonsei University, Seoul (Korea, Republic of)

    2015-10-15

    The mechanical uncertainty of multi-leaf collimator (MLC) movements, gantry rotations and beam control systems as well as inaccurate dose calculations of small or irregular fields result in discrepancies between planned dose distributions as intended to be delivered to the patient, and the actual delivery to the patient. In this study, we designed a weighting factor which considers the size and irregularity of field apertures at each control point (CP) by utilizing the thinning algorithm, an image processing technique. After that, we combined this weighting factor with the previously suggested MIt, which considers the mechanical uncertainty of VMAT. In doing so, we attempted to design a modulation index which considers both mechanical and dose calculation uncertainties due to excessive modulation of VMAT plans. The MI{sub c} (f = 0.5) demonstrated considerable power to predict VMAT delivery accuracy showing strong correlations to various measures of VMAT delivery accuracy.

  6. A repeated-measures analysis of the effects of soft tissues on wrist range of motion in the extant phylogenetic bracket of dinosaurs: Implications for the functional origins of an automatic wrist folding mechanism in Crocodilia.

    Science.gov (United States)

    Hutson, Joel David; Hutson, Kelda Nadine

    2014-07-01

    A recent study hypothesized that avian-like wrist folding in quadrupedal dinosaurs could have aided their distinctive style of locomotion with semi-pronated and therefore medially facing palms. However, soft tissues that automatically guide avian wrist folding rarely fossilize, and automatic wrist folding of unknown function in extant crocodilians has not been used to test this hypothesis. Therefore, an investigation of the relative contributions of soft tissues to wrist range of motion (ROM) in the extant phylogenetic bracket of dinosaurs, and the quadrupedal function of crocodilian wrist folding, could inform these questions. Here, we repeatedly measured wrist ROM in degrees through fully fleshed, skinned, minus muscles/tendons, minus ligaments, and skeletonized stages in the American alligator Alligator mississippiensis and the ostrich Struthio camelus. The effects of dissection treatment and observer were statistically significant for alligator wrist folding and ostrich wrist flexion, but not ostrich wrist folding. Final skeletonized wrist folding ROM was higher than (ostrich) or equivalent to (alligator) initial fully fleshed ROM, while final ROM was lower than initial ROM for ostrich wrist flexion. These findings suggest that, unlike the hinge/ball and socket-type elbow and shoulder joints in these archosaurs, ROM within gliding/planar diarthrotic joints is more restricted to the extent of articular surfaces. The alligator data indicate that the crocodilian wrist mechanism functions to automatically lock their semi-pronated palms into a rigid column, which supports the hypothesis that this palmar orientation necessitated soft tissue stiffening mechanisms in certain dinosaurs, although ROM-restricted articulations argue against the presence of an extensive automatic mechanism. Anat Rec, 297:1228-1249, 2014. © 2014 Wiley Periodicals, Inc.

  7. Analyses of the mechanisms of amplitude modulation of aero-acoustic wind turbine sound

    DEFF Research Database (Denmark)

    Fischer, Andreas; Aagaard Madsen, Helge; Kragh, Knud Abildgaard

    2014-01-01

    This paper explores the source mechanism which cause amplitude modulation of the emitted sound of a wind turbine at large distances from the turbine, named as other amplitude modulation. Measurements of the fluctuating surface pressure on a 2.3MW wind turbine showed a considerable variation over...... a blade revolution in the presence of angle of attack variations. If the blade undergoes transient stall, the variation of the surface pressure spectrum was enhanced and shifted to frequencies below 200Hz. The surface pressure spectra could be directly related to the emitted far eld sound. These ndings...

  8. Length-dependent modulation of cytoskeletal remodeling and mechanical energetics in airway smooth muscle.

    Science.gov (United States)

    Kim, Hak Rim; Liu, Katrina; Roberts, Thomas J; Hai, Chi-Ming

    2011-06-01

    Actin cytoskeletal remodeling is an important mechanism of airway smooth muscle (ASM) contraction. We tested the hypothesis that mechanical strain modulates the cholinergic receptor-mediated cytoskeletal recruitment of actin-binding and integrin-binding proteins in intact airway smooth muscle, thereby regulating the mechanical energetics of airway smooth muscle. We found that the carbachol-stimulated cytoskeletal recruitment of actin-related protein-3 (Arp3), metavinculin, and talin were up-regulated at short muscle lengths and down-regulated at long muscle lengths, suggesting that the actin cytoskeleton--integrin complex becomes enriched in cross-linked and branched actin filaments in shortened ASM. The mechanical energy output/input ratio during sinusoidal length oscillation was dependent on muscle length, oscillatory amplitude, and cholinergic activation. The enhancing effect of cholinergic stimulation on mechanical energy output/input ratio at short and long muscle lengths may be explained by the length-dependent modulation of cytoskeletal recruitment and crossbridge cycling, respectively. We postulate that ASM functions as a hybrid biomaterial, capable of switching between operating as a cytoskeleton-based mechanical energy store at short muscle lengths to operating as an actomyosin-powered mechanical energy generator at long muscle lengths. This postulate predicts that targeting the signaling molecules involved in cytoskeletal recruitment may provide a novel approach to dilating collapsed airways in obstructive airway disease.

  9. Transcranial alternating current stimulation: a review of the underlying mechanisms and modulation of cognitive processes.

    Science.gov (United States)

    Herrmann, Christoph S; Rach, Stefan; Neuling, Toralf; Strüber, Daniel

    2013-01-01

    Brain oscillations of different frequencies have been associated with a variety of cognitive functions. Convincing evidence supporting those associations has been provided by studies using intracranial stimulation, pharmacological interventions and lesion studies. The emergence of novel non-invasive brain stimulation techniques like repetitive transcranial magnetic stimulation (rTMS) and transcranial alternating current stimulation (tACS) now allows to modulate brain oscillations directly. Particularly, tACS offers the unique opportunity to causally link brain oscillations of a specific frequency range to cognitive processes, because it uses sinusoidal currents that are bound to one frequency only. Using tACS allows to modulate brain oscillations and in turn to influence cognitive processes, thereby demonstrating the causal link between the two. Here, we review findings about the physiological mechanism of tACS and studies that have used tACS to modulate basic motor and sensory processes as well as higher cognitive processes like memory, ambiguous perception, and decision making.

  10. Origami - Folded Plate Structures

    OpenAIRE

    Buri, Hans Ulrich

    2010-01-01

    This research investigates new methods of designing folded plate structures that can be built with cross-laminated timber panels. Folded plate structures are attractive to both architects and engineers for their structural, spatial, and plastic qualities. Thin surfaces can be stiffened by a series of folds, and thus not only cover space, but also act as load bearing elements. The variation of light and shadow along the folded faces emphasizes the plas...

  11. The Folded t Distribution

    OpenAIRE

    Psarakis, Stelios; Panaretos, John

    1990-01-01

    Measurements are frequently recorder without their algebraic sign. As a consequence the underlying distribution of measurements is replaced by a distribution of absolute measurements. When the underlying distribution is t the resulting distribution is called the “folded-t distribution”. Here we study this distribution, we find the relationship between the folded-t distribution and a special case of the folded normal distribution and we derive relationships of the folded-t distribution to othe...

  12. Interrelated modules in cyanobacterial photosynthesis: the carbon-concentrating mechanism, photorespiration, and light perception.

    Science.gov (United States)

    Montgomery, Beronda L; Lechno-Yossef, Sigal; Kerfeld, Cheryl A

    2016-05-01

    Here we consider the cyanobacterial carbon-concentrating mechanism (CCM) and photorespiration in the context of the regulation of light harvesting, using a conceptual framework borrowed from engineering: modularity. Broadly speaking, biological 'modules' are semi-autonomous functional units such as protein domains, operons, metabolic pathways, and (sub)cellular compartments. They are increasingly recognized as units of both evolution and engineering. Modules may be connected by metabolites, such as NADPH, ATP, and 2PG. While the Calvin-Benson-Bassham Cycle and photorespiratory salvage pathways can be considered as metabolic modules, the carboxysome, the core of the cyanobacterial CCM, is both a structural and a metabolic module. In photosynthetic organisms, which use light cues to adapt to the external environment and which tune the photosystems to provide the ATP and reducing power for carbon fixation, light-regulated modules are critical. The primary enzyme of carbon fixation, RuBisCO, uses CO2 as a substrate, which is accumulated via the CCM. However RuBisCO also has a secondary reaction in which it utilizes O2, a by-product of the photochemical modules, which leads to photorespiration. A complete understanding of the interplay among CCM and photorespiration is predicated on uncovering their connections to the light reactions and the regulatory factors and pathways that tune these modules to external cues. We probe this connection by investigating light inputs into the CCM and photorespiratory pathways in the chromatically acclimating cyanobacterium Fremyella diplosiphon. © The Author 2016. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  13. Thermo-mechanical actuator-based miniature tagging module for localization in capsule endoscopy

    Science.gov (United States)

    Chandrappan, Jayakrishnan; Ruiqi, Lim; Su, Nandar; Yen Yi, Germaine Hoe; Vaidyanathan, Kripesh

    2011-04-01

    Capsule endoscopy is a frontline medical diagnostic tool for the gastro intestinal tract disorders. During diagnosis, efficient localization techniques are essential to specify a pathological area that may require further diagnosis or treatment. This paper presents the development of a miniature tagging module that relies on a novel concept to label the region of interest and has the potential to integrate with a capsule endoscope. The tagging module is a compact thermo-mechanical actuator loaded with a biocompatible micro tag. A low power microheater attached to the module serves as the thermal igniter for the mechanical actuator. At optimum temperature, the actuator releases the micro tag instantly and penetrates the mucosa layer of a GI tract, region of interest. Ex vivo animal trials are conducted to verify the feasibility of the tagging module concept. X-ray imaging is used to detect the location of the micro tag embedded in the GI tract wall. The method is successful, and radiopaque micro tags can provide valuable pre-operative position information on the infected area to facilitate further clinical procedures.

  14. Mechanical Engineering Safety Note: Analysis and Control of Hazards Associated with NIF Capacitor Module Events

    Energy Technology Data Exchange (ETDEWEB)

    Brereton, S

    2001-08-01

    the total free oil available in a capacitor (approximately 10,900 g), on the order of 5% or less. The estimates of module pressure were used to estimate the potential overpressure in the capacitor bays after an event. It was shown that the expected capacitor bay overpressure would be less than the structural tolerance of the walls. Thus, it does not appear necessary to provide any pressure relief for the capacitor bays. The ray tracing analysis showed the new module concept to be 100% effective at containing fragments generated during the events. The analysis demonstrated that all fragments would impact an energy absorbing surface on the way out of the module. Thus, there is high confidence that energetic fragments will not escape the module. However, since the module was not tested, it was recommended that a form of secondary containment on the walls of the capacitor bays (e.g., 1.0 inch of fire-retardant plywood) be provided. Any doors to the exterior of the capacitor bays should be of equivalent thickness of steel or suitably armed with a thickness of plywood. Penetrations in the ceiling of the interior bays (leading to the mechanical equipment room) do not require additional protection to form a secondary barrier. The mezzanine and the air handling units (penetrations lead directly to the air handling units) provide a sufficient second layer of protection.

  15. Modulating the actin cytoskeleton affects mechanically induced signal transduction and differentiation in mesenchymal stem cells.

    Directory of Open Access Journals (Sweden)

    Petra Müller

    Full Text Available Mechanical interactions of mesenchymal stem cells (MSC with the environment play a significant role in controlling the diverse biological functions of these cells. Mechanical forces are transduced by integrins to the actin cytoskeleton that functions as a scaffold to switch mechanical signals into biochemical pathways. To explore the significance of cytoskeletal mechanisms in human MSC we modulated the actin cytoskeleton using the depolymerising drugs cytochalasin D (CytD and latrunculin A (LatA, as well as the stabilizing drug jasplakinolide (Jasp and examined the activation of the signalling molecules ERK and AKT during mechanical loading. All three drugs provoked significant changes in cell morphology and organisation of the cytoskeleton. Application of mechanical forces to β1-integrin receptors using magnetic beads without deformation of the cell shape induced a phosphorylation of ERK and AKT. Of the two drugs that inhibited the cytoskeletal polymerization, LatA completely blocked the activation of ERK and AKT due to mechanical forces, whereas CytD inhibited the activation of AKT but not of ERK. Activation of both signalling molecules by integrin loading was not affected due to cell treatment with the cytoskeleton stabilizing drug Jasp. To correlate the effects of the drugs on mechanically induced activation of AKT and ERK with parameters of MSC differentiation, we studied ALP activity as a marker for osteogenic differentiation and examined the uptake of fat droplets as marker for adipogenic differentiation in the presence of the drugs. All three drugs inhibited ALP activity of MSC in osteogenic differentiation medium. Adipogenic differentiation was enhanced by CytD and Jasp, but not by LatA. The results indicate that modulation of the cytoskeleton using perturbing drugs can differentially modify both mechanically induced signal transduction and MSC differentiation. In addition to activation of the signalling molecules ERK and AKT, other

  16. Mechanism(s) involved in opioid drug abuse modulation of HAND.

    Science.gov (United States)

    Dutta, Raini; Roy, Sabita

    2012-07-01

    Drug abuse and HIV infection are interlinked. From the onset of the HIV/AIDS epidemic, the impact of illicit drug use on HIV disease progression has been a focus of many investigations. Both laboratory-based and epidemiological studies strongly indicate that drug abuse may exacerbate HIV disease progression and increase mortality and morbidity in these patients. Increase susceptibility to opportunistic infection has been implicated as one of the major causes for this detriment. Furthermore, opioids are known to elicit prevalence of neurodegenerative disorders in HIV-infected patients. Numerous authors have delineated various molecular as well as cellular mechanisms associated with neurological complications in these patients. This review gives an overview of these findings. Understanding the mechanisms will allow for the development of targeted therapies aimed at reducing the progression of neurocognitive decline in the drug abusing HIV infected individuals.

  17. p75 neurotrophin receptor signaling: mechanisms for neurotrophic modulation of cell stress?

    Science.gov (United States)

    Dobrowsky, R T; Carter, B D

    2000-08-01

    The recent recognition that the p75 neurotrophin receptor, p75((NTR)), can induce apoptotic signals has contributed to the perception that it acts primarily as a death receptor. Although the molecular mechanisms of p75(NTR) signaling remain to be fully characterized, many of the currently identified pathways activated by p75(NTR) may be generally characterized as stress response signals. This review describes recent advances in identifying the molecular components involved in p75(NTR) signal transduction and suggests that p75(NTR) signaling may more aptly serve as a general mechanism for the transduction and modulation of stress signals.

  18. Protein conformational modulation by photons: a mechanism for laser treatment effects.

    Science.gov (United States)

    Liebert, Ann D; Bicknell, Brian T; Adams, Roger D

    2014-03-01

    Responsiveness to low-level laser treatment (LLTT) at a wavelength of 450-910 nm has established it as an effective treatment of medical, veterinary and dental chronic pain, chronic inflammation conditions (arthritis and macular degeneration), wound repair, and lymphoedema, yet the mechanisms underlying the effectiveness of LLLT remain unclear. However, there is now sufficient evidence from recent research to propose an integrated model of LLLT action. The hypothesis presented in this paper is that external applications of photons (through laser at an appropriate dose) modulates the nervous system through an integrated mechanism. This stimulated mechanism involves protein-to-protein interaction, where two or more proteins bind together to facilitate molecular processes, including modification of proteins by members of SUMO (small ubiquitin-related modifier proteins) and also protein phosphorylation and tyrosination. SUMO has been shown to have a role in multiple nuclear and perinuclear targets, including ion channels, and in the maintenance of telomeres and the post-translational modification of genes. The consequence of laser application in treatment, therefore, can be seen as influencing the transmission of neural information via an integrated and rapid modulation of ion channels, achieved through both direct action on photo-acceptors (such as cytochrome c-oxidase) and through indirect modulation via enzymes, including tyrosine hydroxylase (TH), tyrosine kinases and tyrosine kinase receptors. This exogenous action then facilitates an existing photonic biomodulation mechanism within the body, and initiates ion channel modulation both in the periphery and the central nervous system (CNS). Evidence indicates that the ion channel modulation functions predominately through the potassium channels, including two pore leak channels (K2P), which act as signal integrators from the periphery to the cortex. Photonic action also transforms SUMOylation processes at the cell

  19. Mechanical examination and analysis of W7-X divertor module sub-structures

    Energy Technology Data Exchange (ETDEWEB)

    Smirnow, M., E-mail: michael.smirnow@gmail.com; Boscary, J.; Tittes, H.; Schubert, W.; Peacock, A.

    2015-10-15

    Highlights: • A thermo-structural simulation model of the W7-X target element. • Strain gauge measurements. • Mechanical testing. - Abstract: For the long pulse operation phase, the W7-X stellarator is equipped with an actively water cooled high heat flux (HHF) divertor, consisting of parallel cooled target elements mounted in individual target modules. Due to the thermal deformation of these target elements during heat loading, the pipework that connects the target elements to the water supply manifold is subject to significant forces. Finite element calculations, for target modules TMh1–TMh2, show the superimposed forces of the whole pipework structure on to the manifold resulting in a torsional torque on the manifold support structure and weld. During manufacture, welding of the manifold to its support structure produces thermal induced distortion, resulting in difficulty in maintaining the accuracy of the manifolds. The welding between manifold and support structure was thus minimised in order to reduce this distortion. Finite element calculations showed that the nominal welds were acceptable; however, mechanical stress test on the manifolds mount point was carried out to prove the weld performance under the calculated loading conditions to ensure the safety of the component. For the remaining modules under design TMh1–TMh4 a parametric finite element calculation design study on the effect of the pipe length and routing on the stiffness helped to define minimum requirements for the design. The status of the manifolds for these modules will be shown. The manifolds are also mechanically connected to the port plug-in, therefore the impact of the thermal displacements on this pipework coming from plasma radiation affecting the target elements and from power loads coming from Electron-Cyclotron-Resonance Heating (ECRH) stray field radiation have been calculated. The paper discusses the results of the calculations and presents the outcomes of the stress

  20. Folding RaCe: a robust method for predicting changes in protein folding rates upon point mutations.

    Science.gov (United States)

    Chaudhary, Priyashree; Naganathan, Athi N; Gromiha, M Michael

    2015-07-01

    Protein engineering methods are commonly employed to decipher the folding mechanism of proteins and enzymes. However, such experiments are exceedingly time and resource intensive. It would therefore be advantageous to develop a simple computational tool to predict changes in folding rates upon mutations. Such a method should be able to rapidly provide the sequence position and chemical nature to modulate through mutation, to effect a particular change in rate. This can be of importance in protein folding, function or mechanistic studies. We have developed a robust knowledge-based methodology to predict the changes in folding rates upon mutations formulated from amino and acid properties using multiple linear regression approach. We benchmarked this method against an experimental database of 790 point mutations from 26 two-state proteins. Mutants were first classified according to secondary structure, accessible surface area and position along the primary sequence. Three prime amino acid features eliciting the best relationship with folding rates change were then shortlisted for each class along with an optimized window length. We obtained a self-consistent mean absolute error of 0.36 s(-1) and a mean Pearson correlation coefficient (PCC) of 0.81. Jack-knife test resulted in a MAE of 0.42 s(-1) and a PCC of 0.73. Moreover, our method highlights the importance of outlier(s) detection and studying their implications in the folding mechanism. A web server 'Folding RaCe' has been developed and is available at http://www.iitm.ac.in/bioinfo/proteinfolding/foldingrace.html. gromiha@iitm.ac.in Supplementary data are available at Bioinformatics online. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  1. A promising new mechanism of ionizing radiation detection for positron emission tomography: modulation of optical properties

    Science.gov (United States)

    Tao, Li; Daghighian, Henry M.; Levin, Craig S.

    2016-11-01

    Using conventional scintillation detection, the fundamental limit in positron emission tomography (PET) time resolution is strongly dependent on the inherent temporal variances generated during the scintillation process, yielding an intrinsic physical limit for the coincidence time resolution of around 100 ps. On the other hand, modulation mechanisms of the optical properties of a material exploited in the optical telecommunications industry can be orders of magnitude faster. In this paper we borrow from the concept of optics pump-probe measurement to for the first time study whether ionizing radiation can produce modulations of optical properties, which can be utilized as a novel method for radiation detection. We show that a refractive index modulation of approximately 5× {{10}-6} is induced by interactions in a cadmium telluride (CdTe) crystal from a 511 keV photon source. Furthermore, using additional radionuclide sources, we show that the amplitude of the optical modulation signal varies linearly with both the detected event rate and average photon energy of the radiation source.

  2. A new mechanism of ionizing radiation detection for positron emission tomography: modulation of optical properties

    Science.gov (United States)

    Tao, Li; Daghighian, Henry M.; Levin, Craig S.

    2016-10-01

    Using conventional scintillation detection, the fundamental limit in positron emission tomography (PET) annihilation photon pair coincidence time resolution is strongly dependent on the inherent temporal variances generated during the scintillation process, yielding an intrinsic physical limit of around 100 ps. On the other hand, modulation mechanisms of a material's optical properties as exploited in the optical telecommunications industry can be orders of magnitude faster. In this paper we borrow from the concept of optics pump-probe measurement to study whether ionizing radiation can also produce fast modulations of optical properties, which can be utilized as a novel method for radiation detection. We show that a refractive index modulation of approximately 5x10-6 is induced by interactions in a cadmium telluride (CdTe) crystal from a 511 keV photon source. Furthermore, using additional radionuclide sources, we show that the amplitude of the optical modulation signal varies linearly with both the radiation source flux rate and average photon energy.

  3. Titin/connectin-based modulation of the Frank-Starling mechanism of the heart.

    Science.gov (United States)

    Fukuda, Norio; Granzier, Henk L

    2005-01-01

    The basis of the Frank-Starling mechanism of the heart is the increase in active force when muscle is stretched. Various findings have shown that muscle length, i.e., sarcomere length (SL), modulates activation of cardiac myofilaments at a given concentration of Ca2+ ([Ca2+]). This augmented Ca2+ activation with SL, commonly known as "length-dependent activation", is manifested as the leftward shift of the force-pCa (= -log [Ca2+]) relation as well as by the increase in maximal Ca2+ -activated force. Despite the numerous studies that have been undertaken, the molecular mechanism(s) of length-dependent activation is (are) still not fully understood. The giant sarcomere protein titin/connectin is the largest protein known to date. Titin/connectin is responsible for most passive force in vertebrate striated muscle and also functions as a molecular scaffold during myofibrillogenesis. Recent studies suggest that titin/connectin plays an important role in length-dependent activation by sensing stretch and promoting actomyosin interaction. Here we review and extend this previous work and focus on the mechanism by which titin/connectin might modulate actomyosin interaction.

  4. Dissociable neural mechanisms underlying the modulation of pain and anxiety? An FMRI pilot study.

    Science.gov (United States)

    Wiech, Katja; Edwards, Robert; Moseley, Graham Lorimer; Berna, Chantal; Ploner, Markus; Tracey, Irene

    2014-01-01

    The down-regulation of pain through beliefs is commonly discussed as a form of emotion regulation. In line with this interpretation, the analgesic effect has been shown to co-occur with reduced anxiety and increased activity in the ventrolateral prefrontal cortex (VLPFC), which is a key region of emotion regulation. This link between pain and anxiety modulation raises the question whether the two effects are rooted in the same neural mechanism. In this pilot fMRI study, we compared the neural basis of the analgesic and anxiolytic effect of two types of threat modulation: a "behavioral control" paradigm, which involves the ability to terminate a noxious stimulus, and a "safety signaling" paradigm, which involves visual cues that signal the threat (or absence of threat) that a subsequent noxious stimulus might be of unusually high intensity. Analgesia was paralleled by VLPFC activity during behavioral control. Safety signaling engaged elements of the descending pain control system, including the rostral anterior cingulate cortex that showed increased functional connectivity with the periaqueductal gray and VLPFC. Anxiety reduction, in contrast, scaled with dorsolateral prefrontal cortex activation during behavioral control but had no distinct neural signature during safety signaling. Our pilot data therefore suggest that analgesic and anxiolytic effects are instantiated in distinguishable neural mechanisms and differ between distinct stress- and pain-modulatory approaches, supporting the recent notion of multiple pathways subserving top-down modulation of the pain experience. Additional studies in larger cohorts are needed to follow up on these preliminary findings.

  5. Dissociable neural mechanisms underlying the modulation of pain and anxiety? An FMRI pilot study.

    Directory of Open Access Journals (Sweden)

    Katja Wiech

    Full Text Available The down-regulation of pain through beliefs is commonly discussed as a form of emotion regulation. In line with this interpretation, the analgesic effect has been shown to co-occur with reduced anxiety and increased activity in the ventrolateral prefrontal cortex (VLPFC, which is a key region of emotion regulation. This link between pain and anxiety modulation raises the question whether the two effects are rooted in the same neural mechanism. In this pilot fMRI study, we compared the neural basis of the analgesic and anxiolytic effect of two types of threat modulation: a "behavioral control" paradigm, which involves the ability to terminate a noxious stimulus, and a "safety signaling" paradigm, which involves visual cues that signal the threat (or absence of threat that a subsequent noxious stimulus might be of unusually high intensity. Analgesia was paralleled by VLPFC activity during behavioral control. Safety signaling engaged elements of the descending pain control system, including the rostral anterior cingulate cortex that showed increased functional connectivity with the periaqueductal gray and VLPFC. Anxiety reduction, in contrast, scaled with dorsolateral prefrontal cortex activation during behavioral control but had no distinct neural signature during safety signaling. Our pilot data therefore suggest that analgesic and anxiolytic effects are instantiated in distinguishable neural mechanisms and differ between distinct stress- and pain-modulatory approaches, supporting the recent notion of multiple pathways subserving top-down modulation of the pain experience. Additional studies in larger cohorts are needed to follow up on these preliminary findings.

  6. Mechanical loading prevents the stimulating effect of IL-1{beta} on osteocyte-modulated osteoclastogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Kulkarni, Rishikesh N.; Bakker, Astrid D.; Everts, Vincent [Department of Oral Cell Biology, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam and VU University Amsterdam, Research Institute MOVE, Amsterdam (Netherlands); Klein-Nulend, Jenneke, E-mail: j.kleinnulend@acta.nl [Department of Oral Cell Biology, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam and VU University Amsterdam, Research Institute MOVE, Amsterdam (Netherlands)

    2012-03-30

    Highlights: Black-Right-Pointing-Pointer Osteocyte incubation with IL-1{beta} stimulated osteocyte-modulated osteoclastogenesis. Black-Right-Pointing-Pointer Conditioned medium from IL-1{beta}-treated osteocytes increased osteoclastogenesis. Black-Right-Pointing-Pointer IL-1{beta} upregulated RANKL and downregulated OPG gene expression by osteocytes. Black-Right-Pointing-Pointer CYR61 is upregulated in mechanically stimulated osteocytes. Black-Right-Pointing-Pointer Mechanical loading of osteocytes may abolish IL-1{beta}-induced osteoclastogenesis. -- Abstract: Inflammatory diseases such as rheumatoid arthritis are often accompanied by higher plasma and synovial fluid levels of interleukin-1{beta} (IL-1{beta}), and by increased bone resorption. Since osteocytes are known to regulate bone resorption in response to changes in mechanical stimuli, we investigated whether IL-1{beta} affects osteocyte-modulated osteoclastogenesis in the presence or absence of mechanical loading of osteocytes. MLO-Y4 osteocytes were pre-incubated with IL-1{beta} (0.1-1 ng/ml) for 24 h. Cells were either or not subjected to mechanical loading by 1 h pulsating fluid flow (PFF; 0.7 {+-} 0.3 Pa, 5 Hz) in the presence of IL-1{beta} (0.1-1 ng/ml). Conditioned medium was collected after 1 h PFF or static cultures. Subsequently mouse bone marrow cells were seeded on top of the IL-1{beta}-treated osteocytes to determine osteoclastogenesis. Conditioned medium from mechanically loaded or static IL-1{beta}-treated osteocytes was added to co-cultures of untreated osteocytes and mouse bone marrow cells. Gene expression of cysteine-rich protein 61 (CYR61/CCN1), receptor activator of nuclear factor kappa-B ligand (RANKL), and osteoprotegerin (OPG) by osteocytes was determined immediately after PFF. Incubation of osteocytes with IL-1{beta}, as well as conditioned medium from static IL-1{beta}-treated osteocytes increased the formation of osteoclasts. However, conditioned medium from mechanically loaded IL

  7. Development of the Orion Crew-Service Module Umbilical Retention and Release Mechanism

    Science.gov (United States)

    Delap, Damon C.; Glidden, Joel Micah; Lamoreaux, Christopher

    2013-01-01

    The Orion CSM umbilical retention and release mechanism supports and protects all of the cross-module commodities between the spacecrafts crew and service modules. These commodities include explosive transfer lines, wiring for power and data, and flexible hoses for ground purge and life support systems. The mechanism employs a single separation interface which is retained with pyrotechnically actuated separation bolts and supports roughly two dozen electrical and fluid connectors. When module separation is commanded, either for nominal on-orbit CONOPS or in the event of an abort, the mechanism must release the separation interface and sever all commodity connections within milliseconds of command receipt. There are a number of unique and novel aspects of the design solution developed by the Orion mechanisms team. The design is highly modular and can easily be adapted to other vehiclesmodules and alternate commodity sets. It will be flight tested during Orions Exploration Flight Test 1 (EFT-1) in 2014, and the Orion team anticipates reuse of the design for all future missions. The design packages fluid, electrical, and ordnance disconnects in a single separation interface. It supports abort separations even in cases where aerodynamic loading prevents the deployment of the umbilical arm. Unlike the Apollo CSM umbilical which was a destructive separation device, the Orion design is resettable and flight units can be tested for separation performance prior to flight.Initial development testing of the mechanisms separation interface resulted in binding failures due to connector misalignments. The separation interface was redesigned with a robust linear guide system, and the connector separation and boom deployment were separated into two discretely sequenced events. These changes addressed the root cause of the binding failure by providing better control of connector alignment. The new design was tuned and validated analytically via Monte Carlo simulation. The

  8. A reduced mechanical model for cAMP-modulated gating in HCN channels

    Science.gov (United States)

    Weißgraeber, Stephanie; Saponaro, Andrea; Thiel, Gerhard; Hamacher, Kay

    2017-01-01

    We developed an in silico mechanical model to analyze the process of cAMP-induced conformational modulations in hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, which conduct cations across the membrane of mammalian heart and brain cells. The structural analysis reveals a quaternary twist in the cytosolic parts of the four subunits in the channel tetramer. This motion augments the intrinsic dynamics of the very same protein structure. The pronounced differences between the cAMP bound and unbound form include a mutual interaction between the C-linker of the cyclic nucleotide binding domain (CNBD) and the linker between the S4 and S5 transmembrane domain of the channel. This allows a mechanistic annotation of the twisting motion in relation to the allosteric modulation of voltage-dependent gating of this channel by cAMP. PMID:28074902

  9. Progesterone modulates the LPS-induced nitric oxide production by a progesterone-receptor independent mechanism.

    Science.gov (United States)

    Wolfson, Manuel Luis; Schander, Julieta Aylen; Bariani, María Victoria; Correa, Fernando; Franchi, Ana María

    2015-12-15

    Genital tract infections caused by Gram-negative bacteria induce miscarriage and are one of the most common complications of human pregnancy. LPS administration to 7-day pregnant mice induces embryo resorption after 24h, with nitric oxide playing a fundamental role in this process. We have previously shown that progesterone exerts protective effects on the embryo by modulating the inflammatory reaction triggered by LPS. Here we sought to investigate whether the in vivo administration of progesterone modulated the LPS-induced nitric oxide production from peripheral blood mononuclear cells from pregnant and non-pregnant mice. We found that progesterone downregulated LPS-induced nitric oxide production by a progesterone receptor-independent mechanism. Moreover, our results suggest a possible participation of glucocorticoid receptors in at least some of the anti-inflammatory effects of progesterone.

  10. A reduced mechanical model for cAMP-modulated gating in HCN channels

    Science.gov (United States)

    Weißgraeber, Stephanie; Saponaro, Andrea; Thiel, Gerhard; Hamacher, Kay

    2017-01-01

    We developed an in silico mechanical model to analyze the process of cAMP-induced conformational modulations in hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, which conduct cations across the membrane of mammalian heart and brain cells. The structural analysis reveals a quaternary twist in the cytosolic parts of the four subunits in the channel tetramer. This motion augments the intrinsic dynamics of the very same protein structure. The pronounced differences between the cAMP bound and unbound form include a mutual interaction between the C-linker of the cyclic nucleotide binding domain (CNBD) and the linker between the S4 and S5 transmembrane domain of the channel. This allows a mechanistic annotation of the twisting motion in relation to the allosteric modulation of voltage-dependent gating of this channel by cAMP.

  11. Understanding the collapse mechanism in Langmuir monolayers through polarization modulation-infrared reflection absorption spectroscopy.

    Science.gov (United States)

    Goto, Thiago Eichi; Caseli, Luciano

    2013-07-23

    The collapse of films at the air-water interface is related to a type of 2D-to-3D transition that occurs when a Langmuir monolayer is compressed beyond its stability limit. Studies on this issue are extremely important because defects in ultrathin solid films can be better understood if the molecular mechanisms related to collapse processes are elucidated. This paper explores how the changes of vibration of specific groups of lipid molecules, as revealed by polarization modulation-infrared reflection absorption spectroscopy (PM-IRRAS), are affected by the monolayer collapse. Different mechanisms of collapse were studied, for those lipids that undergo constant-area collapse (such as stearic acid) and for those that undergo constant-pressure collapse (such as DPPC, DPPG, and DODAB). Lipid charges also affect the mechanism of collapse, as demonstrated for two oppositely charged lipids.

  12. Feedback of mechanical effectiveness induces adaptations in motor modules during cycling

    Directory of Open Access Journals (Sweden)

    Cristiano eDe Marchis

    2013-04-01

    Full Text Available Recent studies have reported evidence that the motor system may rely on a modular organization, even if this behavior has yet to be confirmed during motor adaptation. The aim of the present study is to investigate the modular motor control mechanisms underlying the execution of pedaling by untrained subjects in different biomechanical conditions. We use the muscle synergies framework to characterize the muscle coordination of 11 subjects pedaling under two different conditions. The first one consists of a pedaling exercise with a strategy freely chosen by the subjects (Preferred Pedaling Technique,PPT, while the second condition constrains the gesture by means of a real time visual feedback of mechanical effectiveness (Effective Pedaling Technique,EPT. Pedal forces, recorded using a pair of instrumented pedals, were used to calculate the Index of Effectiveness, IE. EMG signals were recorded from 8 muscles of the dominant leg and Nonnegative Matrix Factorization was applied for the extraction of muscle synergies. All the synergy vectors, extracted cycle by cycle for each subject, were pooled across subjects and conditions and underwent a 2-dimensional Sammon's non-linear mapping. 7 representative clusters were identified on the Sammon's projection, and the corresponding 8-dimensional synergy vectors were used to reconstruct the repertoire of muscle activation for all subjects and all pedaling conditions (VAF > 0.8 for each individual muscle pattern. Only 5 out of the 7 identified modules were used by the subjects during the PPT pedaling condition, while 2 additional modules were found specific for the pedaling condition EPT. The temporal recruitment of three identified modules was highly correlated with IE. The structure of the identified modules was found similar to that extracted in other studies of human walking, partly confirming the existence of shared and task specific muscle synergies, and providing further evidence on the modularity of

  13. Feedback of mechanical effectiveness induces adaptations in motor modules during cycling.

    Science.gov (United States)

    De Marchis, Cristiano; Schmid, Maurizio; Bibbo, Daniele; Castronovo, Anna Margherita; D'Alessio, Tommaso; Conforto, Silvia

    2013-01-01

    Recent studies have reported evidence that the motor system may rely on a modular organization, even if this behavior has yet to be confirmed during motor adaptation. The aim of the present study is to investigate the modular motor control mechanisms underlying the execution of pedaling by untrained subjects in different biomechanical conditions. We use the muscle synergies framework to characterize the muscle coordination of 11 subjects pedaling under two different conditions. The first one consists of a pedaling exercise with a strategy freely chosen by the subjects (Preferred Pedaling Technique, PPT), while the second condition constrains the gesture by means of a real time visual feedback of mechanical effectiveness (Effective Pedaling Technique, EPT). Pedal forces, recorded using a pair of instrumented pedals, were used to calculate the Index of Effectiveness (IE). EMG signals were recorded from eight muscles of the dominant leg and Non-negative Matrix Factorization (NMF) was applied for the extraction of muscle synergies. All the synergy vectors, extracted cycle by cycle for each subject, were pooled across subjects and conditions and underwent a 2-dimensional Sammon's non-linear mapping. Seven representative clusters were identified on the Sammon's projection, and the corresponding eight-dimensional synergy vectors were used to reconstruct the repertoire of muscle activation for all subjects and all pedaling conditions (VAF > 0.8 for each individual muscle pattern). Only 5 out of the 7 identified modules were used by the subjects during the PPT pedaling condition, while 2 additional modules were found specific for the pedaling condition EPT. The temporal recruitment of three identified modules was highly correlated with IE. The structure of the identified modules was found similar to that extracted in other studies of human walking, partly confirming the existence of shared and task specific muscle synergies, and providing further evidence on the modularity

  14. Gain Modulation as a Mechanism for Coding Depth from Motion Parallax in Macaque Area MT.

    Science.gov (United States)

    Kim, HyungGoo R; Angelaki, Dora E; DeAngelis, Gregory C

    2017-08-23

    Observer translation produces differential image motion between objects that are located at different distances from the observer's point of fixation [motion parallax (MP)]. However, MP can be ambiguous with respect to depth sign (near vs far), and this ambiguity can be resolved by combining retinal image motion with signals regarding eye movement relative to the scene. We have previously demonstrated that both extra-retinal and visual signals related to smooth eye movements can modulate the responses of neurons in area MT of macaque monkeys, and that these modulations generate neural selectivity for depth sign. However, the neural mechanisms that govern this selectivity have remained unclear. In this study, we analyze responses of MT neurons as a function of both retinal velocity and direction of eye movement, and we show that smooth eye movements modulate MT responses in a systematic, temporally precise, and directionally specific manner to generate depth-sign selectivity. We demonstrate that depth-sign selectivity is primarily generated by multiplicative modulations of the response gain of MT neurons. Through simulations, we further demonstrate that depth can be estimated reasonably well by a linear decoding of a population of MT neurons with response gains that depend on eye velocity. Together, our findings provide the first mechanistic description of how visual cortical neurons signal depth from MP.SIGNIFICANCE STATEMENT Motion parallax is a monocular cue to depth that commonly arises during observer translation. To compute from motion parallax whether an object appears nearer or farther than the point of fixation requires combining retinal image motion with signals related to eye rotation, but the neurobiological mechanisms have remained unclear. This study provides the first mechanistic account of how this interaction takes place in the responses of cortical neurons. Specifically, we show that smooth eye movements modulate the gain of responses of neurons in

  15. In-Situ Measurement of Power Loss for Crystalline Silicon Modules Undergoing Thermal Cycling and Mechanical Loading Stress Testing

    DEFF Research Database (Denmark)

    Spataru, Sergiu; Hacke, Peter; Sera, Dezso

    We analyze the degradation of multi-crystalline silicon photovoltaic modules undergoing simultaneous thermal, mechanical, and humidity-freeze stress testing to develop a dark environmental chamber in-situ measurement procedure for determining module power loss. We analyze dark I-V curves measured...

  16. On Safe Folding

    NARCIS (Netherlands)

    Bossi, Annalisa; Cocco, Nicoletta; Etalle, Sandro; Bruynooghe, Maurice; Wirsing, Martin

    1993-01-01

    In [3] a general fold operation has been introduced for definite programs wrt computed answer substitution semantics. It differs from the fold operation defined by Tamaki and Sato in [26,25] because its application does not depend on the transformation history. This paper extends the results in [3

  17. Bottom-Up and Top-Down Mechanisms of General Anesthetics Modulate Different Dimensions of Consciousness.

    Science.gov (United States)

    Mashour, George A; Hudetz, Anthony G

    2017-01-01

    There has been controversy regarding the precise mechanisms of anesthetic-induced unconsciousness, with two salient approaches that have emerged within systems neuroscience. One prominent approach is the "bottom up" paradigm, which argues that anesthetics suppress consciousness by modulating sleep-wake nuclei and neural circuits in the brainstem and diencephalon that have evolved to control arousal states. Another approach is the "top-down" paradigm, which argues that anesthetics suppress consciousness by modulating the cortical and thalamocortical circuits involved in the integration of neural information. In this article, we synthesize these approaches by mapping bottom-up and top-down mechanisms of general anesthetics to two distinct but inter-related dimensions of consciousness: level and content. We show how this explains certain empirical observations regarding the diversity of anesthetic drug effects. We conclude with a more nuanced discussion of how levels and contents of consciousness interact to generate subjective experience and what this implies for the mechanisms of anesthetic-induced unconsciousness.

  18. Bottom-Up and Top-Down Mechanisms of General Anesthetics Modulate Different Dimensions of Consciousness

    Science.gov (United States)

    Mashour, George A.; Hudetz, Anthony G.

    2017-01-01

    There has been controversy regarding the precise mechanisms of anesthetic-induced unconsciousness, with two salient approaches that have emerged within systems neuroscience. One prominent approach is the “bottom up” paradigm, which argues that anesthetics suppress consciousness by modulating sleep-wake nuclei and neural circuits in the brainstem and diencephalon that have evolved to control arousal states. Another approach is the “top-down” paradigm, which argues that anesthetics suppress consciousness by modulating the cortical and thalamocortical circuits involved in the integration of neural information. In this article, we synthesize these approaches by mapping bottom-up and top-down mechanisms of general anesthetics to two distinct but inter-related dimensions of consciousness: level and content. We show how this explains certain empirical observations regarding the diversity of anesthetic drug effects. We conclude with a more nuanced discussion of how levels and contents of consciousness interact to generate subjective experience and what this implies for the mechanisms of anesthetic-induced unconsciousness. PMID:28676745

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

    Science.gov (United States)

    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.

  20. Multiple mechanisms involved in oxytocin-induced modulation of myometrial contractility

    Institute of Scientific and Technical Information of China (English)

    Anatoly SHMYGOL; Joanna GULLAM; Andrew BLANKS; Steven THORNTON

    2006-01-01

    Oxytocin is a small peptide hormone with multiple sites of action in human body.It regulates a large number of reproduction-related processes in all species.Particularly important is its ability to stimulate uterine contractility.This is achieved by multiple mechanisms involving sarcoplasmic reticulum Ca2+ release and sensitization of the contractile apparatus to Ca2+.In this paper,we review the data published by US and other groups on oxytocin-induced modulation of uterine contractility.We conclude that sensitization of contractile apparatus to Ca2+ is the most relevant physiological effect of oxytocin on human myometrium.

  1. The mechanical power output of the pectoralis muscle of cockatiel (Nymphicus hollandicus): the in vivo muscle length trajectory and activity patterns and their implications for power modulation.

    Science.gov (United States)

    Morris, Charlotte R; Askew, Graham N

    2010-08-15

    In order to meet the varying demands of flight, pectoralis muscle power output must be modulated. In birds with pectoralis muscles with a homogeneous fibre type composition, power output can be modulated at the level of the motor unit (via changes in muscle length trajectory and the pattern of activation), at the level of the muscle (via changes in the number of motor units recruited), and at the level of the whole animal (through the use of intermittent flight). Pectoralis muscle length trajectory and activity patterns were measured in vivo in the cockatiel (Nymphicus hollandicus) at a range of flight speeds (0-16 m s(-1)) using sonomicrometry and electromyography. The work loop technique was used to measure the mechanical power output of a bundle of fascicles isolated from the pectoralis muscle during simulated in vivo length change and activity patterns. The mechanical power-speed relationship was U-shaped, with a 2.97-fold variation in power output (40-120 W kg(-1)). In this species, modulation of neuromuscular activation is the primary strategy utilised to modulate pectoralis muscle power output. Maximum in vivo power output was 22% of the maximum isotonic power output (533 W kg(-1)) and was generated at a lower relative shortening velocity (0.28 V(max)) than the maximum power output during isotonic contractions (0.34 V(max)). It seems probable that the large pectoralis muscle strains result in a shift in the optimal relative shortening velocity in comparison with the optimum during isotonic contractions as a result of length-force effects.

  2. In-Situ Measurement of Power Loss for Crystalline Silicon Modules Undergoing Thermal Cycling and Mechanical Loading Stress Testing

    DEFF Research Database (Denmark)

    Spataru, Sergiu; Hacke, Peter; Sera, Dezso

    We analyze the degradation of multi-crystalline silicon photovoltaic modules undergoing simultaneous thermal, mechanical, and humidity-freeze stress testing to develop a dark environmental chamber in-situ measurement procedure for determining module power loss. We analyze dark I-V curves measured...... due to cell fractures, and the additional series resistance losses observed under illumination. Based on the analysis, we propose an in-situ module power loss monitoring procedure that relies on dark current-voltage measurements taken during the stress test and initial and final module flash testing...

  3. Modulation of learning and memory by cytokines: signaling mechanisms and long term consequences.

    Science.gov (United States)

    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.

  4. Transcranial alternating current stimulation: A review of the underlying mechanisms and modulation of cognitive processes

    Directory of Open Access Journals (Sweden)

    Christoph S Herrmann

    2013-06-01

    Full Text Available Brain oscillations of different frequencies have been associated with a variety of cognitive functions. Convincing evidence supporting those associations has been provided by studies using intracranial stimulation, pharmacological interventions and lesion studies. The emergence of novel non-invasive brain stimulation techniques like repetitive transcranial magnetic stimulation (rTMS and transcranial alternating current stimulation (tACS now allows to modulate brain oscillations directly. Particularly, tACS offers the unique opportunity to causally link brain oscillations of a specific frequency range to cognitive processes, because it uses sinusoidal currents that are bound to one frequency only. Using tACS allows to modulate brain oscillations and in turn to influence cognitive processes, thereby demonstrating the causal link between the two. Here, we review findings about the physiological mechanism of tACS and studies that have used tACS to modulate basic motor and sensory processes as well as higher cognitive processes like memory, ambiguous perception, and decision making.

  5. Variable identification and automatic tuning of the main module of a servo system of parallel mechanism

    Institute of Scientific and Technical Information of China (English)

    YANG Zhiyong; XU Meng; HUANG Tian; NI Yanbing

    2007-01-01

    The variables of the main module of a servo system for miniature reconfigurable parallel mechanism were identified and automatically tuned. With the reverse solution module of the translation, the module with the exerted translation joint was obtained, which included the location, velocity and acceleration of the parallelogram carriage- branch. The rigid dynamic reverse model was set as the virtual work principle. To identify the variables of the servo system, the triangle-shaped input signal with variable frequency was adopted to overcome the disadvantages of the pseudo-random number sequence, i.e., making the change of the vibration amplitude of the motor dramatically, easily impact the servo motor and make the velocity loop open and so on. Moreover, all the variables including,the rotary inertia of the servo system were identified by the additive mass. The overshoot and rise time were the optimum goals, the limited changing load with the attitude was considered, and the range of the controller variables in the servo system was identified. The results of the experiments prove that the method is accurate.

  6. In-Situ Measurement of Power Loss for Crystalline Silicon Modules Undergoing Thermal Cycling and Mechanical Loading Stress Testing: Preprint

    Energy Technology Data Exchange (ETDEWEB)

    Spataru, Sergiu; Hacke, Pater; Sera, Dezso

    2015-09-15

    We analyze the degradation of multi-crystalline silicon photovoltaic modules undergoing simultaneous thermal, mechanical, and humidity stress testing to develop a dark environmental chamber in-situ measurement procedure for determining module power loss. From the analysis we determine three main categories of failure modes associated with the module degradation consisting of: shunting, recombination losses, increased series resistance losses, and current mismatch losses associated with a decrease in photo-current generation by removal of some cell areas due to cell fractures. Based on the analysis, we propose an in-situ module power loss monitoring procedure that relies on dark current-voltage measurements taken during the stress test, and initial and final module flash testing, to determine the power degradation characteristic of the module.

  7. In-Situ Measurement of Power Loss for Crystalline Silicon Modules Undergoing Thermal Cycling and Mechanical Loading Stress Testing: Preprint

    Energy Technology Data Exchange (ETDEWEB)

    Spataru, Sergiu; Hacke, Pater; Sera, Dezso

    2015-09-15

    We analyze the degradation of multi-crystalline silicon photovoltaic modules undergoing simultaneous thermal, mechanical, and humidity stress testing to develop a dark environmental chamber in-situ measurement procedure for determining module power loss. From the analysis we determine three main categories of failure modes associated with the module degradation consisting of: shunting, recombination losses, increased series resistance losses, and current mismatch losses associated with a decrease in photo-current generation by removal of some cell areas due to cell fractures. Based on the analysis, we propose an in-situ module power loss monitoring procedure that relies on dark current-voltage measurements taken during the stress test, and initial and final module flash testing, to determine the power degradation characteristic of the module.

  8. Micro-Thermoelectric Generation Modules Fabricated with Low-Cost Mechanical Machining Processes

    Science.gov (United States)

    Liu, Dawei; Jin, A. J.; Peng, Wenbo; Li, Qiming; Gao, Hu; Zhu, Lianjun; Li, Fu; Zhu, Zhixiang

    2017-05-01

    Micro/small-scale thermoelectric generation modules are able to produce continuous, noise-free and reliable electricity power using low temperature differences that widely exist in nature or industry. These advantages bring them great application prospects in the fields of remote monitoring, microelectronics/micro-electromechanical systems (MEMS), medical apparatus and smart management system, which often require a power source free of maintenance and vibration. In this work, a prototypical thermoelectric module (12 mm × 12 mm × 0.8 mm) with 15 pairs of micro-scale thermoelectric legs (0.2 mm in width and 0.6 mm in height for each leg) is fabricated using a low-cost mechanical machining process. In this process, cutting and polishing are the main methods for the preparation of thermoelectric pairs from commercial polycrystalline materials and for the fabrication of electrode patterns. The as-fabricated module is tested for its power generation properties with the hot side heated by an electrical heater and the cold side by cold air. With the heater temperature of 375 K, the thermoelectric potential is about 9.1 mV, the short circuit current is about 14.5 mA, and the maximum output power is about 32.8 μW. The finite element method is applied to analyze the heat transfer of the module during our test. The temperature difference and heat flux are simulated, according to which the output powers at different temperatures are calculated, and the result is relatively consistent compared to the test results.

  9. Micro-Thermoelectric Generation Modules Fabricated with Low-Cost Mechanical Machining Processes

    Science.gov (United States)

    Liu, Dawei; Jin, A. J.; Peng, Wenbo; Li, Qiming; Gao, Hu; Zhu, Lianjun; Li, Fu; Zhu, Zhixiang

    2016-11-01

    Micro/small-scale thermoelectric generation modules are able to produce continuous, noise-free and reliable electricity power using low temperature differences that widely exist in nature or industry. These advantages bring them great application prospects in the fields of remote monitoring, microelectronics/micro-electromechanical systems (MEMS), medical apparatus and smart management system, which often require a power source free of maintenance and vibration. In this work, a prototypical thermoelectric module (12 mm × 12 mm × 0.8 mm) with 15 pairs of micro-scale thermoelectric legs (0.2 mm in width and 0.6 mm in height for each leg) is fabricated using a low-cost mechanical machining process. In this process, cutting and polishing are the main methods for the preparation of thermoelectric pairs from commercial polycrystalline materials and for the fabrication of electrode patterns. The as-fabricated module is tested for its power generation properties with the hot side heated by an electrical heater and the cold side by cold air. With the heater temperature of 375 K, the thermoelectric potential is about 9.1 mV, the short circuit current is about 14.5 mA, and the maximum output power is about 32.8 μW. The finite element method is applied to analyze the heat transfer of the module during our test. The temperature difference and heat flux are simulated, according to which the output powers at different temperatures are calculated, and the result is relatively consistent compared to the test results.

  10. Endocrine-disrupting chemicals use distinct mechanisms of action to modulate endocrine system function.

    Science.gov (United States)

    Henley, Derek V; Korach, Kenneth S

    2006-06-01

    The term endocrine-disrupting chemicals is used to define a structurally diverse class of synthetic and natural compounds that possess the ability to alter various components of the endocrine system and potentially induce adverse health effects in exposed individuals and populations. Research on these compounds has revealed that they use a variety of both nuclear receptor-mediated and non-receptor-mediated mechanisms to modulate different components of the endocrine system. This review will describe in vitro and in vivo studies that highlight the spectrum of unique mechanisms of action and biological effects of four endocrine-disrupting chemicals--diethylstilbestrol, genistein, di(n-butyl)phthalate, and methoxyacetic acid--to illustrate the diverse and complex nature of this class of compounds.

  11. Vascular remodeling: A redox-modulated mechanism of vessel caliber regulation.

    Science.gov (United States)

    Tanaka, Leonardo Y; Laurindo, Francisco R M

    2017-01-18

    Vascular remodeling, i.e. whole-vessel structural reshaping, determines lumen caliber in (patho)physiology. Here we review mechanisms underlying vessel remodeling, with emphasis in redox regulation. First, we discuss confusing terminology and focus on strictu sensu remodeling. Second, we propose a mechanobiological remodeling paradigm based on the concept of tensional homeostasis as a setpoint regulator. We first focus on shear-mediated models as prototypes of remodeling closely dominated by highly redox-sensitive endothelial function. More detailed discussions focus on mechanosensors, integrins, extracellular matrix, cytoskeleton and inflammatory pathways as potential of mechanisms potentially coupling tensional homeostasis to redox regulation. Further discussion of remodeling associated with atherosclerosis and injury repair highlights important aspects of redox vascular responses. While neointima formation has not shown consistent responsiveness to antioxidants, vessel remodeling has been more clearly responsive, indicating that despite the multilevel redox signaling pathways, there is a coordinated response of the whole vessel. Among mechanisms that may orchestrate redox pathways, we discuss roles of superoxide dismutase activity and extracellular protein disulfide isomerase. We then discuss redox modulation of aneurysms, a special case of expansive remodeling. We propose that the redox modulation of vascular remodeling may reflect (1) remodeling pathophysiology is dominated by a particularly redox-sensitive cell type, e.g., endothelial cells (2) redox pathways are temporospatially coordinated at an organ level across distinct cellular and acellular structures or (3) the tensional homeostasis setpoint is closely connected to redox signaling. The mechanobiological/redox model discussed here can be a basis for improved understanding of remodeling and helps clarifying mechanisms underlying prevalent hard-to-treat diseases.

  12. Signaling mechanism underlying the histamine-modulated action of hypoglossal motoneurons.

    Science.gov (United States)

    Liu, Zi-Long; Wu, Xu; Luo, Yan-Jia; Wang, Lu; Qu, Wei-Min; Li, Shan-Qun; Huang, Zhi-Li

    2016-04-01

    Histamine, an important modulator of the arousal states of the central nervous system, has been reported to contribute an excitatory drive at the hypoglossal motor nucleus to the genioglossus (GG) muscle, which is involved in the pathogenesis of obstructive sleep apnea. However, the effect of histamine on hypoglossal motoneurons (HMNs) and the underlying signaling mechanisms have remained elusive. Here, whole-cell patch-clamp recordings were conducted using neonatal rat brain sections, which showed that histamine excited HMNs with an inward current under voltage-clamp and a depolarization membrane potential under current-clamp via histamine H1 receptors (H1Rs). The phospholipase C inhibitor U-73122 blocked H1Rs-mediated excitatory effects, but protein kinase A inhibitor and protein kinase C inhibitor did not, indicating that the signal transduction cascades underlying the excitatory action of histamine on HMNs were H1R/Gq/11 /phospholipase C/inositol-1,4,5-trisphosphate (IP3). The effects of histamine were also dependent on extracellular Na(+) and intracellular Ca(2+), which took place via activation of Na(+)-Ca(2+) exchangers. These results identify the signaling molecules associated with the regulatory effect of histamine on HMNs. The findings of this study may provide new insights into therapeutic approaches in obstructive sleep apnea. We proposed the post-synaptic mechanisms underlying the modulation effect of histamine on hypoglossal motoneuron. Histamine activates the H1Rs via PLC and IP3, increases Ca(2+) releases from intracellular stores, promotes Na(+) influx and Ca(2+) efflux via the NCXs, and then produces an inward current and depolarizes the neurons. Histamine modulates the excitability of HMNs with other neuromodulators, such as noradrenaline, serotonin and orexin. We think that these findings should provide an important new direction for drug development for the treatment of obstructive sleep apnea.

  13. Single-molecule folding mechanisms of the apo- and Mg2+-bound states of human neuronal calcium sensor-1

    DEFF Research Database (Denmark)

    Naqvi, Mohsin M; Heiðarsson, Pétur Orri; Otazo, Mariela R;

    2015-01-01

    in a variety of cellular processes in which it has been linked to a number of disorders such as schizophrenia and autism. Despite extensive studies on the Ca(2+)-activated state of NCS proteins, little is known about the conformational dynamics of the Mg(2+)-bound and apo states, both of which are populated...... by populating one intermediate state consisting of a folded C-domain and an unfolded N-domain. The interconversion at equilibrium between the different molecular states populated by NCS-1 was monitored in real time through constant-force measurements and the energy landscapes underlying the observed transitions......Neuronal calcium sensor-1 (NCS-1) is the primordial member of a family of proteins responsible primarily for sensing changes in neuronal Ca(2+) concentration. NCS-1 is a multispecific protein interacting with a number of binding partners in both calcium-dependent and independent manners, and acting...

  14. NoFold: RNA structure clustering without folding or alignment.

    Science.gov (United States)

    Middleton, Sarah A; Kim, Junhyong

    2014-11-01

    Structures that recur across multiple different transcripts, called structure motifs, often perform a similar function-for example, recruiting a specific RNA-binding protein that then regulates translation, splicing, or subcellular localization. Identifying common motifs between coregulated transcripts may therefore yield significant insight into their binding partners and mechanism of regulation. However, as most methods for clustering structures are based on folding individual sequences or doing many pairwise alignments, this results in a tradeoff between speed and accuracy that can be problematic for large-scale data sets. Here we describe a novel method for comparing and characterizing RNA secondary structures that does not require folding or pairwise alignment of the input sequences. Our method uses the idea of constructing a distance function between two objects by their respective distances to a collection of empirical examples or models, which in our case consists of 1973 Rfam family covariance models. Using this as a basis for measuring structural similarity, we developed a clustering pipeline called NoFold to automatically identify and annotate structure motifs within large sequence data sets. We demonstrate that NoFold can simultaneously identify multiple structure motifs with an average sensitivity of 0.80 and precision of 0.98 and generally exceeds the performance of existing methods. We also perform a cross-validation analysis of the entire set of Rfam families, achieving an average sensitivity of 0.57. We apply NoFold to identify motifs enriched in dendritically localized transcripts and report 213 enriched motifs, including both known and novel structures.

  15. The effects of modulation period,modulation ratio,and deposition temperature on microstructure and mechanical properties of ZrB2/W multilayers

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    Monolithic ZrB2,W coatings and ZrB2/W multilayers with different modulation periods and modulation ratios were synthesized by ion beam assisted deposition at room temperature and 400°C.X-ray diffraction (XRD),scanning electron microscopy (SEM),surface profiler,and nanoindention were employed to investigate the influences of the deposition temperature and the modulation period on the growth,textures,interface structure,and mechanical properties of the multilayers.The results indicated that the multilayer with modulation period of 13 nm synthesized at room temperature possessed a higher hardness of 23.8 GPa.Deposition temperature gave a significant contribution to mechanical property enhancement.The 400°C-deposition temperature led to a maximum hardness and elastic modulus value of 32.1 and 399.1 GPa for ZrB2/W multilayer with a modulation period of 6.7 nm.Its critical load increased to 42.8 mN and residual stress decreased to -0.7 GPa.A higher deposition temperature can cause an increase in interfacial atomic mixture and mobility of surface species,which induceds an increase in areal atomic density and dislocation pinning.These results as well as small nanoscale grain sizes should be related to hardness increase.

  16. Stochastic Resonance in Protein Folding Dynamics.

    Science.gov (United States)

    Davtyan, Aram; Platkov, Max; Gruebele, Martin; Papoian, Garegin A

    2016-05-04

    Although protein folding reactions are usually studied under static external conditions, it is likely that proteins fold in a locally fluctuating cellular environment in vivo. To mimic such behavior in in vitro experiments, the local temperature of the solvent can be modulated either harmonically or using correlated noise. In this study, coarse-grained molecular simulations are used to investigate these possibilities, and it is found that both periodic and correlated random fluctuations of the environment can indeed accelerate folding kinetics if the characteristic frequencies of the applied fluctuations are commensurate with the internal timescale of the folding reaction; this is consistent with the phenomenon of stochastic resonance observed in many other condensed-matter processes. To test this theoretical prediction, the folding dynamics of phosphoglycerate kinase under harmonic temperature fluctuations are experimentally probed using Förster resonance energy transfer fluorescence measurements. To analyze these experiments, a combination of theoretical approaches is developed, including stochastic simulations of folding kinetics and an analytical mean-field kinetic theory. The experimental observations are consistent with the theoretical predictions of stochastic resonance in phosphoglycerate kinase folding. When combined with an alternative experiment on the protein VlsE using a power spectrum analysis, elaborated in Dave et al., ChemPhysChem 2016, 10.1002/cphc.201501041, the overall data overwhelmingly point to the experimental confirmation of stochastic resonance in protein folding dynamics.

  17. Macromolecule-Assisted de novo Protein Folding

    Science.gov (United States)

    Choi, Seong Il; Son, Ahyun; Lim, Keo-Heun; Jeong, Hotcherl; Seong, Baik L.

    2012-01-01

    In the processes of protein synthesis and folding, newly synthesized polypeptides are tightly connected to the macromolecules, such as ribosomes, lipid bilayers, or cotranslationally folded domains in multidomain proteins, representing a hallmark of de novo protein folding environments in vivo. Such linkage effects on the aggregation of endogenous polypeptides have been largely neglected, although all these macromolecules have been known to effectively and robustly solubilize their linked heterologous proteins in fusion or display technology. Thus, their roles in the aggregation of linked endogenous polypeptides need to be elucidated and incorporated into the mechanisms of de novo protein folding in vivo. In the classic hydrophobic interaction-based stabilizing mechanism underlying the molecular chaperone-assisted protein folding, it has been assumed that the macromolecules connected through a simple linkage without hydrophobic interactions and conformational changes would make no effect on the aggregation of their linked polypeptide chains. However, an increasing line of evidence indicates that the intrinsic properties of soluble macromolecules, especially their surface charges and excluded volume, could be important and universal factors for stabilizing their linked polypeptides against aggregation. Taken together, these macromolecules could act as folding helpers by keeping their linked nascent chains in a folding-competent state. The folding assistance provided by these macromolecules in the linkage context would give new insights into de novo protein folding inside the cell. PMID:22949867

  18. Optical methods for measuring DNA folding

    Science.gov (United States)

    Smith, Adam D.; Ukogu, Obinna A.; Devenica, Luka M.; White, Elizabeth D.; Carter, Ashley R.

    2017-03-01

    One of the most important biological processes is the dynamic folding and unfolding of deoxyribonucleic acid (DNA). The folding process is crucial for DNA to fit within the boundaries of the cell, while the unfolding process is essential for DNA replication and transcription. To accommodate both processes, the cell employs a highly active folding mechanism that has been the subject of intense study over the last few decades. Still, many open questions remain. What are the pathways for folding or unfolding? How does the folding equilibrium shift? And, what is the energy landscape for a particular process? Here, we review these emerging questions and the in vitro, optical methods that have provided answers, introducing the topic for those physicists seeking to step into biology. Specifically, we discuss two iconic experiments for DNA folding, the tethered particle motion (TPM) experiment and the optical tweezers experiment.

  19. Some aspects of vocal fold bowing.

    Science.gov (United States)

    Tanaka, S; Hirano, M; Chijiwa, K

    1994-05-01

    Bowing of the vocal fold frequently occurs in patients with vocal fold paralysis (VFP), those with sulcus vocalis, and those who have had laser surgery. Additionally, there are vocal folds that present bowing with no noticeable organic lesion. For the purpose of investigating the causes and mechanisms of vocal fold bowing, consecutive fiberscopic videorecordings of 127 patients with VFP, 33 with sulcus vocalis, 33 with laser surgery, and 33 with dysphonia having no clinically noticeable organic lesion were reviewed. Sixty-nine percent of the paralyzed vocal folds had bowing, and the occurrence of bowing was significantly related to the activity of the thyroarytenoid muscle as measured by electromyography. The cricothyroid activity had no significant relationship to vocal fold bowing. All vocal folds with sulcus presented with bowing. Thirty-five percent of the vocal folds that had had laser surgery had bowing. The extent of tissue removal was closely related to the occurrence of bowing. Twelve cases with no organic lesion had vocal fold bowing. Of these 12 patients, 8 were male and 9 were older than 60 years. Some aging process in the mucosa was presumed to be the cause of the bowing in this age group of patients without clinically noticeable organic lesions. Causes of vocal fold bowing in the younger group of patients without organic lesions were not determined in this study.

  20. Does Branched-Chain Amino Acids Supplementation Modulate Skeletal Muscle Remodeling through Inflammation Modulation? Possible Mechanisms of Action

    Directory of Open Access Journals (Sweden)

    Humberto Nicastro

    2012-01-01

    Full Text Available Skeletal muscle protein turnover is modulated by intracellular signaling pathways involved in protein synthesis, degradation, and inflammation. The proinflammatory status of muscle cells, observed in pathological conditions such as cancer, aging, and sepsis, can directly modulate protein translation initiation and muscle proteolysis, contributing to negative protein turnover. In this context, branched-chain amino acids (BCAAs, especially leucine, have been described as a strong nutritional stimulus able to enhance protein translation initiation and attenuate proteolysis. Furthermore, under inflammatory conditions, BCAA can be transaminated to glutamate in order to increase glutamine synthesis, which is a substrate highly consumed by inflammatory cells such as macrophages. The present paper describes the role of inflammation on muscle remodeling and the possible metabolic and cellular effects of BCAA supplementation in the modulation of inflammatory status of skeletal muscle and the consequences on protein synthesis and degradation.

  1. Muscle pain induced by static contraction in rats is modulated by peripheral inflammatory mechanisms.

    Science.gov (United States)

    Santos, Diogo Francisco da Silva Dos; Melo Aquino, Bruna de; Jorge, Carolina Ocanha; Azambuja, Graciana de; Schiavuzzo, Jalile Garcia; Krimon, Suzy; Neves, Juliana Dos Santos; Parada, Carlos Amilcar; Oliveira-Fusaro, Maria Claudia Gonçalves

    2017-09-01

    Muscle pain is an important health issue and frequently related to static force exertion. The aim of this study is to evaluate whether peripheral inflammatory mechanisms are involved with static contraction-induced muscle pain in rats. To this end, we developed a model of muscle pain induced by static contraction performed by applying electrical pulses through electrodes inserted into muscle. We also evaluated the involvement of neutrophil migration, bradykinin, sympathetic amines and prostanoids. A single session of sustained static contraction of gastrocnemius muscle induced acute mechanical muscle hyperalgesia without affecting locomotor activity and with no evidence of structural damage in muscle tissue. Static contraction increased levels of creatine kinase but not lactate dehydrogenase, and induced neutrophil migration. Dexamethasone (glucocorticoid anti-inflammatory agent), DALBK (bradykinin B1 antagonist), Atenolol (β1 adrenoceptor antagonist), ICI 118,551 (β2 adrenoceptor antagonist), indomethacin (cyclooxygenase inhibitor), and fucoidan (non-specific selectin inhibitor) all reduced static contraction-induced muscle hyperalgesia; however, the bradykinin B2 antagonist, bradyzide, did not have an effect on static contraction-induced muscle hyperalgesia. Furthermore, an increased hyperalgesic response was observed when the selective bradykinin B1 agonist des-Arg(9)-bradykinin was injected into the previously stimulated muscle. Together, these findings demonstrate that static contraction induced mechanical muscle hyperalgesia in gastrocnemius muscle of rats is modulated through peripheral inflammatory mechanisms that are dependent on neutrophil migration, bradykinin, sympathetic amines and prostanoids. Considering the clinical relevance of muscle pain, we propose the present model of static contraction-induced mechanical muscle hyperalgesia as a useful tool for the study of mechanisms underlying static contraction-induced muscle pain. Copyright © 2017 IBRO

  2. Molecular modeling and computational analyses suggests that the Sinorhizobium meliloti periplasmic regulator protein ExoR adopts a superhelical fold and is controlled by a unique mechanism of proteolysis.

    Science.gov (United States)

    Wiech, Eliza M; Cheng, Hai-Ping; Singh, Shaneen M

    2015-03-01

    The Sinorhizobium meliloti periplasmic ExoR protein and the ExoS/ChvI two-component system form a regulatory mechanism that directly controls the transformation of free-living to host-invading cells. In the absence of crystal structures, understanding the molecular mechanism of interaction between ExoR and the ExoS sensor, which is believed to drive the key regulatory step in the invasion process, remains a major challenge. In this study, we present a theoretical structural model of the active form of ExoR protein, ExoRm , generated using computational methods. Our model suggests that ExoR possesses a super-helical fold comprising 12 α-helices forming six Sel1-like repeats, including two that were unidentified in previous studies. This fold is highly conducive to mediating protein-protein interactions and this is corroborated by the identification of putative protein binding sites on the surface of the ExoRm protein. Our studies reveal two novel insights: (a) an extended conformation of the third Sel1-like repeat that might be important for ExoR regulatory function and (b) a buried proteolytic site that implies a unique proteolytic mechanism. This study provides new and interesting insights into the structure of S. meliloti ExoR, lays the groundwork for elaborating the molecular mechanism of ExoRm cleavage, ExoRm -ExoS interactions, and studies of ExoR homologs in other bacterial host interactions.

  3. Multiple folding pathways of proteins with shallow knots and co-translational folding

    CERN Document Server

    Chwastyk, Mateusz

    2015-01-01

    We study the folding process in the shallowly knotted protein MJ0366 within two variants of a structure-based model. We observe that the resulting topological pathways are much richer than identified in previous studies. In addition to the single knot-loop events, we find novel, and dominant, two-loop mechanisms. We demonstrate that folding takes place in a range of temperatures and the conditions of most successful folding are at temperatures which are higher than those required for the fastest folding. We also demonstrate that nascent conditions are more favorable to knotting than off-ribosome folding.

  4. Modulation of the Pasteur effect in retinal cells: implications for understanding compensatory metabolic mechanisms.

    Science.gov (United States)

    Winkler, Barry S; Sauer, Michael W; Starnes, Catherine A

    2003-06-01

    The purpose of the present experiments was to enhance understanding of the factors that are critical for the survival of retinal cells exposed to mitochondrial inhibition. Confluent cultures of Müller cells (rMC-1) and human retinal pigment epithelial cells (hRPE) were incubated in Dulbecco's minimal essential medium in the presence and absence of 1x10(-5)M Antimycin A, an inhibitor of mitochondrial electron transport. To modulate the rates of aerobic and anaerobic glycolysis, cells were incubated in media containing varying concentrations of glucose and 1-100 micro M of iodoacetic acid (IAA), an inhibitor of glyceraldehdye-3-phosphate dehydrogenase (G3PDH). Measurements were made of G3PDH, lactic acid production, and cellular ATP levels, along with an examination of cellular morphology, the latter providing an index of cellular viability. Control rMC-1 and hRPE produced lactate aerobically, respectively, at 0.48 and 1.50 micro molhr(-1)/10(6) cells. Anaerobically, lactate production increased 2-fold in rMC-1 and 3-fold in hRPE. Anaerobic ATP levels in both types of cells were maintained at control levels over 8hr. Experimental conditions were sought that would modulate only the capacity of rMC-1 and hRPE to increase glycolysis following mitochondrial inhibition, i.e. alter their Pasteur effect. We used low concentrations of IAA to partially inhibit G3PDH. Incubation of rMC-1 with IAA for 6hr caused a graded inhibition of G3PDH: 70% inhibition with 1 micro M, 90% with 5 micro M, 97% with 10 micro M, and 100% with 100 micro M. While the aerobic and anaerobic rates of lactic acid production were not altered by 1 micro M IAA, both were suppressed completely by 100 micro M IAA. However, incubation of rMC-1 with 5 micro M IAA caused a decrease of 30% in the rate of anaerobic lactic acid production but no change in the rate of aerobic glycolysis. Moreover, with 5 micro M IAA, rMC-1 incubated aerobically maintained ATP levels, but anaerobic ATP content decreased to a low

  5. Identification of an allosteric modulator of the serotonin transporter with novel mechanism of action.

    Science.gov (United States)

    Kortagere, Sandhya; Fontana, Andreia Cristina Karklin; Rose, Deja Renée; Mortensen, Ole Valente

    2013-09-01

    Serotonin transporters (SERTs) play an essential role in the termination and regulation of serotonin signaling in the brain. SERT is also the target of antidepressants and psychostimulants. Molecules with novel activities and modes of interaction with regard to SERT function are of great scientific and clinical interest. We explored structural regions outside the putative serotonin translocation pathway to identify potential binding sites for allosteric transporter modulators (ATMs). Mutational studies revealed a pocket of amino acids outside the orthosteric substrate binding sites located in the interface between extracellular loops 1 and 3 that when mutated affect transporter function. Using the structure of the bacterial transporter homolog leucine transporter as a template, we developed a structural model of SERT. We performed molecular dynamics simulations to further characterize the allosteric pocket that was identified by site-directed mutagenesis studies and employed this pocket in a virtual screen for small-molecule modulators of SERT function. In functional transport assays, we found that one of the identified molecules, ATM7, increased the reuptake of serotonin, possibly by facilitating the interaction of serotonin with transport-ready conformations of SERT when concentrations of serotonin were low and rate limiting. In addition, ATM7 potentiates 3,4-methylenedioxy-N-methylamphetamine (MDMA, "Ecstasy")-induced reversed transport by SERT. Taking advantage of a conformationally sensitive residue in transmembrane domain 6, we demonstrate that ATM7 mechanistically stabilizes an outward-facing conformation of SERT. Taken together these observations demonstrate that ATM7 acts through a novel mechanism that involves allosteric modulation of SERT function.

  6. Mechanisms That Modulate Peripheral Oxygen Delivery during Exercise in Heart Failure.

    Science.gov (United States)

    Kisaka, Tomohiko; Stringer, William W; Koike, Akira; Agostoni, Piergiuseppe; Wasserman, Karlman

    2017-07-01

    Oxygen uptake ([Formula: see text]o2) measured at the mouth, which is equal to the cardiac output (CO) times the arterial-venous oxygen content difference [C(a-v)O2], increases more than 10- to 20-fold in normal subjects during exercise. To achieve this substantial increase in oxygen uptake [[Formula: see text]o2 = CO × C(a-v)O2] both CO and the arterial-venous difference must simultaneously increase. Although this occurs in normal subjects, patients with heart failure cannot achieve significant increases in cardiac output and must rely primarily on changes in the arterial-venous difference to increase [Formula: see text]o2 during exercise. Inadequate oxygen delivery to the tissue during exercise in heart failure results in tissue anaerobiosis, lactic acid accumulation, and reduction in exercise tolerance. H(+) is an important regulatory and feedback mechanism to facilitate additional oxygen delivery to the tissue (Bohr effect) and further aerobic production of ATP when tissue anaerobic metabolism increases the production of lactate (anaerobic threshold). This H(+) production in the muscle capillary promotes the continued unloading of oxygen (oxyhemoglobin desaturation) while maintaining the muscle capillary Po2 (Fick principle) at a sufficient level to facilitate aerobic metabolism and overcome the diffusion barriers from capillary to mitochondria ("critical capillary Po2," 15-20 mm Hg). This mechanism is especially important during exercise in heart failure where cardiac output increase is severely constrained. Several compensatory mechanisms facilitate peripheral oxygen delivery during exercise in both normal persons and patients with heart failure.

  7. IDO2 Modulates T Cell-Dependent Autoimmune Responses through a B Cell-Intrinsic Mechanism.

    Science.gov (United States)

    Merlo, Lauren M F; DuHadaway, James B; Grabler, Samantha; Prendergast, George C; Muller, Alexander J; Mandik-Nayak, Laura

    2016-06-01

    Mechanistic insight into how adaptive immune responses are modified along the self-nonself continuum may offer more effective opportunities to treat autoimmune disease, cancer, and other sterile inflammatory disorders. Recent genetic studies in the KRN mouse model of rheumatoid arthritis demonstrate that the immunomodulatory molecule IDO2 modifies responses to self-antigens; however, the mechanisms involved are obscure. In this study, we show that IDO2 exerts a critical function in B cells to support the generation of autoimmunity. In experiments with IDO2-deficient mice, adoptive transplant experiments demonstrated that IDO2 expression in B cells was both necessary and sufficient to support robust arthritis development. IDO2 function in B cells was contingent on a cognate, Ag-specific interaction to exert its immunomodulatory effects on arthritis development. We confirmed a similar requirement in an established model of contact hypersensitivity, in which IDO2-expressing B cells are required for a robust inflammatory response. Mechanistic investigations showed that IDO2-deficient B cells lacked the ability to upregulate the costimulatory marker CD40, suggesting IDO2 acts at the T-B cell interface to modulate the potency of T cell help needed to promote autoantibody production. Overall, our findings revealed that IDO2 expression by B cells modulates autoimmune responses by supporting the cross talk between autoreactive T and B cells.

  8. Four types of (super)conformal mechanics: D-module reps and invariant actions

    CERN Document Server

    Holanda, N L

    2014-01-01

    (Super)conformal mechanics in one dimension is induced by parabolic or hyperbolic/trigonometric transformations, either homogeneous (for a scaling dimension $\\lambda$) or inhomogeneous (at $\\lambda=0$, with $\\rho$ an inhomogeneity parameter). Four types of inequivalent (super)conformal actions are thus obtained. With the exclusion of the homogeneous parabolic case, dimensional constants are present. Both the inhomogeneity and the insertion of $\\lambda$ generalize the construction of Papadopoulos [CQG 30 (2013) 075018; arXiv:1210.1719]. Inhomogeneous $D$-module reps are presented for the $d=1$ superconformal algebras $osp(1|2)$, $sl(2|1)$, $B(1,1)$ and $A(1,1)$. For centerless superVirasoro algebras $D$-module reps are presented (in the homogeneous case for ${\\cal N}=1,2,3,4$; in the inhomogeneous case for ${\\cal N}=1,2,3$). The four types of $d=1$ superconformal actions are derived for ${\\cal N}=1,2,4$ systems. When ${\\cal N}=4$, the homogeneously-induced actions are $D(2,1;\\alpha)$-invariant ($\\alpha$ is cri...

  9. Four types of (super)conformal mechanics: D-module reps and invariant actions

    Energy Technology Data Exchange (ETDEWEB)

    Holanda, N.L.; Toppan, F., E-mail: linneu@cbpf.br, E-mail: toppan@cbpf.br

    2014-03-15

    (Super)conformal mechanics in one dimension is induced by parabolic or hyperbolic/trigonometric transformations, either homogeneous (for a scaling dimension λor inhomogeneous (at λ = 0, with ρ an inhomogeneity parameter). Four types of inequivalent (super)conformal actions are thus obtained. With the exclusion of the homogeneous parabolic case, dimensional constants are present. Both the inhomogeneity and the insertion of λ generalize the construction of Papadopoulos [CQG 30 (2013) 075018; arXiv:1210.1719]. Inhomogeneous D-module reps are presented for the d = 1 superconformal algebras osp(1∣2), sl(2∣1), B(1, 1) and A(1, 1). For centerless super Virasoro algebras D-module reps are presented (in the homogeneous case for N = 1; 2; 3; 4; in the inhomogeneous case for N = 1, 2, 3). The four types of d = 1 superconformal actions are derived for N = 1, 2, 4 systems. When N = 4, the homogeneously-induced actions are D(2, 1; α)-invariant (α is critically linked to λ); the inhomogeneously-induced actions are A(1, 1)-invariant. In d = 2, for a single bosonic field, the homogeneous transformations induce a conformally invariant power-law action, while the inhomogeneous transformations induce the conformally invariant Liouville action. (author)

  10. Protein conservation and variation suggest mechanisms of cell type-specific modulation of signaling pathways.

    Directory of Open Access Journals (Sweden)

    Martin H Schaefer

    2014-06-01

    Full Text Available Many proteins and signaling pathways are present in most cell types and tissues and yet perform specialized functions. To elucidate mechanisms by which these ubiquitous pathways are modulated, we overlaid information about cross-cell line protein abundance and variability, and evolutionary conservation onto functional pathway components and topological layers in the pathway hierarchy. We found that the input (receptors and the output (transcription factors layers evolve more rapidly than proteins in the intermediary transmission layer. In contrast, protein expression variability decreases from the input to the output layer. We observed that the differences in protein variability between the input and transmission layer can be attributed to both the network position and the tendency of variable proteins to physically interact with constitutively expressed proteins. Differences in protein expression variability and conservation are also accompanied by the tendency of conserved and constitutively expressed proteins to acquire somatic mutations, while germline mutations tend to occur in cell type-specific proteins. Thus, conserved core proteins in the transmission layer could perform a fundamental role in most cell types and are therefore less tolerant to germline mutations. In summary, we propose that the core signal transmission machinery is largely modulated by a variable input layer through physical protein interactions. We hypothesize that the bow-tie organization of cellular signaling on the level of protein abundance variability contributes to the specificity of the signal response in different cell types.

  11. ERK1-Based Pathway as a New Selective Mechanism To Modulate CCR5 with Natural Antibodies.

    Science.gov (United States)

    Venuti, Assunta; Pastori, Claudia; Siracusano, Gabriel; Riva, Agostino; Sciortino, Maria Teresa; Lopalco, Lucia

    2015-10-01

    Natural human Abs, recognizing an epitope within the first extramembrane loop of CCR5 (the main HIV coreceptor), induce a long-lasting internalization (48 h) of the protein, whereas all known CCR5 modulating molecules show a short-term kinetics (60-90 min). Despite extensive studies on the regulation of CCR5 signaling cascades, which are the effect of concomitant CCR5 internalization by exogenous stimuli such as Abs, downstream signaling continues to be poorly understood. In this article, we report a hitherto unrecognized mechanism of CCR5 modulation mediated by G protein-dependent ERK1 activity. We further demonstrate that ERK1 is localized mainly in the cytoplasmic compartment and that it interacts directly with the CCR5 protein, thus provoking possible CCR5 degradation with a subsequent de novo synthesis, and that re-expression of CCR5 on the cell membrane required several days. In contrast, the RANTES treatment induces a recovery of the receptor on the cell membrane in short-term kinetics without the involvement of de novo protein synthesis. The said new pathway could be relevant not only to better understand the molecular basis of all pathologic conditions in which CCR5 is involved but also to generate new tools to block viral infections, such as the use of recombinant Abs.

  12. Molecular mechanism of epididymal protease inhibitor modulating the liquefaction of human semen

    Institute of Scientific and Technical Information of China (English)

    Zeng-Jun Wang; Wei Zhang; Ning-Han Feng; Ning-Hong Song; Hong-Fei Wu; Yuan-Geng Sui

    2008-01-01

    Aim: To study the molecular mechanism of epididymal protease inhibitor (Eppin) modulating the process of prostate specific antigen (PSA) digesting semenogelin (Sg). Methods: Human Sg cDNA (nucleotides 82-849) and Eppin cDNA (nucleotides 70-423) were generated by polymerase chain reaction (PCR) and cloned into pET-100D/TOPO. Recombinant Eppin and Sg (rEppin and rSg) were produced by BL21 (DE3). The association of Eppin with Sg was studied by far-western immunoblot and radioautography. In vitro the digestion of rSg by PSA in the presence or absence of rEppin was studied. The effect of anti-Q20E (N-terminal) and C-terminal of Eppin on Eppin-Sg binding was monitored. Results: Eppin binds Sg on the surface of human spermatozoa with the C-terminal of Eppin (amino acids 75-133). rSg was digested with PSA and many low molecular weight fragments were produced. When rEppin is bound to rSg, then digested by PSA, incomplete digestion and a 15-kDa fragment results. Antibody binding to the N-terminal of rEppin did not affect rSg digestion. Addition of antibodies to the C-terminal of rEppin inhibited the modulating effect of rEppin. Conclusion: Eppin protects a 15-kDa fragment of rSg from hydrolysis by PSA.

  13. [Myoanabolic steroids and selective androgen receptor modulators: mechanism of action and perspectives].

    Science.gov (United States)

    Tóth, Miklós

    2009-11-01

    Interest in anabolic steroids has been renewed in the last decade with the discovery of tissue-selective androgen receptor modulators exhibiting high myotropic and small androgenic activity. An explanation put forward by us in 1982 for the mechanism of the preferential myotropic effect of nandrolone (19-nortestosterone) exploits the fundamental difference between the 5alpha-reductase concentrations in skeletal muscle and androgenic target tissue. In androgenic tissue, testosterone is converted to the more potent 5alpha-dihydrotestosterone whereas nandrolone is converted to a less potent derivative. As 5alpha-reduction is negligible in skeletal muscle, this explains why nandrolone shows a greater myotropic to androgenic ratio when compared with testosterone. Anabolic steroids that do not undergo 5alpha-reduction exert myotropic-androgenic dissociation because their effect in androgenic tissues is not amplified by 5alpha-reduction. Tissue selectivity by receptor modulators may be achieved by inducing specific conformational changes of the androgen receptor that affect its interaction with transcriptional coregulators. Anabolic activity is mediated by the stimulation of ribosomal RNA synthesis therefore regulation of this synthesis by anabolic steroids would deserve detailed studies.

  14. Prediction of the anti-inflammatory mechanisms of curcumin by module-based protein interaction network analysis

    Directory of Open Access Journals (Sweden)

    Yanxiong Gan

    2015-11-01

    Full Text Available Curcumin, the medically active component from Curcuma longa (Turmeric, is widely used to treat inflammatory diseases. Protein interaction network (PIN analysis was used to predict its mechanisms of molecular action. Targets of curcumin were obtained based on ChEMBL and STITCH databases. Protein–protein interactions (PPIs were extracted from the String database. The PIN of curcumin was constructed by Cytoscape and the function modules identified by gene ontology (GO enrichment analysis based on molecular complex detection (MCODE. A PIN of curcumin with 482 nodes and 1688 interactions was constructed, which has scale-free, small world and modular properties. Based on analysis of these function modules, the mechanism of curcumin is proposed. Two modules were found to be intimately associated with inflammation. With function modules analysis, the anti-inflammatory effects of curcumin were related to SMAD, ERG and mediation by the TLR family. TLR9 may be a potential target of curcumin to treat inflammation.

  15. Mechanical modulation of nascent stem cell lineage commitment in tissue engineering scaffolds.

    Science.gov (United States)

    Song, Min Jae; Dean, David; Knothe Tate, Melissa L

    2013-07-01

    Taking inspiration from tissue morphogenesis in utero, this study tests the concept of using tissue engineering scaffolds as delivery devices to modulate emergent structure-function relationships at early stages of tissue genesis. We report on the use of a combined computational fluid dynamics (CFD) modeling, advanced manufacturing methods, and experimental fluid mechanics (micro-piv and strain mapping) for the prospective design of tissue engineering scaffold geometries that deliver spatially resolved mechanical cues to stem cells seeded within. When subjected to a constant magnitude global flow regime, the local scaffold geometry dictates the magnitudes of mechanical stresses and strains experienced by a given cell, and in a spatially resolved fashion, similar to patterning during morphogenesis. In addition, early markers of mesenchymal stem cell lineage commitment relate significantly to the local mechanical environment of the cell. Finally, by plotting the range of stress-strain states for all data corresponding to nascent cell lineage commitment (95% CI), we begin to "map the mechanome", defining stress-strain states most conducive to targeted cell fates. In sum, we provide a library of reference mechanical cues that can be delivered to cells seeded on tissue engineering scaffolds to guide target tissue phenotypes in a temporally and spatially resolved manner. Knowledge of these effects allows for prospective scaffold design optimization using virtual models prior to prototyping and clinical implementation. Finally, this approach enables the development of next generation scaffolds cum delivery devices for genesis of complex tissues with heterogenous properties, e.g., organs, joints or interface tissues such as growth plates.

  16. Mechanical Modulation of Nascent Stem Cell Lineage Commitment in Tissue Engineering Scaffolds

    Science.gov (United States)

    Song, Min Jae; Dean, David; Tate, Melissa L. Knothe

    2013-01-01

    Taking inspiration from tissue morphogenesis in utero, this study tests the concept of using tissue engineering scaffolds as delivery devices to modulate emergent structure-function relationships at early stages of tissue genesis. We report on the use of a combined computational fluid dynamics (CFD) modeling, advanced manufacturing methods, and experimental fluid mechanics (micro-piv and strain mapping) for the prospective design of tissue engineering scaffold geometries that deliver spatially resolved mechanical cues to cells seeded within. When subjected to a constant magnitude global flow regime, the local scaffold geometry dictates the magnitudes of mechanical stresses and strains experienced by a given cell, and in a spatially resolved fashion, similar to patterning during morphogenesis. In addition, early markers of mesenchymal stem cell lineage commitment relate significantly to the local mechanical environment of the cell. Finally, by plotting the range of stress-strain states for all data corresponding to nascent cell lineage commitment (95% CI), we begin to “map the mechanome”, defining stress-strain states most conducive to targeted cell fates. In sum, we provide a library of reference mechanical cues that can be delivered to cells seeded on tissue engineering scaffolds to guide target tissue phenotypes in a temporally and spatially resolved manner. Knowledge of these effects allows for prospective scaffold design optimization using virtual models prior to prototyping and clinical implementation. Finally, this approach enables the development of next generation scaffolds cum delivery devices for genesis of complex tissues with heterogenous properties, e.g., organs, joints or interface tissues such as growth plates. PMID:23660249

  17. Simulations of Protein Folding

    CERN Document Server

    Cahill, M; Cahill, K E; Cahill, Michael; Fleharty, Mark; Cahill, Kevin

    2000-01-01

    We have developed a simple, phenomenological, Monte-Carlo code that predicts the three-dimensional structure of globular proteins from the DNA sequences that define them. We have applied this code to two small proteins, the villin headpiece (1VII) and cole1 rop (1ROP). Our code folded the 36-residue villin headpiece to a mean rms distance of less than 5 A from its native structure as revealed by NMR; it folded a 56-residue fragment of the protein cole1 rop to within 11 A of its native structure. The denatured starting configurations of these two proteins were, respectively, 29 A and 55 A distant from their native structures.

  18. Modulating light with light via giant nano-opto-mechanical nonlinearity of plasmonic metamaterial

    CERN Document Server

    Ou, Jun-Yu; Zhang, Jianfa; Zheludev, Nikolay I

    2015-01-01

    From the demonstration of saturable absorption by Vavilow and Levshin in 1926, and with invention of the laser, unavailability of strongly nonlinear materials was a key obstacle for developing optical signal processing, in particular in transparent telecommunication networks. Today, most advanced photonic switching materials exploit gain dynamics and near-band and excitonic effects in semiconductors, nonlinearities in organic media with weakly-localized electrons and nonlinearities enhanced by hybridization with metamaterials. Here we report on a new type of artificial nonlinearity that is nano-opto-mechanical in nature. It was observed in an artificial metamaterial array of plasmonic meta-molecules supported by a flexible nano-membrane. Here nonlinearity is underpinned by the reversible reconfiguration of its structure induced by light. In a film of only 100 nanometres thickness we demonstrated modulation of light with light using milliwatt power telecom diode lasers.

  19. Fast Simulation of Mechanical Heterogeneity in the Electrically Asynchronous Heart Using the MultiPatch Module.

    Directory of Open Access Journals (Sweden)

    John Walmsley

    2015-07-01

    Full Text Available Cardiac electrical asynchrony occurs as a result of cardiac pacing or conduction disorders such as left bundle-branch block (LBBB. Electrically asynchronous activation causes myocardial contraction heterogeneity that can be detrimental for cardiac function. Computational models provide a tool for understanding pathological consequences of dyssynchronous contraction. Simulations of mechanical dyssynchrony within the heart are typically performed using the finite element method, whose computational intensity may present an obstacle to clinical deployment of patient-specific models. We present an alternative based on the CircAdapt lumped-parameter model of the heart and circulatory system, called the MultiPatch module. Cardiac walls are subdivided into an arbitrary number of patches of homogeneous tissue. Tissue properties and activation time can differ between patches. All patches within a wall share a common wall tension and curvature. Consequently, spatial location within the wall is not required to calculate deformation in a patch. We test the hypothesis that activation time is more important than tissue location for determining mechanical deformation in asynchronous hearts. We perform simulations representing an experimental study of myocardial deformation induced by ventricular pacing, and a patient with LBBB and heart failure using endocardial recordings of electrical activation, wall volumes, and end-diastolic volumes. Direct comparison between simulated and experimental strain patterns shows both qualitative and quantitative agreement between model fibre strain and experimental circumferential strain in terms of shortening and rebound stretch during ejection. Local myofibre strain in the patient simulation shows qualitative agreement with circumferential strain patterns observed in the patient using tagged MRI. We conclude that the MultiPatch module produces realistic regional deformation patterns in the asynchronous heart and that

  20. Deformation in layered Zechstein-III K-Mg salts with high mechanical contrasts. Core analysis revealing strain concentrations and the development of fracturing and folding into a tectonic mélange.

    Science.gov (United States)

    Raith, Alexander; Urai, Janos L.

    2017-04-01

    In fully developed evaporite cycles, effective viscosity contrasts of up to five orders of magnitude are possible between different layers, but the structures and mechanics in evaporites with such extreme mechanical stratification are not well understood. During the late stage of an evaporation cycle potassium and magnesium (K-Mg) salts are precipitated. These K-Mg salts are of economic interest but also a known drilling hazard due to their very low viscosity. A better understanding of salt tectonics with extreme mechanical stratification is needed for better exploration and production of potassium-magnesium salts and to predict the internal structure of potential nuclear waste repositories in salt We analyzed a unique carnallite (KMgCl3*6H20) - and bischofite (MgCl2*6H20) - rich drill core from the Zechstein III-1b subunit in the Veendam Pillow in the Netherlands, which has a complex tectonic history with multiple phases of extension and compression as shown by seismic reflection data. Salt withdrawal followed by convergent flow into the salt pillow produced ruptures and folds in the underlying ZIII- Anhydrite-Carbonate Stringer and formed the outer shape of the soft ZIII-1b layer. The slabbed core was analyzed by macroscale photography, bulk chemical methods, XRD and optical microscopy. Results show high strain in the weaker bischofite- and carnallite- rich layers, with associated dynamic recrystallization at very low differential stress, completely overprinting the original texture. Stronger layers formed by alternating beds of halite and carnallite show complex recumbent folding on different scales commonly interrupted by sub-horizontal shear zones with brittle deformation, veins and boudinage. We attribute this tectonic fragmentation to be associated with a softening of the complete ZIII-1b subunit during its deformation. The result is a tectonic mélange with cm - to 10m size blocks with internal folds and boudinage. We infer that these structures and

  1. Investigating the molecular mechanism of positive and negative allosteric modulators in the calcium-sensing receptor dimer

    DEFF Research Database (Denmark)

    Jacobsen, Stine Engesgaard; Gether, Ulrik; Bräuner-Osborne, Hans

    2017-01-01

    Allosteric modulators that are targeting the calcium-sensing receptor (CaSR) hold great therapeutic potential, and elucidating the molecular basis for modulation would thus benefit the development of novel therapeutics. In the present study, we aimed at investigating the mechanism of allosteric...... one of these mutants was potentiated by a positive allosteric modulator, we showed that receptor activity was further potentiated in a trans-activation heterodimer containing a single allosteric site, however only when the allosteric site was located in the subunit responsible for G protein coupling...

  2. Structural studies on flavin reductase PheA2 reveal binding of NAD in an unusual folded conformation and support novel mechanism of action

    NARCIS (Netherlands)

    Heuvel, van den R.H.H.; Westphal, A.H.; Heck, A.J.R.; Walsh, M.A.; Rovida, S.; Berkel, van W.J.H.; Mattevi, A.

    2004-01-01

    The catabolism of toxic phenols in the thermophilic organism Bacillus thermoglucosidasius A7 is initiated by a two-component enzyme system. The smaller flavin reductase PheA2 component catalyzes the NADH-dependent reduction of free FAD according to a ping-pong bisubstrate-biproduct mechanism. The

  3. Folding worlds between pages

    CERN Multimedia

    Meier, Matthias

    2010-01-01

    "We all remember pop-up books form our childhood. As fascinated as we were back then, we probably never imagined how much engineering know-how went into these books. Pop-up engineer Anton Radevsky has even managed to fold a 27-kilometre particle accelerator into a book" (4 pages)

  4. Folds and Etudes

    Science.gov (United States)

    Bean, Robert

    2007-01-01

    In this article, the author talks about "Folds" and "Etudes" which are images derived from anonymous typing exercises that he found in a used copy of "Touch Typing Made Simple". "Etudes" refers to the musical tradition of studies for a solo instrument, which is a typewriter. Typing exercises are repetitive attempts to type words and phrases…

  5. ProbFold

    DEFF Research Database (Denmark)

    Sahoo, Sudhakar; Świtnicki, Michał P; Pedersen, Jakob Skou

    2016-01-01

    ) with probabilistic graphical models. This approach allows rapid adaptation and integration of new probing data types. AVAILABILITY AND IMPLEMENTATION: ProbFold is implemented in C ++. Models are specified using simple textual formats. Data reformatting is done using separate C ++ programs. Source code, statically...

  6. Structure Characterization of the Folding Intermediates of Proteins

    Institute of Scientific and Technical Information of China (English)

    1999-01-01

    Although the native state and the fully unfolded state of proteins have been extensively studied, the folding pathway and intermediates in the protein folding process have not been thoroughly investigated.To understand the mechanisms of protein folding, the early intermediates in the protein folding process must be clearly characterized.The present paper is a mini review containing 20 references involving studies on folding intermediates of several proteins.

  7. Rhythms and blues: modulation of oscillatory synchrony and the mechanism of action of antidepressant treatments.

    Science.gov (United States)

    Leuchter, Andrew F; Hunter, Aimee M; Krantz, David E; Cook, Ian A

    2015-05-01

    Treatments for major depressive disorder (MDD) act at different hierarchical levels of biological complexity, ranging from the individual synapse to the brain as a whole. Theories of antidepressant medication action traditionally have focused on the level of cell-to-cell interaction and synaptic neurotransmission. However, recent evidence suggests that modulation of synchronized electrical activity in neuronal networks is a common effect of antidepressant treatments, including not only medications, but also neuromodulatory treatments such as repetitive transcranial magnetic stimulation. Synchronization of oscillatory network activity in particular frequency bands has been proposed to underlie neurodevelopmental and learning processes, and also may be important in the mechanism of action of antidepressant treatments. Here, we review current research on the relationship between neuroplasticity and oscillatory synchrony, which suggests that oscillatory synchrony may help mediate neuroplastic changes related to neurodevelopment, learning, and memory, as well as medication and neuromodulatory treatment for MDD. We hypothesize that medication and neuromodulation treatments may have related effects on the rate and pattern of neuronal firing, and that these effects underlie antidepressant efficacy. Elucidating the mechanisms through which oscillatory synchrony may be related to neuroplasticity could lead to enhanced treatment strategies for MDD.

  8. Rhythms and blues: modulation of oscillatory synchrony and the mechanism of action of antidepressant treatments

    Science.gov (United States)

    Leuchter, Andrew F.; Hunter, Aimee M.; Krantz, David E.; Cook, Ian A.

    2015-01-01

    Treatments for major depressive disorder (MDD) act at different hierarchical levels of biological complexity, ranging from the individual synapse to the brain as a whole. Theories of antidepressant medication action traditionally have focused on the level of cell-to-cell interaction and synaptic neurotransmission. However, recent evidence suggests that modulation of synchronized electrical activity in neuronal networks is a common effect of antidepressant treatments, including not only medications, but also neuromodulatory treatments such as repetitive transcranial magnetic stimulation. Synchronization of oscillatory network activity in particular frequency bands has been proposed to underlie neurodevelopmental and learning processes, and also may be important in the mechanism of action of antidepressant treatments. Here, we review current research on the relationship between neuroplasticity and oscillatory synchrony, which suggests that oscillatory synchrony may help mediate neuroplastic changes related to neurodevelopment, learning, and memory, as well as medication and neuromodulatory treatment for MDD. We hypothesize that medication and neuromodulation treatments may have related effects on the rate and pattern of neuronal firing, and that these effects underlie antidepressant efficacy. Elucidating the mechanisms through which oscillatory synchrony may be related to neuroplasticity could lead to enhanced treatment strategies for MDD. PMID:25809789

  9. Influence of modulation period and modulation ratio on structure and mechanical properties of TiBN/CrN coatings deposited by multi-arc ion plating

    Energy Technology Data Exchange (ETDEWEB)

    Zhou, S.Y.; Yan, S.J.; Han, B. [Key Laboratory of Artificial Micro- and Nano-Materials of Ministry of Education and School of Physics and Technology, Wuhan University, 430072 Wuhan (China); Yang, B. [School of Power and Mechanical Engineering, Wuhan University, 430072 Wuhan (China); Lin, B.Z.; Zhang, Z.D.; Ai, Z.W. [Key Laboratory of Artificial Micro- and Nano-Materials of Ministry of Education and School of Physics and Technology, Wuhan University, 430072 Wuhan (China); Pelenovich, V.O. [Key Laboratory of Artificial Micro- and Nano-Materials of Ministry of Education and School of Physics and Technology, Wuhan University, 430072 Wuhan (China); Institute of Ion-Plasma and Laser Technologies, Academy of Sciences of Uzbekistan, 700135 Tashkent (Uzbekistan); Fu, D.J., E-mail: djfu@whu.edu.cn [Key Laboratory of Artificial Micro- and Nano-Materials of Ministry of Education and School of Physics and Technology, Wuhan University, 430072 Wuhan (China)

    2015-10-01

    Highlights: • TiBN/CrN multilayers were synthesized with varied modulation period and ratio. • The maximum hardness of 38.6 GPa is observed at Λ = 11.7 nm and R = 5:1. • The lowest multilayer COF of 0.32 is lower than that of CrN (0.56). • The wear rate of the coatings is improved and related to H/E and H{sup 3}/E{sup *2} ratios. - Abstract: TiBN/CrN multilayered superlattice coatings with modulation periods Λ (bilayer thickness) ranging from 22.5 to 4.2 nm and modulation ratio R (the thickness ratio of CrN and TiBN layers) ranging from 6:1 to 3:1 were synthesized using an industrial-scale cathodic arc ion plating system in an Ar–N{sub 2} gas mixture. X-ray diffraction (XRD), transmission electron microscopy (TEM) and nanoindention were employed to investigate the influence of modulation period and ratio on microstructure and mechanical properties of the multilayers. The sharp interfaces and nanoscale multilayered modulation were confirmed by TEM. TiBN/CrN multilayer coatings were crystallized with orientations at the (1 1 1), (2 0 0) and (2 2 0) crystallographic planes and the microstructure was strengthened at (2 0 0) preferred orientation. The maximum hardness of 38.6 GPa and elastic modulus of 477 GPa were obtained at Λ = 11.7 nm and R = 5:1. The lowest value of the friction coefficient at 0.32 sliding against a WC-Co ball was obtained at a bilayer period of 11.7 nm, compared to those of the coatings with other modulation periods and monolithic coatings. The wear rate of the multilayered coatings was also lower than those of the monolithic CrN and TiBN coatings.

  10. Mechanism of action and effect of immune-modulating agents in the treatment of psoriasis.

    Science.gov (United States)

    El-Gharabawy, Rehab M; Ahmed, Amira S; Al-Najjar, Amal H

    2017-01-01

    The aim of this work is to study the possible mechanisms through which different immune-modulating agents can produce their beneficial effects on treatment of psoriasis and to determine whether the supplementation of these agents for psoriasis patients induces regression of psoriasis. One hundred fifty participants were included in this study. The participants were divided into five groups: 1. Normal control group, 2. Psoriasis patients not taking any treatment, 3. Psoriasis patients treated with anti-psoriatic treatment (including coal tar, vitamin D3 analogues and corticosteroids). 4. Psoriasis patients treated with anti-psoriatic treatment and oral metformin (850mg twice daily) and 5. Psoriasis patients treated with anti-psoriatic treatment and oral pioglitazone (15mg once a day). Demographic characteristics, diabetic index, lipid profile and liver function tests were monitored. The CD4+ Tcells, CD8+ Tcells, CD4+/CD8+ ratio, interleukin-2 (IL-2), C-reactive protein (CRP) and ceruloplasmin (CP) were assayed. After treatment of psoriasis patients with a traditional anti-psoriatic drug in combination with metformin and peroxisome proliferator-activated receptor gamma (PPARɤ) agonist (pioglitazone), the CD4+ T cells, IL-2, CRP, CP, ALT and AST levels were statistically significantly decreased compared to psoriasis patients without treatment. Positive and significant correlations between CD4+ % and IL-2, CRP, CP, ALT and AST in psoriasis patients were recorded. The activation of PPAR-γ receptors by pioglitazone results in reduced formation of the proinflammatory cytokines and infiltration by inflammatory cells. Additionally, metformin acts as a modulator of the immune system in psoriasis patients and has a remarkable effect on the early stages of psoriasis. Therefore, either pioglitazone or metformin in combination with traditional anti-psoriatic drugs provides better results in the treatment of psoriasis than does each alone. Copyright © 2016 Elsevier Masson SAS

  11. Modulation of noradrenaline release in rat isolated stomach by prostanoids, but not by histaminergic mechanisms.

    Science.gov (United States)

    Racké, K; Berrino, L; Möhlig, A; Jäger, R; Griepenkerl, I; Bräutigam, M; Reimann, A

    1995-12-01

    Several gastric functions are modulated by the sympathetic nervous system, but local mechanisms involved in the control of noradrenaline release are largely unknown. Overflow of endogenous noradrenaline was studied from isolated rat stomach incubated in Ussing chambers allowing the separate determination of mucosal and serosal overflow. Spontaneous noradrenaline overflow was similar at the mucosal and serosal side, but electrical field stimulation caused a frequency-dependent increase in noradrenaline overflow selectively at the serosal side. Evoked noradrenaline overflow was blocked by tetrodotoxin, not affected by indometacin and markedly enhanced (by about 250%) by yohimbine. In the presence of indometacin and yohimbine, sulprostone (an agonist at EP1/EP3 receptors) and misoprostol (an agonist at EP2/EP3 receptors) reduced the noradrenaline overflow evoked by stimulation at 3 Hz maximally by about 80% (EC50: 6 nmol/l and 11 nmol/l, respectively). The EP1 receptor selective antagonist AH 6809 (6-isopropoxy-9-oxoxanthene-2-carboxylic acid) did not antagonize the inhibition by sulprostone. Noradrenaline overflow evoked by stimulation at 1 Hz and 3 Hz was increased by scopolamine by about 50% and almost completely inhibited by oxotremorine. Neither, histamine nor the H3 receptor selective agonist (R)-alpha-methyl-histamine, nor the H1, H2 and H3 selective receptor antagonists mepyramine, cimetidine and thioperamide significantly affected noradrenaline overflow evoked by stimulation at 1 Hz or 3 Hz. In conclusion, impulse-induced noradrenaline release in the rat stomach is controlled by multiple presynaptic mechanisms involving alpha 2-adrenergic autoreceptors, EP3 prostanoid and muscarine heteroreceptors, whereas histaminergic mechanisms do not appear to be significant.

  12. Deep brain stimulation mechanisms: the control of network activity via neurochemistry modulation.

    Science.gov (United States)

    McIntyre, Cameron C; Anderson, Ross W

    2016-10-01

    Deep brain stimulation (DBS) has revolutionized the clinical care of late-stage Parkinson's disease and shows promise for improving the treatment of intractable neuropsychiatric disorders. However, after over 25 years of clinical experience, numerous questions still remain on the neurophysiological basis for the therapeutic mechanisms of action. At their fundamental core, the general purpose of electrical stimulation therapies in the nervous system are to use the applied electric field to manipulate the opening and closing of voltage-gated sodium channels on neurons, generate stimulation induced action potentials, and subsequently, control the release of neurotransmitters in targeted pathways. Historically, DBS mechanisms research has focused on characterizing the effects of stimulation on neurons and the resulting impact on neuronal network activity. However, when electrodes are placed within the central nervous system, glia are also being directly (and indirectly) influenced by the stimulation. Mounting evidence shows that non-neuronal tissue can play an important role in modulating the neurochemistry changes induced by DBS. The goal of this review is to evaluate how DBS effects on both neuronal and non-neuronal tissue can potentially work together to suppress oscillatory activity (and/or information transfer) between brain regions. These resulting effects of ~ 100 Hz electrical stimulation help explain how DBS can disrupt pathological network activity in the brain and generate therapeutic effects in patients. Deep brain stimulation is an effective clinical technology, but detailed therapeutic mechanisms remain undefined. This review provides an overview of the leading hypotheses, which focus on stimulation-induced disruption of network oscillations and integrates possible roles for non-neuronal tissue in explaining the clinical response to therapeutic stimulation. This article is part of a special issue on Parkinson disease.

  13. Ab initio RNA folding.

    Science.gov (United States)

    Cragnolini, Tristan; Derreumaux, Philippe; Pasquali, Samuela

    2015-06-17

    RNA molecules are essential cellular machines performing a wide variety of functions for which a specific three-dimensional structure is required. Over the last several years, the experimental determination of RNA structures through x-ray crystallography and NMR seems to have reached a plateau in the number of structures resolved each year, but as more and more RNA sequences are being discovered, the need for structure prediction tools to complement experimental data is strong. Theoretical approaches to RNA folding have been developed since the late nineties, when the first algorithms for secondary structure prediction appeared. Over the last 10 years a number of prediction methods for 3D structures have been developed, first based on bioinformatics and data-mining, and more recently based on a coarse-grained physical representation of the systems. In this review we are going to present the challenges of RNA structure prediction and the main ideas behind bioinformatic approaches and physics-based approaches. We will focus on the description of the more recent physics-based phenomenological models and on how they are built to include the specificity of the interactions of RNA bases, whose role is critical in folding. Through examples from different models, we will point out the strengths of physics-based approaches, which are able not only to predict equilibrium structures, but also to investigate dynamical and thermodynamical behavior, and the open challenges to include more key interactions ruling RNA folding.

  14. Immunoregulatory mechanisms in Chagas disease: modulation of apoptosis in T-cell mediated immune responses.

    Science.gov (United States)

    Chaves, Ana Thereza; de Assis Silva Gomes Estanislau, Juliana; Fiuza, Jacqueline Araújo; Carvalho, Andréa Teixeira; Ferreira, Karine Silvestre; Fares, Rafaelle Christine Gomes; Guimarães, Pedro Henrique Gazzinelli; de Souza Fagundes, Elaine Maria; Morato, Maria José; Fujiwara, Ricardo Toshio; da Costa Rocha, Manoel Otávio; Correa-Oliveira, Rodrigo

    2016-04-30

    after in vitro stimulation. Interestingly, the in vitro TcAg stimulation increased considerably the expression of cell death TNF/TNFR superfamily and Caspase family receptors genes in CARD patients. Taken together, our results suggest that apoptosis may be an important mechanism for the control of morbidity in T. cruzi infection by modulating the expression of apoptosis genes, the cytokine environment and/or killing of effector cells.

  15. Quantification of a Helical Origami Fold

    Science.gov (United States)

    Dai, Eric; Han, Xiaomin; Chen, Zi

    2015-03-01

    Origami, the Japanese art of paper folding, is traditionally viewed as an amusing pastime and medium of artistic expression. However, in recent years, origami has served as a source of inspiration for innovations in science and engineering. Here, we present the geometric and mechanical properties of a twisting origami fold. The origami structure created by the fold exhibits several interesting properties, including rigid foldibility, local bistability and finely tunable helical coiling, with control over pitch, radius and handedness of the helix. In addition, the pattern generated by the fold closely mimics the twist buckling patterns shown by thin materials, for example, a mobius strip. We use six parameters of the twisting origami pattern to generate a fully tunable graphical model of the fold. Finally, we present a mathematical model of the local bistability of the twisting origami fold. Our study elucidates the mechanisms behind the helical coiling and local bistability of the twisting origami fold, with potential applications in robotics and deployable structures. Acknowledgment to Branco Weiss Fellowship for funding.

  16. Recursive expectation-maximization clustering: A method for identifying buffering mechanisms composed of phenomic modules

    Science.gov (United States)

    Guo, Jingyu; Tian, Dehua; McKinney, Brett A.; Hartman, John L.

    2010-06-01

    Interactions between genetic and/or environmental factors are ubiquitous, affecting the phenotypes of organisms in complex ways. Knowledge about such interactions is becoming rate-limiting for our understanding of human disease and other biological phenomena. Phenomics refers to the integrative analysis of how all genes contribute to phenotype variation, entailing genome and organism level information. A systems biology view of gene interactions is critical for phenomics. Unfortunately the problem is intractable in humans; however, it can be addressed in simpler genetic model systems. Our research group has focused on the concept of genetic buffering of phenotypic variation, in studies employing the single-cell eukaryotic organism, S. cerevisiae. We have developed a methodology, quantitative high throughput cellular phenotyping (Q-HTCP), for high-resolution measurements of gene-gene and gene-environment interactions on a genome-wide scale. Q-HTCP is being applied to the complete set of S. cerevisiae gene deletion strains, a unique resource for systematically mapping gene interactions. Genetic buffering is the idea that comprehensive and quantitative knowledge about how genes interact with respect to phenotypes will lead to an appreciation of how genes and pathways are functionally connected at a systems level to maintain homeostasis. However, extracting biologically useful information from Q-HTCP data is challenging, due to the multidimensional and nonlinear nature of gene interactions, together with a relative lack of prior biological information. Here we describe a new approach for mining quantitative genetic interaction data called recursive expectation-maximization clustering (REMc). We developed REMc to help discover phenomic modules, defined as sets of genes with similar patterns of interaction across a series of genetic or environmental perturbations. Such modules are reflective of buffering mechanisms, i.e., genes that play a related role in the maintenance

  17. Mechanism for modulation of gating of connexin26-containing channels by taurine

    Science.gov (United States)

    Kieken, Fabien; Tao, Liang; Sorgen, Paul L.; Harris, Andrew L.

    2011-01-01

    The mechanisms of action of endogenous modulatory ligands of connexin channels are largely unknown. Previous work showed that protonated aminosulfonates (AS), notably taurine, directly and reversibly inhibit homomeric and heteromeric channels that contain Cx26, a widely distributed connexin, but not homomeric Cx32 channels. The present study investigated the molecular mechanisms of connexin channel modulation by taurine, using hemichannels and junctional channels composed of Cx26 (homomeric) and Cx26/Cx32 (heteromeric). The addition of a 28–amino acid “tag” to the carboxyl-terminal domain (CT) of Cx26 (Cx26T) eliminated taurine sensitivity of homomeric and heteromeric hemichannels in cells and liposomes. Cleavage of all but four residues of the tag (Cx26Tc) resulted in taurine-induced pore narrowing in homomeric hemichannels, and restored taurine inhibition of heteromeric hemichannels (Cx26Tc/Cx32). Taurine actions on junctional channels were fully consistent with those on hemichannels. Taurine-induced inhibition of Cx26/Cx32T and nontagged Cx26 junctional channels was blocked by extracellular HEPES, a blocker of the taurine transporter, confirming that the taurine-sensitive site of Cx26 is cytoplasmic. Nuclear magnetic resonance of peptides corresponding to Cx26 cytoplasmic domains showed that taurine binds to the cytoplasmic loop (CL) and not the CT, and that the CT and CL directly interact. ELISA showed that taurine disrupts a pH-dependent interaction between the CT and the CT-proximal half of the CL. These studies reveal that AS disrupt a pH-driven cytoplasmic interdomain interaction in Cx26-containing channels, causing closure, and that the Cx26CT has a modulatory role in Cx26 function. PMID:21844220

  18. Selective estrogen receptor modulators (SERMs): Mechanisms of anticarcinogenesis and drug resistance

    Energy Technology Data Exchange (ETDEWEB)

    Lewis, Joan S. [Fox Chase Cancer Center, Alfred G. Knudson Chair of Cancer Research, 333 Cottman Avenue, Philadelphia, PA 19111 (United States); Jordan, V. Craig [Fox Chase Cancer Center, Alfred G. Knudson Chair of Cancer Research, 333 Cottman Avenue, Philadelphia, PA 19111 (United States)]. E-mail: v.craig.jordan@fccc.edu

    2005-12-11

    Despite the beneficial effects of estrogens in women's health, there is a plethora of evidence that suggest an important role for these hormones, particularly 17{beta}-estradiol (E{sub 2}), in the development and progression of breast cancer. Most estrogenic responses are mediated by estrogen receptors (ERs), either ER{alpha} or ER{beta}, which are members of the nuclear receptor superfamily of ligand-dependent transcription factors. Selective estrogen receptor modulators (SERMs) are ER ligands that in some tissues (i.e. bone and cardiovascular system) act like estrogens but block estrogen action in others. Tamoxifen is the first SERM that has been successfully tested for the prevention of breast cancer in high-risk women and is currently approved for the endocrine treatment of all stages of ER-positive breast cancer. Raloxifene, a newer SERM originally developed for osteoporosis, also appears to have preventive effect on breast cancer incidence. Numerous studies have examined the molecular mechanisms for the tissue selective action of SERMs, and collectively they indicate that different ER ligands induce distinct conformational changes in the receptor that influence its ability to interact with coregulatory proteins (i.e. coactivators and corepressors) critical for the regulation of target gene transcription. The relative expression of coactivators and corepressors, and the nature of the ER and its target gene promoter also affect SERM biocharacter. This review summarizes the therapeutic application of SERMs in medicine; particularly breast cancer, and highlights the emerging understanding of the mechanism of action of SERMs in select target tissues, and the inevitable development of resistance.

  19. FOXO3 modulates endothelial gene expression and function by classical and alternative mechanisms.

    Science.gov (United States)

    Czymai, Tobias; Viemann, Dorothee; Sticht, Carsten; Molema, Grietje; Goebeler, Matthias; Schmidt, Marc

    2010-04-02

    FOXO transcription factors represent targets of the phosphatidylinositol 3-kinase/protein kinase B survival pathway controlling important biological processes, such as cell cycle progression, apoptosis, vascular remodeling, stress responses, and metabolism. Recent studies suggested the existence of alternative mechanisms of FOXO-dependent gene expression beyond classical binding to a FOXO-responsive DNA-binding element (FRE). Here we analyzed the relative contribution of those mechanisms to vascular function by comparing the transcriptional and cellular responses to conditional activation of FOXO3 and a corresponding FRE-binding mutant in human primary endothelial cells. We demonstrate that FOXO3 controls expression of vascular remodeling genes in an FRE-dependent manner. In contrast, FOXO3-induced cell cycle arrest and apoptosis occurs independently of FRE binding, albeit FRE-dependent gene expression augments the proapoptotic response. These findings are supported by bioinformatical analysis, which revealed a statistical overrepresentation of cell cycle regulators and apoptosis-related genes in the group of co-regulated genes. Molecular analysis of FOXO3-induced endothelial apoptosis excluded modulators of the extrinsic death receptor pathway and demonstrated important roles for the BCL-2 family members BIM and NOXA in this process. Although NOXA essentially contributed to FRE-dependent apoptosis, BIM was effectively induced in the absence of FRE-binding, and small interfering RNA-mediated BIM depletion could rescue apoptosis induced by both FOXO3 mutants. These data suggest BIM as a critical cell type-specific mediator of FOXO3-induced endothelial apoptosis, whereas NOXA functions as an amplifying factor. Our study provides the first comprehensive analysis of alternatively regulated FOXO3 targets in relevant primary cells and underscores the importance of such genes for endothelial function and integrity.

  20. Genetic Algorithm for the Design of Electro-Mechanical Sigma Delta Modulator MEMS Sensors

    Directory of Open Access Journals (Sweden)

    Michael Kraft

    2011-09-01

    Full Text Available This paper describes a novel design methodology using non-linear models for complex closed loop electro-mechanical sigma-delta modulators (EMΣΔM that is based on genetic algorithms and statistical variation analysis. The proposed methodology is capable of quickly and efficiently designing high performance, high order, closed loop, near-optimal systems that are robust to sensor fabrication tolerances and electronic component variation. The use of full non-linear system models allows significant higher order non-ideal effects to be taken into account, improving accuracy and confidence in the results. To demonstrate the effectiveness of the approach, two design examples are presented including a 5th order low-pass EMΣΔM for a MEMS accelerometer, and a 6th order band-pass EMΣΔM for the sense mode of a MEMS gyroscope. Each example was designed using the system in less than one day, with very little manual intervention. The strength of the approach is verified by SNR performances of 109.2 dB and 92.4 dB for the low-pass and band-pass system respectively, coupled with excellent immunities to fabrication tolerances and parameter mismatch.

  1. Studies on Chemistry and Immuno-modulating Mechanism of a Glycoconjugate from Lycium barbarum L.

    Institute of Scientific and Technical Information of China (English)

    PENG,Xue-Mei(彭雪梅); HUANG,Lin-Juan(黄琳娟); QI,Chun-Hui(齐春会); ZHANG,Yong-Xiang(张永详); TIAN,Geng-Yuan(田庚元)

    2001-01-01

    The detailed structure of an O-glycan derived from the fruitof Lyciun barbariun L.was elucidated based on glycosidiclinkage analysis,comnplete and partial acid hydrolysis,1H-NMR amd 13C NMR spectroscopy.According to the experi-ments,the carbohydrate was in the form of polysacchride(arabinogalactan) chains with highly branched 3,4-galactans and terminal arabinofuranosyl substituents.``The irmmmo-modulating mechanism of glycoconjugate ami its glycan were investigated using tritium thymidine lucor-poration assay,flow cytometry assay and electrophoreticalmobility shift assay (EMSA).The results suggested that theimmunoncfive components of the fruit of Lycium barbarum L.could enlance the splenocyte proliferation in normal mice andthe effects of glycan chain were stronger than those of glyco-conjugate.The target cell was most likely to be B-lympho-cyte,on which existed receptor binding site acting with theglycan.In addition,the immuno-stimulatory effect of glyco-conjugate (LbGp4) amd its glycan (LbGp4-OL) was associat ed with activating the expression of nuclear factor kB (NF-kB) and activator protein 1 (AP-l).``

  2. Antioxidants from black and green tea: from dietary modulation of oxidative stress to pharmacological mechanisms.

    Science.gov (United States)

    Peluso, Ilaria; Serafini, Mauro

    2016-10-16

    The consumption of tea (Camellia sinensis) has been correlated with a low incidence of chronic pathologies, such as cardiovascular disease and cancer, in which oxidative stress plays a critical role. Tea catechins and theaflavins are, respectively, the bioactive phytochemicals responsible for the antioxidant activity of green tea (GT) and black tea (BT). In addition to their redox properties, tea catechins and theaflavins could have also pharmacological activities, such as the ability to lower glucose, lipid and uric acid (UA) levels. These activities are mediated by pharmacological mechanisms such as enzymatic inhibition and interaction with transporters. Epigallocatechin gallate is the most active compound at inhibiting the enzymes involved in cholesterol and UA metabolism (hydroxy-3-methyl-glutaryl-CoA reductase and xanthine oxidase respectively) and affecting glucose transporters. The structural features of catechins that significantly contribute to their pharmacological effect are the presence/absence of the galloyl moiety and the number and positions of the hydroxyl groups on the rings. Although the inhibitory effects on α-glucosidase, maltase, amylase and lipase, multidrug resistance 1, organic anion transporters and proton-coupled folate transport occur at higher concentrations than those apparent in the circulation, these effects could be relevant in the gut. In conclusion, despite the urgent need for further research in humans, the regular consumption of moderate quantities of GT and BT can effectively modulate their antioxidant capacity, mainly in people subjected to oxidative stress, and could improve the metabolism of glucose, lipid and UA.

  3. Nonlinear instability in flagellar dynamics: a novel modulation mechanism in sperm migration?

    KAUST Repository

    Gadelha, H.

    2010-05-12

    Throughout biology, cells and organisms use flagella and cilia to propel fluid and achieve motility. The beating of these organelles, and the corresponding ability to sense, respond to and modulate this beat is central to many processes in health and disease. While the mechanics of flagellum-fluid interaction has been the subject of extensive mathematical studies, these models have been restricted to being geometrically linear or weakly nonlinear, despite the high curvatures observed physiologically. We study the effect of geometrical nonlinearity, focusing on the spermatozoon flagellum. For a wide range of physiologically relevant parameters, the nonlinear model predicts that flagellar compression by the internal forces initiates an effective buckling behaviour, leading to a symmetry-breaking bifurcation that causes profound and complicated changes in the waveform and swimming trajectory, as well as the breakdown of the linear theory. The emergent waveform also induces curved swimming in an otherwise symmetric system, with the swimming trajectory being sensitive to head shape-no signalling or asymmetric forces are required. We conclude that nonlinear models are essential in understanding the flagellar waveform in migratory human sperm; these models will also be invaluable in understanding motile flagella and cilia in other systems.

  4. Anticipatory modulation of neck muscle reflex responses induced by mechanical perturbations of the human forehead.

    Science.gov (United States)

    Kuramochi, Rieko; Kimura, Toshitaka; Nakazawa, Kimitaka; Akai, Masami; Torii, Suguru; Suzuki, Shuji

    2004-08-12

    The aim of this study was to test whether anticipation of upcoming head blow stimuli, which elicit reflex responses in the neck muscle, makes the reflex responses greater or not. In nine healthy subjects the reflex responses were elicited in the sternocleidomastoid (SCM) muscle in the eyes-open (EO) and eyes-closed (EC) conditions, which corresponded to the predictable and unpredictable conditions, respectively. The subjects were instructed not to resist the perturbations after the impact. The results demonstrated that the reflex response of the SCM muscle was significantly smaller in the predictable EO condition than in the unpredictable EC condition (P component, which most probably mediated the stretch reflex pathway. In contrast, no significant difference was observed in the early component, which was presumed to be the vestibular-collic reflex. The reduced stretch reflex response was suggested to be functionally relevant to the task requirement, i.e., to let the neck extension movement occur, and not to resist after the impact of the head blow. It was concluded that the anticipation has an effect on reducing the stretch reflex responses in the neck muscle, but does not have any effect on the presumed vestibular-collic reflex under the present experimental paradigm. It is suggested that the gain of the stretch reflex pathway is modulated by anticipatory information of upcoming mechanical event.

  5. Gene expression modulation and the molecular mechanisms involved in Nelfinavir resistance in Leishmania donovani axenic amastigotes.

    Science.gov (United States)

    Kumar, Pranav; Lodge, Robert; Raymond, Frédéric; Ritt, Jean-François; Jalaguier, Pascal; Corbeil, Jacques; Ouellette, Marc; Tremblay, Michel J

    2013-08-01

    Drug resistance is a major public health challenge in leishmaniasis chemotherapy, particularly in the case of emerging Leishmania/HIV-1 co-infections. We have delineated the mechanism of cell death induced by the HIV-1 protease inhibitor, Nelfinavir, in the Leishmania parasite. In order to further study Nelfinavir-Leishmania interactions, we selected Nelfinavir-resistant axenic amastigotes in vitro and characterized them. RNA expression profiling analyses and comparative genomic hybridizations of closely related Leishmania species were used as a screening tool to compare Nelfinavir-resistant and -sensitive parasites in order to identify candidate genes involved in drug resistance. Microarray analyses of Nelfinavir-resistant and -sensitive Leishmania amastigotes suggest that parasites regulate mRNA levels either by modulating gene copy numbers through chromosome aneuploidy, or gene deletion/duplication by homologous recombination. Interestingly, supernumerary chromosomes 6 and 11 in the resistant parasites lead to upregulation of the ABC class of transporters. Transporter assays using radiolabelled Nelfinavir suggest a greater drug accumulation in the resistant parasites and in a time-dependent manner. Furthermore, high-resolution electron microscopy and measurements of intracellular polyphosphate levels showed an increased number of cytoplasmic vesicular compartments known as acidocalcisomes in Nelfinavir-resistant parasites. Together these results suggest that Nelfinavir is rapidly and dramatically sequestered in drug-induced intracellular vesicles.

  6. Noradrenergic mechanism involved in the nociceptive modulation of hippocampal CA3 region of normal rats.

    Science.gov (United States)

    Jin, Hua; Teng, Yueqiu; Zhang, Xuexin; Yang, Chunxiao; Xu, Manying; Yang, Lizhuang

    2014-06-27

    Norepinephrine (NE) is an important neurotransmitter in the brain, and regulates antinociception. However, the mechanism of action of NE on pain-related neurons in the hippocampal CA3 region is not clear. This study examines the effects of NE, phentolamine on the electrical activities of pain-excited neurons (PENs) and pain-inhibited neurons (PINs) in the hippocampal CA3 region of rats. Trains of electric impulses applied to the right sciatic nerve were used as noxious stimulation. The electrical activities of PENs or PINs in the hippocampal CA3 region were recorded by using a glass microelectrode. Our results revealed that, in the hippocampal CA3 region, the intra-CA3 region microinjection of NE decreased the pain-evoked discharged frequency and prolonged the discharged latency of PEN, and increased the pain-evoked discharged frequency and shortened discharged inhibitory duration (ID) of PIN, exhibiting the specific analgesic effect of NE. While intra-CA3 region microinjection of phentolamine produced the opposite response. It implies that phentolamine can block the effect of endogenous NE to cause the enhanced response of PEN and PIN to noxious stimulation. On the basis of above findings we can deduce that NE, phentolamine and alpha-adrenoceptor are involved in the modulation of nociceptive information transmission in the hippocampal CA3 region.

  7. Genetic algorithm for the design of electro-mechanical sigma delta modulator MEMS sensors.

    Science.gov (United States)

    Wilcock, Reuben; Kraft, Michael

    2011-01-01

    This paper describes a novel design methodology using non-linear models for complex closed loop electro-mechanical sigma-delta modulators (EMΣΔM) that is based on genetic algorithms and statistical variation analysis. The proposed methodology is capable of quickly and efficiently designing high performance, high order, closed loop, near-optimal systems that are robust to sensor fabrication tolerances and electronic component variation. The use of full non-linear system models allows significant higher order non-ideal effects to be taken into account, improving accuracy and confidence in the results. To demonstrate the effectiveness of the approach, two design examples are presented including a 5th order low-pass EMΣΔM for a MEMS accelerometer, and a 6th order band-pass EMΣΔM for the sense mode of a MEMS gyroscope. Each example was designed using the system in less than one day, with very little manual intervention. The strength of the approach is verified by SNR performances of 109.2 dB and 92.4 dB for the low-pass and band-pass system respectively, coupled with excellent immunities to fabrication tolerances and parameter mismatch.

  8. Glycolic acid modulates the mechanical property and degradation of poly(glycerol, sebacate, glycolic acid).

    Science.gov (United States)

    Sun, Zhi-Jie; Wu, Lan; Huang, Wei; Chen, Chang; Chen, Yan; Lu, Xi-Li; Zhang, Xiao-Lan; Yang, Bao-Feng; Dong, De-Li

    2010-01-01

    The development of biodegradable materials with controllable degradation properties is beneficial for a variety of applications. Poly(glycerol-sebacate) (PGS) is a promising candidate of biomaterials; so we synthesize a series of poly(glycerol, sebacate, glycolic acid) (PGSG) with 1:2:0, 1:2:0.2, 1:2:0.4, 1:2:0.6, 1:2:1 mole ratio of glycerol, sebacate, and glycolic acid to elucidate the relation of doped glycolic acid to the degradation rate and mechanical properties. The microstructures of the polymers with different doping of glycolic acid were dissimilar. PGSG with glycolic acid in the ratio of 0.2 displayed an integral degree of ordering, different to those with glycolic acid in the ratio of 0, 0.4, 0.6, and 1, which showed mild phase separation structure. The number, DeltaH(m), and temperature of the PGSG melting peaks tended to decrease with the increasing ratio of doped glycolic acid. In vitro and in vivo degradation tests showed that the degradation rate of PGSG with glycolic acid in the ratio of 0.2 was slowest, but in the ratio range of 0, 0.4, and 0.6, the degradation rate increased with the increase of glycolic acid. All PGSG samples displayed good tissue response and anticoagulant effects. Our data suggest that doping glycolic acid can modulate the microstructure and degree of crosslinking of PGS, thereby control the degradation rate of PGS.

  9. The Fold of Commitment

    DEFF Research Database (Denmark)

    Raastrup Kristensen, Anders; Pedersen, Michael

    2016-01-01

    This paper serves two purposes. First, a rereading of Douglas McGregor’s An uneasy look at performance appraisal serves to show how McGregor’s conceptualization of commitment as a question of integrating personal goals with organizational purpose has helped shape founding the modern understanding...... of corporate community representation. Second, we suggest that French philosopher Gilles Deleuze’s concepts of fold, desire and interests can be useful in comprehending this modern form of corporate representation already present in McGregor’s text....

  10. Implementation and Test of a Secure Mechanism's Modules in Routing Protocol of MANETs with the Theory of Games

    Directory of Open Access Journals (Sweden)

    Karim KONATE

    2012-08-01

    Full Text Available The present work is dedicated to the implementation of a secure mechanism’s modules in routing protocol of MANET with the theory of games. First we are doing an introduction to what the Mobile Ad hoc Networks (MANETs and a presentation of some various attacks in MANETs pertaining to fail routing protocols. We study these attacks and the mechanisms which the secured routing protocols use to counter them. In the second hand we also study a reputation mechanism and we also propose a secure algorithm based on the reputation. Our work ends with a proposal analytical model by the theorical games and an implementation to the modules of our mechanism..

  11. The Numba ductile deformation zone (northwest Cameroon): A geometric analysis of folds based on the Fold Profiler method

    Indian Academy of Sciences (India)

    T N Janko; C Njiki Chatu´e; M Kw´ekam; B E Bella Nk´e; A F Yakeu Sandjo; E M Fozing

    2017-03-01

    The Numba ductile deformation zone (NDDZ) is characterised by folds recorded during the three deformation phases that affected the banded amphibole gneiss. Fold-shape analyses using the program Fold Profiler with the aim to show the importance of folding events in the structural analysis of the NDDZ and its contribution to the Pan-African orogeny in central Africa have been made. Classical field method, conic sections method and Ramsay’s fold classification method were applied to (i) have the general orientation of folds, (ii) analyze the fold shapes and (iii) classify the geometry of the folded bands. Fold axes in banded amphibole gneiss plunge moderately (<15◦) towards the NNE or SSW. The morphology of F₁, F₂ and F₃ folds in the study area clearly points to (i) Z-shape folds with SE vergence and (ii) a dextral sense of shear motion. Conic section method reveals two dominant families: F₁ and F₃ folds belong to parabolic shape folds, while F₂ folds belong to parabolic shape and hyperbolic shape folds. Ramsay’s scheme emphasizes class 1C (for F₁, F₂ and F₃ folds) and class 3 (for F₂ folds) as main fold classes. The co-existence of the various fold shapes can be explained by (i) the structuration of the banded gneiss, (ii) the folding mechanisms that associate shear with a non-least compressive or flattening component in a ductile shear zone and (iii) the change in rheological properties of the band during the period of fold formation. These data allow us to conclude that the Numba region underwent ductile dextral shear and can be integrated (i) in a correlation model with the Central Cameroon Shear Zone(CCSZ) and associated syn-kinematic intrusions and (ii) into the tectonic model of Pan-African belt of central Africa in Cameroon.

  12. Use of Feed-Forward Mechanisms in a Novel Research-Led Module

    Science.gov (United States)

    Morrell, Lesley J.

    2014-01-01

    I describe a novel research-led module that combines reduced academic marking loads with increased feedback to students, and allows students to reflect on and improve attainment prior to summative assessment. The module is based around eight seminar-style presentations (one per week), on which the students write 500-word "news &…

  13. Passive thermal regulation of flat PV modules by coupling the mechanisms of evaporative and fin cooling

    Science.gov (United States)

    Chandrasekar, M.; Senthilkumar, T.

    2016-07-01

    A passive thermal regulation technique with fins in conjunction with cotton wicks is developed in the present work for controlling the temperature of PV module during its operation. Experiments were conducted with the developed technique in the location of Tiruchirappalli (78.6°E and 10.8°N), Tamil Nadu, India with flat 25 Wp PV module and its viability was confirmed. The PV module temperature got reduced by 12 % while the electrical yield is increased by 14 % with the help of the developed cooling system. Basic energy balance equation applicable for PV module was used to evaluate the module temperatures and a fair agreement was obtained between the theoretical and experimental values for the cases of with cooling and without cooling.

  14. Folding of non-Euclidean curved shells

    Science.gov (United States)

    Bende, Nakul; Evans, Arthur; Innes-Gold, Sarah; Marin, Luis; Cohen, Itai; Santangelo, Christian; Hayward, Ryan

    2015-03-01

    Origami-based folding of 2D sheets has been of recent interest for a variety of applications ranging from deployable structures to self-folding robots. Though folding of planar sheets follows well-established principles, folding of curved shells involves an added level of complexity due to the inherent influence of curvature on mechanics. In this study, we use principles from differential geometry and thin shell mechanics to establish fundamental rules that govern folding of prototypical creased shells. In particular, we show how the normal curvature of a crease line controls whether the deformation is smooth or discontinuous, and investigate the influence of shell thickness and boundary conditions. We show that snap-folding of shells provides a route to rapid actuation on time-scales dictated by the speed of sound. The simple geometric design principles developed can be applied at any length-scale, offering potential for bio-inspired soft actuators for tunable optics, microfluidics, and robotics. This work was funded by the National Science Foundation through EFRI ODISSEI-1240441 with additional support to S.I.-G. through the UMass MRSEC DMR-0820506 REU program.

  15. Role and mechanism of Twist1 in modulating the chemosensitivity of FaDu cells.

    Science.gov (United States)

    Lu, Sumei; Yu, Liang; Mu, Yakui; Ma, Juke; Tian, Jiajun; Xu, Wei; Wang, Haibo

    2014-07-01

    Multidrug resistance (MDR) is one of the most important obstacles affecting the efficacy of chemotherapy treatments for numerous types of cancer. In the present study, we have demonstrated the possible function of Twist1 in the chemosensitivity of head and neck squamous cell carcinoma (HNSCC) and have identified that its mechanism maybe associated with MDR1/P-gp regulation. To investigate this, the hypopharyngeal cancer cell line, FaDu, and its MDR cell line induced by taxol, FaDu/T, were employed. Stable transfectants targeted to Twist1 overexpression and Twist1 silencing based on FaDu were also conducted. Morphological observation, flow cytometry, reverse transcription-polymerase chain reaction (RT-PCR), western blotting and laser scanning confocal microscope detection were utilized to detect the associations between Twist1 and the chemosensitivity of FaDu cells. Our results demonstrated that Twist1 and MDR1/P-gp were upregulated in FaDu/T cells in a MDR dose-dependent manner. The anti-apoptotic capabilities of FaDu/T cells were enhanced during MDR progression, with apoptosis-related proteins (Bcl-2, Bax, activated caspase-3 and caspase-9) changing to resist apoptosis. Twist1 overexpression decreased the sensitivity of cells to taxol as revealed by a significant increase in MDR1/P-gp and IC50 (Pcell death, and inhibited Ca2+ release induced by taxol (Pcells also confirmed this result. This study provided evidence that alterations of Twist1 expression modulates the chemosensitivity of FaDu cells to taxol. Therefore, Twist1 knockdown may be a promising treatment regimen for advanced hypopharyngeal carcinoma patients with MDR.

  16. DNA repair pathways underlie a common genetic mechanism modulating onset in polyglutamine diseases

    Science.gov (United States)

    Bettencourt, Conceição; Hensman‐Moss, Davina; Flower, Michael; Wiethoff, Sarah; Brice, Alexis; Goizet, Cyril; Stevanin, Giovanni; Koutsis, Georgios; Karadima, Georgia; Panas, Marios; Yescas‐Gómez, Petra; García‐Velázquez, Lizbeth Esmeralda; Alonso‐Vilatela, María Elisa; Lima, Manuela; Raposo, Mafalda; Traynor, Bryan; Sweeney, Mary; Wood, Nicholas; Giunti, Paola; Durr, Alexandra; Holmans, Peter; Houlden, Henry; Tabrizi, Sarah J.

    2016-01-01

    Objective The polyglutamine diseases, including Huntington's disease (HD) and multiple spinocerebellar ataxias (SCAs), are among the commonest hereditary neurodegenerative diseases. They are caused by expanded CAG tracts, encoding glutamine, in different genes. Longer CAG repeat tracts are associated with earlier ages at onset, but this does not account for all of the difference, and the existence of additional genetic modifying factors has been suggested in these diseases. A recent genome‐wide association study (GWAS) in HD found association between age at onset and genetic variants in DNA repair pathways, and we therefore tested whether the modifying effects of variants in DNA repair genes have wider effects in the polyglutamine diseases. Methods We assembled an independent cohort of 1,462 subjects with HD and polyglutamine SCAs, and genotyped single‐nucleotide polymorphisms (SNPs) selected from the most significant hits in the HD study. Results In the analysis of DNA repair genes as a group, we found the most significant association with age at onset when grouping all polyglutamine diseases (HD+SCAs; p = 1.43 × 10–5). In individual SNP analysis, we found significant associations for rs3512 in FAN1 with HD+SCAs (p = 1.52 × 10–5) and all SCAs (p = 2.22 × 10–4) and rs1805323 in PMS2 with HD+SCAs (p = 3.14 × 10–5), all in the same direction as in the HD GWAS. Interpretation We show that DNA repair genes significantly modify age at onset in HD and SCAs, suggesting a common pathogenic mechanism, which could operate through the observed somatic expansion of repeats that can be modulated by genetic manipulation of DNA repair in disease models. This offers novel therapeutic opportunities in multiple diseases. Ann Neurol 2016;79:983–990 PMID:27044000

  17. Innovation of a Regulatory Mechanism Modulating Semi-determinate Stem Growth through Artificial Selection in Soybean.

    Directory of Open Access Journals (Sweden)

    Yunfeng Liu

    2016-01-01

    Full Text Available It has been demonstrated that Terminal Flowering 1 (TFL1 in Arabidopsis and its functional orthologs in other plants specify indeterminate stem growth through their specific expression that represses floral identity genes in shoot apical meristems (SAMs, and that the loss-of-function mutations at these functional counterparts result in the transition of SAMs from the vegetative to reproductive state that is essential for initiation of terminal flowering and thus formation of determinate stems. However, little is known regarding how semi-determinate stems, which produce terminal racemes similar to those observed in determinate plants, are specified in any flowering plants. Here we show that semi-determinacy in soybean is modulated by transcriptional repression of Dt1, the functional ortholog of TFL1, in SAMs. Such repression is fulfilled by recently enabled spatiotemporal expression of Dt2, an ancestral form of the APETALA1/FRUITFULL orthologs, which encodes a MADS-box factor directly binding to the regulatory sequence of Dt1. In addition, Dt2 triggers co-expression of the putative SUPPRESSOR OF OVEREXPRESSION OF CONSTANS 1 (GmSOC1 in SAMs, where GmSOC1 interacts with Dt2, and also directly binds to the Dt1 regulatory sequence. Heterologous expression of Dt2 and Dt1 in determinate (tfl1 Arabidopsis mutants enables creation of semi-determinacy, but the same forms of the two genes in the tfl1 and soc1 background produce indeterminate stems, suggesting that Dt2 and SOC1 both are essential for transcriptional repression of Dt1. Nevertheless, the expression of Dt2 is unable to repress TFL1 in Arabidopsis, further demonstrating the evolutionary novelty of the regulatory mechanism underlying stem growth in soybean.

  18. Mechanism of the tissue-specific action of the selective androgen receptor modulator S-101479.

    Science.gov (United States)

    Furuya, Kazuyuki; Yamamoto, Noriko; Ohyabu, Yuki; Morikyu, Teruyuki; Ishige, Hirohide; Albers, Michael; Endo, Yasuhisa

    2013-01-01

    Selective androgen receptor modulators (SARMs) comprise a new class of molecules that induce anabolic effects with fewer side effects than those of other anabolic agents. We previously reported that the novel SARM S-101479 had a tissue-selective bone anabolic effect with diminished side effects in female animals. However, the mechanism of its tissue selectivity is not well known. In this report, we show that S-101479 increased alkaline phosphatase activity and androgen receptor (AR) transcriptional activity in osteoblastic cell lines in the same manner as the natural androgen ligand dihydrotestosterone (DHT); conversely, stimulation of AR dimerization was very low compared with that of DHT (34.4%). S-101479 increased bone mineral content in ovariectomized rats without promoting endometrial proliferation. Yeast two-hybrid interaction assays revealed that DHT promoted recruitment of numerous cofactors to AR such as TIF2, SRC1, β-catenin, NCoA3, gelsolin and PROX1 in a dose-dependent manner. SARMs induced recruitment of fewer cofactors than DHT; in particular, S-101479 failed to induce recruitment of canonical p160 coactivators such as SRC1, TIF2 and notably NCoA3 but only stimulated binding of AR to gelsolin and PROX1. The results suggest that a full capability of the AR to dimerize and to effectively and unselectively recruit all canonical cofactors is not a prerequisite for transcriptional activity in osteoblastic cells and resulting anabolic effects in bone tissues. Instead, few relevant cofactors might be sufficient to promote AR activity in these tissues.

  19. Calcium-induced folding and stabilization of the Pseudomonas aeruginosa alkaline protease.

    Science.gov (United States)

    Zhang, Liang; Conway, James F; Thibodeau, Patrick H

    2012-02-03

    Pseudomonas aeruginosa is an opportunistic pathogen that contributes to the mortality of immunocompromised individuals and patients with cystic fibrosis. Pseudomonas infection presents clinical challenges due to its ability to form biofilms and modulate host-pathogen interactions through the secretion of virulence factors. The calcium-regulated alkaline protease (AP), a member of the repeats in toxin (RTX) family of proteins, is implicated in multiple modes of infection. A series of full-length and truncation mutants were purified for structural and functional studies to evaluate the role of Ca(2+) in AP folding and activation. We find that Ca(2+) binding induces RTX folding, which serves to chaperone the folding of the protease domain. Subsequent association of the RTX domain with an N-terminal α-helix stabilizes AP. These results provide a basis for the Ca(2+)-mediated regulation of AP and suggest mechanisms by which Ca(2+) regulates the RTX family of virulence factors.

  20. Self-folding miniature elastic electric devices

    Science.gov (United States)

    Miyashita, Shuhei; Meeker, Laura; Tolley, Michael T.; Wood, Robert J.; Rus, Daniela

    2014-09-01

    Printing functional materials represents a considerable impact on the access to manufacturing technology. In this paper we present a methodology and validation of print-and-self-fold miniature electric devices. Polyvinyl chloride laminated sheets based on metalized polyester film show reliable self-folding processes under a heat application, and it configures 3D electric devices. We exemplify this technique by fabricating fundamental electric devices, namely a resistor, capacitor, and inductor. Namely, we show the development of a self-folded stretchable resistor, variable resistor, capacitive strain sensor, and an actuation mechanism consisting of a folded contractible solenoid coil. Because of their pre-defined kinematic design, these devices feature elasticity, making them suitable as sensors and actuators in flexible circuits. Finally, an RLC circuit obtained from the integration of developed devices is demonstrated, in which the coil based actuator is controlled by reading a capacitive strain sensor.

  1. Cotranslational folding of deeply knotted proteins

    CERN Document Server

    Chwastyk, Mateusz

    2015-01-01

    Proper folding of deeply knotted proteins has a very low success rate even in structure-based models which favor formation of the native contacts but have no topological bias. By employing a structure-based model, we demonstrate that cotranslational folding on a model ribosome may enhance the odds to form trefoil knots for protein YibK without any need to introduce any non-native contacts. The ribosome is represented by a repulsive wall that keeps elongating the protein. On-ribosome folding proceeds through a a slipknot conformation. We elucidate the mechanics and energetics of its formation. We show that the knotting probability in on-ribosome folding is a function of temperature and that there is an optimal temperature for the process. Our model often leads to the establishment of the native contacts without formation of the knot.

  2. a Statistical-Mechanical Study of Some Problems in the Theory of Modulated Phases.

    Science.gov (United States)

    Tang, Leihan

    The thesis presents a statistical mechanical study of modulated phases. It is divided into three parts: (i) defect and defect interactions in classical one-dimensional systems; (ii) ground state of the chiral XY model in a field; (iii) pressure and stress tensor in fluids in a periodic potential. (i) The problem of the definition of defects and their creation and interaction energies is discussed for a general one-dimensional classical model with interactions extending to a finite number of neighbors. We introduce a technique for decomposing a composite defect into two simpler components, and a method for calculating the interaction energy of the latter in terms of an integral along a closed contour in the phase space. A linear map describing small deviations from a reference configuration is used to discuss exponential relaxation in the "tails" of defects, and their interaction energies at large separations. (ii) This part deals with a one-dimensional system of classical planar spins with nearest neighbor chiral interactions in the presence of a magnetic field. The phase diagram of the model at zero temperature is studied using the method of effective potentials and other numerical and analytical techniques. In contrast to the Frenkel -Kontorova model, the interaction potential between spins is not strictly convex, and this leads to some qualitatively different behavior. Among other interesting features, one finds a succession of first-order transitions, sequences of triple points and their accumulation points, and points where the ground-state is infinitely degenerate. (iii) For fluids in a periodic potential the grand canonical potential per unit volume (negative "thermodynamic pressure") differs from the diagonal components of the average stress tensor. This is in contrast to homogeneous fields. The thermodynamic meaning and the microscopic origin of this difference are discussed within the framework of classical statistical mechanics. For one-dimensional hard

  3. Mechanical scanner-less multi-beam confocal microscope with wavefront modulation

    Science.gov (United States)

    Takiguchi, Yu; Seo, Min-Woong; Kagawa, Keiichiro; Takamoto, Hisayoshi; Inoue, Takashi; Kawahito, Shoji; Terakawa, Susumu

    2016-04-01

    We propose a novel full-electronically controlled laser confocal microscope in which a liquid-crystal-on-silicon spatial light modulator and a custom CMOS imaging sensor are synchronized for performing multi-beam confocal imaging. Adaptive wavefront modulation for functional multi-beam excitation can be achieved by displaying appropriate computer generated holograms on the spatial light modulator, in consideration of the numerical aperture of the focusing objective. We also adopted a custom CMOS imaging sensor to realize multi-beam confocal microscopy without any physical pinhole. The confocality of this microscope was verified by improvements in transverse and axial resolutions of fluorescent micro-beads.

  4. Topology Engineering of Proteins in Vivo Using Genetically Encoded, Mechanically Interlocking SpyX Modules for Enhanced Stability

    Science.gov (United States)

    2017-01-01

    Recombinant proteins are traditionally limited to linear configuration. Herein, we report in vivo protein topology engineering using highly efficient, mechanically interlocking SpyX modules named AXB and BXA. SpyX modules are protein domains composed of p53dim (X), SpyTag (A), and SpyCatcher (B). The p53dim guides the intertwining of the two nascent protein chains followed by autocatalytic isopeptide bond formation between SpyTag and SpyCatcher to fulfill the interlocking, leading to a variety of backbone topologies. Direct expression of AXB or BXA produces protein catenanes with distinct ring sizes. Recombinant proteins containing SpyX modules are obtained either as mechanically interlocked obligate dimers if the protein of interest is fused to the N- or C-terminus of SpyX modules, or as star proteins if the protein is fused to both N- and C-termini. As examples, cellular syntheses of dimers of (GB1)2 (where GB1 stands for immunoglobulin-binding domain B1 of streptococcal protein G) and of four-arm elastin-like star proteins were demonstrated. Comparison of the catenation efficiencies in different constructs reveals that BXA is generally much more effective than AXB, which is rationalized by the arrangement of three domains in space. Mechanical interlocking induces considerable stability enhancement. Both AXB and BXA have a melting point ∼20 °C higher than the linear controls and the BXA catenane has a melting point ~2 °C higher than the cyclic control BX’A. Notably, four-arm elastin-like star proteins demonstrate remarkable tolerance against trypsin digestion. The SpyX modules provide a convenient and versatile approach to construct unconventional protein topologies via the “assembly-reaction” synergy, which opens a new horizon in protein science for stability enhancement and function reinforcement via topology engineering. PMID:28573210

  5. A3 Adenosine Receptor Allosteric Modulator Induces an Anti-Inflammatory Effect: In Vivo Studies and Molecular Mechanism of Action

    Directory of Open Access Journals (Sweden)

    Shira Cohen

    2014-01-01

    Full Text Available The A3 adenosine receptor (A3AR is overexpressed in inflammatory cells and in the peripheral blood mononuclear cells of individuals with inflammatory conditions. Agonists to the A3AR are known to induce specific anti-inflammatory effects upon chronic treatment. LUF6000 is an allosteric compound known to modulate the A3AR and render the endogenous ligand adenosine to bind to the receptor with higher affinity. The advantage of allosteric modulators is their capability to target specifically areas where adenosine levels are increased such as inflammatory and tumor sites, whereas normal body cells and tissues are refractory to the allosteric modulators due to low adenosine levels. LUF6000 administration induced anti-inflammatory effect in 3 experimental animal models of rat adjuvant induced arthritis, monoiodoacetate induced osteoarthritis, and concanavalin A induced liver inflammation in mice. The molecular mechanism of action points to deregulation of signaling proteins including PI3K, IKK, IκB, Jak-2, and STAT-1, resulting in decreased levels of NF-κB, known to mediate inflammatory effects. Moreover, LUF6000 induced a slight stimulatory effect on the number of normal white blood cells and neutrophils. The anti-inflammatory effect of LUF6000, mechanism of action, and the differential effects on inflammatory and normal cells position this allosteric modulator as an attractive and unique drug candidate.

  6. How the genome folds

    Science.gov (United States)

    Lieberman Aiden, Erez

    2012-02-01

    I describe Hi-C, a novel technology for probing the three-dimensional architecture of whole genomes by coupling proximity-based ligation with massively parallel sequencing. Working with collaborators at the Broad Institute and UMass Medical School, we used Hi-C to construct spatial proximity maps of the human genome at a resolution of 1Mb. These maps confirm the presence of chromosome territories and the spatial proximity of small, gene-rich chromosomes. We identified an additional level of genome organization that is characterized by the spatial segregation of open and closed chromatin to form two genome-wide compartments. At the megabase scale, the chromatin conformation is consistent with a fractal globule, a knot-free conformation that enables maximally dense packing while preserving the ability to easily fold and unfold any genomic locus. The fractal globule is distinct from the more commonly used globular equilibrium model. Our results demonstrate the power of Hi-C to map the dynamic conformations of whole genomes.

  7. Design of Subsea Control Module Locking Mechanism%水下控制模块锁紧机构设计

    Institute of Scientific and Technical Information of China (English)

    代广文; 赵宏林; 叶天源; 段梦兰; 徐时贤; 朱军龙

    2015-01-01

    The subsea control module (SCM)is an important part of the subsea tree,which is long-term in a state of high pressure underwater,it is crucial to fix and lock the SCM.This article will be according to the relevant norms such as ISO 13628-8,considering the underwater control mod-ule shape and clamping force,on the basis of using solidworks modeling to carry on the design of subsea control module locking mechanism.At the same time,we will use the empirical formula to calculate the strength of the locking mechanism,the strength of the locking mechanism is in the permitted range.The calculation results show that the designed locking mechanism meets the loc-king needs of the subsea control module.%水下控制模块是水下采油树的重要组成部分,其长期处于水下高压状态,对其进行固定和锁紧至关重要。根据 ISO 13628-8等相应规范,在考虑水下控制模块外形及锁紧力的基础上,利用Solidworks 软件建模,对水下控制模块锁紧机构进行设计,同时利用经验公式对锁紧机构的强度进行计算。分析结果表明,设计的锁紧机构满足水下控制模块锁紧的需求。

  8. DREADD Modulation of Transplanted DA Neurons Reveals a Novel Parkinsonian Dyskinesia Mechanism Mediated by the Serotonin 5-HT6 Receptor

    OpenAIRE

    2016-01-01

    Summary Transplantation of DA neurons is actively pursued as a restorative therapy in Parkinson’s disease (PD). Pioneering clinical trials using transplants of fetal DA neuroblasts have given promising results, although a number of patients have developed graft-induced dyskinesias (GIDs), and the mechanism underlying this troublesome side effect is still unknown. Here we have used a new model where the activity of the transplanted DA neurons can be selectively modulated using a bimodal chemog...

  9. Non-cylindrical fold growth in the Zagros fold and thrust belt (Kurdistan, NE-Iraq)

    Science.gov (United States)

    Bartl, Nikolaus; Bretis, Bernhard; Grasemann, Bernhard; Lockhart, Duncan

    2010-05-01

    The Zagros mountains extends over 1800 km from Kurdistan in N-Iraq to the Strait of Hormuz in Iran and is one of the world most promising regions for the future hydrocarbon exploration. The Zagros Mountains started to form as a result of the collision between the Eurasian and Arabian Plates, whose convergence began in the Late Cretaceous as part of the Alpine-Himalayan orogenic system. Geodetic and seismological data document that both plates are still converging and that the fold and thrust belt of the Zagros is actively growing. Extensive hydrocarbon exploration mainly focuses on the antiforms of this fold and thrust belt and therefore the growth history of the folds is of great importance. This work investigates by means of structural field work and quantitative geomorphological techniques the progressive fold growth of the Permam, Bana Bawi- and Safeen- Anticlines located in the NE of the city of Erbil in the Kurdistan region of Northern Iraq. This part of the Zagros fold and thrust belt belongs to the so-called Simply Folded Belt, which is dominated by gentle to open folding. Faults or fault related folds have only minor importance. The mechanical anisotropy of the formations consisting of a succession of relatively competent (massive dolomite and limestone) and incompetent (claystone and siltstone) sediments essentially controls the deformation pattern with open to gentle parallel folding of the competent layers and flexural flow folding of the incompetent layers. The characteristic wavelength of the fold trains is around 10 km. Due to faster erosion of the softer rock layers in the folded sequence, the more competent lithologies form sharp ridges with steeply sloping sides along the eroded flanks of the anticlines. Using an ASTER digital elevation model in combination with geological field data we quantified 250 drainage basins along the different limbs of the subcylindrical Permam, Bana Bawi- and Safeen- Anticlines. Geomorphological indices of the drainage

  10. Phytoestrogens modulate prostaglandin production in bovine endometrium: cell type specificity and intracellular mechanisms.

    Science.gov (United States)

    Woclawek-Potocka, Izabela; Acosta, Tomas J; Korzekwa, Anna; Bah, Mamadou M; Shibaya, Masami; Okuda, Kiyoshi; Skarzynski, Dariusz J

    2005-05-01

    Prostaglandins (PGs) are known to modulate the proper cyclicity of bovine reproductive organs. The main luteolytic agent in ruminants is PGF2alpha, whereas PGE2 has luteotropic actions. Estradiol 17beta (E2) regulates uterus function by influencing PG synthesis. Phytoestrogens structurally resemble E2 and possess estrogenic activity; therefore, they may mimic the effects of E2 on PG synthesis and influence the reproductive system. Using a cell-culture system of bovine epithelial and stromal cells, we determined cell-specific effects of phytoestrogens (i.e., daidzein, genistein), their metabolites (i.e., equol and para-ethyl-phenol, respectively), and E2 on PGF2alpha and PGE2 synthesis and examined the intracellular mechanisms of their actions. Both PGs produced by stromal and epithelial cells were significantly stimulated by phytoestrogens and their metabolites. However, PGF2alpha synthesis by both kinds of cells was greater stimulated than PGE2 synthesis. Moreover, epithelial cells treated with phytoestrogens synthesized more PGF2alpha than stromal cells, increasing the PGF2alpha to PGE2 ratio. The epithelial and stromal cells were preincubated with an estrogen-receptor (ER) antagonist (i.e., ICI), a translation inhibitor (i.e., actinomycin D), a protein kinase A inhibitor (i.e., staurosporin), and a phospholipase C inhibitor (i.e., U73122) for 0.5 hrs and then stimulated with equol, para-ethyl-phenol, or E2. Although the action of E2 on PGF2alpha synthesis was blocked by all reagents, the stimulatory effect of phytoestrogens was blocked only by ICI and actinomycin D in both cell types. Moreover, in contrast to E2 action, phytoestrogens did not cause intracellular calcium mobilization in either epithelial or stromal cells. Phytoestrogens stimulate both PGF2alpha and PGE2 in both cell types of bovine endometrium via an ER-dependent genomic pathway. However, because phytoestrogens preferentially stimulated PGF2alpha synthesis in epithelial cells of bovine

  11. On the origin of the histone fold

    Directory of Open Access Journals (Sweden)

    Söding Johannes

    2007-03-01

    Full Text Available Abstract Background Histones organize the genomic DNA of eukaryotes into chromatin. The four core histone subunits consist of two consecutive helix-strand-helix motifs and are interleaved into heterodimers with a unique fold. We have searched for the evolutionary origin of this fold using sequence and structure comparisons, based on the hypothesis that folded proteins evolved by combination of an ancestral set of peptides, the antecedent domain segments. Results Our results suggest that an antecedent domain segment, corresponding to one helix-strand-helix motif, gave rise divergently to the N-terminal substrate recognition domain of Clp/Hsp100 proteins and to the helical part of the extended ATPase domain found in AAA+ proteins. The histone fold arose subsequently from the latter through a 3D domain-swapping event. To our knowledge, this is the first example of a genetically fixed 3D domain swap that led to the emergence of a protein family with novel properties, establishing domain swapping as a mechanism for protein evolution. Conclusion The helix-strand-helix motif common to these three folds provides support for our theory of an 'ancient peptide world' by demonstrating how an ancestral fragment can give rise to 3 different folds.

  12. Elucidating PID Degradation Mechanisms and In Situ Dark I–V Monitoring for Modeling Degradation Rate in CdTe Thin-Film Modules

    Energy Technology Data Exchange (ETDEWEB)

    Hacke, Peter; Spataru, Sergiu; Johnston, Steve; Terwilliger, Kent; VanSant, Kaitlyn; Kempe, Michael; Wohlgemuth, John; Kurtz, Sarah; Olsson, Anders; Propst, Michelle

    2016-11-01

    A progression of potential-induced degradation (PID) mechanisms are observed in CdTe modules, including shunting/junction degradation and two different manifestations of series resistance depending on the stress level and water ingress. The dark I-V method for in-situ characterization of Pmax based on superposition was adapted for the thin-film modules undergoing PID in view of the degradation mechanisms observed. An exponential model based on module temperature and relative humidity was fit to the PID rate for multiple stress levels in chamber tests and validated by predicting the observed degradation of the module type in the field.

  13. Towards a systematic classification of protein folds

    DEFF Research Database (Denmark)

    Lindgård, Per-Anker; Bohr, Henrik

    1997-01-01

    in the usual protein data base coordinate format can be transformed into the proposed chain representation. Taking into account hydrophobic forces we have found a mechanism for the formation of domains with a unique fold containing predicted magic numbers {4,6,9,12,16,18,...} of secondary structures...

  14. RNA folding: structure prediction, folding kinetics and ion electrostatics.

    Science.gov (United States)

    Tan, Zhijie; Zhang, Wenbing; Shi, Yazhou; Wang, Fenghua

    2015-01-01

    Beyond the "traditional" functions such as gene storage, transport and protein synthesis, recent discoveries reveal that RNAs have important "new" biological functions including the RNA silence and gene regulation of riboswitch. Such functions of noncoding RNAs are strongly coupled to the RNA structures and proper structure change, which naturally leads to the RNA folding problem including structure prediction and folding kinetics. Due to the polyanionic nature of RNAs, RNA folding structure, stability and kinetics are strongly coupled to the ion condition of solution. The main focus of this chapter is to review the recent progress in the three major aspects in RNA folding problem: structure prediction, folding kinetics and ion electrostatics. This chapter will introduce both the recent experimental and theoretical progress, while emphasize the theoretical modelling on the three aspects in RNA folding.

  15. Thermal-mechanical and thermal-hydraulic integrated study of the Helium-Cooled Lithium Lead Test Blanket Module

    Energy Technology Data Exchange (ETDEWEB)

    Chiovaro, P., E-mail: pg.chiovaro@din.unipa.it [Dipartimento di Ingegneria Nucleare, Universita di Palermo, Palermo (Italy); Di Maio, P.A.; Giammusso, R.; Lupo, Q.; Vella, G. [Dipartimento di Ingegneria Nucleare, Universita di Palermo, Palermo (Italy)

    2010-12-15

    The Helium-Cooled Lithium Lead Test Blanket Module (HCLL-TBM) is one of the two TBM to be installed in an ITER equatorial port since day 1 of operation, with the specific aim to investigate the main concept functionalities and issues such as high efficiency helium cooling, resistance to thermo-mechanical stresses, manufacturing techniques, as well as tritium transport, magneto-hydrodynamics effects and corrosion. In particular, in order to show a DEMO-relevant thermo-mechanical and thermal-hydraulic behavior, the HCLL-TBM has to meet several requirements especially as far as its coolant thermofluid-dynamic conditions and its thermal-mechanical field are concerned. The present paper is focused on the assessment of the HCLL-TBM thermal-mechanical performances under both nominal and accidental load conditions, by adopting a computational approach based on the Finite Element Method. A realistic 3D finite element model of the whole HCLL-TBM, in the horizontal first wall design has been set up, consisting of about 597,000 elements and 767,000 nodes. In particular, since the thermal fields of both the module and the coolant are strictly coupled, the helium flow domain has been modeled too and a thermal contact model has been set up to properly simulate the convective heat transfer between the structure wall and the coolant. Pure conductive heat transfer has been assumed within the Pb-Li eutectic alloy of the breeder units. The volumetric density of the nuclear deposited power, recently calculated at Department of Nuclear Engineering of the University of Palermo by the MCNP 4C code, has been applied as distributed thermal load in order to assess the potential influence on the module thermo-mechanical performances of the markedly non-uniform poloidal and toroidal distributions that have been predicted within the Segment Box. Different loading scenarios have been considered as to the heat flux onto the module First Wall. Steady state and transient thermal-mechanical analyses

  16. PUVB-mediated prevention of luminal narrowing after arterial wall injury: modulation of mechanical arterial properties as a putative mechanism of action

    Science.gov (United States)

    Perree, Jop; Kerindongo, Raphaela P.; van Leeuwen, Ton G. J. M.

    2001-10-01

    In a previous study we have found that the photodynamic modality PUVB (8-methoxy-Psoralen + UVB) reduces luminal narrowing after arterial endovascular injury. We hypothesized that PUVB may modulate the arterial mechanical properties and tested this hypothesis by measuring the stress as a function of the strain in segments of carotid artery. Furthermore, we have investigated the potential for PUVB-induced cross-linking of extracellular matrix proteins by gel electrophoresis. It was found that both techniques were suitable for testing our hypotheses as evidenced by a statistically significant difference for the positive control. However, no differences between A) control, B) sensitizer only, C) light only and D) PUVB-treated samples could be found with respect to macro- and micro-mechanical properties. Therefore, the hypothesis that PUVB mediates its luminal narrowing reduction effect by directly changing the arterial mechanical properties should be rejected.

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

    Directory of Open Access Journals (Sweden)

    Jianglong Song

    2013-01-01

    Full Text Available 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.

  18. Mechanisms of masked evaluative priming: Task sets modulate behavioral and electrophysiological priming for picture and words differentially.

    Science.gov (United States)

    Kiefer, Markus; Liegel, Nathalie; Zovko, Monika; Wentura, Dirk

    2016-12-20

    Research with the evaluative priming paradigm has shown that affective evaluation processes reliably influence cognition and behavior, even when triggered outside awareness. However, the precise mechanisms underlying such subliminal evaluative priming effects, response activation vs. semantic processing, are matter of a debate. In the present study, we determined the relative contribution of semantic processing and response activation to masked evaluative priming with pictures and words. To this end, we investigated the modulation of masked pictorial vs. verbal priming by previously activated perceptual versus semantic task sets and assessed the electrophysiological correlates of priming using event-related potential (ERP) recordings. Behavioral and electrophysiological effects showed a differential modulation of pictorial and verbal subliminal priming by previously activated task sets: Pictorial priming was only observed during the perceptual but not during the semantic task set. Verbal priming, in contrast, was found when either task set was activated. Furthermore, only verbal priming was associated with a modulation of the N400 ERP component, an index of semantic processing, whereas a priming-related modulation of earlier ERPs, indexing visuo-motor S-R activation, was found for both picture and words. The results thus demonstrate that different neuro-cognitive processes contribute to unconscious evaluative priming depending on the stimulus format.

  19. Study of the Photo- and Thermoactivation Mechanisms in Nanoscale SOI Modulator

    Directory of Open Access Journals (Sweden)

    Yaakov Mandelbaum

    2017-01-01

    Full Text Available A new nanoscale silicon-based modulator has been investigated at different temperatures. In addition to these two advantages, nanoscale dimensions (versus MEMS temperature sensors and integrated silicon-based material (versus polymers, the third novelty of such optoelectronic device is that it can be activated as a Silicon-On-Insulator Photoactivated Modulator (SOIPAM or as a Silicon-On-Insulator Thermoactivated Modulator (SOITAM. In this work, static and time dependent temperature effects on the current have been investigated. The aim of the time dependent temperature simulation was to set a temporal pulse and to check, for given dimensions, how much time would it take for the temperature profile and for the change in the electrons’ concentration to come back to the steady state. Assuring that the thermal response is fast enough, the device can be operated as a modulator via thermal stimulation or, on the other hand, can be used as thermal sensor/imager. We present here the design, simulation, and model of the second generation which seems capable of speeding up the processing capabilities. This novel device can serve as a building block towards the development of optical/thermal data processing while breaking through the way to all optic processors based on silicon chips that are fabricated via typical microelectronics fabrication process.

  20. What you see is what you get: Brain mechanisms underlying action-modulated perception

    NARCIS (Netherlands)

    Gutteling, T.P.

    2012-01-01

    In order to successfully execute our actions in daily life, it is beneficial to focus on specific features of the incoming visual information. 'Action-modulated perception' refers to the process of enhancing action-relevant perceptual features during the preparation of an action. For instance, when

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

    Science.gov (United States)

    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.

  2. Interpretation of Simultaneous Mechanical-Electrical-Thermal Failure in a Lithium-Ion Battery Module: Preprint

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Chao; Santhanagopalan, Shriram; Stock, Mark J.; Brunhart-Lupo, Nicholas; Gruchalla, Kenny

    2016-12-01

    Lithium-ion batteries are currently the state-of- the-art power sources for electric vehicles, and their safety behavior when subjected to abuse, such as a mechanical impact, is of critical concern. A coupled mechanical-electrical-thermal model for simulating the behavior of a lithium-ion battery under a mechanical crush has been developed. We present a series of production-quality visualizations to illustrate the complex mechanical and electrical interactions in this model.

  3. MECHANICAL POWER TRANSFER SYSTEMS. AGRICULTURAL MACHINERY-SERVICE OCCUPATIONS, MODULE NUMBER 8.

    Science.gov (United States)

    Ohio State Univ., Columbus. Center for Vocational and Technical Education.

    ONE OF A SERIES DESIGNED TO HELP TEACHERS PREPARE POSTSECONDARY-LEVEL STUDENTS FOR THE AGRICULTURAL MACHINERY SERVICE OCCUPATIONS AS PARTS MEN, MECHANICS, MECHANIC'S HELPERS, AND SERVICE SUPERVISORS, THIS GUIDE AIMS TO DEVELOP STUDENT COMPETENCY IN UNDERSTANDING AND APPLYING THE PRINCIPLES OF MECHANICAL POWER TRANSMISSION IN AGRICULTURAL…

  4. Folding and faulting of an elastic continuum

    Science.gov (United States)

    Gourgiotis, Panos A.

    2016-01-01

    Folding is a process in which bending is localized at sharp edges separated by almost undeformed elements. This process is rarely encountered in Nature, although some exceptions can be found in unusual layered rock formations (called ‘chevrons’) and seashell patterns (for instance Lopha cristagalli). In mechanics, the bending of a three-dimensional elastic solid is common (for example, in bulk wave propagation), but folding is usually not achieved. In this article, the route leading to folding is shown for an elastic solid obeying the couple-stress theory with an extreme anisotropy. This result is obtained with a perturbation technique, which involves the derivation of new two-dimensional Green's functions for applied concentrated force and moment. While the former perturbation reveals folding, the latter shows that a material in an extreme anisotropic state is also prone to a faulting instability, in which a displacement step of finite size emerges. Another failure mechanism, namely the formation of dilation/compaction bands, is also highlighted. Finally, a geophysical application to the mechanics of chevron formation shows how the proposed approach may explain the formation of natural structures. PMID:27118925

  5. Folding superfunnel to describe cooperative folding of interacting proteins.

    Science.gov (United States)

    Smeller, László

    2016-07-01

    This paper proposes a generalization of the well-known folding funnel concept of proteins. In the funnel model the polypeptide chain is treated as an individual object not interacting with other proteins. Since biological systems are considerably crowded, protein-protein interaction is a fundamental feature during the life cycle of proteins. The folding superfunnel proposed here describes the folding process of interacting proteins in various situations. The first example discussed is the folding of the freshly synthesized protein with the aid of chaperones. Another important aspect of protein-protein interactions is the folding of the recently characterized intrinsically disordered proteins, where binding to target proteins plays a crucial role in the completion of the folding process. The third scenario where the folding superfunnel is used is the formation of aggregates from destabilized proteins, which is an important factor in case of several conformational diseases. The folding superfunnel constructed here with the minimal assumption about the interaction potential explains all three cases mentioned above. Proteins 2016; 84:1009-1016. © 2016 Wiley Periodicals, Inc.

  6. Generation of buckle folds in Naga fold thrust belt, north-east India

    Science.gov (United States)

    Saha, B.; Dietl, C.

    2009-04-01

    Naga fold thrust belt (NFTB), India, formed as a result of northward migration of the Indian plate initiated in Eocene and its subsequent collision with the Burmese plate during Oligocene. The NW-SE oriented compression generated a spectrum of structures; among them, we intend to focus on the folds- varying from gentle to tight asymmetric in geometry. Large recumbent folds are often associated with thrusting. Buckle folds forming under shallow crustal conditions are frequently reported from NFTB. Buckle folding occurs mainly within sandstones with intercalated shale layers which are in the study area typical for the Barail, Surma and Tipam Groups. We have tried to explain the controlling factors behind the variation of the buckle fold shapes and their varying wavelengths throughout the fold thrust belt with the aid of analogue (sand box) modelling. It is undoubted that competence contrast along with the layer parallel compressive stress are the major influencing factors in generation of buckle folds. Schmalholz and Podladchikov (1999) and Jeng et al. (2002) have shown that when low strain rate and low temperature are applicable, not only the viscosity contrast, but also the elasticity contrast govern the geometry of the developing buckle folds. Rocks deforming under high temperature and high pressure deform in pure viscous manner, whereas, rocks undergoing less confining stress and less temperature, are subjected to pure elastic deformation. However, they are the end members, and most of the deformations are a combination of these two end members, i.e. of viscoelastic nature. Our models are made up of sieved sand (0.5 mm grain size) and mica layers (1-5 mm) This interlayering imparts a mechanical anisotropy in the model. Mica is not a pure viscous material, rather it displays more elastic behaviour. The mica layers in the model produce bedding parallel slip during shortening through internal reorganization of the individual mica crystals leading to the thickening

  7. Selective modulation of cellular voltage dependent calcium channels by hyperbaric pressure - a suggested HPNS partial mechanism

    Directory of Open Access Journals (Sweden)

    Ben eAviner

    2014-05-01

    Full Text Available Professional deep sea divers experience motor and cognitive impairment, known as High Pressure Neurological Syndrome (HPNS, when exposed to pressures of 100 msw (1.1MPa and above, considered to be the result of synaptic transmission alteration. Previous studies have indicated modulation of presynaptic Ca2+ currents at high pressure. We directly measured for the first time pressure effects on the currents of voltage dependent Ca2+ channels (VDCCs expressed in Xenopus oocytes. Pressure selectivity augmented the current in CaV1.2 and depressed it in CaV3.2 channels. Pressure application also affected the channels' kinetics, such as ƮRise, ƮDecay. Pressure modulation of VDCCs seems to play an important role in generation of HPNS signs and symptoms.

  8. Transcranial alternating current stimulation: a review of the underlying mechanisms and modulation of cognitive processes

    OpenAIRE

    Herrmann, Christoph S; Rach, Stefan; Neuling, Toralf; Strüber, Daniel

    2013-01-01

    Brain oscillations of different frequencies have been associated with a variety of cognitive functions. Convincing evidence supporting those associations has been provided by studies using intracranial stimulation, pharmacological interventions and lesion studies. The emergence of novel non-invasive brain stimulation techniques like repetitive transcranial magnetic stimulation (rTMS) and transcranial alternating current stimulation (tACS) now allows to modulate brain oscillations directly. Pa...

  9. Mechanical analysis of the main bus bars in the DFBA shuffling modules

    CERN Document Server

    Ramos, D

    2012-01-01

    The main bus bars (13 kA) inside the shuffling modules of the distribution feed boxes powering the LHC arcs (DFBA) are subjected to high Lorentz forces. The structural behaviour of the bus bars under such forces is here analysed. The results are discussed with respect to a risk of structural failure due to excessive deformation or degradation of the electrical insulation by repeated contact with other surfaces.

  10. Neural mechanisms influencing interlimb coordination during locomotion in humans: presynaptic modulation of forearm H-reflexes during leg cycling.

    Science.gov (United States)

    Nakajima, Tsuyoshi; Mezzarane, Rinaldo A; Klarner, Taryn; Barss, Trevor S; Hundza, Sandra R; Komiyama, Tomoyoshi; Zehr, E Paul

    2013-01-01

    Presynaptic inhibition of transmission between Ia afferent terminals and alpha motoneurons (Ia PSI) is a major control mechanism associated with soleus H-reflex modulation during human locomotion. Rhythmic arm cycling suppresses soleus H-reflex amplitude by increasing segmental Ia PSI. There is a reciprocal organization in the human nervous system such that arm cycling modulates H-reflexes in leg muscles and leg cycling modulates H-reflexes in forearm muscles. However, comparatively little is known about mechanisms subserving the effects from leg to arm. Using a conditioning-test (C-T) stimulation paradigm, the purpose of this study was to test the hypothesis that changes in Ia PSI underlie the modulation of H-reflexes in forearm flexor muscles during leg cycling. Subjects performed leg cycling and static activation while H-reflexes were evoked in forearm flexor muscles. H-reflexes were conditioned with either electrical stimuli to the radial nerve (to increase Ia PSI; C-T interval  = 20 ms) or to the superficial radial (SR) nerve (to reduce Ia PSI; C-T interval  = 37-47 ms). While stationary, H-reflex amplitudes were significantly suppressed by radial nerve conditioning and facilitated by SR nerve conditioning. Leg cycling suppressed H-reflex amplitudes and the amount of this suppression was increased with radial nerve conditioning. SR conditioning stimulation removed the suppression of H-reflex amplitude resulting from leg cycling. Interestingly, these effects and interactions on H-reflex amplitudes were observed with subthreshold conditioning stimulus intensities (radial n., ∼0.6×MT; SR n., ∼ perceptual threshold) that did not have clear post synaptic effects. That is, did not evoke reflexes in the surface EMG of forearm flexor muscles. We conclude that the interaction between leg cycling and somatosensory conditioning of forearm H-reflex amplitudes is mediated by modulation of Ia PSI pathways. Overall our results support a conservation of neural

  11. Neural mechanisms influencing interlimb coordination during locomotion in humans: presynaptic modulation of forearm H-reflexes during leg cycling.

    Directory of Open Access Journals (Sweden)

    Tsuyoshi Nakajima

    Full Text Available Presynaptic inhibition of transmission between Ia afferent terminals and alpha motoneurons (Ia PSI is a major control mechanism associated with soleus H-reflex modulation during human locomotion. Rhythmic arm cycling suppresses soleus H-reflex amplitude by increasing segmental Ia PSI. There is a reciprocal organization in the human nervous system such that arm cycling modulates H-reflexes in leg muscles and leg cycling modulates H-reflexes in forearm muscles. However, comparatively little is known about mechanisms subserving the effects from leg to arm. Using a conditioning-test (C-T stimulation paradigm, the purpose of this study was to test the hypothesis that changes in Ia PSI underlie the modulation of H-reflexes in forearm flexor muscles during leg cycling. Subjects performed leg cycling and static activation while H-reflexes were evoked in forearm flexor muscles. H-reflexes were conditioned with either electrical stimuli to the radial nerve (to increase Ia PSI; C-T interval  = 20 ms or to the superficial radial (SR nerve (to reduce Ia PSI; C-T interval  = 37-47 ms. While stationary, H-reflex amplitudes were significantly suppressed by radial nerve conditioning and facilitated by SR nerve conditioning. Leg cycling suppressed H-reflex amplitudes and the amount of this suppression was increased with radial nerve conditioning. SR conditioning stimulation removed the suppression of H-reflex amplitude resulting from leg cycling. Interestingly, these effects and interactions on H-reflex amplitudes were observed with subthreshold conditioning stimulus intensities (radial n., ∼0.6×MT; SR n., ∼ perceptual threshold that did not have clear post synaptic effects. That is, did not evoke reflexes in the surface EMG of forearm flexor muscles. We conclude that the interaction between leg cycling and somatosensory conditioning of forearm H-reflex amplitudes is mediated by modulation of Ia PSI pathways. Overall our results support a

  12. Influence of Conformational Entropy on the Protein Folding Rate

    Directory of Open Access Journals (Sweden)

    Oxana V. Galzitskaya

    2010-04-01

    Full Text Available One of the most important questions in molecular biology is what determines folding pathways: native structure or protein sequence. There are many proteins that have similar structures but very different sequences, and a relevant question is whether such proteins have similar or different folding mechanisms. To explain the differences in folding rates of various proteins, the search for the factors affecting the protein folding process goes on. Here, based on known experimental data, and using theoretical modeling of protein folding based on a capillarity model, we demonstrate that the relation between the average conformational entropy and the average energy of contacts per residue, that is the entropy capacity, will determine the possibility of the given chain to fold to a particular topology. The difference in the folding rate for proteins sharing more ball-like and less ball-like folds is the result of differences in the conformational entropy due to a larger surface of the boundary between folded and unfolded phases in the transition state for proteins with a more ball-like fold. The result is in agreement with the experimental folding rates for 67 proteins. Proteins with high or low side chain entropy would have extended unfolded regions and would require some additional agents for complete folding. Such proteins are common in nature, and their structural properties are of biological importance.

  13. Efficient single-pixel multispectral imaging via non-mechanical spatio-spectral modulation

    Science.gov (United States)

    Li, Ziwei; Suo, Jinli; Hu, Xuemei; Deng, Chao; Fan, Jingtao; Dai, Qionghai

    2017-01-01

    Combining spectral imaging with compressive sensing (CS) enables efficient data acquisition by fully utilizing the intrinsic redundancies in natural images. Current compressive multispectral imagers, which are mostly based on array sensors (e.g, CCD or CMOS), suffer from limited spectral range and relatively low photon efficiency. To address these issues, this paper reports a multispectral imaging scheme with a single-pixel detector. Inspired by the spatial resolution redundancy of current spatial light modulators (SLMs) relative to the target reconstruction, we design an all-optical spectral splitting device to spatially split the light emitted from the object into several counterparts with different spectrums. Separated spectral channels are spatially modulated simultaneously with individual codes by an SLM. This no-moving-part modulation ensures a stable and fast system, and the spatial multiplexing ensures an efficient acquisition. A proof-of-concept setup is built and validated for 8-channel multispectral imaging within 420~720 nm wavelength range on both macro and micro objects, showing a potential for efficient multispectral imager in macroscopic and biomedical applications.

  14. Effects of knots on protein folding properties.

    Directory of Open Access Journals (Sweden)

    Miguel A Soler

    Full Text Available This work explores the impact of knots, knot depth and motif of the threading terminus in protein folding properties (kinetics, thermodynamics and mechanism via extensive Monte Carlo simulations of lattice models. A knotted backbone has no effect on protein thermodynamic stability but it may affect key aspects of folding kinetics. In this regard, we found clear evidence for a functional advantage of knots: knots enhance kinetic stability because a knotted protein unfolds at a distinctively slower rate than its unknotted counterpart. However, an increase in knot deepness does not necessarily lead to more effective changes in folding properties. In this regard, a terminus with a non-trivial conformation (e.g. hairpin can have a more dramatic effect in enhancing kinetic stability than knot depth. Nevertheless, our results suggest that the probability of the denatured ensemble to keep knotted is higher for proteins with deeper knots, indicating that knot depth plays a role in determining the topology of the denatured state. Refolding simulations starting from denatured knotted conformations show that not every knot is able to nucleate folding and further indicate that the formation of the knotting loop is a key event in the folding of knotted trefoils. They also show that there are specific native contacts within the knotted core that are crucial to keep a native knotting loop in denatured conformations which otherwise have no detectable structure. The study of the knotting mechanism reveals that the threading of the knotting loop generally occurs towards late folding in conformations that exhibit a significant degree of structural consolidation.

  15. Kinetics and Thermodynamics of Membrane Protein Folding

    Directory of Open Access Journals (Sweden)

    Ernesto A. Roman

    2014-03-01

    Full Text Available Understanding protein folding has been one of the great challenges in biochemistry and molecular biophysics. Over the past 50 years, many thermodynamic and kinetic studies have been performed addressing the stability of globular proteins. In comparison, advances in the membrane protein folding field lag far behind. Although membrane proteins constitute about a third of the proteins encoded in known genomes, stability studies on membrane proteins have been impaired due to experimental limitations. Furthermore, no systematic experimental strategies are available for folding these biomolecules in vitro. Common denaturing agents such as chaotropes usually do not work on helical membrane proteins, and ionic detergents have been successful denaturants only in few cases. Refolding a membrane protein seems to be a craftsman work, which is relatively straightforward for transmembrane β-barrel proteins but challenging for α-helical membrane proteins. Additional complexities emerge in multidomain membrane proteins, data interpretation being one of the most critical. In this review, we will describe some recent efforts in understanding the folding mechanism of membrane proteins that have been reversibly refolded allowing both thermodynamic and kinetic analysis. This information will be discussed in the context of current paradigms in the protein folding field.

  16. Exploiting the gain-modulation mechanism in parieto-motor neurons: application to visuomotor transformations and embodied simulation.

    Science.gov (United States)

    Mahé, Sylvain; Braud, Raphaël; Gaussier, Philippe; Quoy, Mathias; Pitti, Alexandre

    2015-02-01

    The so-called self-other correspondence problem in imitation demands to find the transformation that maps the motor dynamics of one partner to our own. This requires a general purpose sensorimotor mechanism that transforms an external fixation-point (partner's shoulder) reference frame to one's own body-centered reference frame. We propose that the mechanism of gain-modulation observed in parietal neurons may generally serve these types of transformations by binding the sensory signals across the modalities with radial basis functions (tensor products) on the one hand and by permitting the learning of contextual reference frames on the other hand. In a shoulder-elbow robotic experiment, gain-field neurons (GF) intertwine the visuo-motor variables so that their amplitude depends on them all. In situations of modification of the body-centered reference frame, the error detected in the visuo-motor mapping can serve then to learn the transformation between the robot's current sensorimotor space and the new one. These situations occur for instance when we turn the head on its axis (visual transformation), when we use a tool (body modification), or when we interact with a partner (embodied simulation). Our results defend the idea that the biologically-inspired mechanism of gain modulation found in parietal neurons can serve as a basic structure for achieving nonlinear mapping in spatial tasks as well as in cooperative and social functions.

  17. Recoverable and Programmable Collapse from Folding Pressurized Origami Cellular Solids

    Science.gov (United States)

    Li, S.; Fang, H.; Wang, K. W.

    2016-09-01

    We report a unique collapse mechanism by exploiting the negative stiffness observed in the folding of an origami solid, which consists of pressurized cells made by stacking origami sheets. Such a collapse mechanism is recoverable, since it only involves rigid folding of the origami sheets and it is programmable by pressure control and the custom design of the crease pattern. The collapse mechanism features many attractive characteristics for applications such as energy absorption. The reported results also suggest a new branch of origami study focused on its nonlinear mechanics associated with folding.

  18. Length-dependent modulation of cytoskeletal remodeling and mechanical energetics in airway smooth muscle

    National Research Council Canada - National Science Library

    Kim, Hak Rim; Liu, Katrina; Roberts, Thomas J; Hai, Chi-Ming

    2011-01-01

    ... and branched actin filaments in shortened ASM. The mechanical energy output/input ratio during sinusoidal length oscillation was dependent on muscle length, oscillatory amplitude, and cholinergic activation...

  19. Teaching computers to fold proteins

    DEFF Research Database (Denmark)

    Winther, Ole; Krogh, Anders Stærmose

    2004-01-01

    A new general algorithm for optimization of potential functions for protein folding is introduced. It is based upon gradient optimization of the thermodynamic stability of native folds of a training set of proteins with known structure. The iterative update rule contains two thermodynamic averages...

  20. Novel sequences propel familiar folds.

    Science.gov (United States)

    Jawad, Zahra; Paoli, Massimo

    2002-04-01

    Recent structure determinations have made new additions to a set of strikingly different sequences that give rise to the same topology. Proteins with a beta propeller fold are characterized by extreme sequence diversity despite the similarity in their three-dimensional structures. Several fold predictions, based in part on sequence repeats thought to match modular beta sheets, have been proved correct.

  1. Folding of β-barrel membrane proteins in lipid bilayers - Unassisted and assisted folding and insertion.

    Science.gov (United States)

    Kleinschmidt, Jörg H

    2015-09-01

    In cells, β-barrel membrane proteins are transported in unfolded form to an outer membrane into which they fold and insert. Model systems have been established to investigate the mechanisms of insertion and folding of these versatile proteins into detergent micelles, lipid bilayers and even synthetic amphipathic polymers. In these experiments, insertion into lipid membranes is initiated from unfolded forms that do not display residual β-sheet secondary structure. These studies therefore have allowed the investigation of membrane protein folding and insertion in great detail. Folding of β-barrel membrane proteins into lipid bilayers has been monitored from unfolded forms by dilution of chaotropic denaturants that keep the protein unfolded as well as from unfolded forms present in complexes with molecular chaperones from cells. This review is aimed to provide an overview of the principles and mechanisms observed for the folding of β-barrel transmembrane proteins into lipid bilayers, the importance of lipid-protein interactions and the function of molecular chaperones and folding assistants. This article is part of a Special Issue entitled: Lipid-protein interactions.

  2. Wearable interrupter module for home-based applications in a telemedical system dedicated to respiratory mechanics measurements.

    Science.gov (United States)

    Jabłoński, Ireneusz

    2011-03-01

    The mobile interrupter module, dedicated to the enhanced interrupter (EIT) measurement of respiratory mechanics in a home environment and capable of cooperation with a telemedical system, is presented. Characterized by noninvasiveness and minimal requirements regarding patient cooperation, the EIT algorithm is especially suitable for newborns, preschool children, and patients suffering from respiratory muscle impairment. Furthermore, this device enables access to raw data--without initial preprocessing--in a fully flexible measurement protocol (which is not available in any commercial apparatus), and the EIT procedure improves insight (the number and precision of assessed parameters) into the physiological system with respect to the classical occlusive methods.

  3. Characterization of the Partially Folded Monomeric Intermediate of Creatine Kinase

    Institute of Scientific and Technical Information of China (English)

    朴龙斗; 周海梦

    2002-01-01

    The importance of understanding the protein folding pathway and intermediates is well recognized on the basis of extensive studies of protein folding in vitro and in vivo. Creatine kinase (CK) is a typical model for studying unfolding and refolding of proteins due to several interesting properties. Recent studies on the folding of CK show that its partially folded monomeric intermediate is present kinetically and is stable at equilibrium. The present paper contains 33 References as a mini review to characterize the properties of CK from studies on the CK folding pathway. Characterization of these intermediates is an essential step toward understanding the mechanism of protein folding. Some well-determined schemes are suggested as protein folding models.

  4. Equi-Gaussian Curvature Folding

    Indian Academy of Sciences (India)

    E M El-Kholy; El-Said R Lashin; Salama N Daoud

    2007-08-01

    In this paper we introduce a new type of folding called equi-Gaussian curvature folding of connected Riemannian 2-manifolds. We prove that the composition and the cartesian product of such foldings is again an equi-Gaussian curvature folding. In case of equi-Gaussian curvature foldings, $f:M→ P_n$, of an orientable surface onto a polygon $P_n$ we prove that (i) $f\\in\\mathcal{F}_{EG}(S^2)\\Leftrightarrow n=3$ (ii) $f\\in\\mathcal{F}_{EG}(T^2)\\Rightarrow n=4$ (iii) $f\\in\\mathcal{F}_{EG}(\\# 2T^2)\\Rightarrow n=5, 6$ and we generalize (iii) for $\\# nT^2$.

  5. A dynamic skull model for simulation of cerebral cortex folding.

    Science.gov (United States)

    Chen, Hanbo; Guo, Lei; Nie, Jingxin; Zhang, Tuo; Hu, Xintao; Liu, Tianming

    2010-01-01

    The mechanisms of human cerebral cortex folding and their interactions during brain development are largely unknown, partly due to the difficulties in biological experiments and data acquisition for the developing fetus brain. Computational modeling and simulation provide a novel approach to the understanding of cortex folding processes in normal or aberrant neurodevelopment. Based on our recently developed computational model of the cerebral cortex folding using neuronal growth model and mechanical skull constraint, this paper presents a computational dynamic model of the brain skull that regulates the cortical folding simulation. Our simulation results show that the dynamic skull model is more biologically realistic and significantly improves our cortical folding simulation results. This work provides further computational support to the hypothesis that skull is an important regulator of cortical folding.

  6. A Case Study of the Mechanisms Modulating the Evolution of Valley Fog

    Science.gov (United States)

    Hang, C.; Nadeau, D. F.; Gultepe, I.; Hoch, S. W.; Román-Cascón, C.; Pryor, K.; Fernando, H. J. S.; Creegan, E. D.; Leo, L. S.; Silver, Z.; Pardyjak, E. R.

    2016-09-01

    We present a valley fog case study in which radiation fog is modulated by topographic effects using data obtained from a field campaign conducted in Heber Valley, Utah from January 7-February 1, 2015, as part of the Mountain Terrain Atmospheric Modeling and Observations (MATERHORN) program. We use data collected on January 9, 2015 to gain insight into relationships between typical shallow radiation fog, turbulence, and gravity waves associated with the surrounding topography. A ≈ 10-30 m fog layer formed by radiative cooling was observed from 0720 to 0900 MST under cold air temperatures (≈-9 °C), near-saturated (relative humidity with respect to water ≈95 %), and calm wind (mostly conditions. Drainage flows were observed occasionally prior to fog formation, which modulated heat exchanges between air masses through the action of internal gravity waves and cold-air pool sloshing. The fog appeared to be triggered by cold-air advection from the south (≈200°) at 0700 MST. Quasi-periodic oscillations were observed before and during the fog event with a time period of about 15 min. These oscillations were detected in surface pressure, temperature, sensible heat flux, incoming longwave radiation, and turbulent kinetic energy measurements. We hypothesize that the quasi-periodic oscillations were caused by atmospheric gravity waves with a time period of about 10-20 min based on wavelet analysis. During the fog event, internal gravity waves led to about 1 °C fluctuations in air temperatures. After 0835 MST when net radiation became positive, fog started to dissipate due to the surface heating and heat absorption by the fog particles. Overall, this case study provides a concrete example of how fog evolution is modulated by very weak thermal circulations in mountainous terrain and illustrates the need for high density vertical and horizontal measurements to ensure that the highly spatially varying physics in complex terrain are sufficient for hypothesis testing.

  7. A novel interference mechanism by a type IIIB CRISPR-Cmr module in Sulfolobus

    DEFF Research Database (Denmark)

    Deng, Ling; Garrett, Roger Antony; Shah, Shiraz Ali

    2013-01-01

    Recent studies on CRISPR-based adaptive immune systems have revealed extensive structural and functional diversity of the interference complexes which often coexist intracellularly. The archaeon Sulfolobus islandicus REY15A encodes three interference modules, one of type IA and two of type IIIB...... targeting. A rationale is provided for the intracellular coexistence of the different interference systems in S.¿islandicus REY15A which cooperate functionally by sharing a single Cas6 protein for crRNA processing and utilize crRNA products from identical CRISPR spacers....

  8. Extracellular protonation modulates cell-cell interaction mechanics and tissue invasion in human melanoma cells

    Science.gov (United States)

    Hofschröer, Verena; Koch, Kevin Alexander; Ludwig, Florian Timo; Friedl, Peter; Oberleithner, Hans; Stock, Christian; Schwab, Albrecht

    2017-01-01

    Detachment of cells from the primary tumour precedes metastatic progression by facilitating cell release into the tissue. Solid tumours exhibit altered pH homeostasis with extracellular acidification. In human melanoma, the Na+/H+ exchanger NHE1 is an important modifier of the tumour nanoenvironment. Here we tested the modulation of cell-cell-adhesion by extracellular pH and NHE1. MV3 tumour spheroids embedded in a collagen matrix unravelled the efficacy of cell-cell contact loosening and 3D emigration into an environment mimicking physiological confinement. Adhesive interaction strength between individual MV3 cells was quantified using atomic force microscopy and validated by multicellular aggregation assays. Extracellular acidification from pHe7.4 to 6.4 decreases cell migration and invasion but increases single cell detachment from the spheroids. Acidification and NHE1 overexpression both reduce cell-cell adhesion strength, indicated by reduced maximum pulling forces and adhesion energies. Multicellular aggregation and spheroid formation are strongly impaired under acidification or NHE1 overexpression. We show a clear dependence of melanoma cell-cell adhesion on pHe and NHE1 as a modulator. These effects are opposite to cell-matrix interactions that are strengthened by protons extruded via NHE1. We conclude that these opposite effects of NHE1 act synergistically during the metastatic cascade. PMID:28205573

  9. Adjustable thermal resistor by reversibly folding a graphene sheet.

    Science.gov (United States)

    Song, Qichen; An, Meng; Chen, Xiandong; Peng, Zhan; Zang, Jianfeng; Yang, Nuo

    2016-08-11

    Phononic (thermal) devices such as thermal diodes, thermal transistors, thermal logic gates, and thermal memories have been studied intensively. However, tunable thermal resistors have not been demonstrated yet. Here, we propose an instantaneously adjustable thermal resistor based on folded graphene. Through theoretical analysis and molecular dynamics simulations, we study the phonon-folding scattering effect and the dependence of thermal resistivity on the length between two folds and the overall length. Furthermore, we discuss the possibility of realizing instantaneously adjustable thermal resistors in experiment. Our studies bring new insights into designing thermal resistors and understanding the thermal modulation of 2D materials by adjusting basic structure parameters.

  10. 川东"侏罗山式"褶皱的数值模拟及成因探讨%Numerical Modeling and Formation Mechanism of the Eastern Sichuan Jura-type Folds

    Institute of Scientific and Technical Information of China (English)

    张必龙; 朱光; JIANG Dazhi; 胡召齐; 向必伟; 张力; 陈印

    2009-01-01

    Numerical modeling of Jura-type (detachment) folds by using the finite-different code FLAC shows that interlayer cohesion contrasts and overlying confining pressures are key factors for development of comb-like and trough-like folds, indicating controlling by interlayer competence contrast and burial depth. When folded strata are in shallow levels, interlayer competence contrast plays an important role in fold styles. Lower interlayer competence contrast will produce trough-like folds whereas higher interlayer competence contrast will lead to comb-like folds. As the depth increases, the pressure gradually plays a major important role and higher overlying pressures will cause trough-like folds only. Lower interlayer competence contrast in the folded strata in the eastern part of the eastern Sichuan fold belt results in trough-like folds both in shallower and deeper levels of the cover, which are consistent with our numerical modeling results. Higher interlayer competence contrast in the western folded strata causes comb-like folds in the shallower levels. However, the fold style in the deeper,lower Paleozoic cover strata in the western belt are mainly controlled by overlying pressures, and the developed fold style should be trough-like folds according to the numerical modeling results.%本文通过采用有限差分法(FLAC)对”侏罗山式”褶皱进行数值模拟发现,层间粘聚力差异和上覆压力是控制隔档式褶皱、隔槽式褶皱样式的主要因素,即层间的能干性差异和埋深的控制.当地层在埋深较浅时,层间能干性差异对褶皱样式起主控作用,能干性差异小时出现隔槽式褶皱,差异大时出现隔档式褶皱.随着埋深加大,压力逐渐起主要作用,这时仅出现隔槽式褶皱.川东东带褶皱地层总体上层间能干性差异小,因而盖层的深部与浅部皆出现隔槽式褶皱,与模拟结果一致.西带褶皱地层总体层间能干性差异大,因而浅部出现隔档式褶皱.

  11. Effect of modulation periods on the microstructure and mechanical properties of DLC/TiC multilayer films deposited by filtered cathodic vacuum arc method

    Energy Technology Data Exchange (ETDEWEB)

    Xu, Zhaoying [Key Laboratory of Advanced Technologies of Materials, Ministry of Education of China, School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu 610031, Sichuan (China); State Key Laboratory of Vanadium and Titanium Resources Comprehensive Utilization, Pangang Group Research Institute Co., Ltd., Panzhihua 617000, Sichuan (China); Sun, H. [Key Laboratory of Advanced Technologies of Materials, Ministry of Education of China, School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu 610031, Sichuan (China); Leng, Y.X., E-mail: yxleng@263.net [Key Laboratory of Advanced Technologies of Materials, Ministry of Education of China, School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu 610031, Sichuan (China); Li, Xueyuan; Yang, Wenmao [Institute of Mechanical Manufacturing Technology, China Academy of Engineering Physics, Mianyang 621900, Sichuan (China); Huang, N. [Key Laboratory of Advanced Technologies of Materials, Ministry of Education of China, School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu 610031, Sichuan (China)

    2015-02-15

    Highlights: • DLC/TiC multilayer films with different modulation periods at same modulation ratio 1:1 were deposited by FCVA. • The residual stress of DLC/TiC multilayer films decreases with the modulation periods decrease. • The hardness of the multilayer DLC films decreases with modulation periods increasing. - Abstract: The high stress of diamond-like carbon (DLC) film limits its thickness and adhesion on substrate. Multilayer structure is one approach to overcome this disadvantage. In this paper, the DLC/TiC multilayer films with different modulation periods (80 nm, 106 nm or 160 nm) at same modulation ratio of 1:1 were deposited on Si(1 0 0) wafer and Ti-6Al-4V substrate by filtered cathodic vacuum arc (FCVA) technology. X-ray diffraction (XRD), transmission electron microscopy (TEM), nanoindention and wear test were employed to investigate the effect of modulation periods on the microstructure and mechanical properties of the multilayer films. The results showed that the residual stress of the DLC/TiC multilayer films could be effectively reduced and the residual stress decreased with the modulation periods decreasing. The hardness of the DLC/TiC multilayer films increased with modulation periods decreasing. The DLC/TiC multilayer film with modulation period of 106 nm had the best wear resistance due to the good combination of hardness, ductility and low compressive stress.

  12. Physical exercise and acute restraint stress differentially modulate hippocampal brain-derived neurotrophic factor transcripts and epigenetic mechanisms in mice.

    Science.gov (United States)

    Ieraci, Alessandro; Mallei, Alessandra; Musazzi, Laura; Popoli, Maurizio

    2015-11-01

    Physical exercise and stressful experiences have been shown to exert opposite effects on behavioral functions and brain plasticity, partly by involving the action of brain-derived neurotrophic factor (BDNF). Although epigenetic modifications are known to play a pivotal role in the regulation of the different BDNF transcripts, it is poorly understood whether epigenetic mechanisms are also implied in the BDNF modulation induced by physical exercise and stress. Here, we show that total BDNF mRNA levels and BDNF transcripts 1, 2, 3, 4, 6, and 7 were reduced immediately after acute restraint stress (RS) in the hippocampus of mice, and returned to control levels 24 h after the stress session. On the contrary, exercise increased BDNF mRNA expression and counteracted the stress-induced decrease of BDNF transcripts. Physical exercise-induced up-regulation of BDNF transcripts was accounted for by increase in histone H3 acetylated levels at specific BDNF promoters, whereas the histone H3 trimethylated lysine 27 and dimethylated lysine 9 levels were unaffected. Acute RS did not change the levels of acetylated and methylated histone H3 at the BDNF promoters. Furthermore, we found that physical exercise and RS were able to differentially modulate the histone deacetylases mRNA levels. Finally, we report that a single treatment with histone deacetylase inhibitors, prior to acute stress exposure, prevented the down-regulation of total BDNF and BDNF transcripts 1, 2, 3, and 6, partially reproducing the effect of physical exercise. Overall, these results suggest that physical exercise and stress are able to differentially modulate the expression of BDNF transcripts by possible different epigenetic mechanisms. © 2015 Wiley Periodicals, Inc.

  13. Mechanisms of action of anesthetics for the modulation of perioperative thrombosis: evidence for immune mechanisms from basic and clinical studies.

    Science.gov (United States)

    Azma, Toshiharu; Tuluc, Florin; Ito, Taishin; Aoyama-Mani, Chikako; Kawahito, Shinji; Kinoshita, Hiroyuki

    2014-01-01

    Thrombotic events occurring in either arteries or veins are the primary causes of fatal perioperative cardiovascular events. Risk factors for deep vein thrombosis, several of which are evidently associated with specific surgical procedures, are quite different from those for arterial thrombosis (e.g., aging or atherosclerotic diseases). Thrombus formed in arteries consists mainly of platelets coated with fibrin (i.e., white thrombus), while venous thrombus formed at relatively lower shear stress consists of all blood components including erythrocytes as well as leukocytes infiltrated with fibrin (red thrombus). Clinical evidence indicates beneficial roles of neuraxial anesthesia/analgesia in the prevention of VTE for patients undergoing high risk surgical procedures. To date, mechanisms of action of drugs used for neuraxial anesthesia/analgesia to prevent venous thrombosis are uncertain. However, accumulation of clinical as well as experimental findings points to the involvement of immune cells (especially monocytes) in red thrombus generation and to the interaction of anesthetics with these cells. We also suggest that adhesion molecules associated with the formation of monocyte platelet aggregates as well as substance P: neurokinin-1 receptor (SP/NK1R) pathway that involves neurogenic inflammation are crucial. Local anesthetics and NK1R antagonists are candidate drugs that may possess the capability to prevent venous thrombotic disorders in perioperative settings.

  14. A simple theory of protein folding kinetics

    CERN Document Server

    Pande, Vijay S

    2010-01-01

    We present a simple model of protein folding dynamics that captures key qualitative elements recently seen in all-atom simulations. The goals of this theory are to serve as a simple formalism for gaining deeper insight into the physical properties seen in detailed simulations as well as to serve as a model to easily compare why these simulations suggest a different kinetic mechanism than previous simple models. Specifically, we find that non-native contacts play a key role in determining the mechanism, which can shift dramatically as the energetic strength of non-native interactions is changed. For protein-like non-native interactions, our model finds that the native state is a kinetic hub, connecting the strength of relevant interactions directly to the nature of folding kinetics.

  15. Catalytic Thr or Ser Residue Modulates Structural Switches in 2-Cys Peroxiredoxin by Distinct Mechanisms

    Science.gov (United States)

    Tairum, Carlos A.; Santos, Melina Cardoso; Breyer, Carlos A.; Geyer, R. Ryan; Nieves, Cecilia J.; Portillo-Ledesma, Stephanie; Ferrer-Sueta, Gerardo; Toledo, José Carlos; Toyama, Marcos H.; Augusto, Ohara; Netto, Luis E. S.; de Oliveira, Marcos A.

    2016-01-01

    Typical 2-Cys Peroxiredoxins (2-Cys Prxs) reduce hydroperoxides with extraordinary rates due to an active site composed of a catalytic triad, containing a peroxidatic cysteine (CP), an Arg, and a Thr (or Ser). 2-Cys Prx are involved in processes such as cancer; neurodegeneration and host-pathogen interactions. During catalysis, 2-Cys Prxs switch between decamers and dimers. Analysis of 2-Cys Prx structures in the fully folded (but not locally unfolded) form revealed a highly conserved, non-conventional hydrogen bond (CH-π) between the catalytic triad Thr of a dimer with an aromatic residue of an adjacent dimer. In contrast, structures of 2-Cys Prxs with a Ser in place of the Thr do not display this CH-π bond. Chromatographic and structural data indicate that the Thr (but not Ser) destabilizes the decamer structure in the oxidized state probably through steric hindrance. As a general trend, mutations in a yeast 2-Cys Prx (Tsa1) favoring the dimeric state also displayed a decreased catalytic activity. Remarkably, yeast naturally contains Thr-Ser variants (Tsa1 and Tsa2, respectively) with distinct oligomeric stabilities in their disulfide states. PMID:27629822

  16. Estradiol-induced modulation of estrogen receptor-beta and GABA within the adult neocortex: a potential transsynaptic mechanism for estrogen modulation of BDNF.

    Science.gov (United States)

    Blurton-Jones, Mathew; Tuszynski, Mark H

    2006-12-01

    Estrogen influences brain-derived neurotrophic factor (BDNF) expression in the neocortex. However, BDNF-producing cortical neurons do not express detectable levels of nuclear estrogen receptors; instead, the most abundant cortical nuclear estrogen receptor, ER-beta, is present in GABAergic neurons, prompting us to test the hypothesis that estrogen effects on BDNF are mediated via cortical inhibitory interneurons. Adult female ovariectomized rats were provided acute estrogen replacement and the number of cortical GABA, ER-beta, and ER-beta/GABA double-labeled neurons was examined. Within 48 hours of injection of 17-beta-estradiol, the number of perirhinal neurons double-labeled for ER-beta/GABA was reduced by 28% (PBDNF-expressing cells, brain sections were double- or triple-labeled for ER-beta, GABAergic, and BDNF immunomarkers. The findings indicated that ER-beta-bearing inhibitory neurons project onto other GABAergic neurons that lack nuclear estrogen receptors; these inhibitory neurons in turn innervate BDNF-expressing excitatory cells. High estrogen states reduce cortical GABA levels, presumably releasing inhibition on BDNF-expressing neurons. This identifies a putative two-step transsynaptic mechanism whereby estrogen availability modulates expression of inhibitory transmitters, resulting in increased BDNF expression.

  17. Microarray and pathway analysis reveal distinct mechanisms underlying cannabinoid-mediated modulation of LPS-induced activation of BV-2 microglial cells.

    Directory of Open Access Journals (Sweden)

    Ana Juknat

    Full Text Available Cannabinoids are known to exert immunosuppressive activities. However, the mechanisms which contribute to these effects are unknown. Using lipopolysaccharide (LPS to activate BV-2 microglial cells, we examined how Δ(9-tetrahydrocannabinol (THC, the major psychoactive component of marijuana, and cannabidiol (CBD the non-psychoactive component, modulate the inflammatory response. Microarray analysis of genome-wide mRNA levels was performed using Illumina platform and the resulting expression patterns analyzed using the Ingenuity Pathway Analysis to identify functional subsets of genes, and the Ingenuity System Database to denote the gene networks regulated by CBD and THC. From the 5338 transcripts that were differentially expressed across treatments, 400 transcripts were found to be upregulated by LPS, 502 by CBD+LPS and 424 by THC+LPS, while 145 were downregulated by LPS, 297 by CBD+LPS and 149 by THC+LPS, by 2-fold or more (p≤0.005. Results clearly link the effects of CBD and THC to inflammatory signaling pathways and identify new cannabinoid targets in the MAPK pathway (Dusp1, Dusp8, Dusp2, cell cycle related (Cdkn2b, Gadd45a as well as JAK/STAT regulatory molecules (Socs3, Cish, Stat1. The impact of CBD on LPS-stimulated gene expression was greater than that of THC. We attribute this difference to the fact that CBD highly upregulated several genes encoding negative regulators of both NFκB and AP-1 transcriptional activities, such as Trib3 and Dusp1 known to be modulated through Nrf2 activation. The CBD-specific expression profile reflected changes associated with oxidative stress and glutathione depletion via Trib3 and expression of ATF4 target genes. Furthermore, the CBD affected genes were shown to be controlled by nuclear factors usually involved in regulation of stress response and inflammation, mainly via Nrf2/Hmox1 axis and the Nrf2/ATF4-Trib3 pathway. These observations indicate that CBD, and less so THC, induce a cellular stress

  18. Formation mechanism and modulation of electromagnetically induced transparency-like transmission in side-coupled structures

    Institute of Scientific and Technical Information of China (English)

    杨辉; 李宏建; 许秀科; 何智慧; 王云; 徐国均

    2015-01-01

    Based on Fabry model and finite-different time-domain (FDTD) method, the plasmonic structure composed of a metal-insulator-metal (MIM) bus waveguide and a side-coupled resonator was investigated. It is found that the transmission features can be regulated by the cavity width and coupling distance. Electromagnetically induced transparency (EIT)-like transmission can be excited by adding anidentical resonator on the pre-existing structure. Combining the foregoing theoretical analysis with coupled mode theory (CMT), the formation process of the EIT-like transmission was detailedly analyzed. EIT-like transmission can also be excited in plasmonic structure with two detuned resonators. By altering the structure parameters, the transparency window can be purposefully modulated. With themeritsof compact structure and simplicity in fabrication, the proposed structures may have a broad prospect of applications in highly integrated optical circuits.

  19. Folding and Fracturing of Rocks: the background

    Science.gov (United States)

    Ramsay, John G.

    2017-04-01

    This book was generated by structural geology teaching classes at Imperial College. I was appointed lecturer during 1957 and worked together with Dr Gilbert Wilson teaching basic structural geology at B.Sc level. I became convinced that the subject, being essentially based on geometric field observations, required a firm mathematical basis for its future development. In particular it seemed to me to require a very sound understanding of stress and strain. My field experience suggested that a knowledge of two- and three-demensional strain was critical in understanding natural tectonic processes. I found a rich confirmation for this in early publications of deformed fossils, oolitic limestones and spotted slates made by several geologists around the beginning of the 20th century (Sorby, Philips, Haughton, Harker) often using surprisingly sophisticated mathematical methods. These methods were discussed and elaborated in Folding and Fracturing of Rocks in a practical way. The geometric features of folds were related to folding mechanisms and the fold related small scale structures such as cleavage, schistosity and lineation explained in terms of rock strain. My work in the Scottish Highlands had shown just how repeated fold superposition could produce very complex geometric features, while further work in other localities suggested that such geometric complications are common in many orogenic zones. From the development of structural geological studies over the past decades it seems that the readers of this book have found many of the ideas set out are still of practical application. The mapping of these outcrop-scale structures should be emphasised in all field studies because they can be seen as ''fingerprints'' of regional scale tectonic processes. My own understanding of structural geology has been inspired by field work and I am of the opinion that future progress in understanding will be likewise based on careful observation and measurement of the features of

  20. Folding gravitational-wave interferometers

    Science.gov (United States)

    Sanders, J. R.; Ballmer, Stefan W.

    2017-01-01

    The sensitivity of kilometer-scale terrestrial gravitational wave interferometers is limited by mirror coating thermal noise. Alternative interferometer topologies can mitigate the impact of thermal noise on interferometer noise curves. In this work, we explore the impact of introducing a single folding mirror into the arm cavities of dual-recycled Fabry–Perot interferometers. While simple folding alone does not reduce the mirror coating thermal noise, it makes the folding mirror the critical mirror, opening up a variety of design and upgrade options. Improvements to the folding mirror thermal noise through crystalline coatings or cryogenic cooling can increase interferometer range by as much as a factor of two over the Advanced LIGO reference design.

  1. Protein folding by distributed computing and the denatured state ensemble.

    Science.gov (United States)

    Marianayagam, Neelan J; Fawzi, Nicolas L; Head-Gordon, Teresa

    2005-11-15

    The distributed computing (DC) paradigm in conjunction with the folding@home (FH) client server has been used to study the folding kinetics of small peptides and proteins, giving excellent agreement with experimentally measured folding rates, although pathways sampled in these simulations are not always consistent with the folding mechanism. In this study, we use a coarse-grain model of protein L, whose two-state kinetics have been characterized in detail by using long-time equilibrium simulations, to rigorously test a FH protocol using approximately 10,000 short-time, uncoupled folding simulations starting from an extended state of the protein. We show that the FH results give non-Poisson distributions and early folding events that are unphysical, whereas longer folding events experience a correct barrier to folding but are not representative of the equilibrium folding ensemble. Using short-time, uncoupled folding simulations started from an equilibrated denatured state ensemble (DSE), we also do not get agreement with the equilibrium two-state kinetics because of overrepresented folding events arising from higher energy subpopulations in the DSE. The DC approach using uncoupled short trajectories can make contact with traditionally measured experimental rates and folding mechanism when starting from an equilibrated DSE, when the simulation time is long enough to sample the lowest energy states of the unfolded basin and the simulated free-energy surface is correct. However, the DC paradigm, together with faster time-resolved and single-molecule experiments, can also reveal the breakdown in the two-state approximation due to observation of folding events from higher energy subpopulations in the DSE.

  2. Teaching computers to fold proteins

    OpenAIRE

    Winther, Ole; Krogh, Anders Stærmose

    2004-01-01

    A new general algorithm for optimization of potential functions for protein folding is introduced. It is based upon gradient optimization of the thermodynamic stability of native folds of a training set of proteins with known structure. The iterative update rule contains two thermodynamic averages which are estimated by (generalized ensemble) Monte Carlo. We test the learning algorithm on a Lennard-Jones (LJ) force field with a torsional angle degrees-of-freedom and a single-atom side-chain. ...

  3. Protein folding by motion planning

    Science.gov (United States)

    Thomas, Shawna; Song, Guang; Amato, Nancy M.

    2005-12-01

    We investigate a novel approach for studying protein folding that has evolved from robotics motion planning techniques called probabilistic roadmap methods (PRMs). Our focus is to study issues related to the folding process, such as the formation of secondary and tertiary structures, assuming we know the native fold. A feature of our PRM-based framework is that the large sets of folding pathways in the roadmaps it produces, in just a few hours on a desktop PC, provide global information about the protein's energy landscape. This is an advantage over other simulation methods such as molecular dynamics or Monte Carlo methods which require more computation and produce only a single trajectory in each run. In our initial studies, we obtained encouraging results for several small proteins. In this paper, we investigate more sophisticated techniques for analyzing the folding pathways in our roadmaps. In addition to more formally revalidating our previous results, we present a case study showing that our technique captures known folding differences between the structurally similar proteins G and L. This research was supported in part by NSF CAREER Award CCR-9624315, NSF Grants ACI-9872126, EIA-9975018, EIA-0103742, EIA-9805823, ACR-0113971, CCR-0113974, EIA-9810937, EIA-0079874 and the Texas Higher Education Coordinating Board grant ATP-000512-0261-2001. ST was supported in part by an NSF Graduate Research Fellowship. GS was supported in part by an IBM PhD Fellowship.

  4. Electrochemistry of folded graphene edges.

    Science.gov (United States)

    Ambrosi, Adriano; Bonanni, Alessandra; Pumera, Martin

    2011-05-01

    There is enormous interest in the investigation of electron transfer rates at the edges of graphene due to possible energy storage and sensing applications. While electrochemistry at the edges and the basal plane of graphene has been studied in the past, the new frontier is the electrochemistry of folded graphene edges. Here we describe the electrochemistry of folded graphene edges and compare it to that of open graphene edges. The materials were characterized in detail by high-resolution transmission electron microscopy, Raman spectroscopy, high-resolution X-ray photoelectron spectroscopy, electrochemical impedance spectroscopy and cyclic voltammetry. We found that the heterogeneous electron transfer rate is significantly lower on folded graphene edges compared to open edge sites for ferro/ferricyanide, and that electrochemical properties of open edges offer lower potential detection of biomarkers than the folded ones. It is apparent, therefore, that for sensing and biosensing applications the folded edges are less active than open edges, which should then be preferred for such applications. As folded edges are the product of thermal treatment of multilayer graphene, such thermal procedures should be avoided when fabricating graphene for electrochemical applications.

  5. BBB on chip: microfluidic platform to mechanically and biochemically modulate blood-brain barrier function

    NARCIS (Netherlands)

    Griep, L.M.; Wolbers, F.; de Wagenaar, B.; ter Braak, Paulus Martinus; Weksler, B.B.; Romero, A.; Couraud, P.O.; Vermes, I.; van der Meer, Andries Dirk; van den Berg, Albert

    The blood-brain barrier (BBB) is a unique feature of the human body, preserving brain homeostasis and preventing toxic substances to enter the brain. However, in various neurodegenerative diseases, the function of the BBB is disturbed. Mechanisms of the breakdown of the BBB are incompletely

  6. Whey protein particles modulate mechanical properties of gels at high protein concentrations

    NARCIS (Netherlands)

    Saglam, D.; Venema, P.; Vries, de R.J.; Berg, van den L.; Linden, van der E.

    2014-01-01

    We have studied the influence of dense whey protein particles on the mechanical properties of whey protein isolate (WPI) gels at high protein concentrations (16–22% (w/w)). Incorporation of dense whey protein particles in the gel, while keeping the total protein concentration constant, leads to a co

  7. Epigenetic mechanisms at work: Exploiting nutrient-specific modulation of genetic networks

    Science.gov (United States)

    “Epigenetics” was used to describe actions of genes with their environment that bring the phenotype into being”. The modern version of epigenetics includes the molecular mechanisms that influence the phenotypic outcome of a gene or genome, in absence of changes to the underlying DNA sequence. A hos...

  8. BBB on chip: microfluidic platform to mechanically and biochemically modulate blood-brain barrier function

    NARCIS (Netherlands)

    Griep, L.M.; Wolbers, F.; Wagenaar, de B.; Braak, ter P.M.; Weksler, B.B.; Romero, A.; Couraud, P.O.; Vermes, I.; Meer, van der A.D.; Berg, van den A.

    2013-01-01

    The blood-brain barrier (BBB) is a unique feature of the human body, preserving brain homeostasis and preventing toxic substances to enter the brain. However, in various neurodegenerative diseases, the function of the BBB is disturbed. Mechanisms of the breakdown of the BBB are incompletely understo

  9. Flexural-slip during visco-elastic buckle folding

    Science.gov (United States)

    Damasceno, Davi R.; Eckert, Andreas; Liu, Xiaolong

    2017-07-01

    Flexural-slip is considered as an important mechanism during folding and a general conceptual and qualitative understanding has been provided by various field studies. However, quantitative evidence of the importance of the flexural-slip mechanism during fold evolution is sparse due to the lack of suitable strain markers. In this study, 2D finite element analysis is used to overcome these disadvantages and to simulate flexural-slip during visco-elastic buckle folding. Variations of single and multilayer layer fold configurations are investigated, showing that flexural-slip is most likely to occur in effective single layer buckle folds, where slip occurs between contacts of competent layers. Based on effective single layer buckle folds, the influence of the number of slip surfaces, the degree of mechanical coupling (based on the friction coefficient), and layer thickness, on the resulting slip distribution are investigated. The results are in agreement with the conceptual flexural-slip model and show that slip is initiated sequentially during the deformation history and is maximum along the central slip surface of the fold limb. The cumulative amount of slip increases as the number of slip surfaces is increased. For a lower degree of mechanical coupling increased slip results in different fold shapes, such as box folds, during buckling. In comparison with laboratory experiments, geometrical relationships and field observations, the numerical modeling results show similar slip magnitudes. It is concluded that flexural-slip should represent a significant contribution during buckle folding, affecting the resulting fold shape for increased amounts of slip.

  10. Self-folding graphene-polymer bilayers

    Energy Technology Data Exchange (ETDEWEB)

    Deng, Tao [Institute of Microelectronics, Tsinghua University, Beijing 100084 (China); Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, Maryland 21218 (United States); Yoon, ChangKyu [Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, Maryland 21218 (United States); Jin, Qianru [Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, Maryland 21218 (United States); Li, Mingen [Department of Physics, Johns Hopkins University, Baltimore, Maryland 21218 (United States); Liu, Zewen [Institute of Microelectronics, Tsinghua University, Beijing 100084 (China); Gracias, David H., E-mail: dgracias@jhu.edu [Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, Maryland 21218 (United States); Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, Maryland 21218 (United States)

    2015-05-18

    In order to incorporate the extraordinary intrinsic thermal, electrical, mechanical, and optical properties of graphene with three dimensional (3D) flexible substrates, we introduce a solvent-driven self-folding approach using graphene-polymer bilayers. A polymer (SU-8) film was spin coated atop chemically vapor deposited graphene films on wafer substrates and graphene-polymer bilayers were patterned with or without metal electrodes using photolithography, thin film deposition, and etching. After patterning, the bilayers were released from the substrates and they self-folded to form fully integrated, curved, and folded structures. In contrast to planar graphene sensors on rigid substrates, we assembled curved and folded sensors that are flexible and they feature smaller form factors due to their 3D geometry and large surface areas due to their multiple rolled architectures. We believe that this approach could be used to assemble a range of high performance 3D electronic and optical devices of relevance to sensing, diagnostics, wearables, and energy harvesting.

  11. Self-folding graphene-polymer bilayers

    Science.gov (United States)

    Deng, Tao; Yoon, ChangKyu; Jin, Qianru; Li, Mingen; Liu, Zewen; Gracias, David H.

    2015-05-01

    In order to incorporate the extraordinary intrinsic thermal, electrical, mechanical, and optical properties of graphene with three dimensional (3D) flexible substrates, we introduce a solvent-driven self-folding approach using graphene-polymer bilayers. A polymer (SU-8) film was spin coated atop chemically vapor deposited graphene films on wafer substrates and graphene-polymer bilayers were patterned with or without metal electrodes using photolithography, thin film deposition, and etching. After patterning, the bilayers were released from the substrates and they self-folded to form fully integrated, curved, and folded structures. In contrast to planar graphene sensors on rigid substrates, we assembled curved and folded sensors that are flexible and they feature smaller form factors due to their 3D geometry and large surface areas due to their multiple rolled architectures. We believe that this approach could be used to assemble a range of high performance 3D electronic and optical devices of relevance to sensing, diagnostics, wearables, and energy harvesting.

  12. Study Modules for Calculus-Based General Physics. [Includes Modules 11-14: Collisions; Equilibrium of Rigid Bodies; Rotational Dynamics; and Fluid Mechanics].

    Science.gov (United States)

    Fuller, Robert G., Ed.; And Others

    This is part of a series of 42 Calculus Based Physics (CBP) modules totaling about 1,000 pages. The modules include study guides, practice tests, and mastery tests for a full-year individualized course in calculus-based physics based on the Personalized System of Instruction (PSI). The units are not intended to be used without outside materials;…

  13. A little elastic for a better performance: kinesiotaping of the motor effector modulates neural mechanisms for rhythmic movements

    Science.gov (United States)

    Bravi, Riccardo; Quarta, Eros; Cohen, Erez J.; Gottard, Anna; Minciacchi, Diego

    2014-01-01

    A rhythmic motor performance is brought about by an integration of timing information with movements. Investigations on the millisecond time scale distinguish two forms of time control, event-based timing and emergent timing. While event-based timing asserts the existence of a central internal timekeeper for the control of repetitive movements, the emergent timing perspective claims that timing emerges from dynamic control of nontemporal movements parameters. We have recently demonstrated that the precision of an isochronous performance, defined as performance of repeated movements having a uniform duration, was insensible to auditory stimuli of various characteristics (Bravi et al., 2014). Such finding has led us to investigate whether the application of an elastic therapeutic tape (Kinesio® Tex taping; KTT) used for treating athletic injuries and a variety of physical disorders, is able to reduce the timing variability of repetitive rhythmic movement. Young healthy subjects, tested with and without KTT, have participated in sessions in which sets of repeated isochronous wrist's flexion-extensions (IWFEs) were performed under various auditory conditions and during their recall. Kinematics was recorded and temporal parameters were extracted and analyzed. Our results show that the application of KTT decreases the variability of rhythmic movements by a 2-fold effect: on the one hand KTT provides extra proprioceptive information activating cutaneous mechanoreceptors, on the other KTT biases toward the emergent timing thus modulating the processes for rhythmic movements. Therefore, KTT appears able to render movements less audio dependent by relieving, at least partially, the central structures from time control and making available more resources for an augmented performance. PMID:25309355

  14. A little elastic for a better performance: kinesiotaping of the motor effector modulates neural mechanisms for rhythmic movements.

    Science.gov (United States)

    Bravi, Riccardo; Quarta, Eros; Cohen, Erez J; Gottard, Anna; Minciacchi, Diego

    2014-01-01

    A rhythmic motor performance is brought about by an integration of timing information with movements. Investigations on the millisecond time scale distinguish two forms of time control, event-based timing and emergent timing. While event-based timing asserts the existence of a central internal timekeeper for the control of repetitive movements, the emergent timing perspective claims that timing emerges from dynamic control of nontemporal movements parameters. We have recently demonstrated that the precision of an isochronous performance, defined as performance of repeated movements having a uniform duration, was insensible to auditory stimuli of various characteristics (Bravi et al., 2014). Such finding has led us to investigate whether the application of an elastic therapeutic tape (Kinesio® Tex taping; KTT) used for treating athletic injuries and a variety of physical disorders, is able to reduce the timing variability of repetitive rhythmic movement. Young healthy subjects, tested with and without KTT, have participated in sessions in which sets of repeated isochronous wrist's flexion-extensions (IWFEs) were performed under various auditory conditions and during their recall. Kinematics was recorded and temporal parameters were extracted and analyzed. Our results show that the application of KTT decreases the variability of rhythmic movements by a 2-fold effect: on the one hand KTT provides extra proprioceptive information activating cutaneous mechanoreceptors, on the other KTT biases toward the emergent timing thus modulating the processes for rhythmic movements. Therefore, KTT appears able to render movements less audio dependent by relieving, at least partially, the central structures from time control and making available more resources for an augmented performance.

  15. Molecular mechanism for the dual alcohol modulation of Cys-loop receptors.

    Directory of Open Access Journals (Sweden)

    Samuel Murail

    Full Text Available Cys-loop receptors constitute a superfamily of pentameric ligand-gated ion channels (pLGICs, including receptors for acetylcholine, serotonin, glycine and γ-aminobutyric acid. Several bacterial homologues have been identified that are excellent models for understanding allosteric binding of alcohols and anesthetics in human Cys-loop receptors. Recently, we showed that a single point mutation on a prokaryotic homologue (GLIC could transform it from a channel weakly potentiated by ethanol into a highly ethanol-sensitive channel. Here, we have employed molecular simulations to study ethanol binding to GLIC, and to elucidate the role of the ethanol-enhancing mutation in GLIC modulation. By performing 1-µs simulations with and without ethanol on wild-type and mutated GLIC, we observed spontaneous binding in both intra-subunit and inter-subunit transmembrane cavities. In contrast to the glycine receptor GlyR, in which we previously observed ethanol binding primarily in an inter-subunit cavity, ethanol primarily occupied an intra-subunit cavity in wild-type GLIC. However, the highly ethanol-sensitive GLIC mutation significantly enhanced ethanol binding in the inter-subunit cavity. These results demonstrate dramatic effects of the F(14'A mutation on the distribution of ligands, and are consistent with a two-site model of pLGIC inhibition and potentiation.

  16. The mechanism of noradrenergic alpha 1 excitatory modulation of pontine reticular formation neurons.

    Science.gov (United States)

    Stevens, D R; McCarley, R W; Greene, R W

    1994-11-01

    The alpha 1 adrenergic receptor occurs in all major divisions of the CNS and is thought to play a role in all behaviors influenced by norepinephrine (NE). In the medial pontine reticular formation (mPRF), the proposed site of adrenergic enhancement of startle responses (Davis, 1984), alpha 1 agonists excite most neurons (Gerber et al., 1990). We here report that alpha 1 excitation results from a reduction of a voltage- and calcium-dependent potassium current, not previously recognized as ligand-modulated. The calcium sensitivity is suggested by its antagonism with Mg2+, Cd2+, Ba2+, low concentrations of tetraethylammonium, and charybdotoxin. The voltage sensitivity of this conductance falls within the membrane potential range critical to action potential generation. Based on this voltage sensitivity, the change in repetitive firing characteristics may be predicted according to a mathematical model of the mPRF neuronal electrophysiology. The predicted response to a 50% decrease in the phenylephrine (PE)-sensitive conductance is similar to the observed responses, with respect to both the current response under voltage-clamp conditions and alterations of the AHP and frequency/current curve. In contrast, modeling a reduction of a voltage-insensitive leak current predicts none of these changes. Thus, the noradrenergic reduction of this current depolarizes the membrane, increases the likelihood of an initial response to depolarizing input, and increases firing rate during sustained depolarization in a manner consistent with an NE role as an excitatory neuromodulator of the mPRF.

  17. Modulating epigenetic mechanisms: the diverse functions of Ski during cortical development.

    Science.gov (United States)

    Baranek, Constanze; Atanasoski, Suzana

    2012-07-01

    In the developing forebrain, neural stem and progenitor cells generate a large variety of neurons with specific functions in the mature cortex. A central issue is to understand the roles of transcriptional networks and regulatory pathways that control these complex developmental processes. The proto-oncogene Ski is a transcriptional regulator linked to the human 1p36 deletion syndrome, which involves a set of phenotypes including nervous system defects. Ski shows a dynamic expression pattern during cortical development and, accordingly, the phenotype of Ski-deficient cortices is complex, involving altered cell cycle characteristics of neural progenitors, disturbed timing of neurogenesis and mis-specification of projection neurons. Ski is likely to play a role in various pathways by virtue of its ability to interact with a range of signaling molecules, thereby modulating transcriptional activity of corresponding target genes. Ski regulates proliferation and differentiation of various cell types, and more recent data from my laboratory demonstrates that Ski is also involved in the specification of cortical projection neurons. This Point-of-View elucidates the role of Ski as an essential linker between sequence-specific transcription factors and non-DNA binding cofactors with chromatin modifying activities. In particular, it puts forward the hypothesis that the diverse functions of Ski as a co-repressor might be related to its association with distinct HDAC-complexes.

  18. Brain mechanisms of persuasion: how ‘expert power’ modulates memory and attitudes

    Science.gov (United States)

    Smidts, Ale; Fernández, Guillén

    2008-01-01

    Human behaviour is affected by various forms of persuasion. The general persuasive effect of high expertise of the communicator, often referred to as ’expert power’, is well documented. We found that a single exposure to a combination of an expert and an object leads to a long-lasting positive effect on memory for and attitude towards the object. Using functional magnetic resonance imaging, we probed the neural processes predicting these behavioural effects. Expert context was associated with distributed left-lateralized brain activity in prefrontal and temporal cortices related to active semantic elaboration. Furthermore, experts enhanced subsequent memory effects in the medial temporal lobe (i.e. in hippocampus and parahippocampal gyrus) involved in memory formation. Experts also affected subsequent attitude effects in the caudate nucleus involved in trustful behaviour, reward processing and learning. These results may suggest that the persuasive effect of experts is mediated by modulation of caudate activity resulting in a re-evaluation of the object in terms of its perceived value. Results extend our view of the functional role of the dorsal striatum in social interaction and enable us to make the first steps toward a neuroscientific model of persuasion. PMID:19015077

  19. Apoptosis as anticancer mechanism: function and dysfunction of its modulators and targeted therapeutic strategies.

    Science.gov (United States)

    Pistritto, Giuseppa; Trisciuoglio, Daniela; Ceci, Claudia; Garufi, Alessia; D'Orazi, Gabriella

    2016-04-01

    Apoptosis is a form of programmed cell death that results in the orderly and efficient removal of damaged cells, such as those resulting from DNA damage or during development. Apoptosis can be triggered by signals from within the cell, such as genotoxic stress, or by extrinsic signals, such as the binding of ligands to cell surface death receptors. Deregulation in apoptotic cell death machinery is an hallmark of cancer. Apoptosis alteration is responsible not only for tumor development and progression but also for tumor resistance to therapies. Most anticancer drugs currently used in clinical oncology exploit the intact apoptotic signaling pathways to trigger cancer cell death. Thus, defects in the death pathways may result in drug resistance so limiting the efficacy of therapies. Therefore, a better understanding of the apoptotic cell death signaling pathways may improve the efficacy of cancer therapy and bypass resistance. This review will highlight the role of the fundamental regulators of apoptosis and how their deregulation, including activation of anti-apoptotic factors (i.e., Bcl-2, Bcl-xL, etc) or inactivation of pro-apoptotic factors (i.e., p53 pathway) ends up in cancer cell resistance to therapies. In addition, therapeutic strategies aimed at modulating apoptotic activity are briefly discussed.

  20. Shrink Wrapping Cells in a Defined Extracellular Matrix to Modulate the Chemo-Mechanical Microenvironment.

    Science.gov (United States)

    Palchesko, Rachelle N; Szymanski, John M; Sahu, Amrita; Feinberg, Adam W

    2014-09-01

    Cell-matrix interactions are important for the physical integration of cells into tissues and the function of insoluble, mechanosensitive signaling networks. Studying these interactions in vitro can be difficult because the extracellular matrix (ECM) proteins that adsorb to in vitro cell culture surfaces do not fully recapitulate the ECM-dense basement membranes to which cells such as cardiomyocytes and endothelial cells adhere to in vivo. Towards addressing this limitation, we have developed a surface-initiated assembly process to engineer ECM proteins into nanostructured, microscale sheets that can be shrink wrapped around single cells and small cell ensembles to provide a functional and instructive matrix niche. Unlike current cell encapsulation technology using alginate, fibrin or other hydrogels, our engineered ECM is similar in density and thickness to native basal lamina and can be tailored in structure and composition using the proteins fibronectin, laminin, fibrinogen, and/or collagen type IV. A range of cells including C2C12 myoblasts, bovine corneal endothelial cells and cardiomyocytes survive the shrink wrapping process with high viability. Further, we demonstrate that, compared to non-encapsulated controls, the engineered ECM modulates cytoskeletal structure, stability of cell-matrix adhesions and cell behavior in 2D and 3D microenvironments.

  1. [Effects of SERMs on bone health. Mechanisms of bone mass control by selective estrogen receptor modulator].

    Science.gov (United States)

    Imai, Yuuki; Kato, Shigeaki

    2010-03-01

    The bone mass, which is controlled by the balances between bone formation and bone resorption can be reduced by estrogen deficiency in post-menopausal osteoporosis. Reduced bone mass can be recovered by hormone replacement therapy (HRT) , however, HRT has various side effects. Although SERMs can rescue the bone mass with less side effect compared to HRT, the precise mechanisms of this effect is still elusive. From the results of the analyses for osteoclast specific estrogen receptor (ER) alphaknockout mice and the genome wide approach of ERalphabinding site, estrogen and SERMs can, at least in part, protect the bone mass by inducing the expression of Fas ligand and controling the life span of osteoclasts. More precise molecular mechanisms of the effect of SERM, especially in tissue/cell type specificity, may help to investigate new SERM, which is more specific and effective to treat post-menopausal osteoporosis.

  2. Structure-based prediction of protein-folding transition paths

    CERN Document Server

    Jacobs, William M

    2016-01-01

    We propose a general theory to describe the distribution of protein-folding transition paths. We show that transition paths follow a predictable sequence of high-free-energy transient states that are separated by free-energy barriers. Each transient state corresponds to the assembly of one or more discrete, cooperative units, which are determined directly from the native structure. We show that the transition state on a folding pathway is reached when a small number of critical contacts are formed between a specific set of substructures, after which folding proceeds downhill in free energy. This approach suggests a natural resolution for distinguishing parallel folding pathways and provides a simple means to predict the rate-limiting step in a folding reaction. Our theory identifies a common folding mechanism for proteins with diverse native structures and establishes general principles for the self-assembly of polymers with specific interactions.

  3. Mechanisms underlying the noradrenergic modulation of longitudinal coordination during swimming in Xenopus laevis tadpoles

    DEFF Research Database (Denmark)

    Merrywest, Simon D; McDearmid, Jonathan R; Kjaerulff, Ole

    2003-01-01

    the mechanisms underlying the reduction of RC-delay s by NA. When recording from motor neurons caudal to the twelfth postotic cleft, the mid-cycle inhibition was weak and sometimes absent, compared to more rostral locations. NA enhanced and even unmasked inhibition in these caudal neurons and enhanced inhibition......, will preferentially facilitate rebound firing in caudal neurons, advancing their firing relative to more rostral neurons, whilst additionally increasing the networks ability to sustain the longer cycle periods under NA....

  4. Painful faces-induced attentional blink modulated by top-down and bottom-up mechanisms

    OpenAIRE

    2015-01-01

    Pain-related stimuli can capture attention in an automatic (bottom-up) or intentional (top-down) fashion. Previous studies have examined attentional capture by pain-related information using spatial attention paradigms that involve mainly a bottom-up mechanism. In the current study, we investigated the pain information–induced attentional blink (AB) using a rapid serial visual presentation (RSVP) task, and compared the effects of task-irrelevant and task-relevant pain distractors. Relationshi...

  5. Painful faces-induced attentional blink modulated by top–down and bottom–up mechanisms

    OpenAIRE

    2015-01-01

    Pain-related stimuli can capture attention in an automatic (bottom–up) or intentional (top–down) fashion. Previous studies have examined attentional capture by pain-related information using spatial attention paradigms that involve mainly a bottom–up mechanism. In the current study, we investigated the pain information-induced attentional blink (AB) using a rapid serial visual presentation (RSVP) task, and compared the effects of task-irrelevant and task-relevant pain distractors. Relationshi...

  6. Vagal stimulation modulates inflammation through a ghrelin mediated mechanism in traumatic brain injury

    OpenAIRE

    Bansal, V; Ryu, SY; Lopez, N; Allexan, S; Krzyzaniak, M; Eliceiri, B; Baird, A.; Coimbra, R

    2012-01-01

    Traumatic brain injury (TBI) releases a cascade of inflammatory cytokines. Vagal nerve stimulation (VNS) and ghrelin have known anti-inflammatory effects; furthermore, ghrelin release is stimulated by acetylcholine. We hypothesized VNS decreases post-TBI inflammation through a ghrelin-mediated mechanism. TBI was created in five groups of mice: sham, TBI, TBI/ghrelin, TBI/VNS, and TBI/VNS/ghrelin receptor antagonist (GRa). Serum and tissue ghrelin, and serum TNF-αwere measured. Ghrelin increas...

  7. Modulation of HIV-1 virulence via the host glucocorticoid receptor: towards further understanding the molecular mechanisms of HIV-1 pathogenesis.

    Science.gov (United States)

    Hapgood, Janet Patricia; Tomasicchio, Michele

    2010-07-01

    The glucocorticoid receptor (GR) is a steroid receptor that regulates diverse functions, which include the immune response. In humans, the GR acts via binding to cortisol, resulting in the transcriptional modulation of key host genes. Several lines of evidence suggest that the host GR could be a key protein exploited by HIV at multiple levels to ensure its pathogenic success. Endogenous and therapeutic glucocorticoids play important roles in patients with HIV due to their well-established effects on immune function. AIDS patients develop glucocorticoid hypersensitivity, consistent with a mechanism involving an HIV-1-induced increase in expression or activity of the GR. Both the HIV-1 accessory protein Vpr and the host GR affect transcription of viral proteins from the long terminal repeat (LTR) region of the HIV-1 promoter. In addition, Vpr modulates host GR function to affect transcription of host genes, most likely via direct interaction with the GR. Vpr appears to regulate GR function by acting as a co-activator for the GR. Since both the GR and Vpr are involved in apoptosis in T cells and dendritic cells, crosstalk between these proteins may also regulate apoptosis in these and other cells. Given that cortisol is not the only ligand that activates the GR, other endogenous as well as synthetic GR ligands such as progestins may also modulate HIV pathogenesis, in particular in the cervicovaginal environment. Investigating the molecular determinants, ligand-selectivity and role in HIV pathogenesis of the GR-Vpr interaction may lead to new strategies for development of anti-HIV drugs.

  8. Strong modulation of ectopic focus as a mechanism of repetitive interpolated ventricular bigeminy with heart rate doubling.

    Science.gov (United States)

    Takayanagi, Kan; Nakahara, Shiro; Toratani, Noritaka; Chida, Ryuji; Kobayashi, Sayuki; Sakai, Yoshihiko; Takeuchi, Akihiro; Ikeda, Noriaki

    2013-10-01

    Repetitive interpolated ventricular bigeminy (RIVB) can introduce a doubling of the ventricular rate. To clarify the mechanism of RIVB, we hypothesized that it was introduced by a strong modulation of the ventricular automatic focus. RIVB, defined as more than 7 bigeminy events, was detected by instantaneous heart rate and bigeminy interval (BI) tachograms in 1450 successive patients with frequent ventricular premature contractions (≥3000 per day). Postextrasystolic interval bigeminy interval curves were plotted to determine the degree of modulation. Mean sinus cycle length bigeminy interval curves were plotted for selection. RIVB was simulated by using a computer-based parasystole model. RIVB was observed in 7 patients (age 60 ± 16 years; 2 men and 5 women) with a heart rate of 58.2 ± 6.5 beats/min during a rest period both during the day and at night. The tachograms disclosed the onset of the RIVB with a doubled ventricular rate to 112.3 ± 8.5 beats/min. On the postextrasystolic interval bigeminy interval curves, compensatory bigeminy and interpolated bigeminy constituted overlapping regression lines with slopes close to 1.00 and RIVB was located in the lower left portion. RIVB lasting for up to 3 hours was quickly detected by mean sinus cycle length bigeminy interval curve. The PQ interval immediately after RIVB was prolonged in comparison with baseline (0.18 ± 0.02 to 0.21 ± 0.02 seconds; P heart rate. Our findings support the hypothesis that RIVB was introduced by strongly modulated ventricular pacemaker accelerated by an intervening normal QRS. © 2013 Heart Rhythm Society. All rights reserved.

  9. Cytoskeletal Configuration Modulates Mechanically Induced Changes in Mesenchymal Stem Cell Osteogenesis, Morphology, and Stiffness

    Science.gov (United States)

    Pongkitwitoon, Suphannee; Uzer, Gunes; Rubin, Janet; Judex, Stefan

    2016-10-01

    Mesenchymal stem cells (MSC) responding to mechanical cues generated by physical activity is critical for skeletal development and remodeling. Here, we utilized low intensity vibrations (LIV) as a physiologically relevant mechanical signal and hypothesized that the confined cytoskeletal configuration imposed by 2D culture will enable human bone marrow MSCs (hBMSC) to respond more robustly when LIV is applied in-plane (horizontal-LIV) rather than out-of-plane (vertical-LIV). All LIV signals enhanced hBMSC proliferation, osteogenic differentiation, and upregulated genes associated with cytoskeletal structure. The cellular response was more pronounced at higher frequencies (100 Hz vs 30 Hz) and when applied in the horizontal plane. Horizontal but not vertical LIV realigned the cell cytoskeleton, culminating in increased cell stiffness. Our results show that applying very small oscillatory motions within the primary cell attachment plane, rather than perpendicular to it, amplifies the cell’s response to LIV, ostensibly facilitating a more effective transfer of intracellular forces. Transcriptional and structural changes in particular with horizontal LIV, together with the strong frequency dependency of the signal, emphasize the importance of intracellular cytoskeletal configuration in sensing and responding to high-frequency mechanical signals at low intensities.

  10. Functional Subunits of Eukaryotic Chaperonin CCT/TRiC in Protein Folding

    Directory of Open Access Journals (Sweden)

    M. Anaul Kabir

    2011-01-01

    Full Text Available Molecular chaperones are a class of proteins responsible for proper folding of a large number of polypeptides in both prokaryotic and eukaryotic cells. Newly synthesized polypeptides are prone to nonspecific interactions, and many of them make toxic aggregates in absence of chaperones. The eukaryotic chaperonin CCT is a large, multisubunit, cylindrical structure having two identical rings stacked back to back. Each ring is composed of eight different but similar subunits and each subunit has three distinct domains. CCT assists folding of actin, tubulin, and numerous other cellular proteins in an ATP-dependent manner. The catalytic cooperativity of ATP binding/hydrolysis in CCT occurs in a sequential manner different from concerted cooperativity as shown for GroEL. Unlike GroEL, CCT does not have GroES-like cofactor, rather it has a built-in lid structure responsible for closing the central cavity. The CCT complex recognizes its substrates through diverse mechanisms involving hydrophobic or electrostatic interactions. Upstream factors like Hsp70 and Hsp90 also work in a concerted manner to transfer the substrate to CCT. Moreover, prefoldin, phosducin-like proteins, and Bag3 protein interact with CCT and modulate its function for the fine-tuning of protein folding process. Any misregulation of protein folding process leads to the formation of misfolded proteins or toxic aggregates which are linked to multiple pathological disorders.

  11. Distinct Contribution of Electrostatics, Initial Conformational Ensemble, and Macromolecular Stability in RNA Folding

    Energy Technology Data Exchange (ETDEWEB)

    Laederach,A.; Shcherbakova, I.; Jonikas, M.; Altman, R.; Brenowitz, M.

    2007-01-01

    We distinguish the contribution of the electrostatic environment, initial conformational ensemble, and macromolecular stability on the folding mechanism of a large RNA using a combination of time-resolved 'Fast Fenton' hydroxyl radical footprinting and exhaustive kinetic modeling. This integrated approach allows us to define the folding landscape of the L-21 Tetrahymena thermophila group I intron structurally and kinetically from its earliest steps with unprecedented accuracy. Distinct parallel pathways leading the RNA to its native form upon its Mg2+-induced folding are observed. The structures of the intermediates populating the pathways are not affected by variation of the concentration and type of background monovalent ions (electrostatic environment) but are altered by a mutation that destabilizes one domain of the ribozyme. Experiments starting from different conformational ensembles but folding under identical conditions show that whereas the electrostatic environment modulates molecular flux through different pathways, the initial conformational ensemble determines the partitioning of the flux. This study showcases a robust approach for the development of kinetic models from collections of local structural probes.

  12. Modulation of Cell Sialoglycophenotype: A Stylish Mechanism Adopted by Trypanosoma cruzi to Ensure Its Persistence in the Infected Host

    Science.gov (United States)

    Freire-de-Lima, Leonardo; da Fonseca, Leonardo M.; da Silva, Vanessa A.; da Costa, Kelli M.; Morrot, Alexandre; Freire-de-Lima, Célio G.; Previato, Jose O.; Mendonça-Previato, Lucia

    2016-01-01

    Trypanosoma cruzi, the etiological agent of Chagas disease exhibits multiple mechanisms to guarantee its establishment and persistence in the infected host. It has been well demonstrated that T. cruzi is not able to synthesize sialic acids (Sia). To acquire the monosaccharide, the parasite makes use of a multifunctional enzyme called trans-sialidase (Tc-TS). Since this enzyme has no analogous in the vertebrate host, it has been used as a target in drug therapy development. Tc-TS preferentially catalyzes the transfer of Sia from the host glycoconjugates to the terminal β-galactopyranosyl residues of mucin-like molecules present on the parasite’s cell surface. Alternatively, the enzyme can sialylate/re-sialylate glycoconjugates expressed on the surface of host cells. Since its discovery, several studies have shown that T. cruzi employs the Tc-TS activity to modulate the host cell sialoglycophenotype, thus favoring its perpetuation in the infected vertebrate. In this review, we summarize the dynamic of host/parasite sialoglycophenotype modulation, highlighting its role in the subversion of host immune response in order to promote the establishment of persistent chronic infection. PMID:27242722

  13. Chiral, J-Aggregate-Forming Dyes for Alternative Signal Modulation Mechanisms in Self-Immolative Enzyme-Activatable Optical Probes.

    Science.gov (United States)

    Sloniec-Myszk, Jagoda; Resch-Genger, Ute; Hennig, Andreas

    2016-02-11

    Enzyme-activatable optical probes are important for future advances in cancer imaging, but may easily suffer from low signal-to-background ratios unless not optimized. To address this shortcoming, numerous mechanisms to modulate the fluorescence signal have been explored. We report herein newly synthesized probes based on self-immolative linkers containing chiral J-aggregate-forming dyes. Signal modulation by formation of chiral J-aggregates is yet unexplored in optical enzyme probe design. The comprehensive characterization of the probes by absorption, CD, fluorescence, and time-resolved fluorescence spectroscopy revealed dye-dye interactions not observed for the free dyes in solution as well as dye-protein interactions with the enzyme. This suggested that J-aggregate formation is challenging to achieve with current probe design and that interactions of the dyes with the enzyme may interfere with achieving high signal-to-background ratios. The detailed understanding of the interactions provided herein provides valuable guidelines for the future design of similar probes.

  14. Leukemia Mediated Endothelial Cell Activation Modulates Leukemia Cell Susceptibility to Chemotherapy through a Positive Feedback Loop Mechanism.

    Directory of Open Access Journals (Sweden)

    Bahareh Pezeshkian

    Full Text Available In acute myeloid leukemia (AML, the chances of achieving disease-free survival are low. Studies have demonstrated a supportive role of endothelial cells (ECs in normal hematopoiesis. Here we show that similar intercellular relationships exist in leukemia. We demonstrate that leukemia cells themselves initiate these interactions by directly modulating the behavior of resting ECs through the induction of EC activation. In this inflammatory state, activated ECs induce the adhesion of a sub-set of leukemia cells through the cell adhesion molecule E-selectin. These adherent leukemia cells are sequestered in a quiescent state and are unaffected by chemotherapy. The ability of adherent cells to later detach and again become proliferative following exposure to chemotherapy suggests a role of this process in relapse. Interestingly, differing leukemia subtypes modulate this process to varying degrees, which may explain the varied response of AML patients to chemotherapy and relapse rates. Finally, because leukemia cells themselves induce EC activation, we postulate a positive-feedback loop in leukemia that exists to support the growth and relapse of the disease. Together, the data defines a new mechanism describing how ECs and leukemia cells interact during leukemogenesis, which could be used to develop novel treatments for those with AML.

  15. Boron nitride nanotube-mediated stimulation modulates F/G-actin ratio and mechanical properties of human dermal fibroblasts

    Science.gov (United States)

    Ricotti, Leonardo; das Neves, Ricardo Pires; Ciofani, Gianni; Canale, Claudio; Nitti, Simone; Mattoli, Virgilio; Mazzolai, Barbara; Ferreira, Lino; Menciassi, Arianna

    2014-02-01

    F/G-actin ratio modulation is known to have an important role in many cell functions and in the regulation of specific cell behaviors. Several attempts have been made in the latest decades to finely control actin production and polymerization, in order to promote certain cell responses. In this paper we demonstrate the possibility of modulating F/G-actin ratio and mechanical properties of normal human dermal fibroblasts by using boron nitride nanotubes dispersed in the culture medium and by stimulating them with ultrasound transducers. Increasing concentrations of nanotubes were tested with the cells, without any evidence of cytotoxicity up to 10 μg/ml concentration of nanoparticles. Cells treated with nanoparticles and ultrasound stimulation showed a significantly higher F/G-actin ratio in comparison with the controls, as well as a higher Young's modulus. Assessment of Cdc42 activity revealed that actin nucleation/polymerization pathways, involving Rho GTPases, are probably influenced by nanotube-mediated stimulation, but they do not play a primary role in the significant increase of F/G-actin ratio of treated cells, such effect being mainly due to actin overexpression.

  16. Planetary Rotation Modulation of Various Measured Plasma Parameters in Saturns Magnetosphere: a Possible Mechanism

    Science.gov (United States)

    Mitchell, D. G.; Brandt, P. C.; Carbary, J. F.; Krimigis, S. M.; Mauk, B. E.; Paranicas, C. P.; Roelof, E. C.; Jones, G.; Krupp, N.; Lagg, A.; Gurnett, D. A.; Kurth, W. S.; Dougherty, M. K.; Southwood, D. J.; Saur, J.; Zarka, P.

    2006-05-01

    The period of Saturn kilometric radiation (SKR) modulation established by Voyagers 1 and 2 in 1980 and 1981 (10 hours, 39 minutes, 22.4 +/- 7s) has been adopted by the International Astronomical Union as the official rotation period of Saturn. Other quantities seen to exhibit modulation at about the same period include the magnetic field, energetic electron spectral slope, and energetic neutral atom (ENA) emission. However first the Ulysses spacecraft, and later Cassini, have measured a significantly different the SKR period than the Voyagers (approximately 10 hours, 45minutes). This change is problematic, because if the field is truly locked to Saturns rotation, this would imply a huge change in angular momentum over a relatively short period. Furthermore, no consensus model has been accepted to explain how the effects of the rotation are communicated from the planetary body out to distances as large as over 20 Rs (Saturn radii). In this paper, we explore the possibility that the observed SKR period is not Saturns intrinsic rotation period, but rather stems from friction between the ionosphere and Saturns zonal wind flows. We suggest that the SKR location reflects a high conductivity anomaly in Saturns ionosphere, whereby rigid rotation is imposed on that part of the magnetosphere that connects via the magnetic field and field-aligned currents with this high conductivity anomaly (this is similar to the hypothesis of the camshaft model for the magnetic perturbation suggested by Espinosa et al., 2003). In that work, Espinosa et al. suggest that the high conductivity region exists because of a high order magnetic anomaly, that affects ionospheric conductivity locally. We extend that model to include a feed-back loop with the magnetosphere. In this scenario, a magnetospheric disturbance initially triggered by interaction with the field-aligned currents results in additional energy deposition in the ionosphere. This further increases the ionospheric conductivity, but

  17. Sucrose is an early modulator of the key hormonal mechanisms controlling bud outgrowth in Rosa hybrida.

    Science.gov (United States)

    Barbier, François; Péron, Thomas; Lecerf, Marion; Perez-Garcia, Maria-Dolores; Barrière, Quentin; Rolčík, Jakub; Boutet-Mercey, Stéphanie; Citerne, Sylvie; Lemoine, Remi; Porcheron, Benoît; Roman, Hanaé; Leduc, Nathalie; Le Gourrierec, José; Bertheloot, Jessica; Sakr, Soulaiman

    2015-05-01

    Sugar has only recently been identified as a key player in triggering bud outgrowth, while hormonal control of bud outgrowth is already well established. To get a better understanding of sugar control, the present study investigated how sugar availability modulates the hormonal network during bud outgrowth in Rosa hybrida. Other plant models, for which mutants are available, were used when necessary. Buds were grown in vitro to manipulate available sugars. The temporal patterns of the hormonal regulatory network were assessed in parallel with bud outgrowth dynamics. Sucrose determined bud entrance into sustained growth in a concentration-dependent manner. Sustained growth was accompanied by sustained auxin production in buds, and sustained auxin export in a DR5::GUS-expressing pea line. Several events occurred ahead of sucrose-stimulated bud outgrowth. Sucrose upregulated early auxin synthesis genes (RhTAR1, RhYUC1) and the auxin efflux carrier gene RhPIN1, and promoted PIN1 abundance at the plasma membrane in a pPIN1::PIN1-GFP-expressing tomato line. Sucrose downregulated both RwMAX2, involved in the strigolactone-transduction pathway, and RhBRC1, a repressor of branching, at an early stage. The presence of sucrose also increased stem cytokinin content, but sucrose-promoted bud outgrowth was not related to that pathway. In these processes, several non-metabolizable sucrose analogues induced sustained bud outgrowth in R. hybrida, Pisum sativum, and Arabidopsis thaliana, suggesting that sucrose was involved in a signalling pathway. In conclusion, we identified potential hormonal candidates for bud outgrowth control by sugar. They are central to future investigations aimed at disentangling the processes that underlie regulation of bud outgrowth by sugar.

  18. TAFA4, a Chemokine-like Protein, Modulates Injury-Induced Mechanical and Chemical Pain Hypersensitivity in Mice

    Directory of Open Access Journals (Sweden)

    Marie-Claire Delfini

    2013-10-01

    Full Text Available C-low-threshold mechanoreceptors (C-LTMRs are unique among C-unmyelinated primary sensory neurons. These neurons convey two opposite aspects of touch sensation: a sensation of pleasantness, and a sensation of injury-induced mechanical pain. Here, we show that TAFA4 is a specific marker of C-LTMRs. Genetic labeling in combination with electrophysiological recordings show that TAFA4+ neurons have intrinsic properties of mechano-nociceptors. TAFA4-null mice exhibit enhanced mechanical and chemical hypersensitivity following inflammation and nerve injury as well as increased excitability of spinal cord lamina IIi neurons, which could be reversed by intrathecal or bath application of recombinant TAFA4 protein. In wild-type C57/Bl6 mice, intrathecal administration of TAFA4 strongly reversed carrageenan-induced mechanical hypersensitivity, suggesting a potent analgesic role of TAFA4 in pain relief. Our data provide insights into how C-LTMR-derived TAFA4 modulates neuronal excitability and controls the threshold of somatic sensation.

  19. TAFA4, a chemokine-like protein, modulates injury-induced mechanical and chemical pain hypersensitivity in mice.

    Science.gov (United States)

    Delfini, Marie-Claire; Mantilleri, Annabelle; Gaillard, Stéphane; Hao, Jizhe; Reynders, Ana; Malapert, Pascale; Alonso, Serge; François, Amaury; Barrere, Christian; Seal, Rebecca; Landry, Marc; Eschallier, Alain; Alloui, Abdelkrim; Bourinet, Emmanuel; Delmas, Patrick; Le Feuvre, Yves; Moqrich, Aziz

    2013-10-31

    C-low-threshold mechanoreceptors (C-LTMRs) are unique among C-unmyelinated primary sensory neurons. These neurons convey two opposite aspects of touch sensation: a sensation of pleasantness, and a sensation of injury-induced mechanical pain. Here, we show that TAFA4 is a specific marker of C-LTMRs. Genetic labeling in combination with electrophysiological recordings show that TAFA4+ neurons have intrinsic properties of mechano-nociceptors. TAFA4-null mice exhibit enhanced mechanical and chemical hypersensitivity following inflammation and nerve injury as well as increased excitability of spinal cord lamina IIi neurons, which could be reversed by intrathecal or bath application of recombinant TAFA4 protein. In wild-type C57/Bl6 mice, intrathecal administration of TAFA4 strongly reversed carrageenan-induced mechanical hypersensitivity, suggesting a potent analgesic role of TAFA4 in pain relief. Our data provide insights into how C-LTMR-derived TAFA4 modulates neuronal excitability and controls the threshold of somatic sensation.

  20. Gate-modulated transport properties and mechanism for nanowire cross junction based on SnO2 semiconductor

    Science.gov (United States)

    Chen, Xi; Tong, Yanhong; Wang, Guorui; Tang, Qingxin; Liu, Yichun

    2015-12-01

    The transport properties and mechanism of the three-terminal field-effect nanowire cross junction have been systematically investigated. An interesting phenomenon, such as applied voltage bias on nanowire cross junction makes the ON/OFF current ratio of the transistor improved by over 2 orders of magnitude, has been observed. Different from the two-terminal nanowire cross junctions, the cross junction induced potential barrier in three-terminal counterparts is found to be capable to prevent the current of the top semiconductor nanowire from injecting into the bottom nanowire at off state, while to make the current of the top semiconductor nanowire contribute to the current of the bottom nanowire at on state, resulting in the current switch between on state and off state by the gate voltage modulation.

  1. PIP2 regulation of KCNQ channels: biophysical and molecular mechanisms for lipid modulation of voltage-dependent gating

    Directory of Open Access Journals (Sweden)

    Mark Alan Zaydman

    2014-05-01

    Full Text Available Voltage-gated potassium (Kv channels contain voltage-sensing (VSD and pore-gate (PGD structural domains. During voltage-dependent gating, conformational changes in the two domains are coupled giving rise to voltage-dependent opening of the channel. In addition to membrane voltage, KCNQ (Kv7 channel opening requires the membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP2. Recent studies suggest that PIP2 serves as a cofactor to mediate VSD-PGD coupling in KCNQ1 channels. In this review, we put these findings in the context of the current understanding of voltage-dependent gating, lipid modulation of Kv channel activation, and PIP2-regulation of KCNQ channels. We suggest that lipid-mediated coupling of functional domains is a common mechanism among KCNQ channels that may be applicable to other Kv channels and membrane proteins.

  2. PIP2 regulation of KCNQ channels: biophysical and molecular mechanisms for lipid modulation of voltage-dependent gating.

    Science.gov (United States)

    Zaydman, Mark A; Cui, Jianmin

    2014-01-01

    Voltage-gated potassium (Kv) channels contain voltage-sensing (VSD) and pore-gate (PGD) structural domains. During voltage-dependent gating, conformational changes in the two domains are coupled giving rise to voltage-dependent opening of the channel. In addition to membrane voltage, KCNQ (Kv7) channel opening requires the membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP2). Recent studies suggest that PIP2 serves as a cofactor to mediate VSD-PGD coupling in KCNQ1 channels. In this review, we put these findings in the context of the current understanding of voltage-dependent gating, lipid modulation of Kv channel activation, and PIP2-regulation of KCNQ channels. We suggest that lipid-mediated coupling of functional domains is a common mechanism among KCNQ channels that may be applicable to other Kv channels and membrane proteins.

  3. IFN-induced modulation of histocompatibility antigens on human cells. Background, mechanisms and perspectives

    DEFF Research Database (Denmark)

    Hokland, M; Basse, P; Justesen, J

    1989-01-01

    (MHC) antigens. The latter effects have been characterized as immunomodulatory, whereas the well-known inhibition of growth of malignant cells has been termed anti-proliferative. This review summarizes the current knowledge of the enhancement of MHC products by IFNs. Whereas the basic methodologies...... to the classical anti-viral mechanism. This concept proposes that the MHC-enhancing effect of IFNs is a vital part of the immunological defense against virus infections and an integral part of the anti-viral effects of IFN proteins. Udgivelsesdato: 1988-Nov...

  4. Atom-by-atom analysis of global downhill protein folding

    Science.gov (United States)

    Sadqi, Mourad; Fushman, David; Muñoz, Victor

    2006-07-01

    Protein folding is an inherently complex process involving coordination of the intricate networks of weak interactions that stabilize native three-dimensional structures. In the conventional paradigm, simple protein structures are assumed to fold in an all-or-none process that is inaccessible to experiment. Existing experimental methods therefore probe folding mechanisms indirectly. A widely used approach interprets changes in protein stability and/or folding kinetics, induced by engineered mutations, in terms of the structure of the native protein. In addition to limitations in connecting energetics with structure, mutational methods have significant experimental uncertainties and are unable to map complex networks of interactions. In contrast, analytical theory predicts small barriers to folding and the possibility of downhill folding. These theoretical predictions have been confirmed experimentally in recent years, including the observation of global downhill folding. However, a key remaining question is whether downhill folding can indeed lead to the high-resolution analysis of protein folding processes. Here we show, with the use of nuclear magnetic resonance (NMR), that the downhill protein BBL from Escherichia coli unfolds atom by atom starting from a defined three-dimensional structure. Thermal unfolding data on 158 backbone and side-chain protons out of a total of 204 provide a detailed view of the structural events during folding. This view confirms the statistical nature of folding, and exposes the interplay between hydrogen bonding, hydrophobic forces, backbone conformation and side-chain entropy. From the data we also obtain a map of the interaction network in this protein, which reveals the source of folding cooperativity. Our approach can be extended to other proteins with marginal barriers (less than 3RT), providing a new tool for the study of protein folding.

  5. Differential equations and folding of $n$-mani-folds

    Directory of Open Access Journals (Sweden)

    I. Mousa

    2005-09-01

    Full Text Available In this paper we will describe some topological and geometric characters of $n$-manifold by using the properties of differential equations. The folding and unfolding of $n$-manifold into itself will be deduced from viewpoint of the differential equations.

  6. Staying cool when things get hot: Emotion regulation modulates neural mechanisms of memory encoding

    Directory of Open Access Journals (Sweden)

    Jasmeet P Hayes

    2010-12-01

    Full Text Available During times of emotional stress, individuals often engage in emotion regulation to reduce the experiential and physiological impact of negative emotions. Interestingly, emotion regulation strategies also influence memory encoding of the event. Cognitive reappraisal is associated with enhanced memory while expressive suppression is associated with impaired explicit memory of the emotional event. However, the mechanism by which these emotion regulation strategies affect memory is unclear. We used event-related fMRI to investigate the neural mechanisms that give rise to memory formation during emotion regulation. Twenty-five participants viewed negative pictures while alternately engaging in cognitive reappraisal, expressive suppression, or passive viewing. As part of the subsequent memory design, participants returned to the laboratory two weeks later for a surprise memory test. Behavioral results showed a reduction in negative affect and a retention advantage for reappraised stimuli relative to the other conditions. Imaging results showed that successful encoding during reappraisal was uniquely associated with greater co-activation of the left inferior frontal gyrus, amygdala and hippocampus, suggesting a possible role for elaborative encoding of negative memories. This study provides neurobehavioral evidence that engaging in cognitive reappraisal is advantageous to both affective and mnemonic processes.

  7. Distinct promoter activation mechanisms modulate noise-driven HIV gene expression

    Science.gov (United States)

    Chavali, Arvind K.; Wong, Victor C.; Miller-Jensen, Kathryn

    2015-12-01

    Latent human immunodeficiency virus (HIV) infections occur when the virus occupies a transcriptionally silent but reversible state, presenting a major obstacle to cure. There is experimental evidence that random fluctuations in gene expression, when coupled to the strong positive feedback encoded by the HIV genetic circuit, act as a ‘molecular switch’ controlling cell fate, i.e., viral replication versus latency. Here, we implemented a stochastic computational modeling approach to explore how different promoter activation mechanisms in the presence of positive feedback would affect noise-driven activation from latency. We modeled the HIV promoter as existing in one, two, or three states that are representative of increasingly complex mechanisms of promoter repression underlying latency. We demonstrate that two-state and three-state models are associated with greater variability in noisy activation behaviors, and we find that Fano factor (defined as variance over mean) proves to be a useful noise metric to compare variability across model structures and parameter values. Finally, we show how three-state promoter models can be used to qualitatively describe complex reactivation phenotypes in response to therapeutic perturbations that we observe experimentally. Ultimately, our analysis suggests that multi-state models more accurately reflect observed heterogeneous reactivation and may be better suited to evaluate how noise affects viral clearance.

  8. NAD kinase controls animal NADP biosynthesis and is modulated via evolutionarily divergent calmodulin-dependent mechanisms.

    Science.gov (United States)

    Love, Nick R; Pollak, Nadine; Dölle, Christian; Niere, Marc; Chen, Yaoyao; Oliveri, Paola; Amaya, Enrique; Patel, Sandip; Ziegler, Mathias

    2015-02-03

    Nicotinamide adenine dinucleotide phosphate (NADP) is a critical cofactor during metabolism, calcium signaling, and oxidative defense, yet how animals regulate their NADP pools in vivo and how NADP-synthesizing enzymes are regulated have long remained unknown. Here we show that expression of Nadk, an NAD(+) kinase-encoding gene, governs NADP biosynthesis in vivo and is essential for development in Xenopus frog embryos. Unexpectedly, we found that embryonic Nadk expression is dynamic, showing cell type-specific up-regulation during both frog and sea urchin embryogenesis. We analyzed the NAD kinases (NADKs) of a variety of deuterostome animals, finding two conserved internal domains forming a catalytic core but a highly divergent N terminus. One type of N terminus (found in basal species such as the sea urchin) mediates direct catalytic activation of NADK by Ca(2+)/calmodulin (CaM), whereas the other (typical for vertebrates) is phosphorylated by a CaM kinase-dependent mechanism. This work indicates that animal NADKs govern NADP biosynthesis in vivo and are regulated by evolutionarily divergent and conserved CaM-dependent mechanisms.

  9. Spontaneous electrical activity of guinea-pig sinoatrial cells under modulation of two different pacemaker mechanisms

    Directory of Open Access Journals (Sweden)

    Francesca Cacciani

    2014-01-01

    Full Text Available The main cellular determinants of cardiac automaticity are the hyperpolarization-activated cationic current If, and the electrogenic Na+/Ca2+ exchanger which generates an inward current after each action potential (AP. Our goal was to evaluate their relative role in pacemaking, by means of application of Ivabradine (IVA (specific If blocker and Ryanodine (RYA (known to abolish calcium transient on enzimatically isolated guinea-pig pacemaker cells. Spontaneous APs were recorded in patch-clamp whole cell configuration at 36°C from 7 cells perfused with the following sequence of solutions: physiological normal tyrode (NT, IVA 3 mM, NT and RYA 3 mM. Cycle length (CL, ms and diastolic depolarization rate (DDR, V/s were also calculated. Both blockers displayed similar effects, increasing CL (by 27 and 30%, respectively, and decreasing DDR (by 34 and 42% with respect to NT exposure. These results suggest that both mechanisms are involved into pacemaking mechanism at a similar degree.

  10. Modelling the folding of DNA origami

    Science.gov (United States)

    Arbona, J. M.; Elezgaray, J.; Aimé, J. P.

    2012-10-01

    DNA-based nanostructures built from a long single-stranded DNA scaffold, known as DNA origamis, are at the basis of many applications. Despite their widespread development, many basic questions concerning the mechanisms of formation of DNA origamis have not yet been addressed. For instance, the robustness of different designs against factors such as the internal topology, or the influence of the staple pattern, are handled empirically. We have developed a model for the folding and melting processes of DNA origamis that is able to reproduce accurately several thermodynamic quantities measurable from UV absorption experiments. This model incorporates not only the origami sequence but also its topology. We show that cooperativity is key to quantitatively understand the folding process. The model can also be used to design a new distribution of crossovers that increases the robustness of the DNA template, a necessary step for technological development.

  11. Positive allosteric modulation of TRPV1 as a novel analgesic mechanism

    Directory of Open Access Journals (Sweden)

    Lebovitz Evan E

    2012-09-01

    Full Text Available Abstract Background The prevalence of long-term opiate use in treating chronic non-cancer pain is increasing, and prescription opioid abuse and dependence are a major public health concern. To explore alternatives to opioid-based analgesia, the present study investigates a novel allosteric pharmacological approach operating through the cation channel TRPV1. This channel is highly expressed in subpopulations of primary afferent unmyelinated C- and lightly-myelinated Aδ-fibers that detect low and high rates of noxious heating, respectively, and it is also activated by vanilloid agonists and low pH. Sufficient doses of exogenous vanilloid agonists, such as capsaicin or resiniferatoxin, can inactivate/deactivate primary afferent endings due to calcium overload, and we hypothesized that positive allosteric modulation of agonist-activated TRPV1 could produce a selective, temporary inactivation of nociceptive nerve terminals in vivo. We previously identified MRS1477, a 1,4-dihydropyridine that potentiates vanilloid and pH activation of TRPV1 in vitro, but displays no detectable intrinsic agonist activity of its own. To study the in vivo effects of MRS1477, we injected the hind paws of rats with a non-deactivating dose of capsaicin, MRS1477, or the combination. An infrared diode laser was used to stimulate TRPV1-expressing nerve terminals and the latency and intensity of paw withdrawal responses were recorded. qRT-PCR and immunohistochemistry were performed on dorsal root ganglia to examine changes in gene expression and the cellular specificity of such changes following treatment. Results Withdrawal responses of the capsaicin-only or MRS1477-only treated paws were not significantly different from the untreated, contralateral paws. However, rats treated with the combination of capsaicin and MRS1477 exhibited increased withdrawal latency and decreased response intensity consistent with agonist potentiation and inactivation or lesion of TRPV1-containing

  12. Mesoscale Modeling of Chromatin Folding

    Science.gov (United States)

    Schlick, Tamar

    2009-03-01

    Eukaryotic chromatin is the fundamental protein/nucleic acid unit that stores the genetic material. Understanding how chromatin fibers fold and unfold in physiological conditions is important for interpreting fundamental biological processes like DNA replication and transcription regulation. Using a mesoscopic model of oligonucleosome chains and tailored sampling protocols, we elucidate the energetics of oligonucleosome folding/unfolding and the role of each histone tail, linker histones, and divalent ions in regulating chromatin structure. The resulting compact topologies reconcile features of the zigzag model with straight linker DNAs with the solenoid model with bent linker DNAs for optimal fiber organization and reveal dynamic and energetic aspects involved.

  13. Dynamic Modeling and Control of Distributed Heat Transfer Mechanisms: Application to a Membrane Distillation Module

    KAUST Repository

    Eleiwi, Fadi

    2015-12-01

    Sustainable desalination technologies are the smart solution for producing fresh water and preserve the environment and energy by using sustainable renewable energy sources. Membrane distillation (MD) is an emerging technology which can be driven by renewable energy. It is an innovative method for desalinating seawater and brackish water with high quality production, and the gratitude is to its interesting potentials. MD includes a transfer of water vapor from a feed solution to a permeate solution through a micro-porous hydrophobic membrane, rejecting other non-volatile constituents present in the influent water. The process is driven by the temperature difference along the membrane boundaries. Different control applications and supervision techniques would improve the performance and the efficiency of the MD process, however controlling the MD process requires comprehensive mathematical model for the distributed heat transfer mechanisms inside the process. Our objective is to propose a dynamic mathematical model that accounts for the time evolution of the involved heat transfer mechanisms in the process, and to be capable of hosting intermittent energy supplies, besides managing the production rate of the process, and optimizing its energy consumption. Therefore, we propose the 2D Advection-Diffusion Equation model to account for the heat diffusion and the heat convection mechanisms inside the process. Furthermore, experimental validations have proved high agreement between model simulations and experiments with less than 5% relative error. Enhancing the MD production is an anticipated goal, therefore, two main control strategies are proposed. Consequently, we propose a nonlinear controller for a semi-discretized version of the dynamic model to achieve an asymptotic tracking for a desired temperature difference. Similarly, an observer-based feedback control is used to track sufficient temperature difference for better productivity. The second control strategy

  14. Hypoosmotic cell swelling as a novel mechanism for modulation of cloned HCN2 channels

    DEFF Research Database (Denmark)

    Calloe, Kirstine; Elmedyb, Pernille; Olesen, Søren-Peter

    2005-01-01

    This work demonstrates cell swelling as a new regulatory mechanism for the cloned hyperpolarization-activated, cyclic nucleotide-gated channel 2 (HCN2). HCN2 channels were coexpressed with aquaporin1 in Xenopus laevis oocytes and currents were monitored using a two-electrode voltage-clamp. HCN2...... channels were activated by hyperpolarization to -100 mV and the currents were measured before and during hypoosmotic cell swelling. Cell swelling increased HCN2 currents by 30% without changing the kinetics of the currents. Injection of 50 nl intracellular solution resulted in a current increase of 20......%, indicating that an increase in cell volume also under isoosmotic conditions may lead to activation of HCN2. In the absence of aquaporin1 only negligible changes in oocyte cell volume occur during exposure to hypoosmotic media and no significant change in HCN2 channel activity was observed during perfusion...

  15. Amplitude and frequency modulation control of sound production in a mechanical model of the avian syrinx

    DEFF Research Database (Denmark)

    Elemans, Coen; Muller, Mees; Larsen, Ole Næsbye

    2009-01-01

    of combining experimental data and mathematical modelling has greatly improved the understanding of neural control and peripheral motor dynamics of sound generation in birds. Here, we present a simple mechanical model of the syrinx that facilitates detailed study of vibrations and sound production. Our model...... resembles the ‘starling resistor', a collapsible tube model, and consists of a tube with a single membrane in its casing, suspended in an external pressure chamber and driven by various pressure patterns. With this design, we can separately control ‘bronchial' pressure and tension in the oscillating...... properties of the distal tube, most likely because of its reflective properties to sound waves. Our model is a gross simplification of the complex morphology found in birds, and more closely resembles mathematical models of the syrinx. Our results confirm several assumptions underlying existing mathematical...

  16. Modulation of membrane currents and mechanical activity by niflumic acid in rat vascular smooth muscle.

    Science.gov (United States)

    Kirkup, A J; Edwards, G; Green, M E; Miller, M; Walker, S D; Weston, A H

    1996-12-12

    The effects of niflumic acid on whole-cell membrane currents and mechanical activity were examined in the rat portal vein. In freshly dispersed portal vein cells clamped at -60 mV in caesium (Cs+)-containing solutions, niflumic acid (1-100 microM) inhibited calcium (Ca2+)-activated chloride currents (IC1(Ca)) induced by caffeine (10 mM) and by noradrenaline (10 microM). In a potassium (K+)-containing solution and at a holding potential of - 10 mV, niflumic acid (10-100 microM) induced an outward K+ current (IK(ATP)) which was sensitive to glibenclamide (10-30 microM). At concentrations < 30 microM and at a holding potential of -2 mV, niflumic acid had no effect on the magnitude of the caffeine- or noradrenaline-stimulated current (IBK(Ca)) carried by the large conductance, Ca(2+)-sensitive K+ channel (BKCa). However, at a concentration of 100 microM, niflumic acid significantly inhibited IBK(Ca)) evoked by caffeine (10 mM) but not by NS1619 (1-(2'-hydroxy-5'-trifluoromethylphenyl)-5-trifluoromethyl-2(3 H) benzimidazolone; 20 microM). In Cs(+)-containing solutions, niflumic acid (10-100 microM) did not inhibit voltage-sensitive Ca2+ currents. In intact portal veins, niflumic acid (1-300 microM) inhibited spontaneous mechanical activity, an action which was partially antagonised by glibenclamide (1-10 microM), and contractions produced by noradrenaline (10 microM), an effect which was glibenclamide-insensitive. It is concluded that inhibition of ICl(Ca) and stimulation of IK(ATP) both contribute to the mechano-inhibitory actions of niflumic acid in the rat portal vein.

  17. Cerebral ABC transporter-common mechanisms may modulate neurodegenerative diseases and depression in elderly subjects.

    Science.gov (United States)

    Pahnke, Jens; Fröhlich, Christina; Paarmann, Kristin; Krohn, Markus; Bogdanovic, Nenad; Årsland, Dag; Winblad, Bengt

    2014-11-01

    In elderly subjects, depression and dementia often coincide but the actual reason is currently unknown. Does a causal link exist or is it just a reactive effect of the knowledge to suffer from dementia? The ABC transporter superfamily may represent a causal link between these mental disorders. Since the transporters ABCB1 and ABCC1 have been discovered as major β-amyloid-exporting molecules at the blood-brain barrier and ABCC1 was found to be directly activated by St. John's wort (SJW), depression and dementia certainly share an important pathophysiologic link. It was recognized that herbal anti-depressant formulations made from SJW are at least as effective for the treatment of unipolar depression in old age as classical pharmacotherapy, while having fewer side effects (Cochrane reports, 2008). SJW is known to activate various metabolizing and transport systems in the body, with cytochrome P450 enzymes and ABC transporters being most important. Does the treatment of depression in elderly subjects using pharmacological compounds or phytomedical extracts target a mechanism that also accounts for peptide storage in Alzheimer's disease and perhaps other proteopathies of the brain? In this review we summarize recent data that point to a common mechanism and present the first promising causal treatment results of demented elderly subjects with distinct SJW extracts. Insufficient trans-barrier clearance may indeed present a common problem in all the proteopathies of the brain where toxic peptides are deposited in a location-specific manner. Thus, activation of efflux molecules holds promise for future treatment of this large group of devastating disorders.

  18. Statistical mechanics of reward-modulated learning in decision-making networks.

    Science.gov (United States)

    Katahira, Kentaro; Okanoya, Kazuo; Okada, Masato

    2012-05-01

    The neural substrates of decision making have been intensively studied using experimental and computational approaches. Alternative-choice tasks accompanying reinforcement have often been employed in investigations into decision making. Choice behavior has been empirically found in many experiments to follow Herrnstein's matching law. A number of theoretical studies have been done on explaining the mechanisms responsible for matching behavior. Various learning rules have been proved in these studies to achieve matching behavior as a steady state of learning processes. The models in the studies have consisted of a few parameters. However, a large number of neurons and synapses are expected to participate in decision making in the brain. We investigated learning behavior in simple but large-scale decision-making networks. We considered the covariance learning rule, which has been demonstrated to achieve matching behavior as a steady state (Loewenstein & Seung, 2006 ). We analyzed model behavior in a thermodynamic limit where the number of plastic synapses went to infinity. By means of techniques of the statistical mechanics, we can derive deterministic differential equations in this limit for the order parameters, which allow an exact calculation of the evolution of choice behavior. As a result, we found that matching behavior cannot be a steady state of learning when the fluctuations in input from individual sensory neurons are so large that they affect the net input to value-encoding neurons. This situation naturally arises when the synaptic strength is sufficiently strong and the excitatory input and the inhibitory input to the value-encoding neurons are balanced. The deviation from matching behavior is caused by increasing variance in the input potential due to the diffusion of synaptic efficacies. This effect causes an undermatching phenomenon, which has been often observed in behavioral experiments.

  19. Polymer uncrossing and knotting in protein folding, and their role in minimal folding pathways.

    Directory of Open Access Journals (Sweden)

    Ali R Mohazab

    Full Text Available We introduce a method for calculating the extent to which chain non-crossing is important in the most efficient, optimal trajectories or pathways for a protein to fold. This involves recording all unphysical crossing events of a ghost chain, and calculating the minimal uncrossing cost that would have been required to avoid such events. A depth-first tree search algorithm is applied to find minimal transformations to fold [Formula: see text], [Formula: see text], [Formula: see text], and knotted proteins. In all cases, the extra uncrossing/non-crossing distance is a small fraction of the total distance travelled by a ghost chain. Different structural classes may be distinguished by the amount of extra uncrossing distance, and the effectiveness of such discrimination is compared with other order parameters. It was seen that non-crossing distance over chain length provided the best discrimination between structural and kinetic classes. The scaling of non-crossing distance with chain length implies an inevitable crossover to entanglement-dominated folding mechanisms for sufficiently long chains. We further quantify the minimal folding pathways by collecting the sequence of uncrossing moves, which generally involve leg, loop, and elbow-like uncrossing moves, and rendering the collection of these moves over the unfolded ensemble as a multiple-transformation "alignment". The consensus minimal pathway is constructed and shown schematically for representative cases of an [Formula: see text], [Formula: see text], and knotted protein. An overlap parameter is defined between pathways; we find that [Formula: see text] proteins have minimal overlap indicating diverse folding pathways, knotted proteins are highly constrained to follow a dominant pathway, and [Formula: see text] proteins are somewhere in between. Thus we have shown how topological chain constraints can induce dominant pathway mechanisms in protein folding.

  20. Bodies Folded in Migrant Crypts

    DEFF Research Database (Denmark)

    Galis, Vasilis; Tzokas, Spyros; Tympas, Aristotle

    2016-01-01

    and human migrants generates a dis/abled subject. In this context, dis/ability may be a cause or consequence of migration, both in physical/material (the folding of bodies in the crypt) and cultural/semiotic terms, and may become a barrier to accessing protection, to entering and/or crossing a country...

  1. Gothic Elements in Folding Beijing

    Institute of Scientific and Technical Information of China (English)

    Hua Yan

    2016-01-01

    The study claims that Folding Beijing can not only be read as science fiction but also as Gothic literature,in which perspective,Gothic Elements such as Gothic Setting, Gothic Wanderer and Transgressions,and Gothic Terror are discussed respectively.

  2. Mechanisms of priming of pop-out: Stored representations or feature-gain modulations?

    Science.gov (United States)

    Lee, Hyunkyu; Mozer, Michael C; Vecera, Shaun P

    2009-07-01

    Previous research has shown that repetition of a task-relevant attention-capturing feature facilitates pop-out search. This priming of pop-out effect is due to some residual memory from recent trials. We explore two possible mechanisms of priming of pop-out: a top-down attentional benefit from a memory of the previous target representation that is stored in visual short-term memory (VSTM) and a bottom-up change of attentional gains from perceptual features of the previously attended target. We manipulated participants' ability to form a memory trace in VSTM by occupying it with a distractor task and found that occupying VSTM did not interfere with priming of pop-out. We next manipulated attentional gains associated with feature values by inserting an irrelevant task between pop-out searches. We found that the color of the target from the intervening perceptual task influenced pop-out search: The current pop-out search was facilitated when the intervening task's target matched the target color of the pop-out search. These results suggest that priming of pop-out might not be due to a memory trace of the previous targets in VSTM but, rather, might be due to changes in attentional control based on priming from relatively low-level feature representations of previously attended objects.

  3. Nephrolithiasis: Molecular Mechanism of Renal Stone Formation and the Critical Role Played by Modulators

    Directory of Open Access Journals (Sweden)

    Kanu Priya Aggarwal

    2013-01-01

    Full Text Available Urinary stone disease is an ailment that has afflicted human kind for many centuries. Nephrolithiasis is a significant clinical problem in everyday practice with a subsequent burden for the health system. Nephrolithiasis remains a chronic disease and our fundamental understanding of the pathogenesis of stones as well as their prevention and cure still remains rudimentary. Regardless of the fact that supersaturation of stone-forming salts in urine is essential, abundance of these salts by itself will not always result in stone formation. The pathogenesis of calcium oxalate stone formation is a multistep process and essentially includes nucleation, crystal growth, crystal aggregation, and crystal retention. Various substances in the body have an effect on one or more of the above stone-forming processes, thereby influencing a person’s ability to promote or prevent stone formation. Promoters facilitate the stone formation while inhibitors prevent it. Besides low urine volume and low urine pH, high calcium, sodium, oxalate and urate are also known to promote calcium oxalate stone formation. Many inorganic (citrate, magnesium and organic substances (nephrocalcin, urinary prothrombin fragment-1, osteopontin are known to inhibit stone formation. This review presents a comprehensive account of the mechanism of renal stone formation and the role of inhibitors/promoters in calcium oxalate crystallisation.

  4. Block of the Mevalonate Pathway Triggers Oxidative and Inflammatory Molecular Mechanisms Modulated by Exogenous Isoprenoid Compounds

    Directory of Open Access Journals (Sweden)

    Paola Maura Tricarico

    2014-04-01

    Full Text Available Deregulation of the mevalonate pathway is known to be involved in a number of diseases that exhibit a systemic inflammatory phenotype and often neurological involvements, as seen in patients suffering from a rare disease called mevalonate kinase deficiency (MKD. One of the molecular mechanisms underlying this pathology could depend on the shortage of isoprenoid compounds and the subsequent mitochondrial damage, leading to oxidative stress and pro-inflammatory cytokines’ release. Moreover, it has been demonstrated that cellular death results from the balance between apoptosis and pyroptosis, both driven by mitochondrial damage and the molecular platform inflammasome. In order to rescue the deregulated pathway and decrease inflammatory markers, exogenous isoprenoid compounds were administered to a biochemical model of MKD obtained treating a murine monocytic cell line with a compound able to block the mevalonate pathway, plus an inflammatory stimulus. Our results show that isoprenoids acted in different ways, mainly increasing the expression of the evaluated markers [apoptosis, mitochondrial dysfunction, nucleotide-binding oligomerization-domain protein-like receptors 3 (NALP3, cytokines and nitric oxide (NO]. Our findings confirm the hypothesis that inflammation is triggered, at least partially, by the shortage of isoprenoids. Moreover, although further studies are necessary, the achieved results suggest a possible role for exogenous isoprenoids in the treatment of MKD.

  5. Block of the mevalonate pathway triggers oxidative and inflammatory molecular mechanisms modulated by exogenous isoprenoid compounds.

    Science.gov (United States)

    Tricarico, Paola Maura; Kleiner, Giulio; Valencic, Erica; Campisciano, Giuseppina; Girardelli, Martina; Crovella, Sergio; Knowles, Alessandra; Marcuzzi, Annalisa

    2014-04-22

    Deregulation of the mevalonate pathway is known to be involved in a number of diseases that exhibit a systemic inflammatory phenotype and often neurological involvements, as seen in patients suffering from a rare disease called mevalonate kinase deficiency (MKD). One of the molecular mechanisms underlying this pathology could depend on the shortage of isoprenoid compounds and the subsequent mitochondrial damage, leading to oxidative stress and pro-inflammatory cytokines' release. Moreover, it has been demonstrated that cellular death results from the balance between apoptosis and pyroptosis, both driven by mitochondrial damage and the molecular platform inflammasome. In order to rescue the deregulated pathway and decrease inflammatory markers, exogenous isoprenoid compounds were administered to a biochemical model of MKD obtained treating a murine monocytic cell line with a compound able to block the mevalonate pathway, plus an inflammatory stimulus. Our results show that isoprenoids acted in different ways, mainly increasing the expression of the evaluated markers [apoptosis, mitochondrial dysfunction, nucleotide-binding oligomerization-domain protein-like receptors 3 (NALP3), cytokines and nitric oxide (NO)]. Our findings confirm the hypothesis that inflammation is triggered, at least partially, by the shortage of isoprenoids. Moreover, although further studies are necessary, the achieved results suggest a possible role for exogenous isoprenoids in the treatment of MKD.

  6. Androgen modulation of social decision making mechanisms in the brain: an integrative and embodied perspective

    Directory of Open Access Journals (Sweden)

    Rui F Oliveira

    2014-07-01

    Full Text Available Apart from their role in reproduction androgens also respond to social challenges and this response has been seen as a way to regulate the expression of behaviour according to the perceived social environment (Challenge hypothesis, Wingfield et al. 1990. This hypothesis implies that social decision-making mechanisms localized in the central nervous system (CNS are open to the influence of peripheral hormones that ultimately are under the control of the CNS through the hypothalamic-pituitary-gonadal axis. Therefore, two puzzling questions emerge at two different levels of biological analysis: (1 Why does the brain, which perceives the social environment and regulates androgen production in the gonad, need feedback information from the gonad to adjust its social decision-making processes? (2 How does the brain regulate gonadal androgen responses to social challenges and how do these feedback into the brain? In this paper, we will address these two questions using the integrative approach proposed by Niko Tinbergen, who proposed that a full understanding of behaviour requires its analysis at both proximate (physiology, ontogeny and ultimate (ecology, evolution levels.

  7. Nephrolithiasis: molecular mechanism of renal stone formation and the critical role played by modulators.

    Science.gov (United States)

    Aggarwal, Kanu Priya; Narula, Shifa; Kakkar, Monica; Tandon, Chanderdeep

    2013-01-01

    Urinary stone disease is an ailment that has afflicted human kind for many centuries. Nephrolithiasis is a significant clinical problem in everyday practice with a subsequent burden for the health system. Nephrolithiasis remains a chronic disease and our fundamental understanding of the pathogenesis of stones as well as their prevention and cure still remains rudimentary. Regardless of the fact that supersaturation of stone-forming salts in urine is essential, abundance of these salts by itself will not always result in stone formation. The pathogenesis of calcium oxalate stone formation is a multistep process and essentially includes nucleation, crystal growth, crystal aggregation, and crystal retention. Various substances in the body have an effect on one or more of the above stone-forming processes, thereby influencing a person's ability to promote or prevent stone formation. Promoters facilitate the stone formation while inhibitors prevent it. Besides low urine volume and low urine pH, high calcium, sodium, oxalate and urate are also known to promote calcium oxalate stone formation. Many inorganic (citrate, magnesium) and organic substances (nephrocalcin, urinary prothrombin fragment-1, osteopontin) are known to inhibit stone formation. This review presents a comprehensive account of the mechanism of renal stone formation and the role of inhibitors/promoters in calcium oxalate crystallisation.

  8. 2-Deoxy Glucose Modulates Expression and Biological Activity of VEGF in a SIRT-1 Dependent Mechanism.

    Science.gov (United States)

    Kunhiraman, Haritha; Edatt, Lincy; Thekkeveedu, Sruthi; Poyyakkara, Aswini; Raveendran, Viji; Kiran, Manikantan Syamala; Sudhakaran, Perumana; Kumar, Sameer V B

    2017-02-01

    Reprogramming of energy metabolism particularly switching over of cells to aerobic glycolysis leading to accumulation of lactate is a hallmark of cancer. Lactate can induce angiogenesis, an important process underlying tumor growth and metastasis. VEGF is one of the most important cytokines which regulate this process and the present study was designed to examine if blocking glycolytic pathway in tumor cells can affect its angiogenic potency with respect to VEGF. For this, the expression and biological activity of VEGF synthesized and secreted by tumor derived cell lines in the presence or absence of 2-deoxy glucose (2-DG), an inhibitor of glycolysis was determined. The results suggested that inhibition of glycolysis using sub-lethal doses of 2-DG down-regulated the expression of VEGF and also significantly reduced its biological activity. Further mechanistic studies revealed that the down regulation of VEGF gene expression by 2-DG was due to an increase in SIRT-1 activity and the reduced biological activity was found to be due to an increase in the PAR modification of VEGF. Activity of SIRT-1 and PAR modification of VEGF in turn, was found to be correlated to the cellular NAD(+) levels. The results presented here therefore suggest that treatment of cancer cells with 2-DG can significantly reduce its overall angiogenic potency through transcriptional and post-translational mechanisms. J. Cell. Biochem. 118: 252-262, 2017. © 2016 Wiley Periodicals, Inc.

  9. Painful faces-induced attentional blink modulated by top-down and bottom-up mechanisms

    Directory of Open Access Journals (Sweden)

    Chun eZheng

    2015-06-01

    Full Text Available Pain-related stimuli can capture attention in an automatic (bottom-up or intentional (top-down fashion. Previous studies have examined attentional capture by pain-related information using spatial attention paradigms that involve mainly a bottom-up mechanism. In the current study, we investigated the pain information–induced attentional blink (AB using a rapid serial visual presentation (RSVP task, and compared the effects of task-irrelevant and task-relevant pain distractors. Relationships between accuracy of target identification and individual traits (i.e., empathy and catastrophizing thinking about pain were also examined. The results demonstrated that task-relevant painful faces had a significant pain information–induced AB effect, whereas task-irrelevant faces a near-significant trend of this effect, supporting the notion that pain-related stimuli can influence the temporal dynamics of attention. Furthermore, we found a significant negative correlation between response accuracy and pain catastrophizing score in task-relevant trials. These findings suggest that active scanning of environmental information related to pain produces greater deficits in cognition than does unintentional attention toward pain, which may represent the different ways in which healthy individuals and patients with chronic pain process pain-relevant information. These results may provide insight into the understanding of maladaptive attentional processing in patients with chronic pain.

  10. Painful faces-induced attentional blink modulated by top–down and bottom–up mechanisms

    Science.gov (United States)

    Zheng, Chun; Wang, Jin-Yan; Luo, Fei

    2015-01-01

    Pain-related stimuli can capture attention in an automatic (bottom–up) or intentional (top–down) fashion. Previous studies have examined attentional capture by pain-related information using spatial attention paradigms that involve mainly a bottom–up mechanism. In the current study, we investigated the pain information-induced attentional blink (AB) using a rapid serial visual presentation (RSVP) task, and compared the effects of task-irrelevant and task-relevant pain distractors. Relationships between accuracy of target identification and individual traits (i.e., empathy and catastrophizing thinking about pain) were also examined. The results demonstrated that task-relevant painful faces had a significant pain information-induced AB effect, whereas task-irrelevant faces showed a near-significant trend of this effect, supporting the notion that pain-related stimuli can influence the temporal dynamics of attention. Furthermore, we found a significant negative correlation between response accuracy and pain catastrophizing score in task-relevant trials. These findings suggest that active scanning of environmental information related to pain produces greater deficits in cognition than does unintentional attention toward pain, which may represent the different ways in which healthy individuals and patients with chronic pain process pain-relevant information. These results may provide insight into the understanding of maladaptive attentional processing in patients with chronic pain. PMID:26082731

  11. Painful faces-induced attentional blink modulated by top-down and bottom-up mechanisms.

    Science.gov (United States)

    Zheng, Chun; Wang, Jin-Yan; Luo, Fei

    2015-01-01

    Pain-related stimuli can capture attention in an automatic (bottom-up) or intentional (top-down) fashion. Previous studies have examined attentional capture by pain-related information using spatial attention paradigms that involve mainly a bottom-up mechanism. In the current study, we investigated the pain information-induced attentional blink (AB) using a rapid serial visual presentation (RSVP) task, and compared the effects of task-irrelevant and task-relevant pain distractors. Relationships between accuracy of target identification and individual traits (i.e., empathy and catastrophizing thinking about pain) were also examined. The results demonstrated that task-relevant painful faces had a significant pain information-induced AB effect, whereas task-irrelevant faces showed a near-significant trend of this effect, supporting the notion that pain-related stimuli can influence the temporal dynamics of attention. Furthermore, we found a significant negative correlation between response accuracy and pain catastrophizing score in task-relevant trials. These findings suggest that active scanning of environmental information related to pain produces greater deficits in cognition than does unintentional attention toward pain, which may represent the different ways in which healthy individuals and patients with chronic pain process pain-relevant information. These results may provide insight into the understanding of maladaptive attentional processing in patients with chronic pain.

  12. Epiphytes modulate Posidonia oceanica photosynthetic production, energetic balance, antioxidant mechanisms and oxidative damage

    Directory of Open Access Journals (Sweden)

    Monya Mendes Costa

    2015-12-01

    Full Text Available Epiphytes impose physical barriers to light penetration into seagrass leaves causing shading, which may decrease the production of oxygen reactive species (ROS, but also constitute a physical aggression that may trigger the production of ROS, leading to oxidative damage. Here we investigate the effects of epiphytes on Posidonia oceanica under both interactive perspectives, light attenuation and oxidative stress. Specifically the role of epiphytes in net photosynthesis, chlorophyll a and b, photoprotection (Violaxanthin+Anteraxanthin+Zeaxanthin cycle, soluble sugar and starch contents, enzymatic (ascorbate peroxidase (APX and dehydroascorbate reductase (DHAR and global (trolox equivalent antioxidant capacity (TEAC and oxygen radical antioxidant capacity (ORAC antioxidant responses, phenolics and oxidative damage (malondialdehyde are tested. Leaves with epiphytes showed higher chlorophyll b and lower content in VAZ cycle carotenoids. Epiphyte shading was the probable reason for the lower VAZ de-epoxidation-ratio of leaves with epiphytes. In spite of being shaded, leaves with epiphytes showed higher antioxidant levels, indicating that epiphytes trigger the production of ROS. Both ORAC and TEAC and also APX and DHAR activities were higher in leaves with epiphytes, indicating that this response was related with its presence. Malondialdehyde concentrations also suggest oxidative damage caused by epiphytes. We conclude that the epiphyte load causes oxidative stress in P. oceanica and the mechanisms to scavenge ROS were not completely effective to avoid cell damage.

  13. Ubiquitination mediates Kv1.3 endocytosis as a mechanism for protein kinase C-dependent modulation

    Science.gov (United States)

    Martínez-Mármol, Ramón; Styrczewska, Katarzyna; Pérez-Verdaguer, Mireia; Vallejo-Gracia, Albert; Comes, Núria; Sorkin, Alexander; Felipe, Antonio

    2017-01-01

    The voltage-dependent potassium channel Kv1.3 plays essential physiological functions in the immune system. Kv1.3, regulating the membrane potential, facilitates downstream Ca2+ -dependent pathways and becomes concentrated in specific membrane microdomains that serve as signaling platforms. Increased and/or delocalized expression of the channel is observed at the onset of several autoimmune diseases. In this work, we show that adenosine (ADO), which is a potent endogenous modulator, stimulates PKC, thereby causing immunosuppression. PKC activation triggers down-regulation of Kv1.3 by inducing a clathrin-mediated endocytic event that targets the channel to lysosomal-degradative compartments. Therefore, the abundance of Kv1.3 at the cell surface decreases, which is clearly compatible with an effective anti-inflammatory response. This mechanism requires ubiquitination of Kv1.3, catalyzed by the E3 ubiquitin-ligase Nedd4-2. Postsynaptic density protein 95 (PSD-95), a member of the MAGUK family, recruits Kv1.3 into lipid-raft microdomains and protects the channel against ubiquitination and endocytosis. Therefore, the Kv1.3/PSD-95 association fine-tunes the anti-inflammatory response in leukocytes. Because Kv1.3 is a promising multi-therapeutic target against human pathologies, our results have physiological relevance. In addition, this work elucidates the ADO-dependent PKC-mediated molecular mechanism that triggers immunomodulation by targeting Kv1.3 in leukocytes. PMID:28186199

  14. On the modulation effect of pulsing and static magnetic fields and mechanical vibrations on barley seed hydration.

    Science.gov (United States)

    Amyan, Armine; Ayrapetyan, Sinerik

    2004-01-01

    The changes of wet and dry weights of barley seed in different periods of swelling were studied in seeds treated with Extremely Low Frequency Electromagnetic Fields (ELF EMF), Static Magnetic Fields (SMF) and Mechanical Vibrations (MV) in cold (4 degrees C) and warm (20 degrees C) distilled water as well as in seeds non-treated (control). The metabolic dependent seed hydration, dry weight loss and water binding in seed were modulated by preliminary EMF, SMF and MV-induced treatment of distilled water. The specific electrical conductivity (SEC) of control and treated distilled water was measured before the seed incubation. Frequency and intensity "windows" (i.e. range of frequency or intensity) for the effect of EMF, MV and SMF (correspondingly) on seed hydration, solubility and water binding in seed were studied. These "windows" were different in various phases of seed swelling. It is suggested that water structure modification is the result of valence angle changes (SMF and EMF) and dipole molecules vibration (EMF and MV) has different effects on the process of hydration, solubility and water binding in seed. These results are important from the point of understanding the mechanisms of the biological effect of EMF, as well as from the point of agriculture.

  15. Effect of initial plastic strain on mechanical training of non-modulated Ni–Mn–Ga martensite structure

    Energy Technology Data Exchange (ETDEWEB)

    Szczerba, M.J., E-mail: m.szczerba@imim.pl [Institute of Metallurgy and Materials Science, Polish Academy of Sciences, 25 Reymonta Street, 30-059 Kraków (Poland); Chulist, R. [Institute of Metallurgy and Materials Science, Polish Academy of Sciences, 25 Reymonta Street, 30-059 Kraków (Poland); Kopacz, S.; Szczerba, M.S. [Department of Materials Science and Non-Ferrous Metals Engineering, AGH University of Science and Technology, 30 Mickiewicza Ave., 30-059 Kraków (Poland)

    2014-08-12

    The influence of plastic pre-straining on the mechanical training process of Ni–Mn–Ga single crystals with a non-modulated martensite structure was examined using uniaxial quasi static compression tests and electron backscatter diffraction technique. Firstly, the optimal pre-straining temperature, for which a large plastic strain can be imposed to as-grown crystals with low flow stress and low rate of strain hardening, was established. Then, the maximum value of plastic pre-straining which allows performing successful room temperature mechanical training was found to be of about 20% of total sample thickness reduction. Below this value, training process leads to single variant state, which is able to accommodate true plastic strain of about 0.14 in each step of further training. Above 20% of deformation a multiple martensite variant state of characteristic triangular arrangements is generated. The latter structure cannot practically afford any plastic accommodation during further training; thus the training process fails to operate.

  16. Effect and proposed mechanism of vitamin C modulating amino acid regulation of autophagic proteolysis.

    Science.gov (United States)

    Karim, Md Razaul; Kadowaki, Motoni

    2017-08-10

    Autophagy is an intracellular bulk degradation process, induced under nutrient starvation. Failure of autophagy has been recognized as a contributor to aging and multiple age related neurodegenerative diseases. Improving autophagy is a beneficial anti-aging strategy, however very few physiological regulators have been identified. Here, we demonstrate that vitamin C is a nutritional stimulator of autophagy. Supplementation of fresh hepatocytes with vitamin C increased autophagic proteolysis significantly in the presence of amino acids in a dose- and time-dependent manner, although no effect was observed in the absence of amino acids. In addition, inhibitor studies with 3-methyladenine, chloroquine, leupeptin and β-lactone confirmed that vitamin C is active through the lysosomal autophagy and not the proteasome pathway. Furthermore, the autophagy marker LC3 protein was significantly increased by vitamin C, suggesting its possible site of action is at the formation step. Both the reduced (ascorbic acid, AsA) and oxidized form (dehydroascorbic acid, DHA) of vitamin C exhibited equal enhancing effect, indicating that the effect does not depend on the anti-oxidation functionality of vitamin C. To understand the mechanism, we established that the effective dose (50 μM) was 15× lower than the intracellular content suggesting these would be only a minor influx from the extracellular pool. Moreover, transporter inhibitor studies in an AsA deficient ODS model rat revealed more accurately that the enhancing effect on autophagic proteolysis still existed, even though the intracellular influx of AsA was blocked. Taken together, these results provide evidence that vitamin C can potentially act through extracellular signaling. Copyright © 2017. Published by Elsevier B.V.

  17. Neurotrophic Modulation of Myelinated Cutaneous Innervation and Mechanical Sensory Loss in Diabetic Mice

    Science.gov (United States)

    Christianson, Julie A.; Ryals, Janelle M.; Johnson, Megan S.; Dobrowsky, Rick T.; Wright, Douglas E.

    2007-01-01

    Human diabetic patients often lose touch and vibratory sensations, but to date, most studies on diabetes-induced sensory nerve degeneration have focused on epidermal C-fibers. Here, we explored the effects of diabetes on cutaneous myelinated fibers in relation to the behavioral responses to tactile stimuli from diabetic mice. Weekly behavioral testing began prior to STZ administration and continued until 8 weeks, at which time myelinated fiber innervation was examined in the footpad by immunohistochemistry using antiserum to NF-H and MBP. Diabetic mice developed reduced behavioral responses to non-noxious (monofilaments) and noxious (pin prick) stimuli. In addition, diabetic mice displayed a 50% reduction in NF-H-positive myelinated innervation of the dermal footpad compared to non-diabetic mice. To test whether two neurotrophins NGF and/or NT-3 known to support myelinated cutaneous fibers could influence myelinated innervation, diabetic mice were treated intrathecally for two weeks with NGF, NT-3, NGF and NT-3. Neurotrophin-treated mice were then compared to diabetic mice treated with insulin for two weeks. NGF and insulin treatment both increased paw withdrawal to mechanical stimulation in diabetic mice, whereas NT-3 or a combination of NGF and NT-3 failed to alter paw withdrawal responses. Surprisingly, all treatments significantly increased myelinated innervation compared to control-treated diabetic mice, demonstrating that myelinated cutaneous fibers damaged by hyperglycemia respond to intrathecal administration of neurotrophins. Moreover, NT-3 treatment increased epidermal Merkel cell numbers associated with nerve fibers, consistent with increased numbers of NT-3-responsive slowly adapting A-fibers. These studies suggest that myelinated fiber loss may contribute as significantly as unmyelinated epidermal loss in diabetic neuropathy, and the contradiction between neurotrophin-induced increases in dermal innervation and behavior emphasize the need for multiple

  18. Amplitude and frequency modulation control of sound production in a mechanical model of the avian syrinx.

    Science.gov (United States)

    Elemans, Coen P H; Muller, Mees; Larsen, Ole Naesbye; van Leeuwen, Johan L

    2009-04-01

    Birdsong has developed into one of the important models for motor control of learned behaviour and shows many parallels with speech acquisition in humans. However, there are several experimental limitations to studying the vocal organ - the syrinx - in vivo. The multidisciplinary approach of combining experimental data and mathematical modelling has greatly improved the understanding of neural control and peripheral motor dynamics of sound generation in birds. Here, we present a simple mechanical model of the syrinx that facilitates detailed study of vibrations and sound production. Our model resembles the 'starling resistor', a collapsible tube model, and consists of a tube with a single membrane in its casing, suspended in an external pressure chamber and driven by various pressure patterns. With this design, we can separately control 'bronchial' pressure and tension in the oscillating membrane and generate a wide variety of 'syllables' with simple sweeps of the control parameters. We show that the membrane exhibits high frequency, self-sustained oscillations in the audio range (>600 Hz fundamental frequency) using laser Doppler vibrometry, and systematically explore the conditions for sound production of the model in its control space. The fundamental frequency of the sound increases with tension in three membranes with different stiffness and mass. The lower-bound fundamental frequency increases with membrane mass. The membrane vibrations are strongly coupled to the resonance properties of the distal tube, most likely because of its reflective properties to sound waves. Our model is a gross simplification of the complex morphology found in birds, and more closely resembles mathematical models of the syrinx. Our results confirm several assumptions underlying existing mathematical models in a complex geometry.

  19. Amyloid beta modulated the selectivity of heme-catalyzed protein tyrosine nitration: an alternative mechanism for selective protein nitration.

    Science.gov (United States)

    Yuan, Can; Li, Hailing; Gao, Zhonghong

    2012-10-01

    Protein tyrosine nitration is a post-translational modification associated with numerous pathological conditions. The biological consequences of this modification strongly depend on the site selectivity. Unfortunately, to date there is still no reliable model for predicting the selectivity of protein tyrosine nitration. Previously, we found that amyloid beta (Aβ) changed the selectivity of enolase tyrosine nitration upon binding to heme. It seemed that there was a link between the hydrophilicity of Aβ and the site-specific tyrosine nitration. We further investigated the role of the hydrophilicity of the molecules that bind to heme in the selectivity of protein tyrosine nitration. We found that Aβ(1-16), Aβ(1-20), and Aβ(1-40), upon binding to heme and interacting with glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in a site-specific manner, differently modulated the site selectivity of heme-catalyzed GAPDH tyrosine nitration. The modulation is associated with the hydrophilicity of the Aβ peptides, which changed the surrounding environment of the heme. At the same time, the Aβ-heme complexes were found to be more effective at inactivating GAPDH than heme alone, and the selective tyrosine nitration that was catalyzed by Aβ-heme played an important role. These findings suggest an alternative mechanism for the selectivity of protein tyrosine nitration, which may lead to a better understanding of the factors that influence protein tyrosine nitration selectivity and the important roles of Aβ and heme in the pathogenesis of Alzheimer's disease, where Aβ accumulation and Aβ-dependent protein nitration play central roles.

  20. Analysis of the thermo-mechanical behaviour of the DEMO Water-Cooled Lithium Lead breeding blanket module under normal operation steady state conditions

    Energy Technology Data Exchange (ETDEWEB)

    Di Maio, P.A.; Arena, P. [Dipartimento di Energia, Ingegneria dell’Informazione e Modelli Matematici, Università di Palermo, Viale delle Scienze, 90128 Palermo (Italy); Aubert, J. [CEA Saclay, DEN/DANS/DM2S/SEMT, 91191 Gif sur Yvette Cedex (France); Bongiovì, G. [Dipartimento di Energia, Ingegneria dell’Informazione e Modelli Matematici, Università di Palermo, Viale delle Scienze, 90128 Palermo (Italy); Chiovaro, P., E-mail: pierluigi.chiovaro@unipa.it [Dipartimento di Energia, Ingegneria dell’Informazione e Modelli Matematici, Università di Palermo, Viale delle Scienze, 90128 Palermo (Italy); Giammusso, R. [ENEA – C.R. Brasimone, 40032 Camugnano (Italy); Li Puma, A. [CEA Saclay, DEN/DANS/DM2S/SEMT, 91191 Gif sur Yvette Cedex (France); Tincani, A. [ENEA – C.R. Brasimone, 40032 Camugnano (Italy)

    2015-10-15

    Highlights: • A DEMO WCLL blanket module thermo-mechanical behaviour has been investigated. • Two models of the WCLL blanket module have been set-up adopting a code based on FEM. • The water flow domain in the module has been considered. • A set of uncoupled steady state thermo-mechanical analyses has been carried out. • Critical temperature is not overcome. Safety verifications are generally satisfied. - Abstract: Within the framework of DEMO R&D activities, a research cooperation has been launched between ENEA, the University of Palermo and CEA to investigate the thermo-mechanical behaviour of the outboard equatorial module of the DEMO1 Water-Cooled Lithium Lead (WCLL) blanket under normal operation steady state scenario. The research campaign has been carried out following a theoretical–computational approach based on the Finite Element Method (FEM) and adopting a qualified commercial FEM code. In particular, two different 3D FEM models (Model 1 and Model 2), reproducing respectively the central and the lateral poloidal–radial slices of the WCLL blanket module, have been set up. A particular attention has been paid to the modelling of water flow domain, within both the segment box channels and the breeder zone tubes, to simulate realistically the coolant-box thermal coupling. Results obtained are herewith reported and critically discussed.

  1. Protein Folding:. Physics on Products of Evolution

    Science.gov (United States)

    Go, Nobuhiro

    2001-09-01

    Proteins are self-assembling molecular systems. A polypeptide chain of a protein molecule folds into a globular three-dimensional structure, which is specific to the amino acid sequence of the chain. A protein molecule is in the "native state" when folded into its specific three-dimensional structure. Only in the native state, a protein molecule carries out its biological function. This extraordinary self-assembly ability of proteins can be explained based on the three generally accepted empirical observations in proteins: (1) Two-state character; Folding and unfolding transitions in small globular proteins are generally of the two-state character. (2) Consistency principle; Various components of intra-molecular interactions responsible for stabilizing the native state of globular proteins are consistent to each other in their native state. (3) Principle of marginal stability; The native folded states of globular proteins are generally only marginally stable against their unfolded states. Deduction of the self-assembly ability from the three observations is a problem of physical nature. Very sophisticated theories have been developed recently as to this point. I shall give a very simple and intuitive discussion on this point. Asking why protein molecules show the three observations is another problem. Observation (1) can be derived from the globularity of native states. Observations (2) and (3) can be understood only by considering the evolutionary history of protein molecules, i.e., only polypeptide chains with very specific amino acid sequences selected during the history of evolution show properties of observations (2) and (3). Here we see a case where the mechanism of an extraordinary ability of biopolymers is elucidated in terms of physics, and physics expects that only a very small fraction of amino acid sequences have such an ability. Nature has left the job of finding able sequences to the history of evolution.

  2. Modulation of Protein Quality Control Systems as Novel Mechanisms Underlying Functionality of Food Phytochemicals

    Directory of Open Access Journals (Sweden)

    Kohta Ohnishi

    2013-10-01

    phytochemicals, such as curcumin, phenethyl isothiocyanate, ursolic acid, and lycopene, were significantly active, whereas most nutrients were virtually inactive. These results may be associated with the fact that phytochemicals, but not nutrients, are foreign chemicals to animals, as noted above.Functional Foods in Health and Disease 2013; 3(10:400-415 Page 402 of 415 Conclusion: Up-regulation of antioxidant and xenobiotics-metabolizing enzymes has been reported to be an adaptive response in animals exposed to phytochemicals. Our present results imply that the process also increases the capacity to counteract proteo-stresses through activation of PQC systems. This putative phenomenon, representing the concept of hormesis[5], may be associated with mechanisms underlying the physiological functions of phytochemicals. Therefore, chronic ingestion of this class of chemicals may result in ‘chemical training’, in which self-defense systems are continuously activated for adaptation to phytochemical-driven stresses.

  3. Evolutionary computer programming of protein folding and structure predictions.

    Science.gov (United States)

    Nölting, Bengt; Jülich, Dennis; Vonau, Winfried; Andert, Karl

    2004-07-07

    In order to understand the mechanism of protein folding and to assist the rational de-novo design of fast-folding, non-aggregating and stable artificial enzymes it is very helpful to be able to simulate protein folding reactions and to predict the structures of proteins and other biomacromolecules. Here, we use a method of computer programming called "evolutionary computer programming" in which a program evolves depending on the evolutionary pressure exerted on the program. In the case of the presented application of this method on a computer program for folding simulations, the evolutionary pressure exerted was towards faster finding deep minima in the energy landscape of protein folding. Already after 20 evolution steps, the evolved program was able to find deep minima in the energy landscape more than 10 times faster than the original program prior to the evolution process.

  4. Dissecting Ubiquitin Folding Using the Self-Organized Polymer Model.

    Science.gov (United States)

    Reddy, Govardhan; Thirumalai, D

    2015-08-27

    Folding of Ubiquitin (Ub), a functionally important protein found in eukaryotic organisms, is investigated at low and neutral pH at different temperatures using simulations of the coarse-grained self-organized-polymer model with side chains (SOP-SC). The melting temperatures (Tm's), identified with the peaks in the heat capacity curves, decrease as pH decreases, in qualitative agreement with experiments. The calculated radius of gyration, showing dramatic variations with pH, is in excellent agreement with scattering experiments. At Tm, Ub folds in a two-state manner at low and neutral pH. Clustering analysis of the conformations sampled in equilibrium folding trajectories at Tm, with multiple transitions between the folded and unfolded states, shows a network of metastable states connecting the native and unfolded states. At low and neutral pH, Ub folds with high probability through a preferred set of conformations resulting in a pH-dependent dominant folding pathway. Folding kinetics reveal that Ub assembly at low pH occurs by multiple pathways involving a combination of nucleation-collapse and diffusion collision mechanism. The mechanism by which Ub folds is dictated by the stability of the key secondary structural elements responsible for establishing long-range contacts and collapse of Ub. Nucleation collapse mechanism holds if the stability of these elements are marginal, as would be the case at elevated temperatures. If the lifetimes associated with these structured microdomains are on the order of hundreds of microseconds, then Ub folding follows the diffusion-collision mechanism with intermediates, many of which coincide with those found in equilibrium. Folding at neutral pH is a sequential process with a populated intermediate resembling that sampled at equilibrium. The transition state structures, obtained using a Pfold analysis, are homogeneous and globular with most of the secondary and tertiary structures being native-like. Many of our findings for

  5. Elucidation of the mechanism of the regulatory function of the Ig1 module of the fibroblast growth factor receptor 1

    DEFF Research Database (Denmark)

    Kiselyov, Vladislav; Kochoyan, Artur; Poulsen, Flemming;

    2006-01-01

    The extracellular part of the fibroblast growth factor (FGF) receptor (FGFR) consists of up to three Ig modules (Ig1-Ig3), in which the Ig2 and Ig3 modules determine affinity and specificity for FGF and heparin. The FGFR isoforms lacking the Ig1 module have higher affinity for FGF and heparin than...... the triple Ig-module isoforms, suggesting that the Ig1 module is involved in the regulation of the FGFR-ligand interaction. We show here by surface plasmon resonance and NMR analyses that the Ig1 module binds to the Ig2 module, and identify by NMR the binding sites involved in the Ig1-Ig2 interaction....... The identified binding site in the Ig2 module was found to be in the area of the FGF-Ig2 and Ig2-heparin contact sites, thus providing direct structural evidence that the Ig1 module functions as a competitive autoinhibitor of the FGFR-ligand interaction. Furthermore, the Ig1 binding site of the Ig2 module...

  6. Structural and functional studies of the modulator NS9283 reveal agonist-like mechanism of action at α4β2 nicotinic acetylcholine receptors

    DEFF Research Database (Denmark)

    Olsen, Jeppe A; Ahring, Philip K; Kastrup, Jette Sandholm Jensen;

    2014-01-01

    Modulation of Cys loop receptor ion channels is a proven drug discovery strategy, but many underlying mechanisms of the mode of action are poorly understood. We report the x-ray structure of the acetylcholine-binding protein from Lymnaea stagnalis with NS9283, a stoichiometry selective positive m...

  7. Elucidating PID Degradation Mechanisms and In Situ Dark I-V Monitoring for Modeling Degradation Rate in CdTe Thin-Film Modules

    DEFF Research Database (Denmark)

    Hacke, Peter; Spataru, Sergiu; Johnston, Steve

    2016-01-01

    A progression of potential-induced degradation (PID) mechanisms are observed in CdTe modules, including shunting/junction degradation and two different manifestations of series resistance depending on the stress level and water ingress. The dark I-V method for in-situ characterization of Pmax based...

  8. Protein Folding Pathways Revealed by Essential Dynamics Sampling.

    Science.gov (United States)

    Narzi, Daniele; Daidone, Isabella; Amadei, Andrea; Di Nola, Alfredo

    2008-11-11

    The characterization of the protein folding process represents one of the major challenges in molecular biology. Here, a method to simulate the folding process of a protein to its native state is reported, the essential dynamics sampling (EDS) method, and is successfully applied to detecting the correct folding pathways of two small proteins, the all-β SH3 domain of Src tyrosine kinase transforming protein (SH3) and the α/β B1 domain of streptococcal protein G (GB1). The main idea of the method is that a subset of the natural modes of fluctuation in the native state is key in directing the folding process. A biased molecular dynamics simulation is performed, in which the restrained degrees of freedom are chosen among those obtained by a principal component, or essential dynamics, analysis of the positional fluctuations of the Cα atoms in the native state. Successful folding is obtained if the restraints are applied only to the eigenvectors with lowest eigenvalues, representing the most rigid quasi-constraint motions. If the essential eigenvectors, the ones accounting for most of the variance, are used, folding is not successful. These results clearly show that the eigenvectors with lowest eigenvalues contain the main mechanical information necessary to drive the folding process, while the essential eigenvectors represent the large concerted motions which can occur without folding/unfolding the protein.

  9. Drug release-modulating mechanism of hydrophilic hydroxypropylmethylcellulose matrix tablets: distribution of atoms and carrier and texture analysis.

    Science.gov (United States)

    Park, Jun-Bom; Lim, Jisung; Kang, Chin-Yang; Lee, Beom-Jin

    2013-12-01

    Although release profiles of drug from hydrophilic matrices have been well recognized, the visual distribution of hydroxypropylmethylcellulose (HPMC) and atoms inside of internal structures of hydrophilic HPMC matrices has not been characterized. In this paper, drug release mechanism from HPMC matrix tablet was investigated based on the release behaviors of HPMC, physical properties of gelled HPMC tablet and atomic distributions of formulation components using diverse instruments. A matrix tablet consisting of hydroxypropyl methylcellulose (HPMC 6, 4,000 and 100,000 mPa·s), chlorpheniramine maleate (CPM) as a model and fumed silicon dioxide (Aerosil(®) 200) was prepared via direct compression. The distribution of atoms and HPMC imaging were characterized using scanning electron microscope (SEM)/ energy-dispersive X-ray spectroscopy (EDX), and near-infrared (NIR) analysis, respectively as a function of time. A texture analyzer was also used to characterize the thickness and maintenance of gel layer of HPMC matrix tablet. The HPMC matrix tablets showed Higuchi release kinetics with no lag time against the square root of time. High viscosity grades of HPMC gave retarded release rate because of the greater swelling and gel thickness as characterized by texture analyzer. According to the NIR imaging, low-viscosity-grade HPMC (6 mPa·s) quickly leached out onto the surface of the tablet, while the high-viscosity-grade HPMC (4000 mPa·s) formed much thicker gel layer around the tablet and maintained longer via slow erosion, resulting in retarded drug release. The atomic distribution of the drug (chlorine, carbon, oxygen), HPMC (carbon, oxygen) and silicon dioxide (silica, oxygen) and NIR imaging of HPMC corresponded with the dissolution behaviors of drug as a function of time. The use of imaging and texture analyses could be applicable to explain the release- modulating mechanism of hydrophilic HPMC matrix tablets.

  10. The Pronociceptive Effect of Paradoxical Sleep Deprivation in Rats: Evidence for a Role of Descending Pain Modulation Mechanisms.

    Science.gov (United States)

    Tomim, Dabna H; Pontarolla, Felipe M; Bertolini, Jessica F; Arase, Mauricio; Tobaldini, Glaucia; Lima, Marcelo M S; Fischer, Luana

    2016-04-01

    The mechanisms underlying the pronociceptive effect of paradoxical sleep deprivation (PSD) are not known. In this study, we asked whether PSD increases tonic nociception in the formalin test, decreases the antinociceptive effect of morphine administered into the periaqueductal gray matter (PAG), and disrupts endogenous descending pain modulation. PSD for either 24 or 48 h significantly increased formalin-induced nociception and decreased mechanical nociceptive paw withdrawal threshold. The maximal antinociceptive effect induced by morphine (0.9-9 nmol, intra-PAG) was significantly decreased by PSD. The administration of a low dose of the GABAA receptor antagonist, bicuculline (30-300 pmol, intra-PAG), decreased nociception in control rats, but not in paradoxical-sleep-deprived ones. Furthermore, the administration of the cholecystokinin (CCK) 2 receptor antagonist, YM022 (0.5-2 pmol) in the rostral ventral medulla (RVM), decreased nociception in paradoxical-sleep-deprived rats but not in control ones. While a dose of the CCK 2 receptor agonist, CCK-8 (8-24 pmol intra-RVM), increased nociception in control rats, but not in paradoxical-sleep-deprived ones. In addition, the injection of lidocaine (QX-314, 2%, intra-RVM) decreased nociception in sleep-deprived rats, but not in control rats, while the lesion of the dorsolateral funiculus prevented the pronociceptive effect of PSD. Finally, PSD significantly increased c-Fos expression in the RVM. Therefore, PSD increases pain independently of its duration or of the characteristic of the nociceptive stimulus and decreases morphine analgesia at the PAG. PSD appears to increase pain by decreasing descending pain inhibitory activity and by increasing descending pain facilitatory activity.

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

    Science.gov (United States)

    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.

  12. Microglial VPAC1R mediates a novel mechanism of neuroimmune-modulation of hippocampal precursor cells via IL-4 release.

    Science.gov (United States)

    Nunan, Robert; Sivasathiaseelan, Harri; Khan, Damla; Zaben, Malik; Gray, William

    2014-08-01

    Neurogenesis, the production of new neurons from neural stem/progenitor cells (NSPCs), occurs throughout adulthood in the dentate gyrus of the hippocampus, where it supports learning and memory. The innate and adaptive immune systems are increasingly recognized as important modulators of hippocampal neurogenesis under both physiological and pathological conditions. However, the mechanisms by which the immune system regulates hippocampal neurogenesis are incompletely understood. In particular, the role of microglia, the brains resident immune cell is complex, as they have been reported to both positively and negatively regulate neurogenesis. Interestingly, neuronal activity can also regulate the function of the immune system. Here, we show that depleting microglia from hippocampal cultures reduces NSPC survival and proliferation. Furthermore, addition of purified hippocampal microglia, or their conditioned media, is trophic and proliferative to NSPCs. VIP, a neuropeptide released by dentate gyrus interneurons, enhances the proliferative and pro-neurogenic effect of microglia via the VPAC1 receptor. This VIP-induced enhancement is mediated by IL-4 release, which directly targets NSPCs. This demonstrates a potential neuro-immuno-neurogenic pathway, disruption of which may have significant implications in conditions where combined cognitive impairments, interneuron loss, and immune system activation occurs, such as temporal lobe epilepsy and Alzheimer's disease.

  13. DREADD Modulation of Transplanted DA Neurons Reveals a Novel Parkinsonian Dyskinesia Mechanism Mediated by the Serotonin 5-HT6 Receptor.

    Science.gov (United States)

    Aldrin-Kirk, Patrick; Heuer, Andreas; Wang, Gang; Mattsson, Bengt; Lundblad, Martin; Parmar, Malin; Björklund, Tomas

    2016-06-01

    Transplantation of DA neurons is actively pursued as a restorative therapy in Parkinson's disease (PD). Pioneering clinical trials using transplants of fetal DA neuroblasts have given promising results, although a number of patients have developed graft-induced dyskinesias (GIDs), and the mechanism underlying this troublesome side effect is still unknown. Here we have used a new model where the activity of the transplanted DA neurons can be selectively modulated using a bimodal chemogenetic (DREADD) approach, allowing either enhancement or reduction of the therapeutic effect. We show that exclusive activation of a cAMP-linked (Gs-coupled) DREADD or serotonin 5-HT6 receptor, located on the grafted DA neurons, is sufficient to induce GIDs. These findings establish a mechanistic link between the 5-HT6 receptor, intracellular cAMP, and GIDs in transplanted PD patients. This effect is thought to be mediated through counteraction of the D2 autoreceptor feedback inhibition, resulting in a dysplastic DA release from the transplant.

  14. The impact of intraglottal vortices on vocal fold dynamics

    Science.gov (United States)

    Erath, Byron; Pirnia, Alireza; Peterson, Sean

    2016-11-01

    During voiced speech a critical pressure is produced in the lungs that separates the vocal folds and creates a passage (the glottis) for airflow. As air passes through the vocal folds the resulting aerodynamic loading, coupled with the tissue properties of the vocal folds, produces self-sustained oscillations. Throughout each cycle a complex flow field develops, characterized by a plethora of viscous flow phenomena. Air passing through the glottis creates a jet, with periodically-shed vortices developing due to flow separation and the Kelvin-Helmholtz instability in the shear layer. These vortices have been hypothesized to be a crucial mechanism for producing vocal fold vibrations. In this study the effect of vortices on the vocal fold dynamics is investigated experimentally by passing a vortex ring over a flexible beam with the same non-dimensional mechanical properties as the vocal folds. Synchronized particle image velocimetry data are acquired in tandem with the beam dynamics. The resulting impact of the vortex ring loading on vocal fold dynamics is discussed in detail. This work was supported by the National Science Foundation Grant CBET #1511761.

  15. Protein folding and the organization of the protein topology universe

    DEFF Research Database (Denmark)

    Lindorff-Larsen,, Kresten; Røgen, Peter; Paci, Emanuele

    2005-01-01

    residues and, in addition, that the topology of the transition state is closer to that of the native state than to that of any other fold in the protein universe. Here, we review the evidence for these conclusions and suggest a molecular mechanism that rationalizes these findings by presenting a view...... of protein folds that is based on the topological features of the polypeptide backbone, rather than the conventional view that depends on the arrangement of different types of secondary-structure elements. By linking the folding process to the organization of the protein structure universe, we propose...

  16. Ventricular-Fold Dynamics in Human Phonation

    Science.gov (United States)

    Bailly, Lucie; Bernardoni, Nathalie Henrich; Müller, Frank; Rohlfs, Anna-Katharina; Hess, Markus

    2014-01-01

    Purpose: In this study, the authors aimed (a) to provide a classification of the ventricular-fold dynamics during voicing, (b) to study the aerodynamic impact of these motions on vocal-fold vibrations, and (c) to assess whether ventricular-fold oscillations could be sustained by aerodynamic coupling with the vocal folds. Method: A 72-sample…

  17. Synovial folds in equine articular process joints

    DEFF Research Database (Denmark)

    Thomsen, Line Nymann; Berg, Lise Charlotte; Markussen, Bo;

    2013-01-01

    Cervical synovial folds have been suggested as a potential cause of neck pain in humans. Little is known about the extent and characteristics of cervical synovial folds in horses.......Cervical synovial folds have been suggested as a potential cause of neck pain in humans. Little is known about the extent and characteristics of cervical synovial folds in horses....

  18. Folded MEMS approach to NMRG

    Science.gov (United States)

    Gundeti, Venu Madhav

    Atomic gyroscopes have a potential for good performance advantages and several attempts are being made to miniaturize them. This thesis describes the efforts made in implementing a Folded MEMS based NMRG. The micro implementations of all the essential components for NMRG (Nuclear Magnetic Resonance Gyroscope) are described in detail in regards to their design, fabrication, and characterization. A set of micro-scale Helmholtz coils are described and the homogeneity of the generated magnetic field is analyzed for different designs of heaters. The dielectric mirrors and metallic mirrors are compared in terms of reflectivity and polarization change up on reflection. A pyramid shaped folded backbone structure is designed, fabricated, and assembled along with all the required components. A novel double-folded structure 1/4th the size of original version is fabricated and assembled. Design and modeling details of a 5 layered shield with shielding factor > 106 and total volume of around 90 cc are also presented. A table top setup for characterization of atomic vapor cell is described in detail. A micro vapor cell based Rb magnetometer with a sensitivity of 108 pT/√Hz is demonstrated. The challenges due to DC heating are addressed and mitigated using an AC heater. Several experiments related to measuring the relaxation time of Xe are provided along with results. For Xe131, relaxation times of T1 = 23.78 sec, T2 = 18.06 sec and for Xe129, T1 = 21.65 sec and T2 = 20.45 sec are reported.

  19. Conformation and sequence evidence for two-fold symmetry in left-handed beta-helix fold.

    Science.gov (United States)

    Shen, Xiaojuan

    2011-09-21

    The left-handed beta-helix (LβH) has received interest recently as it folds as a possible solution for the structure of misfolded proteins associated with prion and Huntington's diseases. Through a combination of sequence and structure analysis, we uncover a novel feature that is common to this unique fold: a two-fold symmetry in both sequence and structure, and this feature always coupled with extended loops in the middle of the helix. Since the results reveal a two-fold symmetric pattern both in the sequence and structure, it may indicate that the symmetry in tertiary structure is coded by the symmetry in primary sequence, which agrees with Anfisen's proposal that a protein's amino-acid sequence specify its three-dimensional structure. It may also indicate that LβH adopts a two-fold repeat pattern during the evolution process and symmetry helps maintaining the stability of the helix structure. The two-fold symmetric pattern and extended loops might be important in maintaining stability of helix proteins. This discovery can be useful in understanding the folding mechanisms of this protein fold and provide insights in the relation between sequences and structures.

  20. Low Power Folded Cascode OTA

    Directory of Open Access Journals (Sweden)

    Swati Kundra

    2012-03-01

    Full Text Available Low power is one of the key research area in today’s electronic industry. Need of low power has created a major pattern shift in the field of electronics where power dissipation is equally important as area, performance etc. Several low power portable electronic equipments, low voltage design techniques havebeen developed and have driven analog designers to create techniques eg. Self cascode mosfet and stacking technique. For this aim in mind we designed a Folded Cascode using low power techniques and analyzed its various properties through the Spice simulations for 0.13 micron CMOS technology from TSMC and thesupply voltage 1.8V.

  1. Low Power Folded Cascode OTA

    Directory of Open Access Journals (Sweden)

    Swati Kundra

    2012-02-01

    Full Text Available Low power is one of the key research area in today’s electronic industry. Need of low power has created a major pattern shift in the field of electronics where power dissipation is equally important as area, performance etc. Several low power portable electronic equipments, low voltage design techniques have been developed and have driven analog designers to create techniques eg. Self cascode mosfet and stacking technique. For this aim in mind we designed a Folded Cascode using low power techniques and analyzed its various properties through the Spice simulations for 0.13 micron CMOS technology from TSMC and the supply voltage 1.8V.

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

    DEFF Research Database (Denmark)

    Karlshøj, Stefanie; Amarandi, Roxana Maria; Larsen, Olav;

    2016-01-01

    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...

  3. Modulation of circulating vasoactive peptides and extracellular matrix proteins are two novel mechanisms in the cardioprotective action of acarbose.

    Science.gov (United States)

    Rudovich, Natalia; Pivovarova, Olga; Bernigau, Wolfgang; Sparwasser, Andrea; Tacke, Christopher; Murahovshi, Veronica; Mertes, Gabriele; Birkenfeld, Andreas L; Bergmann, Andreas; Weickert, Martin O; Pfeiffer, Andreas F

    2016-12-01

    Acarbose, an alpha-glucosidase inhibitor, unexpectedly reduced the incidence of hypertension and cardiovascular endpoints in the STOP-NIDDM study. Based on the growing evidence of a link between vasoregulatory peptides and metabolic traits, we hypothesized that changes of the Glycemic Index by acarbose may modulate vasoregulatory peptide levels via regulation of postprandial metabolism. Subjects with type 2 diabetes and with metabolic syndrome were treated with acarbose (12 weeks, 300mg/d) in a double-blind, placebo-controlled, cross-over intervention. Changes in fasting and postprandial levels of midregional pro-atrial natriuretic peptide (MR-proANP), C-terminal pro-endothelin-1 (CT-proET-1) and midregional pro-adrenomedullin (MR-proADM), WNT1 Inducible Signaling Pathway Protein 1 (WISP1) as well as fasting and postprandial glucose/insulin levels in the liquid meal test were assessed. Acarbose strongly decreased postprandial insulin concentrations in subjects with metabolic syndrome (P=0.004), and postprandial glucose excursions in both groups. Postprandial MR-proANP and CT-proET-1 levels increased after acarbose treatment (P<0.01 and P<0.05, respectively) in subjects with metabolic syndrome only. No effect of acarbose treatment on MR-prADM was observed in both groups. All three peptides were correlated with each over, but neither with insulin sensitivity in euglycemic clamps, nor with adiponectin levels. WISP1 decreased after acarbose treatment in subjects with metabolic syndrome. Plasma MR- proANP and CT-proET-1 concentrations, but not MR-prADM concentrations, were affected by treatment with acarbose over 12 weeks. Our findings provide new possible mechanisms of acarbose action in diabetes and metabolic syndrome.

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

    Science.gov (United States)

    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.

  5. Co-expression module analysis reveals biological processes, genomic gain, and regulatory mechanisms associated with breast cancer progression

    Directory of Open Access Journals (Sweden)

    Derow Catherine K

    2010-05-01

    Full Text Available Abstract Background Gene expression signatures are typically identified by correlating gene expression patterns to a disease phenotype of interest. However, individual gene-based signatures usually suffer from low reproducibility and interpretability. Results We have developed a novel algorithm Iterative Clique Enumeration (ICE for identifying relatively independent maximal cliques as co-expression modules and a module-based approach to the analysis of gene expression data. Applying this approach on a public breast cancer dataset identified 19 modules whose expression levels were significantly correlated with tumor grade. The correlations were reproducible for 17 modules in an independent breast cancer dataset, and the reproducibility was considerably higher than that based on individual genes or modules identified by other algorithms. Sixteen out of the 17 modules showed significant enrichment in certain Gene Ontology (GO categories. Specifically, modules related to cell proliferation and immune response were up-regulated in high-grade tumors while those related to cell adhesion was down-regulated. Further analyses showed that transcription factors NYFB, E2F1/E2F3, NRF1, and ELK1 were responsible for the up-regulation of the cell proliferation modules. IRF family and ETS family proteins were responsible for the up-regulation of the immune response modules. Moreover, inhibition of the PPARA signaling pathway may also play an important role in tumor progression. The module without GO enrichment was found to be associated with a potential genomic gain in 8q21-23 in high-grade tumors. The 17-module signature of breast tumor progression clustered patients into subgroups with significantly different relapse-free survival times. Namely, patients with lower cell proliferation and higher cell adhesion levels had significantly lower risk of recurrence, both for all patients (p = 0.004 and for those with grade 2 tumors (p = 0.017. Conclusions The ICE

  6. Alignment Methods Developed for the Validation of the Thermal and Mechanical Behaviour of the Two Beam Test Modules for the CLIC Project

    CERN Document Server

    Mainaud Durand, Helene; Sosin, Mateusz; Rude, Vivien

    2014-01-01

    CLIC project will consist of more than 20 000 two meters long modules. A test setup made of three modules is being built at CERN to validate the assembly and integration of all components and technical systems and to validate the short range strategy of pre-alignment. The test setup has been installed in a room equipped with a sophisticated system of ventilation able to reproduce the environmental conditions of the CLIC tunnel. Some of the components have been equipped with electrical heaters to simulate the power dissipation, combined with a water cooling system integrated in the RF components. Using these installations, to have a better understanding of the thermal and mechanical behaviour of a module under different operation modes, machine cycles have been simulated; the misalignment of the components and their supports has been observed. This paper describes the measurements methods developed for such a project and the results obtained.

  7. Elucidation of the mechanism of the regulatory function of the Ig1 module of the fibroblast growth factor receptor 1

    DEFF Research Database (Denmark)

    Kiselyov, Vladislav; Kochoyan, Artur; Poulsen, Flemming

    2006-01-01

    The extracellular part of the fibroblast growth factor (FGF) receptor (FGFR) consists of up to three Ig modules (Ig1-Ig3), in which the Ig2 and Ig3 modules determine affinity and specificity for FGF and heparin. The FGFR isoforms lacking the Ig1 module have higher affinity for FGF and heparin than....... The identified binding site in the Ig2 module was found to be in the area of the FGF-Ig2 and Ig2-heparin contact sites, thus providing direct structural evidence that the Ig1 module functions as a competitive autoinhibitor of the FGFR-ligand interaction. Furthermore, the Ig1 binding site of the Ig2 module...... overlaps the Ig2-Ig2 contact site. This suggests that the function of the Ig1 module is not only regulation of the FGFR-ligand binding affinity but also prevention of spontaneous FGFR dimerization (through a direct Ig2-Ig2 interaction) in the absence of FGF....

  8. Analysis of protein folds using protein contact networks

    Indian Academy of Sciences (India)

    Pankaj Barah; Somdatta Sinha

    2008-08-01

    Proteins are important biomolecules, which perform diverse structural and functional roles in living systems. Starting from a linear chain of amino acids, proteins fold to different secondary structures, which then fold through short- and long-range interactions to give rise to the final three-dimensional shapes useful to carry out the biophysical and biochemical functions. Proteins are defined as having a common `fold' if they have major secondary structural elements with same topological connections. It is known that folding mechanisms are largely determined by a protein's topology rather than its interatomic interactions. The native state protein structures can, thus, be modelled, using a graph-theoretical approach, as coarse-grained networks of amino acid residues as `nodes' and the inter-residue interactions/contacts as `links'. Using the network representation of protein structures and their 2D contact maps, we have identified the conserved contact patterns (groups of contacts) representing two typical folds – the EF-hand and the ubiquitin-like folds. Our results suggest that this direct and computationally simple methodology can be used to infer about the presence of specific folds from the protein's contact map alone.

  9. How the folding rates of two- and multistate proteins depend on the amino acid properties.

    Science.gov (United States)

    Huang, Jitao T; Huang, Wei; Huang, Shanran R; Li, Xin

    2014-10-01

    Proteins fold by either two-state or multistate kinetic mechanism. We observe that amino acids play different roles in different mechanism. Many residues that are easy to form regular secondary structures (α helices, β sheets and turns) can promote the two-state folding reactions of small proteins. Most of hydrophilic residues can speed up the multistate folding reactions of large proteins. Folding rates of large proteins are equally responsive to the flexibility of partial amino acids. Other properties of amino acids (including volume, polarity, accessible surface, exposure degree, isoelectric point, and phase transfer energy) have contributed little to folding kinetics of the proteins. Cysteine is a special residue, it triggers two-state folding reaction and but inhibits multistate folding reaction. These findings not only provide a new insight into protein structure prediction, but also could be used to direct the point mutations that can change folding rate.

  10. Stretching Folding Instability and Nanoemulsions

    CERN Document Server

    Chan, Chon U

    2009-01-01

    Here we show a folding-stretching instability in a microfluidic flow focusing device using silicon oil (100cSt) and water. The fluid dynamics video demonstrates an oscillating thread of oil focused by two co-flowing streams of water. We show several high-speed sequences of these oscillations with 30,000 frames/s. Once the thread is decelerated in a slower moving pool downstream an instability sets in and water-in-oil droplets are formed. We reveal the details of the pinch-off with 500,000 frames/s. The pinch-off is so repeatable that complex droplet patterns emerge. Some of droplets are below the resolution limit, thus smaller than 1 micrometer in diameter.

  11. Topological Solitons and Folded Proteins

    CERN Document Server

    Chernodub, M N; Niemi, Antti J

    2010-01-01

    We propose that protein loops can be interpreted as topological domain-wall solitons. They interpolate between ground states that are the secondary structures like alpha-helices and beta-strands. Entire proteins can then be folded simply by assembling the solitons together, one after another. We present a simple theoretical model that realizes our proposal and apply it to a number of biologically active proteins including 1VII, 2RB8, 3EBX (Protein Data Bank codes). In all the examples that we have considered we are able to construct solitons that reproduce secondary structural motifs such as alpha-helix-loop-alpha-helix and beta-sheet-loop-beta-sheet with an overall root-mean-square-distance accuracy of around 0.7 Angstrom or less for the central alpha-carbons, i.e. within the limits of current experimental accuracy.

  12. Protein folding and wring resonances

    DEFF Research Database (Denmark)

    Bohr, Jakob; Bohr, Henrik; Brunak, Søren

    1997-01-01

    The polypeptide chain of a protein is shown to obey topological contraints which enable long range excitations in the form of wring modes of the protein backbone. Wring modes of proteins of specific lengths can therefore resonate with molecular modes present in the cell. It is suggested that prot......The polypeptide chain of a protein is shown to obey topological contraints which enable long range excitations in the form of wring modes of the protein backbone. Wring modes of proteins of specific lengths can therefore resonate with molecular modes present in the cell. It is suggested...... that protein folding takes place when the amplitude of a wring excitation becomes so large that it is energetically favorable to bend the protein backbone. The condition under which such structural transformations can occur is found, and it is shown that both cold and hot denaturation (the unfolding...

  13. Kinetics, Ca2+ dependence, and biophysical properties of integrin-mediated mechanical modulation of transmitter release from frog motor nerve terminals

    Science.gov (United States)

    Chen, B. M.; Grinnell, A. D.

    1997-01-01

    Neurotransmitter release from frog motor nerve terminals is strongly modulated by change in muscle length. Over the physiological range, there is an approximately 10% increase in spontaneous and evoked release per 1% muscle stretch. Because many muscle fibers do not receive suprathreshold synaptic inputs at rest length, this stretch-induced enhancement of release constitutes a strong peripheral amplifier of the spinal stretch reflex. The stretch modulation of release is inhibited by peptides that block integrin binding of natural ligands. The modulation varies linearly with length, with a delay of no more than approximately 1-2 msec and is maintained constant at the new length. Moreover, the stretch modulation persists in a zero Ca2+ Ringer and, hence, is not dependent on Ca2+ influx through stretch activated channels. Eliminating transmembrane Ca2+ gradients and buffering intraterminal Ca2+ to approximately normal resting levels does not eliminate the modulation, suggesting that it is not the result of release of Ca2+ from internal stores. Finally, changes in temperature have no detectable effect on the kinetics of stretch-induced changes in endplate potential (EPP) amplitude or miniature EPP (mEPP) frequency. We conclude, therefore, that stretch does not act via second messenger pathways or a chemical modification of molecules involved in the release pathway. Instead, there is direct mechanical modulation of release. We postulate that tension on integrins in the presynaptic membrane is transduced mechanically into changes in the position or conformation of one or more molecules involved in neurotransmitter release, altering sensitivity to Ca2+ or the equilibrium for a critical reaction leading to vesicle fusion.

  14. Vocal fold ion transport and mucin expression following acrolein exposure.

    Science.gov (United States)

    Levendoski, Elizabeth Erickson; Sivasankar, M Preeti

    2014-05-01

    The vocal fold epithelium is exposed to inhaled particulates including pollutants during breathing in everyday environments. Yet, our understanding of the effects of pollutants on vocal fold epithelial function is extremely limited. The objective of this study was to investigate the effect of the pollutant acrolein on two vocal fold epithelial mechanisms: ion transport and mucin (MUC) synthesis. These mechanisms were chosen as each plays a critical role in vocal defense and in maintaining surface hydration which is necessary for optimal voice production. Healthy, native porcine vocal folds (N = 85) were excised and exposed to an acrolein or sham challenge. A 60-min acrolein, but not sham challenge significantly reduced ion transport and inhibited cyclic adenosine monophosphate-dependent, increases in ion transport. Decreases in ion transport were associated with reduced sodium absorption. Within the same timeline, no significant acrolein-induced changes in MUC gene or protein expression were observed. These results improve our understanding of the effects of acrolein on key vocal fold epithelial functions and inform the development of future investigations that seek to elucidate the impact of a wide range of pollutant exposures on vocal fold health.

  15. Five-fold twin formation during annealing of nanocrystalline Cu

    Energy Technology Data Exchange (ETDEWEB)

    Bringa, E M; Farkas, D; Caro, A; Wang, Y M; McNaney, J; Smith, R

    2009-05-20

    Contrary to the common belief that many-fold twins, or star twins, in nanophase materials are due to the action of significant external stresses, we report molecular dynamics simulations of annealing in 5 nm grain size samples annealed at 800 K for nearly 0.5 nsec at 0 external pressure showing the formation of five-fold star twins during annealing under the action of the large internal stresses responsible for grain growth and microstructural evolution. The structure of the many-fold twins is remarkably similar to those we have found to occur under uniaxial shock loading, of samples of nanocrystalline NiW with a grain size of {approx}5-30 nm. The mechanism of formation of the many-fold twins is discussed in the light of the simulations and experiments.

  16. Co- and post-translational protein folding in the ER

    DEFF Research Database (Denmark)

    Ellgaard, Lars; McCaul, Nicholas; Chatsisvili, Anna

    2016-01-01

    and the variety of ER-specific protein modifications. Here, we review chaperone-assisted co- and post-translational folding and assembly in the ER and underline the influence of protein modifications on these processes. We emphasize how method development has helped advance the field by allowing researchers......The biophysical rules that govern folding of small, single-domain proteins in dilute solutions are now quite well understood. The mechanisms underlying co-translational folding of multidomain and membrane-spanning proteins in complex cellular environments are often less clear. The endoplasmic...... reticulum (ER) produces a plethora of membrane and secretory proteins, which must fold and assemble correctly before ER exit - if these processes fail, misfolded species accumulate in the ER or are degraded. The ER differs from other cellular organelles in terms of the physicochemical environment...

  17. Modern Analysis of Protein Folding by Differential Scanning Calorimetry.

    Science.gov (United States)

    Ibarra-Molero, Beatriz; Naganathan, Athi N; Sanchez-Ruiz, Jose M; Muñoz, Victor

    2016-01-01

    Differential scanning calorimetry (DSC) is a very powerful tool for investigating protein folding and stability because its experimental output reflects the energetics of all conformations that become minimally populated during thermal unfolding. Accordingly,